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Integrated Continuous Pharmaceutical Technologies—A Review

  • András Domokos
    András Domokos
    Budapest University of Technology and Economics, Organic Chemistry and Technology Department, H-1111 Budapest, Hungary
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    Orcidhttp://orcid.org/0000-0003-1968-4679
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  • Brigitta Nagy
    Brigitta Nagy
    Budapest University of Technology and Economics, Organic Chemistry and Technology Department, H-1111 Budapest, Hungary
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  • Botond Szilágyi
    Botond Szilágyi
    Budapest University of Technology and Economics, Faculty of Chemical Technology and Biotechnology, H-1111 Budapest, Hungary
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  • György Marosi
    György Marosi
    Budapest University of Technology and Economics, Organic Chemistry and Technology Department, H-1111 Budapest, Hungary
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  • Zsombor Kristóf Nagy*
    Zsombor Kristóf Nagy
    Budapest University of Technology and Economics, Organic Chemistry and Technology Department, H-1111 Budapest, Hungary
    *Telephone: +36-1-463-4129. Email: [email protected]. Postal address: 3 Műegyetem rkp., H-1111 Budapest, Hungary.
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    Orcidhttp://orcid.org/0000-0003-2651-7756
Cite this: Org. Process Res. Dev. 2021, 25, 4, 721–739
Publication Date (Web):March 2, 2021
https://doi.org/10.1021/acs.oprd.0c00504
Copyright © 2021 The Authors. Published by American Chemical Society
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Abstract

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Innovation in the pharmaceutical industry has been limited for a long time to the research and development of new active compounds; meanwhile, the structure of the production, dominated by batchwise technologies, has not changed to date. As has already been demonstrated in several other industrial sectors, continuous manufacturing (CM) has many advantages over batch processes. Faster, cheaper, and more flexible production can be developed with a significantly higher level of quality assurance. In the recent years the main regulatory agencies recognized the need for a change in drug production and started to promote continuous technologies and encourage pharmaceutical companies to develop and adapt such processes. As a result, by today extensive research was conducted in the various fields of pharmaceutical technologies from drug substance to drug product manufacturing. Many publications deal with synthetic steps carried out in flow reactors and crystallizations implemented in a continuous manner, and on the formulation side continuous filtration, drying, granulation, and blending have all been studied to a lesser or greater extent. Moreover, besides the modification of these traditional processes to continuous operation, novel, intrinsically continuous technologies are being studied as well. In order to entirely exploit the advantages of CM, the mainly separately developed processes need to be integrated to form end-to-end systems from the raw materials to the final dosage forms. However, even the integration of two technological steps is a challenging task. The development of end-to-end systems requires deep process understanding and a holistic approach toward process development and optimization. The aim of this work is to give insight into the state-of-the-art and new directions in integrated continuous pharmaceutical technologies by critically reviewing the recent literature of the broad field.

KEYWORDS:

1. Introduction—Challenges of 21st Century Pharmaceutical Manufacturing

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By the end of the 20th century, most of the largest industrial sectors built production lines based on assembly line, continuous technologies. (1) This could be observed in the electronic, automobile, food, and petrochemical industries as well. In contrast, the pharmaceutical production traditionally relies on batch processes. The facilities are designed for the large-scale batch production of “blockbuster” drugs using large volume centralized batch manufacturing plants. (2)
This approach divides the manufacturing process into many separate steps which are clearly isolated in space and time. (3) The two major parts of drug production, i.e. synthesis, isolation, and purification (drug substance manufacturing) and formulation (drug product manufacturing), are often located in different geographical regions, including different countries. (4) This elongates the supply chains drastically and increases transportation times on the order of weeks. (2,5,6) During the batch manufacturing process, samples are taken from each produced batch, which are carried to separate laboratories to conduct in-process-control measurements before moving the material to the next operation. (7) Since the production of a pharmaceutical product can take up to 10–20 steps, this cumbersome procedure together with the long supply chains could result in 12–24 months of overall production. (1,2,5) Moreover, these long supply chains have modest resilience against sudden regulation changes and lockdowns, which was generated by the recent SARS-COV-2 outbreak. This situation made governments of many countries consider self-sufficiency in the supply chain. (8)
Pharmaceuticals are manufactured in a “campaign-like” manner, meaning that a given intermediate is prepared in successive batches, collecting a certain amount of material together before moving to the next step. (2,9) This manufacturing practice requires substantial storage capacity, which inherently raises the production and thus the product cost. (2,5) Additionally, storing large amounts of hazardous active pharmaceutical intermediates contributes to the safety issues of the manufacturing process. (10)
Scale-up is always a great challenge during the development of batch technologies, as the process behavior can show strong scale-dependence, which is often associated with hydrodynamic effects. Thus, the processes optimized on laboratory scale sometimes require thorough reoptimization, which might be challenging, since ensuring adequate supply for the clinical trials is the priority. (11) Hence, usually the first operating procedure is accepted for industrial-scale operation and submitted to regulatory approval. After reaching the market, any modifications aiming at the improvement of production efficiency must go through the time- and money-consuming approval procedure again. (12)
The greatest drawback of the batch-based structure of pharmaceutical manufacturing is presumably the currently common practice of quality assurance. In the case of drug products, ensuring consistent quality is of utmost importance, which is intended to be achieved by strict regulatory control. (4) The applied practice is the Quality by Testing (QbT) method, which consists of the analysis of samples taken from the raw materials, the intermediates after each step, and the final products. (13,14) If any of the parameters is out of the regulatory-approved specifications, the entire batch must be reprocessed or discarded causing significant delays and extra costs. (7) The fluctuations are intended to be minimized by the tightly controlled process parameters. (4)
The presented structure of the drug production makes the pharmaceutical industry slow and highly inflexible and thus unable to give quick answers to the changes in demand. (15) This poses a potential public health threat as the root causes of numerous reported drug shortages can be traced back to the problems of the current manufacturing strategy of the industry. (16,17) Furthermore, recent trends in drug product development show that fewer and fewer blockbusters can be brought to the market, and the cost of new pharmaceutical research and development outpaced market growth. (3,5,10,18) There is an increasing need for a more agile, robust, and efficient manufacturing structures in order to keep up with changes in market demand, to reduce costs, and to produce pharmaceuticals more reliably with improved quality. (15)

2. Advantages of Continuous Manufacturing

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As has already been shown in other industrial sectors, significant improvements can be accomplished in the production by replacing the batch processes with continuous technologies. (1) Unlike batchwise manufacturing, in the case of continuous processes, the raw materials and the product are continuously fed into and discharged from the equipment. All the materials are continuously flowing through the system, eliminating the idle time between the different technological steps. (15) After a start-up period, continuous processes converge into a steady state, during which the process parameters remain constant in time. (4) Monitoring and maintaining these variables on the fixed set point is much easier than handling the dynamic nature of batch operations. Therefore, by the development of appropriate analytical methods even constant product quality can be attained. (4) In the case of an error, the deficient product section can be traced back accurately; hence, discarding the entire amount of material is no longer necessary. (19)
Continuous technologies are usually developed as a whole, integrating the consecutive steps into one system. (20) Such a system in the pharmaceutical industry would result in a drastically different and improved production strategy. (10) By connecting the currently separated manufacturing sections, such as the drug substance and drug product manufacturing, the elongated supply chains could be cut down. (3,6) As materials could flow directly to the next step, the huge and expensive inventory capacity maintained for storing the intermediates becomes unnecessary, and the factory footprint can be reduced as well. (15) Because of the high-level automation and the lack of termination between the technological steps, human intervention and exposure can be minimized, reducing the toxicity- and safety-related issues of traditional batch manufacturing (e.g., the production of anticancer drugs and hormones is safe only in severe protective equipment). (21) Due to the typically lower material holdup of a continuous system compared to the batch counterpart, the hazards and safety issues of the reagents, solvents, or other involved materials are inherently reduced.
The productivity can be increased simply by operating the system for a longer time, facilitating provision of a rapid response for sudden changes in demand. (10,22) There is no need for a classical scale-up procedure, since it is enough to utilize parallel processing lines of the equipment used in laboratory, which accelerates the whole drug development process and reduces the time to market. (10) In the case of continuous technologies, process optimization is usually faster and easier, which means that a more understood and optimized process can be submitted for regulatory approval. Additionally, the investment and operating costs of continuous technologies are lower, and the expenses can be reduced even by 40%. (23,24)

3. First Steps toward Continuous Pharmaceutical Manufacturing

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The necessity to improve the efficiency of current batch-based drug manufacturing processes drew the attention of the industry, the academia, and the regulatory agencies to continuous technologies. The vision of a faster, cheaper, more flexible, and more robust production initiated the paradigm shift of the frozen-in pharmaceutical industry. (25,26)
In 2005 the American Chemical Society (ACS) Green Chemistry Institute (GCI) and several global pharmaceutical corporations, such as Novartis, Pfizer, Roche, Sanofi, Eli Lilly, Johnson & Johnson, and others founded the ACS GCI Roundtable. (27) This roundtable defined “continuous processing” as one of its research priorities. (28,29) The U.S. Food and Drug Administration (FDA) issued the first framework about promoting the application of Process Analytical Technologies (PAT) in 2004. (30) PAT includes real-time process monitoring and control supported by advanced data processing, with which better process understanding and improved product quality can be accomplished. (31) In the following years, several further guidelines were launched by the FDA, (32) the International Council for Harmonization (ICH), (33−37) and also the European Medicines Agency (EMA) (38) in the topic of quality improvement through the development and adaption of continuous technologies. Recently the FDA declared continuous manufacturing (CM) as one of the most important tools in the modernization of the pharmaceutical industry. (39)
According to the guidelines, quality should be designed into the product; thus, the Quality by Design (QbD) approach is preferred for quality assurance instead of QbT. (7,40) Pharmaceutical QbD means a systematic approach toward development, starting with defining the critical quality attributes (CQAs) of the product, identifying the critical material attributes (CMAs) of the starting materials and the critical process parameters (CPPs) as well. By linking CMAs and CPPs to the CQAs, it is possible to understand how the product quality is affected by changing the process parameters and the material attributes. As a result, an operating space of parameters can be defined, and within this processing region (design space) the desired product quality can be reached. As another step forward, the concept of Quality-by-Control (QbC) has been proposed in the recent years. (41) The QbC paradigm takes the QbD approaches to a higher level by applying active feedback control for process design. (14) Thus, in some cases the suitable operating conditions can be found much faster, and significantly less material is required. (42)
By today nearly all the major innovator pharmaceutical companies are working on continuous technologies. (19) As a result, a handful of drug products were released on the market which are produced at least partially using regulatory-approved continuous technologies by Vertex (lumacaftor, ivacaftor, tezacaftor), by Johnson & Johnson (darunavir), by Eli Lilly (abemaciclib), and by Pfizer (glasdegib). (9,14,43,44) These examples show that changing from batch to continuous technologies is truly advantageous economically as well: Johnson & Johnson achieved significant reduction in manufacturing cycle time, footprint, and testing duration. (45,46) Much effort was required to achieve this progress; however, there is clearly much room for improvement. Obviously, the movement toward CM is a long and costly journey, which requires extensive research. (47) It is necessary to evaluate the applicability of existing technologies in a continuous manner and to develop novel continuous processes not yet utilized. (19) Moreover, changing the current mind set and training of CM experts also takes a long time.
There is a growing body of literature of continuous pharmaceutical manufacturing, covering the entire production line. Considerable research has been conducted for example in the field of flow chemistry, (48) continuous crystallization, or continuous blending and tableting. (20) Moreover, the possible real-time monitoring strategies of the continuous processes using in-line PAT tools have been studied extensively. (31,49) However, besides examining the different continuous processes, connecting the individual steps is a much greater challenge. (50) In order to fully exploit the promise of CM, the separated technological processes must be integrated, forming end-to-end systems from the raw materials to the final dosage forms. According to the literature, significantly fewer publications deal with continuous technologies in which at least two consecutive steps are coupled in any way. Moreover, the development of end-to-end continuous systems from the raw materials to the end products is presented only by a handful of papers. This also might be the result of the currently separated synthetic and formulation section, as scientists and experts usually do not have expertise in both fields. It is clearly visible that a complete change in mind set is required for a more integrated development approach toward continuous technologies. (4,9)

4. Recent Progress in Continuous Pharmaceutical Technologies

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The following sections aim to present the progress accomplished to date in the most important areas of continuous pharmaceutical manufacturing. First, the flow chemical transformations and multistep syntheses of active pharmaceutical ingredients (APIs) will be discussed, followed by continuous crystallization and filtration. After these, the continuous blending and tableting of pharmaceuticals will be presented. Emphasis will be put on publications dealing with more than one consecutive technological step, integrated in a continuous manner to show the progress accomplished toward end-to-end pharmaceutical manufacturing. A few techniques from a usual pharmaceutical manufacturing line, such as granulation, milling, and drying are left out of this review, as several well-organized and up-to-date studies focus on these research areas. (51−55)

4.1. Multistep Flow Synthesis of Pharmaceuticals

4.1.1. Principles of Flow Chemistry

The multistep synthesis of complex organic molecules from simple precursors represents a significant achievement but is also one of the greatest challenges of the synthetic organic chemistry. (56) The traditional batchwise synthetic route consists of a series of batch reactions with workup procedures, purification, and isolation after each step (Figure 1a). Although this approach is the basis of all modern syntheses, such a procedure is usually time-consuming and wasteful compared to the single-cell multistep biosynthetic pathways known in nature. (56)

Figure 1

Figure 1. (a) Traditional batchwise multistep synthesis and (b) continuous flow approach for the telescoped synthesis of complex molecules (adapted from ref (56)).

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Continuous flow chemistry offers several options for the implementation of organic syntheses. (57) In flow systems the materials are flowing in tubes with small diameter (usually between 50 and 1000 μm), and the reactions take place in these so-called microreactors (Figure 2). (58) The starting materials are fed by pumps, and mixer elements provide the sufficient mixing of the liquid streams (which is often an issue due to the low Reynolds numbers in these systems). Back-pressure regulators (BPRs) can be applied at the end of the tubes to pressurize the system, allowing increase of the boiling point. Directly connectable devices are available for the purification of the reaction mixtures, i.e. liquid–liquid extractors. Besides homogeneous systems, solid–liquid or gas–liquid reactions are also accessible with packed bed reactors or tube-in-tube reactors. (59−62) Furthermore, microwave flow reactors can be applied to compare the effect of microwave conditions to conventional heating. (63−65) The in-line monitoring of the flow reactions is possible by applying e.g. flow-through spectroscopic analytical techniques including UV–visible, (66) fluorescence, (67) Raman, (68) and infrared spectroscopy. (69)

Figure 2

Figure 2. General structure of a typical continuous flow systems.

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These systems have a number of advantages over traditional batchwise reactors. The small cross-section of the tubes means that the heat transfer area to reactor volume ratio is about 50–60 times bigger (calculating with the same kg per a day throughout). (21) The small channel dimensions of the reactors allow precise control over process parameters: quick heat transfer or efficient and accurate illumination during photochemical reactions. (70,71) In the pressurized system significantly elevated temperatures can be applied, thus accelerating the reactions and making new pathways possible that are otherwise not accessible. (72) Reduced reaction time, excellent yield and selectivity, enhanced safety, and good reproducibility were reported in the literature numerous times. (73−75) Naturally, new challenges have arisen with the new technology, for example dealing with solid materials and the issue of clogging, the integration with in-line purification techniques, or the cost of flow equipment, which all must be handled during the development of a flow chemistry process.
Owing to the advantages of flow chemistry, the number of publications focusing on synthetic organic flow systems has increased significantly in recent years. The International Union of Pure and Applied Chemistry (IUPAC) organization named flow chemistry among the top ten emerging technologies in chemistry. (76) The majority of publications deal with different chemical transformations implemented in flow reactors and comparing them to the batch result. Many excellent review papers have been published summarizing the progress in this area, highlighting the barriers of this new technique, and providing a guide for researchers whether it can be advantageous to develop a flow system for a certain process. (57−59,72,73,77−82)

4.1.2. Flow Synthesis of Pharmaceuticals

By connecting several flow reactors, multistep syntheses can be carried out in an uninterrupted system. (56,83) The great benefit of this approach is that the isolation of intermediates can be eliminated, simplifying and accelerating this process (Figure 1b). Without transportation and off-line quality testing after each step, the footprint of the production facility can be reduced, improving flexibility at the same time. This is especially true for the synthesis of APIs, as these complex compounds often require 6–10 synthetic steps from the starting materials. (78) Usually some compromises are inevitable and the synthetic route is split up to shorter sequences for intermediate purification of the reaction mixtures or for solvent switch. (84) Integrating the operation steps, including in-line purification, workup, and real-time analysis requires holistic optimization and deep process understanding. Nevertheless, the telescoped synthesis of APIs under flow conditions has a growing body of literature (70,72,80,83,85,86) and due to the challenge of the integration of in-line purification into a flow system, this topic is also gaining more and more attention. (59,87,88) In Table 1 APIs with reported continuous flow total synthesis are summarized. Regarding the industrial application of flow chemistry, in 2018 Hughes collected seven examples from the patent literature for API synthesis, during which at least one reaction step is carried out under flow conditions. (89) However, in these cases it was not public whether these routes are used for commercial manufacturing or not.
Table 1. Examples for Published Multistep API Flow Syntheses
APIYear of publicationRef
Ibuprofen2009 (90)
Nabumetone2011 (91)
Fluoxetine2011 (92)
Artemisinin2012 (93)
Imatinib2013 (94)
Tamoxifen2013 (95)
Diphenhydramine HCl2013 (96)
Amitriptyline2013 (97)
Olanzapine2013 (98)
Rufinamide2014 (99)
LY28867212014 (100)
Aliskiren hemifumarate2014 (101)
Efavirenz2015 (102)
Rolipram + phenibut2015 (103)
Telmisartan2015 (104)
Ibuprofen2015 (105)
Ribociclib2016 (106)
Diphenhydramine HCl2016 (1)
Lidocaine HCl2016 (1)
Diazepam2016 (1)
Fluoxetine HCl2016 (1)
Pregabalin2017 (107)
Flucytosine2017 (108)
Captopril2017 (109)
Prexasertib2017 (110)
Clozapine2018 (111)
Hydroxychloroquine2018 (112)
Dolutegravir2018 (113)
16-DPA2018 (114)
Nicardipine HCl2018 (115)
Ciprofloxacin HCl2018 (115)
Neostigmine HCl2018 (115)
Rufinamide2018 (115)
Acetylsalicylic acid2018 (116)
Hymexazol2019 (117)
Vortioxetine2019 (118)
Flibanserin2019 (119)
Imatinib2019 (120)
Treprostinil2019 (121)
Ibuprofen2019 (122)
Lomustine2019 (123)
Linezolid2019 (124)
Lesinurad2020 (125)

4.1.3. API Flow Syntheses Integrated with Downstream Processes

In order to build end-to-end systems, the developed multistep flow synthesis of the APIs must be connectable to the subsequent technological steps. The final reaction is usually followed by the purification of the synthesized API, which can be carried out by numerous methods, including liquid–liquid extraction, chromatography, etc., but the compound must be brought to solid form with a continuous crystallization step. This is usually carried out in mixed suspension mixed product removal (MSMPR) crystallizers of plug flow reactors (PFRs) (for more details see section 4.2.1).
Only a handful of studies describe synthetic routes with emphasis on the connectability to the subsequent continuous workup processes. In a publication by Snead et al., in-line purification was integrated with the flow synthesis of diphenhydramine hydrochloride, followed by semibatch crystallization. (96) Ingham et al. presented a system in 2015 for the integration of three connected chemical steps coupled with liquid–liquid extraction, solvent exchange, and continuous filtration as well. (126) Similarly, the two-step synthesis of ribociclib—published by Pellegatti et al. in 2016—was followed by an in-house built in-line liquid–liquid extraction and a semibatch crystallization. (106) Although not synthesizing an API, Lichtenegger et al. developed a system in which flow chemical transformations were truly connected to continuous crystallization in PFRs. (127) With the incorporated in-line analysis and process control strategies, 6-h long operations were carried out without human intervention. In 2018, Balogh et al. developed and published the flow synthesis of acetylsalicylic acid (ASA). (116) The final reaction mixture was suitable for directly coupled formulation by electrospinning (see later in section 4.5). Tacsi et al. studied the continuous crystallization of ASA in an MSMPR crystallizer, in which the starting solution was the final reaction mixture of the flow synthesis of the API. (128) Thus, after the scale-up of the flow synthesis to relevant flow rates for continuous crystallization, the two developed processes could be run in an integrated fashion. In 2019, Rimez et al. published a two-step continuous tubular system incorporating a synthetic step and plug flow crystallization for the production of ASA crystals in 2019. (129) They further examined the crystallization step in a subsequent study, which might be ready for the connection to other flow chemical processes. (130)
In the research area of flow syntheses coupled to continuous workup procedures, a great work was accomplished by Ely Lilly and Company. (131) They conducted extensive research in the area of flow chemistry and the integration of the synthetic steps. Johnson et al. published a scaled-up system with flow synthesis, continuous crystallization, and filtration. (132) They carried out a high-pressure continuous asymmetric hydrogenation reaction in a PFR and then continuous liquid–liquid extraction for purification. Following this step, a semibatch solvent exchange distillation process, a two-stage MSMPR crystallization, and batch filtration were executed. The entire system was integrated, and stable operation was achieved on a kilogram per a week production scale. In the next paper they developed the synthesis of a drug candidate, LY2886721. (100) The system consisted of a flow chemical step and continuous reactive crystallization. In this study the authors presented the optimization of the processes, the scale-up and development of the equipment, and longer operational tests as well. In a follow-up study, Cole et al. developed the fully integrated continuous synthesis of prexasertib under cGMP conditions at a throughput of roughly 3 kg/day. (110) Eight reaction steps were incorporated in one system, and the previously described continuous liquid–liquid extractor, semibatch solvent exchange device, MSMPR crystallization, and batch filtration were all utilized during operation. The developed equipment and the knowledge of this study were transferred to the CM center of Ely Lilly and Company in Kinsale, Ireland.

4.2. Continuous Crystallization and Filtration

Crystallization is a key purification and separation technique in the pharmaceutical industry, and it is a critical step in connecting synthesis and formulation. (133) More than 90% of the currently marketed APIs are going through at least one crystallization step during their production. (134) The crystal size and shape have a strong impact not only on the downstream operations through bulk density or flowability but also on the dissolution rate and bioavailability of the final drug product. The importance of the process drew attention to continuous crystallization in the recent years. (135−138) In the technological line crystallization is followed by filtration for the isolation of the solid product. (139) This technique is usually assessed by the filterability of the crystals, the moisture content of the filter cake, and the recovered mass. Also, the process might affect the crystal size through agglomeration. (140) Continuous filtration is a relatively new area of study in the pharmaceutical industry, and only a handful of papers were published. In the following sections, continuous crystallization and filtration will be discussed focusing on connected and integrated continuous crystallization–filtration systems.

4.2.1. Continuous Crystallization

Currently, the vast majority of crystallizations in the pharmaceutical industry is carried out in stirred batch reactors. (138) These systems have been used for decades, and the processes are thoroughly optimized and reasonably well-understood. (136) However, there are still significant issues with batch-to-batch variability, which can lead to substantial difficulties in the downstream processing of the crystal product. (133) The root cause of batch-to-batch variability is the highly nonlinear crystallization kinetics, as well as the high sensitivity of secondary nucleation (primary nucleation is virtually eliminated by seeding) on the process parameters and seed quality, which, in practice, cannot be fully eliminated.
The implementation of novel continuous processes can provide a number of advantages in the area of crystallization. Continuous technologies naturally require smaller and thus cheaper equipment, reducing the production footprint. (135) As an example, for a given crystallization process to reach the same annual productivity a 250 L continuous reactor would be sufficient, while in batch mode a 5000 L reactor could provide the appropriate amount of crystalline product. (133) From an engineering perspective, the steady-state operation eliminates the inherent dynamic nature of the batch systems. By this, the continuous systems offer improved control and reproducibility over the physical characteristics of the product. By setting the appropriate operating conditions, the key parameters such as particle size and shape can be accurately controlled. (135) Additionally, certain downstream processes might be eliminated which are usually applied as particle size correction steps, e.g. granulation or milling. However, in the steady state of continuous crystallizations—unlike with batch systems—the equilibrium cannot be reached, decreasing the maximum attainable yield of the process. This can be overcome by the application of optimized recycle loops. Fouling of transfer lines and blockages are new challenges that arose with the new technology, which have to be addressed during process development. (135)
In the case of continuous crystallization, the API solution (and the antisolvent, if necessary) is continuously fed into the equipment, while the product slurry is continuously withdrawn. Numerous different systems have been published for the implementation of such a process. (136) The two most widespread technologies are the MSMPR crystallizers and the PFRs (Figure 3). (138)

Figure 3

Figure 3. Schematic drawing of (a) a mixed suspension mixed product removal crystallizer and (b) a plug flow reactor.

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The MSMPR crystallizers are conventional jacketed stirred tank reactors, with continuous input of starting material and continuous product removal. The practical advantage of these systems is that the existing stirred tank equipment can be further utilized and can help to convert the existing batch crystallization processes to continuous operation. (135) By connecting several MSMPR reactors into a multistage cascade system, flexible temperature profiles can be used resulting in better control over crystallization mechanisms, (141) and the final stage concentration can be adjusted close to equilibrium for yield considerations. (134,142) On the challenges side, the continuous tank systems have broad residence time distributions, and the scale-up difficulties of the original batch processes cannot be overcome easily. MSMPR crystallization of APIs is a frequently studied topic in the literature. (135,137) The effects of process parameters, (143) different setups, (142,144) strategies, (141,145) and novel slurry transfer systems (146−148) are all examined in detail.
In tubular crystallizers the API solution is continuously flowing through a tube with constant flow rate. (135) The great benefit of these systems is the excellent process control due to the relatively small tube diameter being often on the order of centimeters, easy scale-up (similarly as described at flow reactors, in section 4.1), and the narrow residence time distribution, which can provide improved product uniformity. The steady state of tubular systems is comparable with the batch operation (with degenerate residence time distribution, a basic assumption of PFRs, is identical), which is a useful property when it comes to the batch to continuous transition. The literature of PFRs includes a substantial number of papers about the continuous crystallization of APIs. (130,149−153) An important variant of PFRs is the continuous oscillatory baffled crystallizer (COBC), where a piston provides an oscillatory flow which, in combination with and the internal orifices (baffles), can greatly reduce the sedimentation and clogging even at low net flow rates, i.e. long residence times. COBCs are applied for the processing of pharmaceuticals more and more frequently, mainly among academic researchers. (154−158) Nevertheless, the fouling in tubular crystallizers, PFRs or COBCs, is a significantly greater issue than in the case of MSMPR crystallizers. (159) Several strategies can be found in the literature to overcome this challenge, e.g. model-based antifouling control via temperature cycling, adding extra additive or solvent, increasing the conveying intensity, and applying new internal features to enhance mixing. (135,137,160)

4.2.2. Continuous Filtration

The produced crystals are separated from the mother liquor in the filtration step. (139) This is a technique often developed by practical and empirical understanding due to the complex nature of cake growth and properties and to the interacting process parameters. (161) Therefore, it is necessary to carry out experiments with the actual slurry on the required scale since predicting filtration performance is cumbersome. (162) In the pharmaceutical industry filtration is generally carried out in batch mode, but there are already a few examples for continuous filtration devices. (161,163) The low number of publications dealing with pharmaceutical-related continuous filtration is probably due to the fact that it is a complex technical challenge and involves the use of less established technologies. (25)
The few examples that can be found in the field of pharmaceutical-related continuous filtration are discussed in this section. Cross flow filtration is a well-known continuous filtration technique, mainly utilized during the processing of biological products to concentrate slurries. (164,165) Gursch et al. and Kossik et al. reported studies related to this technique for API suspensions with a membrane-based device (166,167) and a rotary drum filter. (168,169) Researchers at MIT designed, built, and tested the prototype of a small-scale continuous pharmaceutical filtration instrument using linear motion. (170) Pfizer developed a semicontinuous filter-drier with a 3-way valve, which filtered small amounts of slurry (15–30 mL) every cycle, yielding a kg per a day productivity. (171) In 2015, BHS Sonthofen marketed a manufacturing scale (up to 85 kg/h) continuous indexing belt filter with pressing and steam-drying capabilities. (172) This apparatus was tested in a study by Hohmann et al., in which they investigated the performance of a modular miniplant during the continuous downstream processing of an amino acid, l-alanine. The system comprised a wiped-film evaporator, a tubular crystallizer, and a vacuum belt continuous filter. (173) A continuous filter dryer prototype unit, CFD20 (Alconbury Weston Ltd.) was tested by Ottoboni et al. (Figure 4a). (140) Compared to standard batch filtration, similar results were obtained with the CFD20, but significantly less manual intervention was required due to the higher degree of automation.

Figure 4

Figure 4. (a) Picture of the CFD20 device applied by Ottoboni et al. (140) and (b) design of the hybrid filtration-drying-dissolution unit developed by Wong et al. (174) Reproduced with permission from refs (140) and (174). Copyright 2013 American Chemical Society and Copyright 2019 Elsevier.

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4.2.3. Integrated Continuous Crystallization and Filtration

A few publications were found from the research area of continuous crystallization, in which the filtration step was addressed in any way. In 2012, Wong et al. presented a study about a single-stage MSMPR crystallizer with a recycle system. (175) In this system standard batch filtration was directly connected after crystallization using a coarse glass filter disk with a filter paper having 1 μm thickness. In 2014, Ferguson et al. built a similar single-stage MSMPR system with a filtration step connected directly to the outlet. (176) After the filtration of crystals, the mother liquor was subjected to an organic solvent nanofiltration method in order to eliminate the impurities and increase the concentration of the remaining dissolved API, deferasirox. Acevedo et al. connected a single-stage MSMPR reactor to a continuous filtration carousel (CFC) device (similar to the one used by Ottoboni et al. (140)). (177) A buffer tank was applied between the two steps, and after the optimization of filtration parameters, stable operation was achieved with this two-step system. In 2019, Liu et al. further examined the connectability of the CFC with continuous crystallization in a novel oscillatory baffle reactor (OBR). (178) In this study, paracetamol and benzoic acid were crystallized, and the filtration performance showed significant dependence on crystal size and shape. Wong et al. designed and built a compact system of a continuous MSMPR crystallizer (with novel scraped surface impeller design) coupled with a hybrid filtration-drying-dissolution unit (Figure 4b). (174) Three APIs with different shape attributes were used as model compounds: fluoxetine hydrochloride, ibuprofen, and diphenhydramine hydrochloride. By applying scraped wall crystallization, improvements were accomplished in terms of better kinetics and reduced aggregation, and the semibatch application of the hybrid device saved a considerable amount of time and material, while appropriate performance was achieved with each step. Capellades et al. designed and investigated a similar device, in which filtration, drying, and mechanical processing were integrated. (179) A unique impeller was applied to enhance the processability of needle-like crystals of ciprofloxacin hydrochloride, and this way they successfully reduced the amount of lumps in the material following filtration and drying. Nagy et al. developed the model of an integrated continuous crystallization-filtration system in 2020. (180) In this publication the effect of slurry properties on filtration performance was studied, and simulations were carried out with the integrated system which showed good correspondence with experimental data.

4.3. Continuous Powder Blending and Tableting

Blending of powders is an essential step in many industrial sectors such as the manufacture of chemicals, construction materials, foods, and drugs. (181) Ensuring the homogeneity of the produced powder blend is pivotal, and it is especially true for drug products. (182) The appropriate distribution of the API in the excipients is the key to produce final dosage forms, i.e. tablets with acceptable drug content uniformity. Continuous blending has long been known in the mentioned industries; (183) however, in the pharmaceutical industry, batch mixers are applied in the vast majority of cases to date. (184) The rising of continuous pharmaceutical manufacturing in recent years gave a new push to continuous blending as well.
Continuous blending has a number of advantages over the traditional batchwise method, similar to the case of the earlier described technologies in previous sections. (182) Steady state operation can be reached within a few minutes, in which process control is much more accurate, improving quality. (184) The equipment used for process development can be used for production, eliminating the difficulty of scale-up and reducing the footprint. The continuous operation makes the integration possible with the following continuous tableting step. Thus, the overall efficiency and final product quality can be increased. These advantages can significantly reduce costs during development and manufacturing of pharmaceuticals. (185)
The main body of most continuous blenders is a cylindrical chamber with an average diameter of 3.5–20 cm and an average length of 25–75 cm (Figure 5a). At one end of the cylindrical chamber there is a vertical inlet (hopper) for feeding the materials into the blender. (9) At the other end, the chamber is open allowing the produced powder mixture to leave the device. Motor-driven rotating impellers can be found in the chamber, which mix the components. Bladed, ribbon or ribbon-bladed impellers can be applied, which direct the flow in axial direction (Figure 5). (184)

Figure 5

Figure 5. (a) Schematic drawing and (b) photograph of a twin-screw continuous blender; and photographs of a (c) paddle and (d) a ribbon blender.

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Vanarase et al. published a study about an experimental investigation of the mixing performance and flow behavior in a continuous blender using a pharmaceutical mixture. (186) The impeller rotation rate was found to be the most important process parameter affecting the mixing performance, and the blade configuration also had an effect on powder homogeneity. A similar study was conducted by Osorio et al. in 2016 using a novel continuous blender. (187)
Different strategies can be applied to reach a final dosage form after the blending step. (188) The most common and widespread tablet formulation is produced mostly in high-throughput rotary tableting machines. (189) The simplest way is the so-called “direct compression” technology, during which the blend of the API and the excipients is directly sent to tableting (Figure 6a). Otherwise granulation can be applied to improve powder characteristics and to reduce the risk of segregation after blending (Figure 6c). In this field, either wet or dry granulation can be applied, followed by drying, milling, and another blending step before tableting. Roller compaction is another way to modify the particle size (Figure 6b). Moreover, the powder mixture can directly be filled into capsules. (190)

Figure 6

Figure 6. Different strategies for the production of final dosage forms after blending: (a) direct compression, (b) roller compaction followed by milling and another blending step, and (c) granulation, drying, milling, and blending again (adapted from ref (188)).

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As interest in CM is growing in the pharmaceutical industry, more and more research is performed on integrated powder-to-tablet manufacturing lines. (26) This approach is much more beneficial than using single unit operations, since interactions between the individual steps might affect the quality of the final product. Direct compression is the easiest way to develop such an integrated system. (191) In this case controlling the flowability and compressibility of the components is paramount to obtain tablets of good quality. Järvinen et al. studied the effects of the rotation rate of the mixing impeller, the total feed rate, and the drug content on tablet properties and drug release in an integrated continuous blending-direct compression line. (189) All results showed good drug release, while process parameters affected tablet uniformity. Ervasti et al. produced HPMC-ibuprofen extended release tablets on a similar continuous blending-direct compression manufacturing line. (192) The importance of good flowability was also underlined, as the best results were obtained with the good-flowing samples with large particle size. Researchers at the University of Eastern Finland constructed a modular CM line. (193) This system was tested in a study by Simonaho et al. during the continuous production of tablets with three different system configurations. Van Snick et al. conducted a study for the production of sustained release tablets with a continuous direct compression system. (194) Azad et al. designed and built a compact, portable, reconfigurable, and automated tableting machine at MIT. On-demand flexible tablet manufacturing was feasible with this device, which was demonstrated in two studies with several compounds. (195,196)
In order to ensure the uniformity of the powder product of the continuous blending, real-time analytical techniques have to be applied. Several measurement methods are known, such as spectroscopy (NIR, Raman), image analysis, acoustic techniques, and many others, which are carefully collected in reviews. (197−200) These analytical methods were applied successfully in numerous cases. Nagy et al. used Raman spectroscopy for the monitoring and feedback control of a continuous blending and tableting process. (201) Successful experiments were carried out with the model system of caffeine, glucose, and magnesium stearate, introducing the Process Analytical Controlled Technology (PACT) method. In a recent paper published by Palmer et al., the performance of a direct compression system was tested for a wide range of process parameters and material attributes. (202) The API content in the powder blend was monitored by a NIR probe. The DoE framework was applied to find the relationship between process parameters, material properties, and the quality of the produced tablets. Numerous further examples can be found for the development of continuous blending processes, for the investigation of the connectability with continuous tableting, and for the implementation of in-line analysis in a complex continuous blending-tableting system. (203−210)

4.4. Novel Continuous Formulation Techniques

On the way moving from batch production toward CM, besides evaluating the applicability of the traditional production steps for continuous operation, novel methods should be evaluated as well. Many technologies exist which are inherently continuous, and the spread of CM in the pharmaceutical industry can bring the breakthrough for these processes. Such techniques are for example electrospinning (ES) and hot-melt extrusion (HME), allowing the preparation of amorphous solid dispersions (ASDs). (211) ASDs are innovative drug delivery systems designed to enhance the bioavailability of poorly soluble drugs. Since a substantial amount of recently discovered APIs have very low water solubility, the importance of such innovative drug delivery systems is increasing. (212)

4.4.1. Hot-Melt Extrusion and Dropwise Additive Manufacturing

Among the formulation methods of ASDs, HME is probably the most popular technique. HME was originally adapted from the plastic industry. (213) During the process, a drug-polymer mixture is fed into the heated equipment, where usually corotating screws transport the melted material toward the end of the extruder. After cooling, the product is forwarded to cutting or grinding. This technique is intrinsically continuous, having as the main advantage over ES the solvent-free operation. As a limitation, HME is suitable exclusively for thermostable APIs.
HME has been applied several times for the continuous formulation of pharmaceutical products. Drug-loaded pellets, granules, or tablets were produced by HME in the studies of Kalivoda et al. and Gryczke et al. (214,215) In a publication by Baronsky-Probst et al., the continuous production of pharmaceutical tamper-resistant tablets was carried out by HME. In their work a DoE approach was applied to investigate the relationship between CPPs and CQAs of the product. NIR spectroscopy was used as a PAT tool for real-time analysis, which greatly facilitated the rapid product quality evaluation. (216) HME has industrial applications, too: melt granulation was used in the formulation of a Novartis product comprising metformin and vildagliptin. (217,218)
Dropwise additive manufacturing is another innovative method for the production of final drug products. (219) The principle of the process is the predictable and controllable deposition of a droplet containing an API onto an edible substrate, such as a polymeric film or a placebo tablet. Solvent-, melt-, and suspension-based processes can be developed, and continuous operation is easily attainable. (220) Among several applications, Radcliffe et al. utilized the method using nonideal particulate suspensions for the production of high-dose drug products. (221) Içten et al. presented a supervisory control system for the reproducible production of a melt-based solid oral formulation by drop-on-demand manufacturing. (219)
Dropwise techniques like injection molding and 3D printing have been coupled to HME as well, (222) allowing the production of either sustained- or immediate-release matrix tablets. (223) Zhang et al. investigated the differences between tablets produced by HME and 3D printing and direct compression of milled extrudates and tablets prepared from physical mixtures of the ingredients. (224) In another publication, carvedilol-loaded 3D-printed floating tablets were produced. (225) It was found that the integration of HME and printing techniques is advantageous for both bioavailability improvement and production efficiency. This is a promising approach for personized medicine; albeit, its throughput is significantly lower than e.g. in tableting. (213)

4.4.2. Electrospinning

ES is a well-known technique for the production of ASDs by applying high voltage on a solution containing an API and a polymer excipient (Figure 7). (226−228) The pharmaceutical utilization of the technique is reported in a vast amount of literature, since the versatility of the available polymers allows the formation of ASDs with sustained, controlled, and ultrafast release. (229−236)

Figure 7

Figure 7. Schematic representation of a single-needle electrospinning process, with the scanning electron microscopic picture of the electrospun material on the right.

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The applicability of electrospinning for the continuous production of orally dissolving web (ODW) formulations containing a poorly soluble API (carvedilol) was presented in 2019. (237) As regards the industrial applicability of ES, scaling the laboratory-size ES process up to industrially relevant volumes has recently been presented. (238,239) The downstream processing of the electrospun material, enabling the direct integration of ES into the CM line, has also been published. (213,240) Despite the promising studies, the high potential shown in laboratory systems, and its intrinsically continuous manner, ES has not become a widely applied industrial technique yet.

4.5. End-to-End Continuous Production of Final Dosage Forms

Although significant progress has been made in the field of continuous pharmaceutical manufacturing covering the entire production line from drug substance to drug product manufacturing, the majority of published research works treats the operations separately. Only a few examples refer to processes that were developed with connectability to other technological steps in mind, and even fewer publications were found in which two or more continuous processes have been truly integrated. However, in order to fully exploit the advantages of continuous technologies, the connection of more and more technological steps must be pursued. The final aim would be the development of end-to-end systems, in which the materials are flowing through from raw materials to the final dosage forms in one complete, continuous system (Figure 8). In the following part the published examples for such systems will be presented.

Figure 8

Figure 8. Concept of end-to-end continuous pharmaceutical manufacturing from raw materials to final products with real-time quality control (adapted from ref (227)).

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The Novartis-MIT Center for Continuous Manufacturing was one of the first locations where intensive and thorough continuous process research was conducted. The model API was aliskiren hemifumarate, which was synthesized starting from an advanced intermediate. The first example for the end-to-end production of heat-mold tablets of the API was designed and built, in which all technological steps, including flow synthesis, continuous crystallizations, filtrations, and extractions, were integrated and automated (Figure 9a). (10,101,241) In a follow-up work the previous, container-sized continuous production unit was reduced to the size of a typical refrigerator. (1,242) This was designed in a reconfigurable manner, and four different APIs (diphenhydramine hydrochloride, lidocaine hydrochloride, diazepam, and fluoxetine hydrochloride) could be synthesized. The flow synthesis was followed by batch downstream steps of crystallization, filtration, and redissolution to obtain liquid dosage forms. This platform was further improved by incorporating continuous crystallization, semicontinuous filtration, washing, dispensing, and drying (Figure 9b). (115) In this second-generation system nicardipine hydrochloride, ciprofloxacin hydrochloride, neostigmine hydrochloride, and rufinamide were synthesized, purified, and formulated into the previously mentioned liquid oral dosage form. The first fully automated end-to-end commercial ready CM pilot plant was developed by Continuus Pharmaceuticals, a spinoff company of the Novartis-MIT collaboration, and presented by Hu et al. in 2019. (243) This system consisted of a dissolution unit for the raw materials, a five-stage reactive MSMPR crystallization cascade, a continuous filter followed by resuspension, a novel continuous drum dryer, and hot melt extrusion for the preparation of the final heat-mold tablets. PAT probes were applied for real-time analysis, e.g. in the reactive crystallization and for the monitoring of particle size after filtration. The E-factor analysis of the system in another publication revealed substantial improvements compared to batch manufacturing. (244) The same group published the design and commercialization of a pilot-scale end-to-end CM system, where the significantly lower capital and operating costs were highlighted. (245)

Figure 9

Figure 9. Examples for published continuous end-to-end manufacturing systems for the production of (a) heat-mold tablets of aliskiren hemifumarate (10) and (b) liquid dosage forms of nicardipine hydrochloride, ciprofloxacin hydrochloride, neostigmine hydrochloride, and rufinamide. (115) Reproduced with permissions from refs (10) and (115). Copyright 2013 John Wiley and Sons and Copyright 2018 John Wiley and Sons.

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The end-to-end production of an ODW final dosage form containing ASA was published by Balogh et al. in 2018, presenting the development and optimization of the two-step flow synthesis of the API. (116) High voltage was applied on the reaction mixture leaving the second microreactor; thus, the synthesized API was processed directly by ES to form a nanofibrous product (Figure 10). The ASA-loaded nanofibers produced from the flow reaction mixture were collected on the surface of a continuously moving carrier film, and the formed double-layered strip was cut it into smaller pieces ready for patient administration.

Figure 10

Figure 10. End-to-end production of acetylsalicylic acid-loaded electrospun orally dissolving web dosage forms. The API was synthesized in a 2-step process in flow microreactors and formulated into nanofibers by applying high voltage on the reaction mixture. Reproduced with permission from ref (116). Copyright 2018 Elsevier.

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The first example for the end-to-end production of conventional compressed tablets was presented in 2020 on a proof of concept level. (246) In this study the MSMPR crystallization of the flow reaction mixture of ASA was directly connected to continuous filtration in a CFC device (the same used by Acevedo et al. and Liu et al. in earlier studies (177,178)). The continuously filtered product was moved to a continuous blending step with the tableting excipient microcrystalline cellulose (Figure 11). The materials were fed into a continuous twin-screw blender, and a conveyor belt carried the produced blend to an eccentric tablet press, which pressed it into 500 mg tablets of 100 mg dose strength. The continuous production of ASA-loaded tablets was accomplished with a throughput of 300 g/h, which could provide 14400 dosage units per day. The in-line analysis of the powder blend showed very low fluctuation in ASA concentration, which was in good agreement with the at-line and off-line analysis of the produced tablets.

Figure 11

Figure 11. Feeding of MCC and ASA into the hopper of the continuous blender (left); NIR probe mounted above the belt conveyor after blending (middle); continuous blender, belt conveyor, and tableting machine integrated in one CM line (right) (adapted from ref (246)).

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Although technically not an end-to-end solution, it is noteworthy to mention the study of Hadiwinoto et al., where the production of a final dosage form in an integrated continuous system was accomplished. (247) Spray drying was connected directly to process the slurry produced by a tubular crystallizer, which was demonstrated for two APIs (rifapentine and beclomethasone dipropionate). Process performance was evaluated, and the continuous operation was optimized to produce a dosage form applicable for pulmonary delivery.

5. Conclusions

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Reviewing the recent literature of the continuous pharmaceutical technologies revealed that significant progress has been made to achieve CM in pharmaceutical manufacturing. In the case of flow synthesis, it is clear that although the total synthesis of a few dozen APIs has already been published, more research is necessary to build continuous end-to-end systems. The multistep synthesis of pharmaceuticals must be developed in a way to be connectable with the following technological steps for the workup of the reaction mixture. A couple of publications were presented, which are excellent examples of how continuous crystallization and (semi-) continuous filtration could be coupled in a continuous manner for pharmaceutical purposes and how it could be built in multistep processes. Although numerous examples exist for integrated continuous blending–tableting systems, connection with the upstream manufacturing was made only in a handful of studies. The majority of continuous technologies are developed separately by examining the individual steps alone. The true integration of the processes is often full of challenges, related to the throughput at which the individual operations are being developed, the effect of impurities, and the propagation of disturbances through the continuous system. The development of true end-to-end CM systems for the production of any type of final dosage form is an important scientific topic, while only a very small number of publications can be found in the literature dealing with it. Therefore, it would be of great interest and high techno-economic impact to develop further end-to-end systems to produce either novel drug delivery systems or conventional tablets. The integration of separate technological steps and unit operations allow leveraging the advantages and promises of CM from every perspective, starting from process safety improvements, through the economic and ecological advantages, to the realization of shorter supply chains and production times. Clearly, developing true end-to-end integrated CM technologies requires wide interdisciplinary efforts, ranging from fundamental chemistry aspects to advanced process monitoring and plant-wide control, and recently, machine learning and artificial intelligence are also involved.

Author Information

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  • Corresponding Author
  • Authors
    • András Domokos - Budapest University of Technology and Economics, Organic Chemistry and Technology Department, H-1111 Budapest, Hungary;  Orcidhttp://orcid.org/0000-0003-1968-4679
    • Brigitta Nagy - Budapest University of Technology and Economics, Organic Chemistry and Technology Department, H-1111 Budapest, Hungary
    • Botond Szilágyi - Budapest University of Technology and Economics, Faculty of Chemical Technology and Biotechnology, H-1111 Budapest, Hungary
    • György Marosi - Budapest University of Technology and Economics, Organic Chemistry and Technology Department, H-1111 Budapest, Hungary
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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This work was supported from grants by National Research, Development and Innovation Office of Hungary (grant numbers: KH-129584, FK-132133, PD-121143). This work was also performed in the frame of FIEK_16-1-2016-0007 project, implemented with the support provided from the National Research, Development and Innovation Fund of Hungary, financed under the FIEK_16 funding scheme. The research reported in this paper and carried out at BME has been supported by the NRDI Fund (TKP2020 IES, Grant No. TKP2020 BME-IKA-VIZ) based on the charter of bolster issued by the NRDI Office under the auspices of the Ministry for Innovation and Technology, supported by the ÚNKP-20-3 New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund.

References

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    Chemical Engineering and Processing (2015), 97 (), 248-258CODEN: CENPEU; ISSN:0255-2701. (Elsevier B.V.)
    This paper presents an approach to evaluating the potential supply chain benefits of adopting continuous processing technologies for a diverse set of pharmaceutical products. The approach integrates upstream 'continuous' processing considerations for the prodn. of active ingredients and final product formulation, with the downstream implications for packing and distribution. Currently, these upstream and downstream operations largely operate as decoupled operations with independent coordination and governance mechanisms, and the approach presented in this paper identifies opportunities for more case-specific integrated end-to-end supply chains enabled by continuous flow technologies. Three specific product (and corresponding processing technol.) case studies are used to demonstrate the utility of the approach in assessing the supply network and system integration opportunities that emerge from the continuous processing of pharmaceutical products.
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    Yu, L. X. Pharmaceutical Quality by Design: Product and Process Development, Understanding, and Control. Pharm. Res. 2008, 25 (4), 781– 791,  DOI: 10.1007/s11095-007-9511-1
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    Pharmaceutical Quality by Design: Product and Process Development, Understanding, and Control
    Yu, Lawrence X.
    Pharmaceutical Research (2008), 25 (4), 781-791CODEN: PHREEB; ISSN:0724-8741. (Springer)
    A review. Purpose. The purpose of this paper is to discuss the pharmaceutical Quality by Design (QbD) and describe how it can be used to ensure pharmaceutical quality. Materials and Methods. The QbD was described and some of its elements identified. Process parameters and quality attributes were identified for each unit operation during manuf. of solid oral dosage forms. The use of QbD was contrasted with the evaluation of product quality by testing alone. Results. The QbD is a systemic approach to pharmaceutical development. It means designing and developing formulations and manufg. processes to ensure predefined product quality. Some of the QbD elements include: Conclusions. Using QbD, pharmaceutical quality is assured by understanding and controlling formulation and manufg. variables. Product testing confirms the product quality. Implementation of QbD will enable transformation of the chem., manufg., and controls (CMC) review of abbreviated new drug applications (ANDAs) into a science-based pharmaceutical quality assessment.
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    Ayati, N.; Saiyarsarai, P.; Nikfar, S. Short and Long Term Impacts of COVID-19 on the Pharmaceutical Sector. Daru, J. Pharm. Sci. 2020, 28, 799,  DOI: 10.1007/s40199-020-00358-5
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    Short and long term impacts of COVID-19 on the pharmaceutical sector
    Ayati Nayyereh; Saiyarsarai Parisa; Nikfar Shekoufeh; Saiyarsarai Parisa; Nikfar Shekoufeh; Nikfar Shekoufeh
    Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences (2020), 28 (2), 799-805 ISSN:.
    BACKGROUND: The novel coronavirus disease 2019 (COVID-19) was characterized as a global pandemic by the WHO on March 11th, 2020. This pandemic had major effects on the health market, the pharmaceutical sector, and was associated with considerable impacts; which may appear in short and long-term time-horizon and need identification and appropriate planning to reduce their socio-economic burden. OBJECTIVES: Current short communication study assessed pharmaceutical market crisis during the COVID-19 era; discussing short- and long-term impacts of the pandemic on the pharmaceutical sector. RESULTS: Short-term impacts of COVID-19 pandemic includes demand changes, regulation revisions, research and development process changes and the shift towards tele-communication and tele-medicine. In addition, industry growth slow-down, approval delays, moving towards self-sufficiency in pharm-production supply chain and trend changes in consumption of health-market products along with ethical dilemma could be anticipated as long-term impacts of COVID-19 pandemic on pharmaceutical sector in both global and local levels. CONCLUSION: The pandemic of COVID-19 poses considerable crisis on the health markets, including the pharmaceutical sector; and identification of these effects, may guide policy-makers towards more evidence-informed planning to overcome accompanying challenges. Graphical abstract .
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    Teżyk, M.; Milanowski, B.; Ernst, A.; Lulek, J. Recent Progress in Continuous and Semi-Continuous Processing of Solid Oral Dosage Forms: A Review. Drug Dev. Ind. Pharm. 2016, 42 (8), 1195– 1214,  DOI: 10.3109/03639045.2015.1122607
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    Recent progress in continuous and semi-continuous processing of solid oral dosage forms: a review
    Tezyk, Michal; Milanowski, Bartlomiej; Ernst, Andrzej; Lulek, Janina
    Drug Development and Industrial Pharmacy (2016), 42 (8), 1195-1214CODEN: DDIPD8; ISSN:0363-9045. (Taylor & Francis Ltd.)
    Continuous processing is an innovative prodn. concept well known and successfully used in other industries for many years. The modern pharmaceutical industry is facing the challenge of transition from a traditional manufg. approach based on batch-wise prodn. to a continuous manufg. model. The aim of this article is to present technol. progress in manufg. based on continuous and semi-continuous processing of the solid oral dosage forms. Single unit processes possessing an alternative processing pathway to batch-wise technol. or, with some modification, an altered approach that may run continuously, and are thus able to seamlessly switch to continuous manufg. are briefly presented. Furthermore, the concept of semi-continuous processing is discussed. Subsequently, more sophisticated prodn. systems created by coupling single unit processes and comprising all the steps of prodn., from powder to final dosage form, were reviewed. Finally, attempts of end-to-end prodn. approach, meaning the linking of continuous synthesis of API from intermediates with the prodn. of final dosage form, are described. There are a growing no. of scientific articles showing an increasing interest in changing the approach to the prodn. of pharmaceuticals in recent years. Numerous scientific publications are a source of information on the progress of knowledge and achievements of continuous processing. These works often deal with issues of how to modify or replace the unit processes in order to enable seamlessly switching them into continuous processing. A growing no. of research papers conc. on integrated continuous manufg. lines in which the prodn. concept of "from powder to tablet" is realized. Four main domains are under investigation: influence of process parameters on intermediates or final dosage forms properties, implementation of process anal. tools, control-managing system responsible for keeping continuous materials flow through the whole manufg. process and the development of new computational methods to assess or simulate these new manufg. techniques. The attempt to connect the primary and secondary prodn. steps proves that development of continuously operating lines is possible. A mind-set change is needed to be able to face, and fully assess, the advantages and disadvantages of switching from batch to continuous mode prodn.
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    Mascia, S.; Heider, P. L.; Zhang, H.; Lakerveld, R.; Benyahia, B.; Barton, P. I.; Braatz, R. D.; Cooney, C. L.; Evans, J. M. B.; Jamison, T. F.; Jensen, K. F.; Myerson, A. S.; Trout, B. L. End-to-End Continuous Manufacturing of Pharmaceuticals: Integrated Synthesis, Purification, and Final Dosage Formation. Angew. Chem. 2013, 125 (47), 12585– 12589,  DOI: 10.1002/ange.201305429
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    Rantanen, J.; Khinast, J. The Future of Pharmaceutical Manufacturing Sciences. J. Pharm. Sci. 2015, 104 (11), 3612– 3638,  DOI: 10.1002/jps.24594
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    The Future of Pharmaceutical Manufacturing Sciences
    Rantanen, Jukka; Khinast, Johannes
    Journal of Pharmaceutical Sciences (2015), 104 (11), 3612-3638CODEN: JPMSAE; ISSN:0022-3549. (John Wiley & Sons, Inc.)
    The entire pharmaceutical sector is in an urgent need of both innovative technol. solns. and fundamental scientific work, enabling the prodn. of highly engineered drug products. Com.-scale manufg. of complex drug delivery systems (DDSs) using the existing technologies is challenging. This review covers important elements of manufg. sciences, beginning with risk management strategies and design of expts. (DoE) techniques. Exptl. techniques should, where possible, be supported by computational approaches. With that regard, state-of-art mechanistic process modeling techniques are described in detail. Implementation of materials science tools paves the way to mol.-based processing of future DDSs. A snapshot of some of the existing tools is presented. Addnl., general engineering principles are discussed covering process measurement and process control solns. Last part of the review addresses future manufg. solns., covering continuous processing and, specifically, hot-melt processing and printing-based technologies. Finally, challenges related to implementing these technologies as a part of future health care systems are discussed. © 2015 The Authors. Journal of Pharmaceutical Sciences published by Wiley Periodicals, Inc. and the American Pharmacists Assocn. J Pharm Sci.
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    Su, Q.; Ganesh, S.; Moreno, M.; Bommireddy, Y.; Gonzalez, M.; Reklaitis, G. V.; Nagy, Z. K. A Perspective on Quality-by-Control (QbC) in Pharmaceutical Continuous Manufacturing. Comput. Chem. Eng. 2019, 125, 216– 231,  DOI: 10.1016/j.compchemeng.2019.03.001
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    A perspective on Quality-by-Control (QbC) in pharmaceutical continuous manufacturing
    Su, Qinglin; Ganesh, Sudarshan; Moreno, Mariana; Bommireddy, Yasasvi; Gonzalez, Marcial; Reklaitis, Gintaras V.; Nagy, Zoltan K.
    Computers & Chemical Engineering (2019), 125 (), 216-231CODEN: CCENDW; ISSN:0098-1354. (Elsevier B.V.)
    The Quality-by-Design (QbD) guidance issued by the US Food and Drug Administration (FDA) has catalyzed the modernization of pharmaceutical manufg. practices including the adoption of continuous manufg. Active process control was highlighted recently as a means to improve the QbD implementation. This advance has since been evolving into the concept of Quality-by-Control (QbC). In this study, the concept of QbC is discussed, including a definition of QbC, a review of the recent developments towards the QbC, and a perspective on the challenges of QbC implementation in continuous manufg. The QbC concept is demonstrated using a rotary tablet press, integrated into a pilot scale continuous direct compaction process. The results conclusively showed that active process control, based on product and process knowledge and advanced model-based techniques, including data reconciliation, model predictive control (MPC), and risk anal., is indispensable to comprehensive QbC implementation, and ensures robustness and efficiency.
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    Lee, S. L.; O’Connor, T. F.; Yang, X.; Cruz, C. N.; Chatterjee, S.; Madurawe, R. D.; Moore, C. M. V; Yu, L. X.; Woodcock, J. Modernizing Pharmaceutical Manufacturing: From Batch to Continuous Production. J. Pharm. Innov. 2015, 10 (3), 191– 199,  DOI: 10.1007/s12247-015-9215-8
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    DiMasi, J. A.; Grabowski, H. G.; Hansen, R. W. Innovation in the Pharmaceutical Industry: New Estimates of R&D Costs. J. Health Econ. 2016, 47, 20– 33,  DOI: 10.1016/j.jhealeco.2016.01.012
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    Innovation in the pharmaceutical industry: New estimates of R&D costs
    DiMasi Joseph A; Grabowski Henry G; Hansen Ronald W
    Journal of health economics (2016), 47 (), 20-33 ISSN:.
    The research and development costs of 106 randomly selected new drugs were obtained from a survey of 10 pharmaceutical firms. These data were used to estimate the average pre-tax cost of new drug and biologics development. The costs of compounds abandoned during testing were linked to the costs of compounds that obtained marketing approval. The estimated average out-of-pocket cost per approved new compound is $1395 million (2013 dollars). Capitalizing out-of-pocket costs to the point of marketing approval at a real discount rate of 10.5% yields a total pre-approval cost estimate of $2558 million (2013 dollars). When compared to the results of the previous study in this series, total capitalized costs were shown to have increased at an annual rate of 8.5% above general price inflation. Adding an estimate of post-approval R&D costs increases the cost estimate to $2870 million (2013 dollars).
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    Nasr, M. M.; Krumme, M.; Matsuda, Y.; Trout, B. L.; Badman, C.; Mascia, S.; Cooney, C. L.; Jensen, K. D.; Florence, A.; Johnston, C.; Konstantinov, K.; Lee, S. L. Regulatory Perspectives on Continuous Pharmaceutical Manufacturing: Moving From Theory to Practice: September 26–27, 2016, International Symposium on the Continuous Manufacturing of Pharmaceuticals. J. Pharm. Sci. 2017, 106, 3199– 3206.  DOI: 10.1016/j.xphs.2017.06.015 .
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    Regulatory Perspectives on Continuous Pharmaceutical Manufacturing: Moving From Theory to Practice
    Nasr, Moheb M.; Krumme, Markus; Matsuda, Yoshihiro; Trout, Bernhardt L.; Badman, Clive; Mascia, Salvatore; Cooney, Charles L.; Jensen, Keith D.; Florence, Alastair; Johnston, Craig; Konstantinov, Konstantin; Lee, Sau L.
    Journal of Pharmaceutical Sciences (Philadelphia, PA, United States) (2017), 106 (11), 3199-3206CODEN: JPMSAE; ISSN:0022-3549. (Elsevier Inc.)
    Continuous manufg. plays a key role in enabling the modernization of pharmaceutical manufg. The fate of this emerging technol. will rely, in large part, on the regulatory implementation of this novel technol. This paper, which is based on the 2nd International Symposium on the Continuous Manufg. of Pharmaceuticals, describes not only the advances that have taken place since the first International Symposium on Continuous Manufg. of Pharmaceuticals in 2014, but the regulatory landscape that exists today. Key regulatory concepts including quality risk management, batch definition, control strategy, process monitoring and control, real-time release testing, data processing and management, and process validation/verification are outlined. Support from regulatory agencies, particularly in the form of the harmonization of regulatory expectations, will be crucial to the successful implementation of continuous manufg. Collaborative efforts, among academia, industry, and regulatory agencies, are the optimal soln. for ensuring a solid future for this promising manufg. technol.
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    Byrn, S.; Futran, M.; Thomas, H.; Jayjock, E.; Maron, N.; Meyer, R. F.; Myerson, A. S.; Thien, M. P.; Trout, B. L. Achieving Continuous Manufacturing for Final Dosage Formation: Challenges and How to Meet Them May 20–21 2014 Continuous Manufacturing Symposium. J. Pharm. Sci. 2015, 104 (3), 792– 802,  DOI: 10.1002/jps.24247
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    Achieving Continuous Manufacturing for Final Dosage Formation: Challenges and How to Meet Them. May 20-21, 2014 Continuous Symposium
    Byrn, Stephen; Futran, Maricio; Thomas, Hayden; Jayjock, Eric; Maron, Nicola; Meyer, Robert F.; Myerson, Allan S.; Thien, Michael P.; Trout, Bernhardt L.
    Journal of Pharmaceutical Sciences (2015), 104 (3), 792-802CODEN: JPMSAE; ISSN:0022-3549. (John Wiley & Sons, Inc.)
    We describe the key issues and possibilities for continuous final dosage formation, otherwise known as downstream processing or drug product manufg. A distinction is made between heterogeneous processing and homogeneous processing, the latter of which is expected to add more value to continuous manufg. We also give the key motivations for moving to continuous manufg., some of the exciting new technologies, and the barriers to implementation of continuous manufg. Continuous processing of heterogeneous blends is the natural first step in converting existing batch processes to continuous. In heterogeneous processing, there are discrete particles that can segregate, vs. in homogeneous processing, components are blended and homogenized such that they do not segregate. Heterogeneous processing can incorporate technologies that are closer to existing technologies, where homogeneous processing necessitates the development and incorporation of new technologies. Homogeneous processing has the greatest potential for reaping the full rewards of continuous manufg., but it takes long-term vision and a more significant change in process development than heterogeneous processing. Heterogeneous processing has the detriment that, as the technologies are adopted rather than developed, there is a strong tendency to incorporate correction steps, what we call below "The Rube Goldberg Problem." Thus, although heterogeneous processing will likely play a major role in the near-term transformation of heterogeneous to continuous processing, it is expected that homogeneous processing is the next step that will follow. Specific action items for industry leaders are:Form precompetitive partnerships, including industry (pharmaceutical companies and equipment manufacturers), government, and universities. These precompetitive partnerships would develop case studies of continuous manufg. and ideally perform joint-technol. development, including development of small-scale equipment and processes. Develop ways to invest internally in continuous manufg. How best to do this will depend on the specifics of a given organization, in particular the current development projects. Upper managers will need to energize their process developers to incorporate continuous manufg. in at least part of their processes to gain experience and demonstrate directly the benefits. Training of continuous manufg. technologies, organizational approaches, and regulatory approaches is a key area that industrial leaders should pursue together. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Assocn. J Pharm Sci.
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    Baxendale, I. R.; Braatz, R. D.; Hodnett, B. K.; Jensen, K. F.; Johnson, M. D.; Sharratt, P.; Sherlock, J.-P.; Florence, A. J. Achieving Continuous Manufacturing: Technologies and Approaches for Synthesis, Workup, and Isolation of Drug Substance May 20–21, 2014 Continuous Manufacturing Symposium. J. Pharm. Sci. 2015, 104 (3), 781– 791,  DOI: 10.1002/jps.24252
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    Achieving Continuous Manufacturing: Technologies and Approaches for Synthesis, Workup, and Isolation of Drug Substance
    Baxendale, Ian R.; Braatz, Richard D.; Hodnett, Benjamin K.; Jensen, Klavs F.; Johnson, Martin D.; Sharratt, Paul; Sherlock, Jon-Paul; Florence, Alastair J.
    Journal of Pharmaceutical Sciences (2015), 104 (3), 781-791CODEN: JPMSAE; ISSN:0022-3549. (John Wiley & Sons, Inc.)
    This whitepaper highlights current challenges and opportunities assocd. with continuous synthesis, workup, and crystn. of active pharmaceutical ingredients (drug substances). We describe the technologies and requirements at each stage and emphasize the different considerations for developing continuous processes compared with batch. In addn. to the specific sequence of operations required to deliver the necessary chem. and phys. transformations for continuous drug substance manuf., consideration is also given to how adoption of continuous technologies may impact different manufg. stages in development from discovery, process development, through scale-up and into full scale prodn. The impact of continuous manuf. on drug substance quality and the assocd. challenges for control and for process safety are also emphasized. In addn. to the technol. and operational considerations necessary for the adoption of continuous manufg. (CM), this whitepaper also addresses the cultural, as well as skills and training, challenges that will need to be met by support from organizations in order to accommodate the new work flows. Specific action items for industry leaders are: Develop flow chem. toolboxes, exploiting the advantages of flow processing and including highly selective chemistries that allow use of simple and effective continuous workup technologies. Availability of modular or plug and play type equipment esp. for workup to assist in straightforward deployment in the lab. As with learning from other industries, standardization is highly desirable and will require cooperation across industry and academia to develop and implement. Implement and exploit process anal. technologies (PAT) for real-time dynamic control of continuous processes. Develop modeling and simulation techniques to support continuous process development and control. Progress is required in multiphase systems such as crystn. Involve all parts of the organization from discovery, research and development, and manufg. in the implementation of CM. Engage with academia to develop the training provision to support the skills base for CM, particularly in flow chem., phys. chem., and chem. engineering skills at the chem.-process interface. Promote and encourage publication and dissemination of examples of CM across the sector to demonstrate capability, engage with regulatory comment, and establish benchmarks for performance and highlight challenges. Develop the economic case for CM of drug substance. This will involve various stakeholders at project and business level, however establishing the crit. economic drivers is crit. to driving the transformation in manufg. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Assocn. J Pharm Sci.
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    Allison, G.; Cain, Y. T.; Cooney, C.; Garcia, T.; Bizjak, T. G.; Holte, O.; Jagota, N.; Komas, B.; Korakianiti, E.; Kourti, D.; Madurawe, R.; Morefield, E.; Montgomery, F.; Nasr, M.; Randolph, W.; Robert, J.-L.; Rudd, D.; Zezza, D. Regulatory and Quality Considerations for Continuous Manufacturing May 20–21, 2014 Continuous Manufacturing Symposium. J. Pharm. Sci. 2015, 104 (3), 803– 812,  DOI: 10.1002/jps.24324
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    Regulatory and Quality Considerations for Continuous Manufacturing. May 20-21, 2014 Continuous Symposium
    Allison, Gretchen; Cain, Yanxi Tan; Cooney, Charles; Garcia, Tom; Bizjak, Tara Gooen; Holte, Oyvind; Jagota, Nirdosh; Komas, Bekki; Korakianiti, Evdokia; Kourti, Dora; Madurawe, Rapti; Morefield, Elaine; Montgomery, Frank; Nasr, Moheb; Randolph, William; Robert, Jean-Louis; Rudd, Dave; Zezza, Diane
    Journal of Pharmaceutical Sciences (2015), 104 (3), 803-812CODEN: JPMSAE; ISSN:0022-3549. (John Wiley & Sons, Inc.)
    This paper assesses the current regulatory environment, relevant regulations and guidelines, and their impact on continuous manufg. It summarizes current regulatory experience and learning from both review and inspection perspectives. It outlines key regulatory aspects, including continuous manufg. process description and control strategy in regulatory files, process validation, and key Good Manufg. Practice (GMP) requirements. In addn., the paper identifies regulatory gaps and challenges and proposes a way forward to facilitate implementation. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Assocn. J Pharm Sci.
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    Schaber, S. D.; Gerogiorgis, D. I.; Ramachandran, R.; Evans, J. M. B.; Barton, P. I.; Trout, B. L. Economic Analysis of Integrated Continuous and Batch Pharmaceutical Manufacturing: A Case Study. Ind. Eng. Chem. Res. 2011, 50 (17), 10083– 10092,  DOI: 10.1021/ie2006752
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    Economic Analysis of Integrated Continuous and Batch Pharmaceutical Manufacturing: A Case Study
    Schaber, Spencer D.; Gerogiorgis, Dimitrios I.; Ramachandran, Rohit; Evans, James M. B.; Barton, Paul I.; Trout, Bernhardt L.
    Industrial & Engineering Chemistry Research (2011), 50 (17), 10083-10092CODEN: IECRED; ISSN:0888-5885. (American Chemical Society)
    The capital, operating, and overall costs of a dedicated continuous manufg. process to synthesize an active pharmaceutical ingredient (API) and formulate it into tablets are estd. for a prodn. scale of 2000 t of tablets per yr, with raw material cost, prodn. yield, and API loading varied over broad ranges. Costs are compared to batch prodn. in a dedicated facility. Synthesis begins with a key org. intermediate three synthetic steps before the final API; results are given for key intermediate (KI) costs of +dollar;100 to +dollar;3000/kg, with drug loadings in the tablet of 10 and 50 wt %. The novel continuous process described here is being developed by an interdisciplinary team of 20 researchers. Since yields are not yet well-known, and continuous processes typically have better yields than batch ones, the overall yields of the continuous processes with recycling were set equal to that of the batch process. Without recycling, yields are 10% lower, but less equipment is required. The continuous process has not been built at large scale, so Wroth factors and other assumptions were used to est. costs. Capital expenditures for continuous prodn. were estd. to be 20 to 76% lower, depending on the drug loading, KI cost, and process chosen; operating expenditures were estd. to be between 40% lower and 9% higher. The novel continuous process with recycling coupled to a novel direct tablet formation process yields the best overall cost savings in each drug loading/KI price scenario: estd. savings range from 9 to 40%. Overall cost savings are also given assuming the yield in the continuous case is 10% above and 10% below that of the batch process. Even when yields in the continuous case are lower than in the batch case, savings can still be achieved because the labor, materials handling, CapEx, and other savings compensate.
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    Wilburn, K. R. The Business Case for Continuous Manufacturing of Pharmaceuticals; Massachusetts Institute of Technology, 2010.
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    Simon, L. L.; Kiss, A. A.; Cornevin, J.; Gani, R. Process Engineering Advances in Pharmaceutical and Chemical Industries: Digital Process Design, Advanced Rectification, and Continuous Filtration. Curr. Opin. Chem. Eng. 2019, 114– 121.  DOI: 10.1016/j.coche.2019.02.005 .
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    Vanhoorne, V.; Vervaet, C. Recent Progress in Continuous Manufacturing of Oral Solid Dosage Forms. Int. J. Pharm. 2020, 579, 119194,  DOI: 10.1016/j.ijpharm.2020.119194
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    Recent progress in continuous manufacturing of oral solid dosage forms
    Vanhoorne, V.; Vervaet, C.
    International Journal of Pharmaceutics (Amsterdam, Netherlands) (2020), 579 (), 119194CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
    A review. Continuous drug product manufg. is slowly being implemented in the pharmaceutical industry. Although the benefits related to the quality and cost of continuous manufg. are widely recognized, several challenges hampered the widespread introduction of continuous manufg. of drug products. Current review presents an overview of state-of-the art research, equipment, process anal. technol. implementations and advanced control strategies. Addnl., guidelines and regulatory viewpoints on implementation of continuous manufg. in the pharmaceutical industry are discussed.
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    Poechlauer, P.; Manley, J.; Broxterman, R.; Gregertsen, B.; Ridemark, M. Continuous Processing in the Manufacture of Active Pharmaceutical Ingredients and Finished Dosage Forms: An Industry Perspective. Org. Process Res. Dev. 2012, 16 (10), 1586– 1590,  DOI: 10.1021/op300159y
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    Continuous Processing in the Manufacture of Active Pharmaceutical Ingredients and Finished Dosage Forms: An Industry Perspective
    Poechlauer, Peter; Manley, Julie; Broxterman, Rinus; Gregertsen, Bjoern; Ridemark, Mats
    Organic Process Research & Development (2012), 16 (10), 1586-1590CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    Continuous manufg. as a way of producing fine chems., active pharmaceutical ingredients, and finished dosage forms is gaining widespread attention. Although potential benefits over traditional batch-wise prodn. have been discussed at many occasions and appear evident, continuous processes are only slowly being implemented. The American Chem. Society Green Chem. Institute Pharmaceutical Roundtable has defined "continuous processing" as one of its research priorities and performed a survey of its members' opinions, the status of implementation, and perceived hurdles blocking implementation of continuous manufg. processes. Here we discuss the most important results of this survey and their relation to present trends in this industry to "go green".
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    Poechlauer, P.; Colberg, J.; Fisher, E.; Jansen, M.; Johnson, M. D.; Koenig, S. G.; Lawler, M.; Laporte, T.; Manley, J.; Martin, B.; O’Kearney-McMullan, A. Pharmaceutical Roundtable Study Demonstrates the Value of Continuous Manufacturing in the Design of Greener Processes. Org. Process Res. Dev. 2013, 17 (12), 1472– 1478,  DOI: 10.1021/op400245s
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    Pharmaceutical Roundtable Study Demonstrates the Value of Continuous Manufacturing in the Design of Greener Processes
    Poechlauer, Peter; Colberg, Juan; Fisher, Elizabeth; Jansen, Michael; Johnson, Martin D.; Koenig, Stefan G.; Lawler, Michael; Laporte, Thomas; Manley, Julie; Martin, Benjamin; O'Kearney-McMullan, Anne
    Organic Process Research & Development (2013), 17 (12), 1472-1478CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    A review. The American Chem. Society (ACS) Green Chem. Institute (GCI) Pharmaceutical Roundtable conducted a study to elucidate the value of continuous processing, which had been defined as a key research area for green engineering. In the course of defining the business case for continuous processing, individual cases were collected and evaluated to det. specific drivers to implement continuous processing and to find key success factors. The magnitude and timing of effects and the relation to the principles of green chem. were investigated.
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    Food and Drug Administration. Guidance for Industry PAT: A Framework for Innovative Pharmaceutical Development, Manufacuring, and Quality Assurance. FDA Off. Doc. 2004, No. September, 16.
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    Simon, L. L.; Pataki, H.; Marosi, G.; Meemken, F.; Hungerbühler, K.; Baiker, A.; Tummala, S.; Glennon, B.; Kuentz, M.; Steele, G.; Kramer, H. J. M.; Rydzak, J. W.; Chen, Z.; Morris, J.; Kjell, F.; Singh, R.; Gani, R.; Gernaey, K. V.; Louhi-Kultanen, M.; Oreilly, J.; Sandler, N.; Antikainen, O.; Yliruusi, J.; Frohberg, P.; Ulrich, J.; Braatz, R. D.; Leyssens, T.; von Stosch, M.; Oliveira, R.; Tan, R. B. H.; Wu, H.; Khan, M.; Ogrady, D.; Pandey, A.; Westra, R.; Delle-Case, E.; Pape, D.; Angelosante, D.; Maret, Y.; Steiger, O.; Lenner, M.; Abbou-Oucherif, K.; Nagy, Z. K.; Litster, J. D.; Kamaraju, V. K.; Chiu, M. Sen. Assessment of Recent Process Analytical Technology (PAT) Trends: A Multiauthor Review. Org. Process Res. Dev. 2015, 19 (1),  DOI: 10.1021/op500261y .
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    Yu, L. X.; Amidon, G.; Khan, M. A.; Hoag, S. W.; Polli, J.; Raju, G. K.; Woodcock, J. Understanding Pharmaceutical Quality by Design. AAPS J. 2014, 16 (4), 771– 783,  DOI: 10.1208/s12248-014-9598-3
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    Understanding Pharmaceutical Quality by Design
    Yu, Lawrence X.; Amidon, Gregory; Khan, Mansoor A.; Hoag, Stephen W.; Polli, James; Raju, G. K.; Woodcock, Janet
    AAPS Journal (2014), 16 (4), 771-783CODEN: AJAOB6; ISSN:1550-7416. (Springer)
    This review further clarifies the concept of pharmaceutical quality by design (QbD) and describes its objectives. QbD elements include the following: (1) a quality target product profile (QTPP) that identifies the crit. quality attributes (CQAs) of the drug product; (2) product design and understanding including identification of crit. material attributes (CMAs); (3) process design and understanding including identification of crit. process parameters (CPPs), linking CMAs and CPPs to CQAs; (4) a control strategy that includes specifications for the drug substance(s), excipient(s), and drug product as well as controls for each step of the manufg. process; and (5) process capability and continual improvement. QbD tools and studies include prior knowledge, risk assessment, mechanistic models, design of expts. (DoE) and data anal., and process anal. technol. (PAT). As the pharmaceutical industry moves toward the implementation of pharmaceutical QbD, a common terminol., understanding of concepts and expectations are necessary. This understanding will facilitate better communication between those involved in risk-based drug development and drug application review.
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    Szilagyi, B.; Eren, A.; Quon, J. L.; Papageorgiou, C. D.; Nagy, Z. K. Application of Model-Free and Model-Based Quality-by-Control (QbC) for the Efficient Design of Pharmaceutical Crystallization Processes. Cryst. Growth Des. 2020, 20 (6), 3979– 3996,  DOI: 10.1021/acs.cgd.0c00295
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    Application of Model-Free and Model-Based Quality-by-Control (QbC) for the Efficient Design of Pharmaceutical Crystallization Processes
    Szilagyi, Botond; Eren, Ayse; Quon, Justin L.; Papageorgiou, Charles D.; Nagy, Zoltan K.
    Crystal Growth & Design (2020), 20 (6), 3979-3996CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
    The design of pharmaceutical crystn. processes is a challenging engineering problem because of the specific and versatile quality requirements of the end-product, amplified by the tight regulatory stds. The current industrial std. for crystn. process design is based on the use of the quality-by-design (QbD) framework, which relies on factorial design of expts. (DoE). Hence, QbD inherently generates a large no. of resource-consuming open loop crystn. expts. This is esp. true when more complex operating conditions need to be designed, such as temp. cycles, which require a large no. of decision variables in the DoE. In contrast, the recently proposed quality-by-control (QbC) approach relies on feedback control algorithms to directly achieve the desired product properties by manipulating the appropriate process conditions. The first aim of this work is to demonstrate the effectiveness of a model-free feedback control strategy, referred to as model-free (mf) QbC. Direct nucleation control (DNC) and supersatn. control (SSC) are applied as a part of the mfQbC approach, which, ideally, requires only two feedback control expts. to obtain a temp. profile that results in obtaining the desired product quality. Although mfQbC provides a rapid process design, it is often suboptimal. In addn., it is shown that the exptl. data generated by mfQbC can be used for process model development and kinetic parameter estn. The validated model enables optimization-based design using the model-based (mb) QbC framework. For this case study, a population balance (PB) based process model is developed, which involves primary and secondary nucleation, growth, and dissoln., as well as a novel formulation of agglomeration, and deagglomeration of crystals. In addn. to taking into account the agglomeration, the no. of agglomerates is also tracked as a balance between the agglomeration and deagglomeration events. The kinetic parameters are estd. using a novel objective function formulation relying on the minimization of the difference between the measured and simulated concns. and crystal size distributions (CSDs) and the maximization of the correlation between the simulated crystal no. d. and measured crystal count data obtained from focused beam reflectance measurement (FBRM). The kinetic parameters are identified based on the exptl. data generated from the mfQbC, which inherently reduced the exptl. effort required for the model development. The temp. profile is optimized for the fine index and agglomeration degree minimization. The repeated open-loop implementation of mfQbC- and mbQbC-designed processes showed that the batch-to-batch variation is low and the product quality is high in both cases. The proposed general framework is illustrated for the systematic quick and optimal design of crystn. processes that require temp. cycles with a low no. of expts. An efficient crystn. design approach is proposed that combines model-free and model-based quality-by-control (QbC) frameworks, based on the use of process anal. technol. (PAT) tools, feedback control approaches, and math. modeling for the design and optimization of crystn. processes. This proof-of-concept study demonstrates that QbC can provide optimal operating conditions to produce crystals with desired crit. quality attributes (CQAs).
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    Szilágyi, B.; Borsos, Á.; Pal, K.; Nagy, Z. K. Experimental Implementation of a Quality-by-Control (QbC) Framework Using a Mechanistic PBM-Based Nonlinear Model Predictive Control Involving Chord Length Distribution Measurement for the Batch Cooling Crystallization of l-Ascorbic Acid. Chem. Eng. Sci. 2019, 195, 335– 346,  DOI: 10.1016/j.ces.2018.09.032
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    Experimental implementation of a Quality-by-Control (QbC) framework using a mechanistic PBM-based nonlinear model predictive control involving chord length distribution measurement for the batch cooling crystallization of L-ascorbic acid
    Szilagyi, Botond; Borsos, Akos; Pal, Kanjakha; Nagy, Zoltan K.
    Chemical Engineering Science (2019), 195 (), 335-346CODEN: CESCAC; ISSN:0009-2509. (Elsevier Ltd.)
    L-Ascorbic acid is synthesized in large industrial scale from glucose and marketed as an immune system strengthening agent and anti-oxidant ingredient. The overall yield of conversion of the precursor glucose to L-ascorbic acid is limited, therefore the crystn. is a critically important step of the L-ascorbic acid prodn. from economic point of view. It is widely accepted that the crystal size distribution (CSD) influences numerous relevant macroscopic properties of the final cryst. product and it also significantly affects the downstream operations. The present paper discusses the chord length distribution (CLD, which is directly related to the CSD) control, during the crystn. of L-ascorbic acid from aq. soln. Batch crystn. process is employed, which is the classical, and still dominant, operation in fine chem. and pharmaceutical industries. A comparative exptl. study of two state-of-the-art Quality-by-Control (QbC) based crystn. design approaches are presented: (1) a model-free QbC based on direct nucleation control (DNC) and (2) a model-based QbC using a novel nonlinear model predicative control (NMPC) framework. In the first investigation, the DNC, a process anal. technol. based state-of-the-art model free control strategy, is applied. Although, DNC requires minimal preliminary system information and often provides robust process control, due to the unusual crystn. behavior of L-ascorbic acid, it leads to long batch times and oscillatory operation. In a second study the benefits of model-based QbC approach are demonstrated, based on using a NMPC approach. A population balance based crystn. process model is built and calibrated by estg. the nucleation and growth kinetics from concn. and CLD measurements. A projection based CSD to CLD forward transformation is used in the estn. of nucleation and growth kinetics. For robustness and adaptive behavior, the NMPC is coupled with a growing horizon state estimator, which is aimed to continuously improve the model by re-adjusting the kinetic consts. The study demonstrates that the model-based QbC framework can lead to rapid and robust crystn. process development with the NMPC system presenting good control behavior under significant plant model mismatch (PMM) conditions.
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    Badman, C.; Cooney, C. L.; Florence, A.; Konstantinov, K.; Krumme, M.; Mascia, S.; Nasr, M.; Trout, B. L. Why We Need Continuous Pharmaceutical Manufacturing and How to Make It Happen. J. Pharm. Sci. 2019, 108 (11), 3521– 3523,  DOI: 10.1016/j.xphs.2019.07.016
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    Why We Need Continuous Pharmaceutical Manufacturing and How to Make It Happen
    Badman, Clive; Cooney, Charles L.; Florence, Alastair; Konstantinov, Konstantin; Krumme, Markus; Mascia, Salvatore; Nasr, Moheb; Trout, Bernhardt L.
    Journal of Pharmaceutical Sciences (Philadelphia, PA, United States) (2019), 108 (11), 3521-3523CODEN: JPMSAE; ISSN:0022-3549. (Elsevier Inc.)
    We make the case for why continuous pharmaceutical manufg. is essential, what the barriers are, and how to overcome them. To overcome them, government action is needed in terms of tax incentives or regulatory incentives that affect time.
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    Hu, C.; Shores, B. T.; Derech, R. A.; Testa, C. J.; Hermant, P.; Wu, W.; Shvedova, K.; Ramnath, A.; Al Ismaili, L. Q.; Su, Q.; Sayin, R.; Born, S. C.; Takizawa, B.; O’Connor, T. F.; Yang, X.; Ramanujam, S.; Mascia, S. Continuous Reactive Crystallization of an API in PFR-CSTR Cascade with in-Line PATs. React. Chem. Eng. 2020, 5 (10), 1950– 1962,  DOI: 10.1039/D0RE00216J
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    Continuous reactive crystallization of an API in PFR-CSTR cascade with in-line PATs
    Hu, Chuntian; Shores, Brianna T.; Derech, Rachel A.; Testa, Christopher J.; Hermant, Paul; Wu, Wei; Shvedova, Khrystyna; Ramnath, Anjana; Al Ismaili, Liyutha Q.; Su, Qinglin; Sayin, Ridade; Born, Stephen C.; Takizawa, Bayan; O'Connor, Thomas F.; Yang, Xiaochuan; Ramanujam, Sukumar; Mascia, Salvatore
    Reaction Chemistry & Engineering (2020), 5 (10), 1950-1962CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)
    The continuous reactive crystn. of an active pharmaceutical ingredient (API) in a plug flow reactor (PFR)-continuous stirred tank reactor (CSTR) cascade system with in-line PATs was developed and investigated. Residence time distribution (RTD) measurements of the PFR (stage 1), the CSTR cascade (stages 2-6), and the combined PFR-CSTR cascade (stages 1-6) were performed to est. the performance of the reactors. Several continuous reactive crystn. expts. were performed, and consistent reaction yields of 91.3 ± 0.5 and 89.6 ± 0.4% were obtained with and without the PFR, resp. The integration of PFR (stage 1) created a very high level of supersatn. by itself, and ∼25% lower supersatn. and a 2.7% higher crystn. yield in the following vessel (stage 2). In stages 3-6, the supersatn. levels and crystn. yields were similar (with and without the PFR). With the PFR, the lower supersatn. in stage 2 resulted in lower nucleation rates and higher crystal growth rates, resulting in a larger crystal size distribution. Also, in-line ReactIR and focused beam reflectance measurement (FBRM) were used to monitor the reactant concn. and crystal chord length, resp., during the reactive crystn. process. The ReactIR predicted reactant concns. in the mother liquor that matched well with corresponding HPLC results (prediction error < 0.17%). The FBRM results showed a relatively stable mean square-weighted chord length of ∼150μm. In addn., the process mass intensities (PMIs) for the batch process, the integrated continuous manufg. (ICM) process without the PFR, and the ICM process with the PFR were 3.49, 1.99, and 1.97, resp.
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    McKenzie, P.; Kiang, S.; Tom, J.; Rubin, A. E.; Futran, M. Can Pharmaceutical Process Development Become High Tech?. AIChE J. 2006, 52 (12), 3990– 3994,  DOI: 10.1002/aic.11022
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    Can pharmaceutical process development become high tech?
    McKenzie, Paul; Kiang, San; Tom, Jean; Rubin, A. Erik; Futran, Mauricio
    AIChE Journal (2006), 52 (12), 3990-3994CODEN: AICEAC; ISSN:0001-1541. (John Wiley & Sons, Inc.)
    A review. While the pharmaceutical industry is well known for its innovation in developing drugs and therapies, and its ability to provide quality medicines to the public, its manufg. efficiency lags behind that of most other industries. This article proposes a new approach for process development based on the following four elements:. The approaches proposed by the FDA, including Process Anal. Technol. (i.e., online measurements) coupled to real time control; the principles of quality by design and risk-based anal.; the use of statistical, multivariate anal.; and providing mechanistic understanding through lab automation, miniaturization, using Design of Expts. (DoE), and an emphasis on phys. org. chem. and kinetics. Shaping the science of process development by applying Instrument, Systems and Automation Society (ISA) S.88 stds. from development through commercialization, which provide a natural language for chem. and pharmaceutical processes, as well as anal. methods. This provides us with a vehicle for creating and systematizing process knowledge and is also a very effective basis on which harmonic interactions between R&D and manufg. can be built. This leads to the use of a no. of electronic tools for the lab., for process modeling, for execution of process recipes in labs, pilot plants and prodn. facilities, and for managing data, linked seamlessly between R&D and manufg. The use of modeling tools to reduce the need for empirical experimentation, for verification of mechanistic understanding and for process control. The use of parallel experimentation using automated work streams for rapid probing of process options, exploring process operating windows ("design space"), and generally increasing productivity.
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    Baxendale, I. R.; Braatz, R. D.; Hodnett, B. K.; Jensen, K. F.; Johnson, M. D.; Sharratt, P.; Sherlock, J.-P.; Florence, A. J. Achieving Continuous Manufacturing: Technologies and Approaches for Synthesis, Workup, and Isolation of Drug Substance May 20–21, 2014 Continuous Manufacturing Symposium. J. Pharm. Sci. 2015, 104 (3), 781– 791,  DOI: 10.1002/jps.24252
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    Achieving Continuous Manufacturing: Technologies and Approaches for Synthesis, Workup, and Isolation of Drug Substance
    Baxendale, Ian R.; Braatz, Richard D.; Hodnett, Benjamin K.; Jensen, Klavs F.; Johnson, Martin D.; Sharratt, Paul; Sherlock, Jon-Paul; Florence, Alastair J.
    Journal of Pharmaceutical Sciences (2015), 104 (3), 781-791CODEN: JPMSAE; ISSN:0022-3549. (John Wiley & Sons, Inc.)
    This whitepaper highlights current challenges and opportunities assocd. with continuous synthesis, workup, and crystn. of active pharmaceutical ingredients (drug substances). We describe the technologies and requirements at each stage and emphasize the different considerations for developing continuous processes compared with batch. In addn. to the specific sequence of operations required to deliver the necessary chem. and phys. transformations for continuous drug substance manuf., consideration is also given to how adoption of continuous technologies may impact different manufg. stages in development from discovery, process development, through scale-up and into full scale prodn. The impact of continuous manuf. on drug substance quality and the assocd. challenges for control and for process safety are also emphasized. In addn. to the technol. and operational considerations necessary for the adoption of continuous manufg. (CM), this whitepaper also addresses the cultural, as well as skills and training, challenges that will need to be met by support from organizations in order to accommodate the new work flows. Specific action items for industry leaders are: Develop flow chem. toolboxes, exploiting the advantages of flow processing and including highly selective chemistries that allow use of simple and effective continuous workup technologies. Availability of modular or plug and play type equipment esp. for workup to assist in straightforward deployment in the lab. As with learning from other industries, standardization is highly desirable and will require cooperation across industry and academia to develop and implement. Implement and exploit process anal. technologies (PAT) for real-time dynamic control of continuous processes. Develop modeling and simulation techniques to support continuous process development and control. Progress is required in multiphase systems such as crystn. Involve all parts of the organization from discovery, research and development, and manufg. in the implementation of CM. Engage with academia to develop the training provision to support the skills base for CM, particularly in flow chem., phys. chem., and chem. engineering skills at the chem.-process interface. Promote and encourage publication and dissemination of examples of CM across the sector to demonstrate capability, engage with regulatory comment, and establish benchmarks for performance and highlight challenges. Develop the economic case for CM of drug substance. This will involve various stakeholders at project and business level, however establishing the crit. economic drivers is crit. to driving the transformation in manufg. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Assocn. J Pharm Sci.
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    Laske, S.; Paudel, A.; Scheibelhofer, O.; Sacher, S.; Hoermann, T.; Khinast, J.; Kelly, A.; Rantannen, J.; Korhonen, O.; Stauffer, F.; De Leersnyder, F.; De Beer, T.; Mantanus, J.; Chavez, P.-F.; Thoorens, B.; Ghiotti, P.; Schubert, M.; Tajarobi, P.; Haeffler, G.; Lakio, S.; Fransson, M.; Sparen, A.; Abrahmsen-Alami, S.; Folestad, S.; Funke, A.; Backx, I.; Kavsek, B.; Kjell, F.; Michaelis, M.; Page, T.; Palmer, J.; Schaepman, A.; Sekulic, S.; Hammond, S.; Braun, B.; Colegrove, B. A Review of PAT Strategies in Secondary Solid Oral Dosage Manufacturing of Small Molecules. J. Pharm. Sci. 2017, 106 (3), 667– 712,  DOI: 10.1016/j.xphs.2016.11.011
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    A Review of PAT Strategies in Secondary Solid Oral Dosage Manufacturing of Small Molecules
    Laske, Stephan; Paudel, Amrit; Scheibelhofer, Otto
    Journal of Pharmaceutical Sciences (2017), 106 (3), 667-712CODEN: JPMSAE; ISSN:0022-3549. (Elsevier Inc.)
    Pharmaceutical solid oral dosage product manufg. is a well-established, yet revolutionizing area. To this end, process anal. technol. (PAT) involves interdisciplinary and multivariate (chem., phys., microbiol., and math.) methods for material (e.g., materials, intermediates, products) and process (e.g., temp., pressure, throughput, etc.) anal. This supports rational process modeling and enhanced control strategies for improved product quality and process efficiency. Therefore, it is often difficult to orient and find the relevant, integrated aspects of the current state-of-the-art. Esp., the link between fundamental research, in terms of sensor and control system development, to the application both in lab. and manufg. scale, is difficult to comprehend. This review compiles a nonexhaustive overview on current approaches from the recognized academia and industrial practices of PAT, including screening, selection, and final implementations in solid oral dosage manufg., through a wide diversity of use cases. Finally, the authors attempt to ext. a common consensus toward developing PAT application guidance for different unit operations of drug product manufg.
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    Nepveux, K.; Sherlock, J. P.; Futran, M.; Thien, M.; Krumme, M. How Development and Manufacturing Will Need to Be Structured-Heads of Development/Manufacturing May 20–21, 2014 Continuous Manufacturing Symposium. J. Pharm. Sci. 2015, 104 (3), 850– 864,  DOI: 10.1002/jps.24286
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    How Development and Manufacturing Will Need to Be Structured-Heads of Development/Manufacturing. May 20-21, 2014 Continuous Manufacturing Symposium
    Nepveux, Kevin; Sherlock, Jon-Paul; Futran, Mauricio; Thien, Michael; Krumme, Markus
    Journal of Pharmaceutical Sciences (2015), 104 (3), 850-864CODEN: JPMSAE; ISSN:0022-3549. (John Wiley & Sons, Inc.)
    Continuous manufg. (CM) is a process technol. that has been used in the chem. industry for large-scale mass prodn. of chems. in single-purpose plants with benefit for many years. Recent interest has been raised to expand CM into the low-vol., high-value pharmaceutical business with its unique requirements regarding readiness for human use and the required quality, supply chain, and liability constraints in this business context. Using a fairly abstr. set of definitions, this paper derives tech. consequences of CM in different scenarios along the development-launch-supply axis in different business models and how they compare to batch processes. Impact of CM on functions in development is discussed and several operational models suitable for originators and other business models are discussed and specific aspects of CM are deduced from CM's tech. characteristics. Organizational structures of current operations typically can support CM implementations with just minor refinements if the CM technol. is limited to single steps or small sequences (bin-to-bin approach) and if the appropriate tech. skill set is available. In such cases, a small, dedicated group focused on CM is recommended. The manufg. strategy, as centralized vs. decentralized in light of CM processes, is discussed and the potential impact of significantly shortened supply lead times on the organization that runs these processes. The ultimate CM implementation may be seen by some as a totally integrated monolithic plant, one that unifies chem. and pharmaceutical operations into one plant. The organization supporting this approach will have to reflect this change in scope and responsibility. The other extreme, admittedly futuristic at this point, would be a highly decentralized approach with multiple smaller hubs; this would require a new and different organizational structure. This processing approach would open up new opportunities for products that, because of stability constraints or individualization to patients, do not allow centralized manufg. approaches at all. Again, the entire enterprise needs to be restructured accordingly. The situation of CM in an outsourced operation business model is discussed. Next steps for the industry are recommended. In summary, opportunistic implementation of isolated steps in existing portfolios can be implemented with minimal organizational changes; the availability of the appropriate skills is the detg. factor. The implementation of more substantial sequences requires business processes that consider the portfolio, not just single products. Exploration and implementation of complete process chains with consequences for quality decisions do require appropriate organizational support. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Assocn. J Pharm Sci 104:850-864, 2015.
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    New trends in the production of pharmaceutical granules: batch versus continuous processing
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    A review with refs. In the pharmaceutical industry, the prodn. of granules is based on a batch concept. This concept offers many advantages with respect to quality assurance as a batch can be accepted or rejected. However, the scale-up of the batch size may lead to problems. The variety of the equipment involved often does not facilitate the scale-up process. In order to avoid scale-up problems, continuous or semi-continuous processes have to be evaluated as alternatives to a batch prodn. Thus, a quasi-continuous prodn. line is presented, which permits the prodn. of small-scale batches, e.g. for clin. trials and for large-scale batches using the same equipment.
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    Vervaet, C.; Remon, J. P. Continuous Granulation in the Pharmaceutical Industry. Chem. Eng. Sci. 2005, 60 (14), 3949– 3957,  DOI: 10.1016/j.ces.2005.02.028
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    A review. Traditionally the manufg. of pharmaceutical dosage forms has been a batch-wise process and continuous processes have limited applications in a pharmaceutical manufg. plant. However, several factors (redn. of cost, improved process efficiency, optimal use of equipment, flexibility in prodn. capacity) are stimulating the pharmaceutical industry to investigate the opportunities offered by continuous processes. This paper discusses some of the techniques which could be implemented in a continuous granulation process of pharmaceuticals.
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    Using continuous flow techniques for multi-step synthesis enables multiple reaction steps to be combined into a single continuous operation. In this mini-review we discuss the current state of the art in this field and highlight recent progress and current challenges facing this emerging area.
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    Plutschack, M. B.; Pieber, B.; Gilmore, K.; Seeberger, P. H. The Hitchhiker’s Guide to Flow Chemistry. Chem. Rev. 2017, 117 (18), 11796– 11893,  DOI: 10.1021/acs.chemrev.7b00183
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    Flow chem. involves the use of channels or tubing to conduct a reaction in a continuous stream rather than in a flask. Flow equipment provides chemists with unique control over reaction parameters, enhancing reactivity or in some cases enabling new reactions. This relatively young technol. has received a remarkable amt. of attention in the past decade with many reports on what can be done in flow. Until recently, however, the question, "Should we do this in flow" has merely been an afterthought. This review introduces readers to the basic principles and fundamentals of flow chem. and critically discusses recent flow chem. accounts.
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    A review. The development and application of continuous flow chem. methods for synthesis is a rapidly growing area of research. In particular, natural products provide demanding challenges to this developing technol. This review highlights successes in the area with an emphasis on new opportunities and technol. advances.
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    Bana, P.; Örkényi, R.; Lövei, K.; Lakó, Á.; Túrós, G. I.; Éles, J.; Faigl, F.; Greiner, I. The Route from Problem to Solution in Multistep Continuous Flow Synthesis of Pharmaceutical Compounds. Bioorg. Med. Chem. 2017, 25 (23), 6180– 6189,  DOI: 10.1016/j.bmc.2016.12.046
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    Bioorganic & Medicinal Chemistry (2017), 25 (23), 6180-6189CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
    Recent advances in the field of continuous flow chem. allow the multistep prepn. of complex mols. such as APIs (Active Pharmaceutical Ingredients) in a telescoped manner. Numerous examples of lab.-scale applications are described, which are pointing towards novel manufg. processes of pharmaceutical compds., in accordance with recent regulatory, economical and quality guidances. The chem. and tech. knowledge gained during these studies is considerable; nevertheless, connecting several individual chem. transformations and the attached analytics and purifn. holds hidden traps. In this review, we summarize innovative solns. for these challenges, in order to benefit chemists aiming to exploit flow chem. systems for the synthesis of biol. active mols.
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    Munirathinam, R.; Huskens, J.; Verboom, W. Supported Catalysis in Continuous-Flow Microreactors. Adv. Synth. Catal. 2015, 357 (6), 1093– 1123,  DOI: 10.1002/adsc.201401081
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    A review. The recent developments in performing heterogeneous catalysis in continuous-flow microreactors was summarized. Three different types, namely, (i) packed-bed, (ii) monolithic, and (iii) wall-coated approaches were discussed to implement various kinds of catalysts in a microreactor. In addn., the applications of these supported catalysts to perform a variety of org. reactions were described. Furthermore, advantages of catalytic microreactors over classical batch reactors on one or more aspects of the reaction, such as rate, conversion, selectivity, and enantioselectivity were presented.
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    Mallia, C. J.; Baxendale, I. R. The Use of Gases in Flow Synthesis. Org. Process Res. Dev. 2016, 20 (2), 327– 360,  DOI: 10.1021/acs.oprd.5b00222
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    The Use of Gases in Flow Synthesis
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    A review. This review will highlight the potential benefits that can be leveraged by using flow chem. to allow gases to be used in research in a safer and more efficient way. An overview of the different approaches used to introduce gases into flow reactors is presented along with a synopsis of the different gaseous reactions classes already successfully translated into flow.
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    Brzozowski, M.; O’Brien, M.; Ley, S. V.; Polyzos, A. Flow Chemistry: Intelligent Processing of Gas–Liquid Transformations Using a Tube-in-Tube Reactor. Acc. Chem. Res. 2015, 48 (2), 349– 362,  DOI: 10.1021/ar500359m
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    Flow Chemistry: Intelligent Processing of Gas-Liquid Transformations Using a Tube-in-Tube Reactor
    Brzozowski, Martin; O'Brien, Matthew; Ley, Steven V.; Polyzos, Anastasios
    Accounts of Chemical Research (2015), 48 (2), 349-362CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
    A review of recent progress in gas-liq. reactions in tube-in-tube (flow) reactors. Flow chem. methodol. has led to measurable improvements in reduced energy consumption, expansion of available reaction conditions, development of multistep methods employing supported reagents, and in-line monitoring of reaction intermediates to ensure the delivery of high quality target compds. Flow chem. approaches have addressed the challenges assocd. with reactions using reactive gases in classical batch synthesis. The small vols. of microreactors ameliorate the hazards of high-pressure gas reactions and enable improved mixing with the liq. phase. Established strategies for gas-liq. reactions in flow have relied on plug-flow (or segmented flow) regimes in which the gas plugs are introduced to a liq. stream and dissoln. of gas relies on interfacial contact of the gas bubble with the liq. phase. This approach confers limited control over gas concn. within the liq. phase and is unsuitable for multistep methods requiring heterogeneous catalysis or solid supported reagents. We have identified the use of a gas-permeable fluoropolymer, Teflon AF-2400, as a simple method of achieving efficient gas-liq. contact to afford homogeneous solns. of reactive gases in flow, with significant control of stoichiometry of reactive gases in a reaction mixt. A tube-in-tube reactor device was developed that consisted of a pair of concentric capillaries in which pressurized gas permeates through an inner Teflon AF-2400 tube and reacts with dissolved substrate within a liq. phase that flows within a second gas impermeable tube. This Account examines efforts toward the development of a simple, unified methodol. for the processing of gaseous reagents in flow by way of development of a tube-in-tube reactor device and applications to key C-C, C-N, and C-O bond forming and hydrogenation reactions. Other applications discussed include multistep reactions using solid-supported reagents, extending the technol. to processes using multiple gas reagents, development of computer-aided imaging techniques to allow automated in-line monitoring of gas concn. and stoichiometry in real time.
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    Tajti, Á.; Tóth, N.; Bálint, E.; Keglevich, G. Esterification of Benzoic Acid in a Continuous Flow Microwave Reactor. J. Flow Chem. 2018, 8 (1), 11– 19,  DOI: 10.1007/s41981-018-0001-x
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    Esterification of benzoic acid in a continuous flow microwave reactor
    Tajti, Adam; Toth, Nora; Balint, Erika; Keglevich, Gyorgy
    Journal of Flow Chemistry (2018), 8 (1), 11-19CODEN: JFCOBJ; ISSN:2063-0212. (Akademiai Kiado)
    The direct esterification of benzoic acid with a series of aliph. alcs. was performed in a continuous flow microwave (MW) reactor. In the first stage, the reactivity of the alcs. towards benzoic acid was mapped in a batch MW reactor. Then, the different esterifications were optimized in the continuous reactor. All parameters including the temp. could be controlled. [Figure not available: see fulltext.].
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    Bálint, E.; Tajti, Á.; Keglevich, G. Application of the Microwave Technique in Continuous Flow Processing of Organophosphorus Chemical Reactions. Materials 2019, 12 (5), 788,  DOI: 10.3390/ma12050788
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    Application of the microwave technique in continuous flow processing of organophosphorus chemical reactions
    Balint, Erika; Tajti, Adam; Keglevich, Gyorgy
    Materials (2019), 12 (5), 788CODEN: MATEG9; ISSN:1996-1944. (MDPI AG)
    The microwave (MW) technique is an efficient tool in the realization of org. reactions, as well as in the anal. field and in the food industry. The continuous flow approach is of special interest as a promising way to scale-up MW-assisted syntheses. Besides summarizing the batch precedents, this review focuses on the utilization of the MW technique in the continuous-flow realization of organophosphorus transformations. The advantages of the continuous flow technique against the batch accomplishment are also shown. A few materials chem.-related applications are also mentioned.
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    Kiss, N. Z.; Henyecz, R.; Keglevich, G. Continuous Flow Esterification of a H-Phosphinic Acid, and Transesterification of H-Phosphinates and H-Phosphonates under Microwave Conditions. Molecules 2020, 25 (3), 719,  DOI: 10.3390/molecules25030719
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    Continuous flow esterification of a H-phosphinic acid, and transesterification of H-phosphinates and H-phosphonates under microwave conditions
    Kiss, Nora Zsuzsa; Henyecz, Reka; Keglevich, Gyorgy
    Molecules (2020), 25 (3), 719CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
    The microwave (MW)-assisted direct esterification of phenyl-H-phosphinic acid, transesterification of the alkyl phenyl-H-phosphinates so obtained, and the similar reaction of dibenzyl phosphite (DBP) were investigated in detail, and the batch accomplishments were translated into a continuous flow operation that, after optimization of the parameters, such as temp. and flow rate, proved to be more productive. Alcoholysis of DBP is a two-step process involving an intermediate phosphite with two different alkoxy groups. The latter species are of synthetic interest, as precursors for optically active reagents.
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    Yue, J.; Falke, F. H.; Schouten, J. C.; Nijhuis, T. A. Microreactors with Integrated UV/Vis Spectroscopic Detection for Online Process Analysis under Segmented Flow. Lab Chip 2013, 13 (24), 4855,  DOI: 10.1039/c3lc50876e
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    Combining reaction and detection in multiphase microfluidic flow is becoming increasingly important for accelerating process development in microreactors. We report the coupling of UV/Vis spectroscopy with microreactors for online process anal. under segmented flow conditions. Two integration schemes are presented: one uses a cross-type flow-through cell subsequent to a capillary microreactor for detection in the transmission mode; the other uses embedded waveguides on a microfluidic chip for detection in the evanescent wave field. Model expts. reveal the capabilities of the integrated systems in real-time concn. measurements and segmented flow characterization. The application of such integration for process anal. during gold nanoparticle prodn. is demonstrated, showing its great potential in process monitoring in microreactors operated under segmented flow.
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    Ryu, G.; Huang, J.; Hofmann, O.; Walshe, C. A.; Sze, J. Y. Y.; McClean, G. D.; Mosley, A.; Rattle, S. J.; DeMello, J. C.; DeMello, A. J.; Bradley, D. D. C. Highly Sensitive Fluorescence Detection System for Microfluidic Lab-on-a-Chip. Lab Chip 2011, 11 (9), 1664,  DOI: 10.1039/c0lc00586j
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    We demonstrate a compact, low cost and practical fluorescence detection system for lab-on-a-chip applications. The system comprises a com. available InGaN light emitting diode (501 nm) as light source, an org. or silicon photodiode detector, absorptive dye coated color filters and linear and reflective polarisers. An injection molded polystyrene microfluidic chip is used as the platform for fluorescence immunoassays for cardiac markers myoglobin and CK-MB. The optical limit of detection (LOD) is measured using a TransFluoSphere suspension at 5.6 × 104 beads μl-1 which can be equated to ∼3 nM fluorescein equiv. concn. The LOD for the human plasma immunoassays is measured as 1.5 ng ml-1 for both myoglobin and CK-MB.
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    Mozharov, S.; Nordon, A.; Littlejohn, D.; Wiles, C.; Watts, P.; Dallin, P.; Girkin, J. M. Improved Method for Kinetic Studies in Microreactors Using Flow Manipulation and Noninvasive Raman Spectrometry. J. Am. Chem. Soc. 2011, 133 (10), 3601– 3608,  DOI: 10.1021/ja1102234
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    Improved Method for Kinetic Studies in Microreactors Using Flow Manipulation and Noninvasive Raman Spectrometry
    Mozharov, Sergey; Nordon, Alison; Littlejohn, David; Wiles, Charlotte; Watts, Paul; Dallin, Paul; Girkin, John M.
    Journal of the American Chemical Society (2011), 133 (10), 3601-3608CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    A novel method has been devised to derive kinetic information about reactions in microfluidic systems. Advantages have been demonstrated over conventional procedures for a Knoevenagel condensation reaction in terms of the time required to obtain the data (fivefold redn.) and the efficient use of reagents (tenfold redn.). The procedure is based on a step change from a low (e.g., 0.6 μL min-1) to a high (e.g., 14 μL min-1) flow rate and real-time noninvasive Raman measurements at the end of the flow line, which allows location-specific information to be obtained without the need to move the measurement probe along the microreactor channel. To validate the method, values of the effective reaction order n were obtained employing two different exptl. methodologies. Using these values of n, rate consts. k were calcd. and compared. The values of k derived from the proposed method at 10 and 40 °C were 0.0356 ± 0.0008 mol-0.3 dm0.9 s-1 (n = 1.3) and 0.24 ± 0.018 mol-0.1 dm0.3 s-1 (n = 1.1), resp., whereas the values obtained using a more laborious conventional methodol. were 0.0335 ± 0.0032 mol-0.4 dm1.2 s-1 (n = 1.4) at 10 °C and 0.244 ± 0.032 mol-0.3 dm0.9 s-1 (n = 1.3) at 40 °C. The new approach is not limited to anal. by Raman spectrometry and can be used with different techniques that can be incorporated into the end of the flow path to provide rapid measurements.
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    Galaverna, R.; Breitkreitz, M. C.; Pastre, J. C. Conversion of d-Fructose to 5-(Hydroxymethyl)Furfural: Evaluating Batch and Continuous Flow Conditions by Design of Experiments and In-Line FTIR Monitoring. ACS Sustain. Chem. Eng. 2018, 6 (3), 4220– 4230,  DOI: 10.1021/acssuschemeng.7b04643
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    Porta, R.; Benaglia, M.; Puglisi, A. Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products. Org. Process Res. Dev. 2016, 20 (1), 2– 25,  DOI: 10.1021/acs.oprd.5b00325
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    Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products
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    Organic Process Research & Development (2016), 20 (1), 2-25CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    A review. Recently, application of the flow technologies for the prepn. of fine chems., such as natural products or Active Pharmaceutical Ingredients (APIs), has become very popular, esp. in academia. Although pharma industry still relies on multipurpose batch or semibatch reactors, it is evident that interest is arising toward continuous flow manufg. of org. mols., including highly functionalized and chiral compds. Continuous flow synthetic methodologies can also be easily combined to other enabling technologies, such as microwave irradn., supported reagents or catalysts, photochem., inductive heating, electrochem., new solvent systems, 3D printing, or microreactor technol. This combination could allow the development of fully automated process with an increased efficiency and, in many cases, improved sustainability. It has been also demonstrated that a safer manufg. of org. intermediates and APIs could be obtained under continuous flow conditions, where some synthetic steps that were not permitted for safety reasons can be performed with min. risk. In this review we focused our attention only on very recent advances in the continuous flow multistep synthesis of org. mols. which found application as APIs, esp. highlighting the contributions described in the literature from 2013 to 2015, including very recent examples not reported in any published review. Without claiming to be complete, we will give a general overview of different approaches, technologies, and synthetic strategies used so far, thus hoping to contribute to minimize the gap between academic research and pharmaceutical manufg. A general outlook about a quite young and relatively unexplored field of research, like stereoselective organocatalysis under flow conditions, will be also presented, and most significant examples will be described; our purpose is to illustrate all of the potentialities of continuous flow organocatalysis and offer a starting point to develop new methodologies for the synthesis of chiral drugs. Finally, some considerations on the perspectives and the possible, expected developments in the field are briefly discussed.
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    A review. Continuous-flow photochem. in microreactors receives a lot of attention from researchers in academia and industry as this technol. provides reduced reaction times, higher selectivities, straightforward scalability, and the possibility to safely use hazardous intermediates and gaseous reactants. In this review, an up-to-date overview is given of photochem. transformations in continuous-flow reactors, including applications in org. synthesis, material science, and water treatment. In addn., the advantages of continuous-flow photochem. are pointed out and a thorough comparison with batch processing is presented.
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    The Continuous-Flow Synthesis of Ibuprofen
    Bogdan, Andrew R.; Poe, Sarah L.; Kubis, Daniel C.; Broadwater, Steven J.; McQuade, D. Tyler
    Angewandte Chemie, International Edition (2009), 48 (45), 8547-8550, S8547/1-S8547/28CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A 3-step, continuous flow microreactor synthesis of ibuprofen comprised (i) TfOH-catalyzed Friedel-Crafts acylation of isobutylbenzene with propionic acid; (ii) oxidative 1,2-aryl migration of resultant 4-isobutylpropiophenone in presence of tri-Me orthoformate, PhI(OAc)2 and TfOH (from step i); and (iii) sapon. of resultant ibuprofen Me ester with KOH to produce ibuprofen in 68% crude yield and 51% yield after recrystn. A 70% yield was obtained for the first two steps, with quant. conversion of 4-isobutylpropiophenone to ibuprofen Me ester.
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  91. 91
    Viviano, M.; Glasnov, T. N.; Reichart, B.; Tekautz, G.; Kappe, C. O. A Scalable Two-Step Continuous Flow Synthesis of Nabumetone and Related 4-Aryl-2-Butanones. Org. Process Res. Dev. 2011, 15 (4), 858– 870,  DOI: 10.1021/op2001047
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    91
    A Scalable Two-Step Continuous Flow Synthesis of Nabumetone and Related 4-Aryl-2-butanones
    Viviano, Monica; Glasnov, Toma N.; Reichart, Benedik; Tekautz, Guenter; Kappe, C. Oliver
    Organic Process Research & Development (2011), 15 (4), 858-870CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    Three different continuous flow strategies for the generation of important 4-aryl-2-butanone derivs. including the anti-inflammatory drug nabumetone [4-(6-methoxy-2-naphthalenyl)-2-butanone] and the aroma compds. raspberry ketone [4-(4-hydroxyphenyl)-2-butanone] and its Me ether [4-(4-methoxyphenyl)-2-butanone] were evaluated. All three protocols involve the initial prepn. of the corresponding 4-aryl-3-buten-2-ones via Mizoroki-Heck, Wittig, or aldol strategies, which is then followed by selective hydrogenation of the C=C double bond to the desired 4-aryl-2-butanones. The synthetic routes to 4-aryl-3-buten-2-ones were first optimized/intensified on small scale to reaction times of 1-10 min using batch microwave heating technol. and then translated to a scalable continuous flow process employing com. available stainless steel capillary tube reactors. For the synthesis of 4-(4-methoxyphenyl)-3-buten-2-one a further scale-up using a custom-built mesofluidic mini-plant flow system capable of processing several liters per h was designed to further expand the scale of the process. The final hydrogenation step was performed using a fixed-bed continuous flow hydrogenator employing Ra/Ni as a catalyst.
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  92. 92
    Ahmed-Omer, B.; Sanderson, A. J. Preparation of Fluoxetine by Multiple Flow Processing Steps. Org. Biomol. Chem. 2011, 9 (10), 3854,  DOI: 10.1039/c0ob00906g
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    92
    Preparation of fluoxetine by multiple flow processing steps
    Ahmed-Omer, Batoul; Sanderson, Adam J.
    Organic & Biomolecular Chemistry (2011), 9 (10), 3854-3862CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
    Microflow technol. is established as a modern and fashionable tool in synthetic org. chem., bringing great improvement and potential, on account of a series of advantages over flask methods. The study presented here focuses on the application of flow chem. process in performing an efficient multiple step syntheses of (±)-fluoxetine as an alternative to conventional synthetic methods, and one of the few examples of total synthesis accomplished by flow technique.
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  93. 93
    Lévesque, F.; Seeberger, P. H. Continuous-Flow Synthesis of the Anti-Malaria Drug Artemisinin. Angew. Chem., Int. Ed. 2012, 51 (7), 1706– 1709,  DOI: 10.1002/anie.201107446
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    93
    Continuous-Flow Synthesis of the Anti-Malaria Drug Artemisinin
    Levesque, Francois; Seeberger, Peter H.
    Angewandte Chemie, International Edition (2012), 51 (7), 1706-1709, S1706/1-S1706/20CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Artemisinin was manufd. by continuous-flow, 3-step photochem. transformation involving a singlet-oxygen-induced ene reaction of dihydroartemisinic acid and addn. of triplet O.
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  94. 94
    Hopkin, M. D.; Baxendale, I. R.; Ley, S. V. An Expeditious Synthesis of Imatinib and Analogues Utilising Flow Chemistry Methods. Org. Biomol. Chem. 2013, 11 (11), 1822– 1839,  DOI: 10.1039/C2OB27002A
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    94
    An expeditious synthesis of imatinib and analogues utilizing flow chemistry methods
    Hopkin, Mark D.; Baxendale, Ian R.; Ley, Steven V.
    Organic & Biomolecular Chemistry (2013), 11 (11), 1822-1839CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
    A flow-based route to imatinib, the API of Gleevec, was developed and the general procedure then used to generate a no. of analogs which were screened for biol. activity against Abl1. The flow synthesis required minimal manual intervention and was achieved despite the poor soly. of many of the reaction components.
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  95. 95
    Murray, P. R. D.; Browne, D. L.; Pastre, J. C.; Butters, C.; Guthrie, D.; Ley, S. V. Continuous Flow-Processing of Organometallic Reagents Using an Advanced Peristaltic Pumping System and the Telescoped Flow Synthesis of (E/Z)-Tamoxifen. Org. Process Res. Dev. 2013, 17 (9), 1192– 1208,  DOI: 10.1021/op4001548
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    95
    Continuous Flow-Processing of Organometallic Reagents Using an Advanced Peristaltic Pumping System and the Telescoped Flow Synthesis of (E/Z)-Tamoxifen
    Murray, Philip R. D.; Browne, Duncan L.; Pastre, Julio C.; Butters, Chris; Guthrie, Duncan; Ley, Steven V.
    Organic Process Research & Development (2013), 17 (9), 1192-1208CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    A review. A new enabling technol. for the pumping of organometallic reagents such as n-butyllithium, Grignard reagents, and DIBAL-H is reported, which utilizes a newly developed, chem. resistant, peristaltic pumping system. Several representative examples of its use in common transformations using these reagents, including metal-halogen exchange, addn., addn.-elimination, conjugate addn., and partial redn., are reported along with examples of telescoping of the anionic reaction products. This platform allows for truly continuous pumping of these highly reactive substances (and examples are demonstrated over periods of several hours) to generate multigram quantities of products. This work culminates in an approach to the telescoped synthesis of (E/Z)-tamoxifen using continuous-flow organometallic reagent-mediated transformations.
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  96. 96
    Snead, D. R.; Jamison, T. F. End-to-End Continuous Flow Synthesis and Purification of Diphenhydramine Hydrochloride Featuring Atom Economy, in-Line Separation, and Flow of Molten Ammonium Salts. Chem. Sci. 2013, 4 (7), 2822,  DOI: 10.1039/c3sc50859e
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    96
    End-to-end continuous flow synthesis and purification of diphenhydramine hydrochloride featuring atom economy, in-line separation, and flow of molten ammonium salts
    Snead, David R.; Jamison, Timothy F.
    Chemical Science (2013), 4 (7), 2822-2827CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
    A continuous end-to-end synthesis and purifn. of diphenhydramine hydrochloride featuring atom economy and waste minimization is described. Combining a 1 : 1 molar ratio of the two starting material streams (chlorodiphenylmethane and N,N-dimethylaminoethanol) in the absence of addnl. solvent at high temp. gives the target compd. directly as a molten salt (ionic liq. above 168 °C) in high yield. This represents the first example of continuous active pharmaceutical ingredient (API) prodn. in this manner. Six of the twelve principles of green chem. as defined by the American Chem. Society are achieved, most prominently waste minimization and atom economy.
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  97. 97
    Kupracz, L.; Kirschning, A. Multiple Organolithium Generation in the Continuous Flow Synthesis of Amitriptyline. Adv. Synth. Catal. 2013, 355 (17), 3375– 3380,  DOI: 10.1002/adsc.201300614
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    97
    Multiple Organolithium Generation in the Continuous Flow Synthesis of Amitriptyline
    Kupracz, Lukas; Kirschning, Andreas
    Advanced Synthesis & Catalysis (2013), 355 (17), 3375-3380CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A continuous flow protocol (continuous flow reactor) for the prepn. of the tricyclic antidepressant (TCA) amitriptyline is reported. The advantages of flow chem. when handling organometallic agents as well as when performing reaction with gases are demonstrated. Continuous lithiation combined with carboxylation and the Parham cyclization, a Grignard addn. and thermolytic water elimination by inductive heating are key features of the multistep protocol. The synthesis of the target compd. was achieved by a reaction of 5-[3-(dimethylamino)propyl]-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ol with [3-(dimethylamino)propyl]magnesium chloride. Only small amts. of butyllithium were required in the lithiation step (process safety).
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  98. 98
    Hartwig, J.; Ceylan, S.; Kupracz, L.; Coutable, L.; Kirschning, A. Heating under High-Frequency Inductive Conditions: Application to the Continuous Synthesis of the Neurolepticum Olanzapine (Zyprexa). Angew. Chem., Int. Ed. 2013, 52 (37), 9813– 9817,  DOI: 10.1002/anie.201302239
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    98
    Heating under High-Frequency Inductive Conditions: Application to the Continuous Synthesis of the Neurolepticum Olanzapine (Zyprexa)
    Hartwig, Jan; Ceylan, Sascha; Kupracz, Lukas; Coutable, Ludovic; Kirschning, Andreas
    Angewandte Chemie, International Edition (2013), 52 (37), 9813-9817CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    High-frequency inductive heating and flow chem. are an ideal match for high-temp. synthesis. This was demonstrated in the multistep flow synthesis of the neurolepticum olanzapine (Zyprexa) that included three reactions with inductive heating and two purifn. steps conducted as continuous processes.
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  99. 99
    Zhang, P.; Russell, M. G.; Jamison, T. F. Continuous Flow Total Synthesis of Rufinamide. Org. Process Res. Dev. 2014, 18 (11), 1567– 1570,  DOI: 10.1021/op500166n
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    99
    Continuous Flow Total Synthesis of Rufinamide
    Zhang, Ping; Russell, M. Grace; Jamison, Timothy F.
    Organic Process Research & Development (2014), 18 (11), 1567-1570CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    Small mols. bearing 1,2,3-triazole functionalities are important intermediates and pharmaceuticals. Common methods to access the triazole moiety generally require the generation and isolation of org. azide intermediates. Continuous flow synthesis provides the opportunity to synthesize and consume the energetic organoazides, without accumulation thereof. In this report, we described a continuous synthesis of the antiseizure medication rufinamide. This route is convergent and features copper tubing reactor-catalyzed cycloaddn. reaction. Each of the three chem. steps enjoys significant benefits and has several advantages by being conducted in flow. The total av. residence time of the synthesis is approx. 11 min, and rufinamide is obtained in 92% overall yield.
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  100. 100
    Polster, C. S.; Cole, K. P.; Burcham, C. L.; Campbell, B. M.; Frederick, A. L.; Hansen, M. M.; Harding, M.; Heller, M. R.; Miller, M. T.; Phillips, J. L.; Pollock, P. M.; Zaborenko, N. Pilot-Scale Continuous Production of LY2886721: Amide Formation and Reactive Crystallization. Org. Process Res. Dev. 2014, 18 (11), 1295– 1309,  DOI: 10.1021/op500204z
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    100
    Pilot-Scale Continuous Production of LY2886721: Amide Formation and Reactive Crystallization
    Polster, Christopher S.; Cole, Kevin P.; Burcham, Christopher L.; Campbell, Bradley M.; Frederick, Andrea L.; Hansen, Marvin M.; Harding, Molly; Heller, Michael R.; Miller, Michael T.; Phillips, Joseph L.; Pollock, Patrick M.; Zaborenko, Nikolay
    Organic Process Research & Development (2014), 18 (11), 1295-1309CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    The design, development, and implementation of a pilot-scale continuous Schotten-Baumann amide bond formation and reactive crystn. to afford LY2886721 is described. The material met all API quality attributes and was comparable to material produced by a defined batch process. The scalability of the reaction and crystn. processes was confirmed during the development process. The pilot-scale equipment set was contained in a walk-in fume hood and operated at a prodn. rate of 3 kg/day in a 72 h continuous run. Significant tech. and business drivers for running the process in continuous flow mode were proposed and examd. during development. The continuous process provided for lab hood commercialization and provided for minimal material at risk in the process. The demonstration also confirmed the risk inherent to operation of a tubular reactor under supersatd. conditions, and fouling occurred in the plug flow reactor. Fouling also occurred in the crystallizer. Recognizing these deficiencies, the process operated within the footprint of a std. walk-in fume hood, providing a successful demonstration of the opportunities afforded by continuous processing for low vol. pharmaceuticals.
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  101. 101
    Heider, P. L.; Born, S. C.; Basak, S.; Benyahia, B.; Lakerveld, R.; Zhang, H.; Hogan, R.; Buchbinder, L.; Wolfe, A.; Mascia, S.; Evans, J. M. B.; Jamison, T. F.; Jensen, K. F. Development of a Multi-Step Synthesis and Workup Sequence for an Integrated, Continuous Manufacturing Process of a Pharmaceutical. Org. Process Res. Dev. 2014, 18 (3), 402– 409,  DOI: 10.1021/op400294z
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    101
    Development of a Multi-Step Synthesis and Workup Sequence for an Integrated, Continuous Manufacturing Process of a Pharmaceutical
    Heider, Patrick L.; Born, Stephen C.; Basak, Soubir; Benyahia, Brahim; Lakerveld, Richard; Zhang, Haitao; Hogan, Rachael; Buchbinder, Louis; Wolfe, Aaron; Mascia, Salvatore; Evans, James M. B.; Jamison, Timothy F.; Jensen, Klavs F.
    Organic Process Research & Development (2014), 18 (3), 402-409CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    The development and operation of the synthesis and workup steps of a fully integrated, continuous manufg. plant for synthesizing aliskiren, a small mol. pharmaceutical, are presented. The plant started with advanced intermediates, two synthetic steps away from the final active pharmaceutical ingredient, and ended with finished tablets. The entire process was run on several occasions, with the data presented herein corresponding to a 240 h run at a nominal throughput of 41 g h-1 of aliskiren. The first reaction was performed solvent-free in a molten condition at a high temp., achieving high yields (90%) and avoiding solid handling and a long residence time (due to higher concns. compared to dil. conditions when run at lower temps. in a solvent). The resulting stream was worked-up inline using liq.-liq. extn. with membrane-based separators that were scaled-up from microfluidic designs. The second reaction involved a Boc deprotection, using aq. HCl that was rapidly quenched with aq. NaOH using an inline pH measurement to control NaOH addn. The reaction maintained high yields (90-95%) under closed-loop control despite process disturbances.
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  102. 102
    Correia, C. A.; Gilmore, K.; McQuade, D. T.; Seeberger, P. H. A Concise Flow Synthesis of Efavirenz. Angew. Chem., Int. Ed. 2015, 54 (16), 4945– 4948,  DOI: 10.1002/anie.201411728
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    102
    A Concise Flow Synthesis of Efavirenz
    Correia, Camille A.; Gilmore, Kerry; McQuade, D. Tyler; Seeberger, Peter H.
    Angewandte Chemie, International Edition (2015), 54 (16), 4945-4948CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Efavirenz is an essential medicine for the treatment of HIV, which is still inaccessible to millions of people worldwide. A novel, semi-continuous process provides rac-Efavirenz with an overall yield of 45% from 1,4-dichlorobenzene. This streamlined proof-of-principle synthesis relies on the efficient copper-catalyzed formation of an aryl isocyanate and a subsequent intramol. cyclization to install the carbamate core of Efavirenz in one step. This three-step method represents the shortest synthesis of the racemic analog of this life-saving drug to date.
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  103. 103
    Tsubogo, T.; Oyamada, H.; Kobayashi, S. Multistep Continuous-Flow Synthesis of (R)- and (S)-Rolipram Using Heterogeneous Catalysts. Nature 2015, 520 (7547), 329– 332,  DOI: 10.1038/nature14343
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    103
    Multistep continuous-flow synthesis of (R)- and (S)-rolipram using heterogeneous catalysts
    Tsubogo, Tetsu; Oyamada, Hidekazu; Kobayashi, Shu
    Nature (London, United Kingdom) (2015), 520 (7547), 329-332CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    Chem. manufg. is conducted using either batch systems or continuous-flow systems. Flow systems have several advantages over batch systems, particularly in terms of productivity, heat and mixing efficiency, safety, and reproducibility. However, for over half a century, pharmaceutical manufg. has used batch systems because the synthesis of complex mols. such as drugs has been difficult to achieve with continuous-flow systems. Here we describe the continuous-flow synthesis of drugs using only columns packed with heterogeneous catalysts. Com. available starting materials were successively passed through four columns contg. achiral and chiral heterogeneous catalysts to produce (R)-rolipram, an anti-inflammatory drug and one of the family of γ-aminobutyric acid (GABA) derivs. In addn., simply by replacing a column packed with a chiral heterogeneous catalyst with another column packed with the opposing enantiomer, we obtained antipole (S)-rolipram. Similarly, we also synthesized (R)-phenibut, another drug belonging to the GABA family. These flow systems are simple and stable with no leaching of metal catalysts. Our results demonstrate that multistep (eight steps in this case) chem. transformations for drug synthesis can proceed smoothly under flow conditions using only heterogeneous catalysts, without the isolation of any intermediates and without the sepn. of any catalysts, co-products, byproducts, and excess reagents. We anticipate that such syntheses will be useful in pharmaceutical manufg.
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  104. 104
    Martin, A. D.; Siamaki, A. R.; Belecki, K.; Gupton, B. F. A Flow-Based Synthesis of Telmisartan. J. Flow Chem. 2015, 5 (3), 145– 147,  DOI: 10.1556/JFC-D-15-00002
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    104
    A flow-based synthesis of telmisartan
    Martin, Alex D.; Siamaki, Ali R.; Belecki, Katherine; Gupton, B. Frank
    Journal of Flow Chemistry (2015), 5 (3), 145-147CODEN: JFCOBJ; ISSN:2062-249X. (Akademiai Kiado)
    A highly efficient continuous synthesis has been developed for telmisartan, the active ingredient in the antihypertensive drug, Micardis. This synthetic route employs a convergent strategy that requires no intermediate purifications or solvent exchanges. The key step in the reaction scheme is a Suzuki cross-coupling reaction between two functionalized benzimidazoles that is catalyzed by a solid-supported Pd catalyst. This flow-based approach utilizes a tubular reactor system coupled with a plug flow packed bed cartridge unit that produces telmisartan in an 81% isolated yield.
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  105. 105
    Snead, D. R.; Jamison, T. F. A Three-Minute Synthesis and Purification of Ibuprofen: Pushing the Limits of Continuous-Flow Processing. Angew. Chem., Int. Ed. 2015, 54 (3), 983– 987,  DOI: 10.1002/anie.201409093
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    105
    A Three-Minute Synthesis and Purification of Ibuprofen: Pushing the Limits of Continuous-Flow Processing
    Snead, David R.; Jamison, Timothy F.
    Angewandte Chemie, International Edition (2015), 54 (3), 983-987CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    In a total residence time of three minutes, ibuprofen was assembled from its elementary building blocks with an av. yield of above 90 % for each step. A scale-up of this five-stage process (3 bond-forming steps, one work-up, and one in-line liq.-liq. sepn.) provided ibuprofen at a rate of 8.09 g h-1 (equiv. to 70.8 kg y-1) using a system with an overall footprint of half the size of a std. lab. fume hood. Aside from the high throughput, several other aspects of this synthesis expand the capabilities of continuous-flow processing, including a Friedel-Crafts acylation run under neat conditions and promoted by AlCl3, an exothermic in-line quench of high concns. of pptn.-prone AlCl3, liq.-liq. sepns. run at or above 200 psi to provide solvent-free product, and the use of highly aggressive oxidants, such as iodine monochloride. The use of simple, inexpensive, and readily available reagents thus affords a practical synthesis of this important generic pharmaceutical.
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    Pellegatti, L.; Hafner, A.; Sedelmeier, J. A Two-Step Continuous-Flow Procedure towards Ribociclib. J. Flow Chem. 2016, 6 (3), 198– 201,  DOI: 10.1556/1846.2016.00017
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    106
    A two-step continuous-flow procedure towards Ribociclib
    Pellegatti, Laurent; Hafner, Andreas; Sedelmeier, Jorg
    Journal of Flow Chemistry (2016), 6 (3), 198-201CODEN: JFCOBJ; ISSN:2062-249X. (Akademiai Kiado)
    This work describes the manufg. of ribociclib following the concept of an end-to-end continuous-flow process. The active pharmaceutical ingredient (API) is produced in a two-step telescoped flow process with integrated in-line liq.-liq. extn. and semibatch crystn.
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  107. 107
    Ishitani, H.; Kanai, K.; Saito, Y.; Tsubogo, T.; Kobayashi, S. Synthesis of (±)-Pregabalin by Utilizing a Three-Step Sequential-Flow System with Heterogeneous Catalysts. Eur. J. Org. Chem. 2017, 2017 (44), 6491– 6494,  DOI: 10.1002/ejoc.201700998
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    107
    Synthesis of (±)-Pregabalin by utilizing a three-step sequential-flow system with heterogeneous catalysts
    Ishitani, Haruro; Kanai, Kan; Saito, Yuki; Tsubogo, Tetsu; Kobayashi, Shu
    European Journal of Organic Chemistry (2017), 2017 (44), 6491-6494CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
    (±)-Pregabalin, a γ-amino acid deriv., has been synthesized by utilizing flow methods. A three-step sequential-flow reaction starting from com. isovaleraldehyde and Me malonate proceeded smoothly with heterogeneous catalysts to afford the precursor of pregabalin in yields of 75-100 %, and a space-time yield of 52.2 g/L d was reached. In addn., a heterogeneous catalyst for the Knoevenagel reactions of aldehydes with malonates, which is the first step of the synthesis, has been developed. Pregabalin was finally obtained by acid-catalyzed hydrolysis of the precursor followed by neutralization.
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  108. 108
    Harsanyi, A.; Conte, A.; Pichon, L.; Rabion, A.; Grenier, S.; Sandford, G. One-Step Continuous Flow Synthesis of Antifungal WHO Essential Medicine Flucytosine Using Fluorine. Org. Process Res. Dev. 2017, 21 (2), 273– 276,  DOI: 10.1021/acs.oprd.6b00420
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    108
    One-Step Continuous Flow Synthesis of Antifungal WHO Essential Medicine Flucytosine Using Fluorine
    Harsanyi, Antal; Conte, Annelyse; Pichon, Laurent; Rabion, Alain; Grenier, Sandrine; Sandford, Graham
    Organic Process Research & Development (2017), 21 (2), 273-276CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    In Africa around 625 000 mortalities per annum (20% of HIV/AIDS related deaths) are due to the affects of the Cryptococcal meningitis (CM) fungal infection. Recently, the World Health Organization (WHO) and the Infectious Disease Society of America (IDSA) recommended that the first line treatment for CM is a combination of amphotericin B and flucytosine, both now WHO Essential Medicines. However, flucytosine is not even registered for use in any African nation due, in part, to its relatively high cost of manuf. and lack of generic manufacturers. Currently, flucytosine is manufd. by an expensive four-step manufg. process. Here we report a one-step continuous flow process involving the reaction of inexpensive cytosine with fluorine gas using stainless steel tubular lab. and pilot-scale silicon carbide reactor devices which is readily scalable to a manufg. process with a low initial capital expenditure.
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  109. 109
    De Vitis, V.; Dall’Oglio, F.; Pinto, A.; De Micheli, C.; Molinari, F.; Conti, P.; Romano, D.; Tamborini, L. Chemoenzymatic Synthesis in Flow Reactors: A Rapid and Convenient Preparation of Captopril. ChemistryOpen 2017, 6 (5), 668– 673,  DOI: 10.1002/open.201700082
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    109
    Chemoenzymatic Synthesis in Flow Reactors: A Rapid and Convenient Preparation of Captopril
    De Vitis, Valerio; Dall'Oglio, Federica; Pinto, Andrea; De Micheli, Carlo; Molinari, Francesco; Conti, Paola; Romano, Diego; Tamborini, Lucia
    ChemistryOpen (2017), 6 (5), 668-673CODEN: CHOPCK; ISSN:2191-1363. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The chemoenzymic flow synthesis of enantiomerically pure captopril, a widely used antihypertensive drug, is accomplished starting from simple, inexpensive, and readily available reagents. The first step is a heterogeneous biocatalyzed regio- and stereoselective oxidn. of cheap prochiral 2-methyl-1,3-propandiol, performed in flow using immobilized whole cells of Acetobacter aceti MIM 2000/28, thus avoiding the use of aggressive and environmentally harmful chem. oxidants. The isolation of the highly hydrophilic intermediate (R)-3-hydroxy-2-methylpropanoic acid is achieved in-line by using a catch-and-release strategy. Then, three sequential high-throughput chem. steps lead to the isolation of captopril in only 75 min. In-line quenching and liq.-liq. sepn. enable breaks in the workflow and other manipulations to be avoided.
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  110. 110
    Cole, K. P.; Groh, J. M. C.; Johnson, M. D.; Burcham, C. L.; Campbell, B. M.; Diseroad, W. D.; Heller, M. R.; Howell, J. R.; Kallman, N. J.; Koenig, T. M.; May, S. A.; Miller, R. D.; Mitchell, D.; Myers, D. P.; Myers, S. S.; Phillips, J. L.; Polster, C. S.; White, T. D.; Cashman, J.; Hurley, D.; Moylan, R.; Sheehan, P.; Spencer, R. D.; Desmond, K.; Desmond, P.; Gowran, O. Kilogram-Scale Prexasertib Monolactate Monohydrate Synthesis under Continuous-Flow CGMP Conditions. Science 2017, 356 (6343), 1144– 1151,  DOI: 10.1126/science.aan0745
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    110
    Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions
    Cole, Kevin P.; Groh, Jennifer McClary; Johnson, Martin D.; Burcham, Christopher L.; Campbell, Bradley M.; Diseroad, William D.; Heller, Michael R.; Howell, John R.; Kallman, Neil J.; Koenig, Thomas M.; May, Scott A.; Miller, Richard D.; Mitchell, David; Myers, David P.; Myers, Steven S.; Phillips, Joseph L.; Polster, Christopher S.; White, Timothy D.; Cashman, Jim; Hurley, Declan; Moylan, Robert; Sheehan, Paul; Spencer, Richard D.; Desmond, Kenneth; Desmond, Paul; Gowran, Olivia
    Science (Washington, DC, United States) (2017), 356 (6343), 1144-1150CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    Advances in drug potency and tailored therapeutics are promoting pharmaceutical manufg. to transition from a traditional batch paradigm to more flexible continuous processing. Here we report the development of a multistep continuous-flow CGMP (current good manufg. practices) process that produced 24 kg of prexasertib monolactate monohydrate suitable for use in human clin. trials. Eight continuous unit operations were conducted to produce the target at roughly 3 kg per day using small continuous reactors, extractors, evaporators, crystallizers, and filters in lab. fume hoods. Success was enabled by advances in chem., engineering, anal. science, process modeling, and equipment design. Substantial tech. and business drivers were identified, which merited the continuous process. The continuous process afforded improved performance and safety relative to batch processes and also improved containment of a highly potent compd.
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  111. 111
    Neyt, N. C.; Riley, D. L. Batch–Flow Hybrid Synthesis of the Antipsychotic Clozapine. React. Chem. Eng. 2018, 3 (1), 17– 24,  DOI: 10.1039/C7RE00146K
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    111
    Batch-flow hybrid synthesis of the antipsychotic clozapine
    Neyt, N. C.; Riley, D. L.
    Reaction Chemistry & Engineering (2018), 3 (1), 17-24CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)
    The development of batch-flow hybrid processes is becoming an attractive prospect through which chemists can make use of the best aspects of both technologies. We have reported the implementation of an on-the-fly purifn. by trituration which can also be utilized to perform solvent swaps. We have demonstrated this concept through the synthesis of the antipsychotic clozapine. In addn., we report a novel means of performing a redn. of an aryl nitro group under flow conditions and an overall improved process route for the total synthesis of clozapine.
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  112. 112
    Yu, E.; Mangunuru, H. P. R.; Telang, N. S.; Kong, C. J.; Verghese, J.; Gilliland, S. E., III; Ahmad, S.; Dominey, R. N.; Gupton, B. F. High-Yielding Continuous-Flow Synthesis of Antimalarial Drug Hydroxychloroquine. Beilstein J. Org. Chem. 2018, 14, 583– 592,  DOI: 10.3762/bjoc.14.45
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    112
    High-yielding continuous-flow synthesis of antimalarial drug hydroxychloroquine
    Yu, Eric; Mangunuru, Hari P. R.; Telang, Nakul S.; Kong, Caleb J.; Verghese, Jenson; Gilliland, Stanley E. III; Ahmad, Saeed; Dominey, Raymond N.; Gupton, B. Frank
    Beilstein Journal of Organic Chemistry (2018), 14 (), 583-592CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)
    Numerous synthetic methods for the continuous prepn. of fine chems. and active pharmaceutical ingredients (API's) have been reported in recent years resulting in a dramatic improvement in process efficiencies. Herein authors report a highly efficient continuous synthesis of the antimalarial drug hydroxychloroquine (HCQ). Key improvements in the new process include the elimination of protecting groups with an overall yield improvement of 52% over the current com. process. The continuous process employs a combination of packed bed reactors with continuous stirred tank reactors for the direct conversion of the starting materials to the product. This high-yielding, multigram-scale continuous synthesis provides an opportunity to achieve increase global access to hydroxychloroquine for treatment of malaria.
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  113. 113
    Ziegler, R. E.; Desai, B. K.; Jee, J.-A.; Gupton, B. F.; Roper, T. D.; Jamison, T. F. 7-Step Flow Synthesis of the HIV Integrase Inhibitor Dolutegravir. Angew. Chem., Int. Ed. 2018, 57 (24), 7181– 7185,  DOI: 10.1002/anie.201802256
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    113
    7-Step Flow Synthesis of the HIV Integrase Inhibitor Dolutegravir
    Ziegler, Robert E.; Desai, Bimbisar K.; Jee, Jo-Ann; Gupton, B. Frank; Roper, Thomas D.; Jamison, Timothy F.
    Angewandte Chemie, International Edition (2018), 57 (24), 7181-7185CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Dolutegravir (DTG), an important active pharmaceutical ingredient (API) used in combination therapy for the treatment of HIV, was synthesized in continuous flow. By adapting the reported GlaxoSmithKline process chem. batch route for Cabotegravir, DTG was produced in 4.5 h in sequential flow operations from com. available materials. Key features of the synthesis include rapid manufg. time for pyridone formation, one-step direct amidation of a functionalized pyridone, and telescoping of multiple steps to avoid isolation of intermediates and enable for greater throughput.
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  114. 114
    Mancino, V.; Cerra, B.; Piccinno, A.; Gioiello, A. Continuous Flow Synthesis of 16-Dehydropregnenolone Acetate, a Key Synthon for Natural Steroids and Drugs. Org. Process Res. Dev. 2018, 22 (5), 600– 607,  DOI: 10.1021/acs.oprd.8b00038
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    114
    Continuous Flow Synthesis of 16-Dehydropregnenolone Acetate, a Key Synthon for Natural Steroids and Drugs
    Mancino, Valentina; Cerra, Bruno; Piccinno, Alessandro; Gioiello, Antimo
    Organic Process Research & Development (2018), 22 (5), 600-607CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    A telescoped multistep process to provide the continuous delivery of 16-dehydropregnenolone acetate (16-DPA) from diosgenin is described. The method was evaluated through batch screenings that helped to identify crit. bottlenecks and flowability, and the best conditions were optimized in flow systems before the individual steps were telescoped together into a single integrated flow process. Further highlights of our approach include the use of efficient in-line extn. operations and reaction monitoring, the avoidance of time-consuming purifications between steps, and improvement of efficiency and safety stds.
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  115. 115
    Zhang, P.; Weeranoppanant, N.; Thomas, D. A.; Tahara, K.; Stelzer, T.; Russell, M. G.; O’Mahony, M.; Myerson, A. S.; Lin, H.; Kelly, L. P.; Jensen, K. F.; Jamison, T. F.; Dai, C.; Cui, Y.; Briggs, N.; Beingessner, R. L.; Adamo, A. Advanced Continuous Flow Platform for On-Demand Pharmaceutical Manufacturing. Chem. - Eur. J. 2018, 24 (11), 2776– 2784,  DOI: 10.1002/chem.201706004
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    115
    Advanced continuous flow platform for on-demand pharmaceutical manufacturing
    Zhang, Ping; Weeranoppanant, Nopphon; Thomas, Dale A.; Tahara, Kohei; Stelzer, Torsten; Russell, Mary Grace; O'Mahony, Marcus; Myerson, Allan S.; Lin, Hongkun; Kelly, Liam P.; Jensen, Klavs F.; Jamison, Timothy F.; Dai, Chunhui; Cui, Yuqing; Briggs, Naomi; Beingessner, Rachel L.; Adamo, Andrea
    Chemistry - A European Journal (2018), 24 (11), 2776-2784CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    As a demonstration of an alternative to the challenges faced with batch pharmaceutical manufg. including the large prodn. footprint and lengthy time-scale, we previously reported a refrigerator-sized continuous flow system for the on-demand prodn. of essential medicines. Building on this technol., herein we report a second-generation, reconfigurable and 25% smaller (by vol.) continuous flow pharmaceutical manufg. platform featuring advances in reaction and purifn. equipment. Consisting of two compact [0.7 (L)×0.5 (D)×1.3 m (H)] stand-alone units for synthesis and purifn./formulation processes, the capabilities of this automated system are demonstrated with the synthesis of nicardipine hydrochloride and the prodn. of concd. liq. doses of ciprofloxacin hydrochloride, neostigmine methylsulfate and rufinamide that meet US Pharmacopeia stds.
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  116. 116
    Balogh, A.; Domokos, A.; Farkas, B.; Farkas, A.; Rapi, Z.; Kiss, D.; Nyiri, Z.; Eke, Z.; Szarka, G.; Örkényi, R.; Mátravölgyi, B.; Faigl, F.; Marosi, G.; Nagy, Z. K. Continuous End-to-End Production of Solid Drug Dosage Forms : Coupling Flow Synthesis and Formulation by Electrospinning. Chem. Eng. J. 2018, 350, 290– 299,  DOI: 10.1016/j.cej.2018.05.188
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    116
    Continuous end-to-end production of solid drug dosage forms: Coupling flow synthesis and formulation by electrospinning
    Balogh, Attila; Domokos, Andras; Farkas, Balazs; Farkas, Attila; Rapi, Zsolt; Kiss, Domokos; Nyiri, Zoltan; Eke, Zsuzsanna; Szarka, Gyorgyi; Orkenyi, Robert; Matravolgyi, Bela; Faigl, Ferenc; Marosi, Gyorgy; Nagy, Zsombor Kristof
    Chemical Engineering Journal (Amsterdam, Netherlands) (2018), 350 (), 290-299CODEN: CMEJAJ; ISSN:1385-8947. (Elsevier B.V.)
    Based on the concept of continuous manufg. an end-to-end benchtop device was developed unprecedented for the prodn. of solid drug dosage forms by connecting flow synthesis and formulation via electrospinning (ES). Together with the optimized two-step continuous-flow synthesis of acetylsalicylic acid (ASA) a water-sol. polymeric excipient (polyvinylpyrrolidone K30, PVPK30) was introduced. The resulting polymeric soln. could be readily electrospun into solid nanofibers with high purity in one single step due to the excellent yet gentle drying effect of ES. The ASA-loaded fibers were electrostatically deposited onto a water-sol. pullulan sheet and the obtained double-layered films were continuously cut into orally dissolving webs (ODWs) as final dosage formulation. The synthesis as well as the dosing of the fibrous films were monitored by Process Anal. Technol. (PAT) tools (IR and Raman spectroscopy) with active feedback on product quality. The successful coupling of flow synthesis and fiber formation confirms that ES enables versatile formulation of pharmaceuticals in future continuous prodn. systems.
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  117. 117
    Ma, X.; Chen, J.; Du, X. A Continuous Flow Process for the Synthesis of Hymexazol. Org. Process Res. Dev. 2019, 23 (6), 1152– 1158,  DOI: 10.1021/acs.oprd.9b00047
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    117
    A Continuous Flow Process for the Synthesis of Hymexazol
    Ma, Xin-peng; Chen, Jin-sha; Du, Xiao-hua
    Organic Process Research & Development (2019), 23 (6), 1152-1158CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    Hymexazol, I, is an efficient and low-toxicity soil fungicide. In this work, a fully continuous flow process for the synthesis of hymexazol has been developed. This process begins with combining Et acetoacetate and hydroxylamine hydrochloride to form a hydroxamic acid intermediate. The reaction soln. is then quenched with concd. hydrochloric acid to obtain the final product, hymexazol. Under the optimized process conditions, the total yield of the target product reached 86%. In addn., prodn. was successfully scaled-up to a kilogram scale. The continuous flow method not only greatly decreases the reaction time but also significantly inhibits the side reactions.
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  118. 118
    Boros, Z.; Nagy-Győr, L.; Kátai-Fadgyas, K.; Kőhegyi, I.; Ling, I.; Nagy, T.; Iványi, Z.; Oláh, M.; Ruzsics, G.; Temesi, O.; Volk, B. Continuous Flow Production in the Final Step of Vortioxetine Synthesis. Piperazine Ring Formation on a Flow Platform with a Focus on Productivity and Scalability. J. Flow Chem. 2019, 9 (2), 101– 113,  DOI: 10.1007/s41981-019-00036-x
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    118
    Continuous flow production in the final step of vortioxetine synthesis. Piperazine ring formation on a flow platform with a focus on productivity and scalability
    Boros, Zoltan; Nagy-Gyor, Laszlo; Katai-Fadgyas, Katalin; Kohegyi, Imre; Ling, Istvan; Nagy, Tamas; Ivanyi, Zoltan; Olah, Mark; Ruzsics, Gyorgy; Temesi, Otto; Volk, Balazs
    Journal of Flow Chemistry (2019), 9 (2), 101-113CODEN: JFCOBJ; ISSN:2063-0212. (Akademiai Kiado)
    In this study, the piperazine formation step of vortioxetine synthesis was investigated under continuous flow conditions. The batch variant of this step could be carried out at lab. scale at 130-135 °C with a long reaction time (27 h) followed by a laborious optimization process, but the formation of a significant amt. of side-products could be detected, thus an efficient purifn. procedure was necessary. In the attempted scale-up of the batch reaction, a complete conversion could not at all be reached, even after elongated reaction times (36 h). The continuous-flow expts. were carried out in a new, purpose-built flow system. The examns. were extended to a wide range of reaction parameters (ratio of solvents, concn. and molar ratio of reagents, geometry of coiled loop reactor, residence time, temp.) and to the feasibility study of scale-up. In the second part of the expts., the fine-tuning of scaled-up reaction parameters of continuous flow synthesis was carried out using a systematic design of expts. approach. Finally 190 °C reaction temp. and 30 min of residence time led to the highest efficacy in the prodn. of vortioxetine drug substance with high yield and purity.
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  119. 119
    Bana, P.; Szigetvári, Á.; Kóti, J.; Éles, J.; Greiner, I. Flow-Oriented Synthetic Design in the Continuous Preparation of the Aryl Piperazine Drug Flibanserin. React. Chem. Eng. 2019, 4 (4), 652– 657,  DOI: 10.1039/C8RE00266E
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    119
    Flow-oriented synthetic design in the continuous preparation of the aryl piperazine drug flibanserin
    Bana, Peter; Szigetvari, Aron; Koti, Janos; Eles, Janos; Greiner, Istvan
    Reaction Chemistry & Engineering (2019), 4 (4), 652-657CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)
    An uninterrupted, four-step continuous-flow sequence was developed for the prepn. of the aryl piperazine-type serotonin receptor modulator drug, flibanserin. The unprecedented route was designed for efficient operation in flow, consisting of heterogeneously catalyzed reductive amination reactions, benzimidazolone formation using the protecting group as a building block, and biphasic flow deprotection integrated with in-line purifn. Gas-liq. and liq.-liq. sepns. facilitate the coupling of the reaction steps and aid removal of excess reagents, which make the system capable of steady-state operation without manual interaction.
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  120. 120
    Fu, W. C.; Jamison, T. F. Modular Continuous Flow Synthesis of Imatinib and Analogues. Org. Lett. 2019, 21 (15), 6112– 6116,  DOI: 10.1021/acs.orglett.9b02259
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    120
    Modular Continuous Flow Synthesis of Imatinib and Analogues
    Fu, Wai Chung; Jamison, Timothy F.
    Organic Letters (2019), 21 (15), 6112-6116CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    A modular continuous flow synthesis of imatinib (I) and analogs is reported. Structurally diverse imatinib analogs are rapidly generated using three readily available building blocks via a flow hydration/chemoselective C-N coupling sequence. The newly developed continuous flow hydration and amidation modules each exhibit a broad scope with good to excellent yields. Overall, the method described does not require solvent switches, in-line purifications, or packed-bed apparatuses due to the judicious manipulation of flow setups and solvent mixts.
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  121. 121
    García-Lacuna, J.; Domínguez, G.; Blanco-Urgoiti, J.; Pérez-Castells, J. Synthesis of Treprostinil: Key Claisen Rearrangement and Catalytic Pauson–Khand Reactions in Continuous Flow. Org. Biomol. Chem. 2019, 17 (43), 9489– 9501,  DOI: 10.1039/C9OB02124H
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    121
    Synthesis of treprostinil: key Claisen rearrangement and catalytic Pauson-Khand reactions in continuous flow
    Garcia-Lacuna, Jorge; Dominguez, Gema; Blanco-Urgoiti, Jaime; Perez-Castells, Javier
    Organic & Biomolecular Chemistry (2019), 17 (43), 9489-9501CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
    A new synthesis of treprostinil is described using a plug flow reactor in two of the key steps. First, a Claisen rearrangement reaction is described in scaled flow at multigram amts. Yields and selectivity of this step are sharply improved compared to those from previous syntheses. Second, the key Pauson-Khand reaction in flow is described under catalytic conditions with 5 mol% of cobalt carbonyl and only 3 equiv. of CO. Scaling up of this reaction safely ensures a good yield of an advanced intermediate which is transformed into treprostinil in three steps. Other improvements are the introduction of the carboxymethyl chain into the phenol from the beginning to reduce the protection-deprotection steps. The synthesis is completed in 14% global yield after 12 linear steps from (S)-epichlorohydrin.
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  122. 122
    Lee, H.; Kim, H.; Kim, D. From p -Xylene to Ibuprofen in Flow: Three-Step Synthesis by a Unified Sequence of Chemoselective C–H Metalations. Chem. - Eur. J. 2019, 25 (50), 11641– 11645,  DOI: 10.1002/chem.201903267
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    122
    From p-Xylene to Ibuprofen in Flow: Three-Step Synthesis by a Unified Sequence of Chemoselective C-H Metalations
    Lee, Hyune-Jea; Kim, Heejin; Kim, Dong-Pyo
    Chemistry - A European Journal (2019), 25 (50), 11641-11645CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Ibuprofen was prepd. from an inactive and inexpensive p-xylene by three-step flow functionalizations through chemoselective metalations of benzyl positions in sequence using an in-situ generated LICKOR-type superbase. The flow approach in the microreactor facilitated the comprehensive exploration of over 100 conditions in the first-step reaction by varying concns., temps., solvents and equiv. of reagents, enabling optimal conditions to be found with 95% yield by significantly suppressing the formation of byproducts followed by the second C-H metalation step in 95% yield. Moreover, gram-scale synthesis of ibuprofen in the final step was achieved by biphasic flow reaction of soln.-phase intermediate with CO2 isolating 2.3 g for 10 min of operation time.
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  123. 123
    Jaman, Z.; Sobreira, T. J. P.; Mufti, A.; Ferreira, C. R.; Cooks, R. G.; Thompson, D. H. Rapid On-Demand Synthesis of Lomustine under Continuous Flow Conditions. Org. Process Res. Dev. 2019, 23 (3), 334– 341,  DOI: 10.1021/acs.oprd.8b00387
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    Rapid On-Demand Synthesis of Lomustine under Continuous Flow Conditions
    Jaman, Zinia; Sobreira, Tiago J. P.; Mufti, Ahmed; Ferreira, Christina R.; Cooks, R. Graham; Thompson, David H.
    Organic Process Research & Development (2019), 23 (3), 334-341CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    Lomustine, an important agent for treatment of brain tumors and Hodgkin's lymphoma, has been synthesized using continuous flow methodol. Desorption electrospray ionization mass spectrometry (DESI-MS) was used to quickly explore a large no. of reaction conditions for one of the reaction steps and guide the efficient translation of optimized conditions to continuous lomustine prodn. Using only four inexpensive com. available starting materials and a total residence time of 9 min, lomustine was prepd. via a linear sequence of two chem. reactions performed sep. in two telescoped flow reactors. Sequential offline extn. and filtration resulted in a 63% overall yield of pure lomustine at a prodn. rate of 110 mg/h. The primary advantages of this approach are the rapid manuf. of lomustine with two telescoped steps to avoid isolation and purifn. of a labile intermediate and the mild conditions used in the nitrosylation step, thereby significantly increasing the purity and yield of this active pharmaceutical ingredient.
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    Russell, M. G.; Jamison, T. F. Seven-Step Continuous Flow Synthesis of Linezolid Without Intermediate Purification. Angew. Chem., Int. Ed. 2019, 58 (23), 7678– 7681,  DOI: 10.1002/anie.201901814
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    Seven-Step Continuous Flow Synthesis of Linezolid Without Intermediate Purification
    Russell, M. Grace; Jamison, Timothy F.
    Angewandte Chemie, International Edition (2019), 58 (23), 7678-7681CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Herein, the blockbuster antibacterial drug linezolid is synthesized from simple starting blocks by a convergent continuous flow sequence involving seven (7) chem. transformations. This is the highest total no. of distinct reaction steps ever performed in continuous flow without conducting solvent exchanges or intermediate purifn. Linezolid was obtained in 73 % isolated yield in a total residence time of 27 min, corresponding to a throughput of 816 mg h-1.
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    Damião, M. C. F. C. B.; Marçon, H. M.; Pastre, J. C. Continuous Flow Synthesis of the URAT1 Inhibitor Lesinurad. React. Chem. Eng. 2020, 5 (5), 865– 872,  DOI: 10.1039/C9RE00483A
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    Continuous flow synthesis of the URAT1 inhibitor lesinurad
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    Reaction Chemistry & Engineering (2020), 5 (5), 865-872CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)
    Herein, the urate anion exchange transporter 1 (URAT1) inhibitor lesinurad is synthesized from com. available building blocks by a five-step linear continuous flow sequence. Our previously developed continuous flow platform was successfully applied to generate the 3-thio-1,2,4-triazole key intermediate 2 in 88% yield, after 55 min of residence time. Condensation, cyclization and S-alkylation were telescoped in a single operation without conducting solvent exchanges and intermediate purifications. Next, 1,2,4-triazole bromination and ester hydrolysis were also performed in continuous flow regime to deliver lesinurad in 68% overall yield in a total residence time of 2 h. Our approach enables the fast generation of lesinurad and can be directly applied to produce major quantities of this important API.
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    Ingham, R. J.; Battilocchio, C.; Fitzpatrick, D. E.; Sliwinski, E.; Hawkins, J. M.; Ley, S. V. A Systems Approach Towards an Intelligent and Self-Controlling Platform for Integrated Continuous Reaction Sequences. Angew. Chem., Int. Ed. 2015, 54 (1), 144– 148,  DOI: 10.1002/anie.201409356
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    Angewandte Chemie, International Edition (2015), 54 (1), 144-148CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Performing reactions in flow can offer major advantages over batch methods. However, lab. flow chem. processes are currently often limited to single steps or short sequences due to the complexity involved with operating a multi-step process. Using new modular components for downstream processing, coupled with control technologies, more advanced multi-step flow sequences can be realized. These tools are applied to the synthesis of 2-aminoadamantane-2-carboxylic acid. A system comprising three chem. steps and three workup steps was developed, having sufficient autonomy and self-regulation to be managed by a single operator.
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    Lichtenegger, G. J.; Maier, M.; Khinast, J. G.; Gruber-Wölfler, H. Continuous Suzuki—Miyaura Reactions with Novel Ce—Sn—Pd Oxides and Integrated Crystallization as Continuous Downstream Protocol. J. Flow Chem. 2016, 6 (3), 244– 251,  DOI: 10.1556/1846.2016.00021
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    Journal of Flow Chemistry (2016), 6 (3), 244-251CODEN: JFCOBJ; ISSN:2062-249X. (Akademiai Kiado)
    An integrated process including continuous-flow syntheses directly coupled to product isolation via continuous crystn. is presented. For the synthesis part, Ce0.495Sn0.495Pd0.01O2-δ was used as heterogeneous catalyst in a custom-made packed-bed reactor (the so-called "Plug and Play" reactor) for continuous Suzuki-Miyaura crosscouplings of various para- and ortho-substituted bromoarenes with phenylboronic acid using environmentally friendly aq. ethanolic mixts. as reaction solvents. The reactions were stable for up to 30 h without any detectable catalyst deactivation. The desired biaryl products were obtained in gram scale with good to excellent yields and high selectivity. For three methyl-, ketyl-, and nitrile-functionalized biphenyl products, isolation was done using water as antisolvent in an integrated crystn. process as continuous downstream protocol. The desired products could be isolated with high purity and with yields of up to 95% for the overall process.
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    Tacsi, K.; Pataki, H.; Domokos, A.; Nagy, B.; Csontos, I.; Markovits, I.; Farkas, F.; Nagy, Z. K.; Marosi, G. Direct Processing of a Flow Reaction Mixture Using Continuous Mixed Suspension Mixed Product Removal Crystallizer. Cryst. Growth Des. 2020, 20 (7), 4433– 4442,  DOI: 10.1021/acs.cgd.0c00252
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    Direct Processing of a Flow Reaction Mixture Using Continuous Mixed Suspension Mixed Product Removal Crystallizer
    Tacsi, Kornelia; Pataki, Hajnalka; Domokos, Andras; Nagy, Brigitta; Csontos, Istvan; Markovits, Imre; Farkas, Ferenc; Nagy, Zsombor Kristof; Marosi, Gyorgy
    Crystal Growth & Design (2020), 20 (7), 4433-4442CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
    Crystn. as the most widespread purifn., sepn., and morphol.-detg. method is a crit. technol. that could be made safer and more economical by using continuous crystn. alternatives. Accordingly, this study aims to develop the continuous crystn. method for direct processing of a flow reaction mixt. of acetylsalicylic acid (ASA) and to provide pure, homogeneous cryst. products for further formulation steps. The solid-liq. sepn. and the purifn. of the acetylsalicylic acid from the multicomponent mixt. were accomplished in a single stage mixed suspension mixed product removal (MSMPR) continuous crystallizer equipped with an overflow and an inner buffer element to ensure the representative withdrawal of the product suspension. The effect of process parameters such as the operating temp. and the length of residence time (RT) on product quality and quantity were studied at two and three levels, resp. Investigating these parameters, we found that higher operating temps. (25°) and longer residence time (47 min) favor appropriate purity (>99.5%), and narrow crystal size distribution. By reducing the operating temp. (2.5°), the yield improved slightly (approx. 77%) and polydisperse products were characterized. The developed crystn. process can link the flow synthesis with the continuous formulation, and consequently serves a further step toward end-to-end prodn. A multicomponent ASA reaction mixt. was processed in a single stage mixed suspension mixed product removal (MSMPR) continuous crystallizer equipped with an overflow tubing and an inner vertical plate served as a buffer element. Depending on the chosen temp. and residence time, the yield, size, and size distribution of the crystals can be modified resulting in a multimodal or unimodal product.
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    Rimez, B.; Septavaux, J.; Scheid, B. The Coupling of In-Flow Reaction with Continuous Flow Seedless Tubular Crystallization. React. Chem. Eng. 2019, 4 (3), 516– 522,  DOI: 10.1039/C8RE00313K
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    The coupling of in-flow reaction with continuous flow seedless tubular crystallization
    Rimez, Bart; Septavaux, Jean; Scheid, Benoit
    Reaction Chemistry & Engineering (2019), 4 (3), 516-522CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)
    The direct coupling between a continuous flow-assisted acetylation reaction of salicylic acid and the subsequent crystn. of aspirin in a continuous flow tubular reactor or nucleator is investigated. The design of the reactor relies on a 3 min residence time, followed by quenching with water prior to cooling inside the tubular nucleator. By appropriate selection of the temp. of the nucleation step, the no. of nuclei formed in the tubular setup is accurately controlled. In this way, pure cryst. aspirin is continuously obtained with a desired mean crystal size between 3μm and 300μm and a reduced dispersion grade, avoiding seeding and micronization steps.
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    Rimez, B.; Septavaux, J.; Debuysschère, R.; Scheid, B. The Creation and Testing of a Fully Continuous Tubular Crystallization Device Suited for Incorporation into Flow Chemistry Setups. J. Flow Chem. 2019, 9 (4), 237– 249,  DOI: 10.1007/s41981-019-00042-z
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    Palmer, E. Lilly commits to continuous manufacturing with Ireland plant, https://www.fiercepharma.com/manufacturing/lilly-commits-to-continuous-manufacturing-ireland-plant.
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    Johnson, M. D.; May, S. A.; Calvin, J. R.; Remacle, J.; Stout, J. R.; Diseroad, W. D.; Zaborenko, N.; Haeberle, B. D.; Sun, W.-M.; Miller, M. T.; Brennan, J. Development and Scale-Up of a Continuous, High-Pressure, Asymmetric Hydrogenation Reaction, Workup, and Isolation. Org. Process Res. Dev. 2012, 16 (5), 1017– 1038,  DOI: 10.1021/op200362h
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    Development and Scale-Up of a Continuous, High-Pressure, Asymmetric Hydrogenation Reaction, Workup, and Isolation
    Johnson, Martin D.; May, Scott A.; Calvin, Joel R.; Remacle, Jacob; Stout, James R.; Diseroad, William D.; Zaborenko, Nikolay; Haeberle, Brian D.; Sun, Wei-Ming; Miller, Michael T.; Brennan, John
    Organic Process Research & Development (2012), 16 (5), 1017-1038CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    A fully continuous process including an asym. hydrogenation reaction operating at 70 bar hydrogen, aq. extn., and crystn. was designed, developed, and demonstrated at pilot scale. This paper highlights safety, quality, and throughput advantages of the continuous reaction and sepns. unit operations. Prodn. of 144 kg of product was accomplished in lab. fume hoods and a lab. hydrogenation bunker over two continuous campaigns. Maximum continuous flow vessel size in the lab. hoods was 22 L glassware, and max. plug flow tube reactor (PFR) size in the bunker was 73 L. The main safety advantages of running the hydrogenation reaction continuous rather than batch were that the flow reactor was smaller for the same throughput and, more importantly, the tubular hydrogenation reactor ran 95% liq. filled at steady state. Therefore, the amt. of hydrogen in the reactor at any one time was less than that of batch. A two-stage mixed suspension-mixed product removal (MSMPR) cascade was used for continuous crystn. Impurity rejection by continuous crystn. was superior to that by batch because scalable residence time and steady-state supersatn. enabled robust and repeatable control of enantiomer rejection in a kinetic regime, although this is a nonstandard approach, debatable as an impurity control strategy. The fully continuous wet-end process running in a lab. infrastructure achieved the same weekly throughput that would be expected from traditional batch processing in a plant module with 400 L vessels.
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    Chen, J.; Sarma, B.; Evans, J. M. B.; Myerson, A. S. Pharmaceutical Crystallization. Cryst. Growth Des. 2011, 11 (4), 887– 895,  DOI: 10.1021/cg101556s
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    Pharmaceutical Crystallization
    Chen, Jie; Sarma, Bipul; Evans, James M. B.; Myerson, Allan S.
    Crystal Growth & Design (2011), 11 (4), 887-895CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
    A review. Crystn. is crucial in the pharmaceutical industry as a sepn. process for intermediates and as the final step in the manuf. of active pharmaceutical ingredients (APIs). In this perspective article to celebrate 10 years of Crystal Growth and Design, we focus on 3 areas related to crystn. in the pharmaceutical industry: (1) advances in our understanding of the fundamentals of nucleation, (2) prodn. and scale-up of novel solid forms, and (3) continuous processing. While the areas discussed are not new, they are areas, in our opinion, of significant current interest to the community engaged in crystn. in the pharmaceutical industry.
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    Wang, T.; Lu, H.; Wang, J.; Xiao, Y.; Zhou, Y.; Bao, Y.; Hao, H. Recent Progress of Continuous Crystallization. J. Ind. Eng. Chem. 2017, 54, 14– 29,  DOI: 10.1016/j.jiec.2017.06.009
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    Recent progress of continuous crystallization
    Wang, Ting; Lu, Haijiao; Wang, Jingkang; Xiao, Yan; Zhou, Yanan; Bao, Ying; Hao, Hongxun
    Journal of Industrial and Engineering Chemistry (Amsterdam, Netherlands) (2017), 54 (), 14-29CODEN: JIECFI; ISSN:1226-086X. (Elsevier B.V.)
    Continuous crystn. has always been a hot topic in industrial crystn. Many efforts have been made to improve the continuous crystn., either by designing novel continuous crystallizers or by proposing improved design and operation of conventional continuous crystallizers. Some new models for continuous crystn. processes have also been proposed and tested in recent years. In this work, the development of continuous crystn. in recent years, including novel crystallizers, control strategies, models and some assistive technologies, is summarized. Promising as it is, continuous crystn. is still not as universal as batch crystn. due to the existence of the drawbacks, such as blockage and encrustation. Therefore, further efforts are needed before wider application of continuous crystn.
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    Wood, B.; Girard, K. P.; Polster, C. S.; Croker, D. M. Progress to Date in the Design and Operation of Continuous Crystallization Processes for Pharmaceutical Applications. Org. Process Res. Dev. 2019, 23 (2), 122– 144,  DOI: 10.1021/acs.oprd.8b00319
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    Progress to Date in the Design and Operation of Continuous Crystallization Processes for Pharmaceutical Applications
    Wood, Barbara; Girard, Kevin P.; Polster, Christopher S.; Croker, Denise M.
    Organic Process Research & Development (2019), 23 (2), 122-144CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    Continuous crystn. has gained interest in the pharmaceutical sector as part of the drive toward the transition from exclusive batch manufg. to integrated continuous manufg. in this industry. As a result, the design and operation of continuous crystn. processes for the prepn. of pharmaceutical materials has been featured strongly in recent scientific literature. This review is an effort to gather together all of the published understanding on continuous crystn. with a pharmaceutical focus and to benchmark progress to date in realizing the potential benefits of transitioning this stalwart pharmaceutical unit operation from batch to continuous configurations.
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    Jiang, M.; Braatz, R. D. Designs of Continuous-Flow Pharmaceutical Crystallizers: Developments and Practice. CrystEngComm 2019, 21 (23), 3534– 3551,  DOI: 10.1039/C8CE00042E
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    Designs of continuous-flow pharmaceutical crystallizers: developments and practice
    Jiang, Mo; Braatz, Richard D.
    CrystEngComm (2019), 21 (23), 3534-3551CODEN: CRECF4; ISSN:1466-8033. (Royal Society of Chemistry)
    Crystn. is an effective, low-cost purifn. & formulation process widely applied to pharmaceuticals and fine chems. This review describes recent advances in research on lab-scale soln.-based continuous crystn., including (1) a 5-step general design procedure; (2) key design/operational parameters; (3) process intensification strategies; and (4) a case study. The continuous crystallizers reviewed include mixed-suspension mixed-product removal, fluidized beds, oscillatory baffled flow, and tubular laminar/segmented/slug-flow crystallizers. Their corresponding design and operational considerations are summarized in terms of general parameters (e.g., residence time), and crystallizer-specific parameters and strategies (e.g., mixing strategies). In-line nucleation and crystal modification methods are categorized, including use of micromixers, wet milling, ultrasonication, temp. cycling, and recycling selection (filtration, sedimentation). Throughout the article, links are drawn with extensive existing knowledge of batch crystallizers, to facilitate the understanding and design of continuous crystallizers.
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    Ma, Y.; Wu, S.; Macaringue, E. G. J.; Zhang, T.; Gong, J.; Wang, J. Recent Progress in Continuous Crystallization of Pharmaceutical Products: Precise Preparation and Control. Org. Process Res. Dev. 2020, 24, 1785 DOI: 10.1021/acs.oprd.9b00362 .
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    Recent Progress in Continuous Crystallization of Pharmaceutical Products: Precise Preparation and Control
    Ma, Yiming; Wu, Songgu; Macaringue, Estevao Genito Joao; Zhang, Teng; Gong, Junbo; Wang, Jingkang
    Organic Process Research & Development (2020), 24 (10), 1785-1801CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    A review. Crystn., as a solid-liq. sepn. process, is employed to purify and isolate a great diversity of cryst. pharmaceutical products. In recent years, continuous crystn. has attracted increasing attention because of the product and process robustness as well as higher productivity. In this work, we review the use of novel continuous crystallizers or modified conventional continuous crystallizers for the prepn. of polymorphs, chiral enantiomers, solvates/hydrates, cocrystals, and spherical crystals. In addn., the theor. framework and verification of the model-based control approaches are demonstrated. The application of process anal. technol. tools in classical feedback loop control strategies in continuous crystn. is also discussed. Despite all this, the application of continuous crystn. still remains challenging because of the existence of drawbacks such as fouling and blockages. Therefore, a systematic discussion should be done before continuous crystn. is more widely applied.
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    Zhang, D.; Xu, S.; Du, S.; Wang, J.; Gong, J. Progress of Pharmaceutical Continuous Crystallization. Engineering 2017, 3 (3), 354– 364,  DOI: 10.1016/J.ENG.2017.03.023
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    Murugesan, S.; Sharma, P. K.; Tabora, J. E. Design of Filtration and Drying Operations. In Chemical Engineering in the Pharmaceutical Industry; Ende, D. J. A., Ed.; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2010; pp 315– 345.  DOI: 10.1002/9780470882221.ch17 .
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    Ottoboni, S.; Price, C. J.; Steven, C.; Meehan, E.; Barton, A.; Firth, P.; Mitchell, A.; Tahir, F. Development of a Novel Continuous Filtration Unit for Pharmaceutical Process Development and Manufacturing. J. Pharm. Sci. 2019, 108 (1), 372– 381,  DOI: 10.1016/j.xphs.2018.07.005
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    Development of a novel continuous filtration unit for pharmaceutical process development and manufacturing
    Ottoboni, Sara; Price, Chris J.; Steven, Christopher; Meehan, Elizabeth; Barton, Alastair; Firth, Paul; Mitchell, Andy; Tahir, Furqan
    Journal of Pharmaceutical Sciences (Philadelphia, PA, United States) (2019), 108 (1), 372-381CODEN: JPMSAE; ISSN:0022-3549. (Elsevier Inc.)
    The lack of a com. lab., pilot and small manufg. scale dead end continuous filtration and drying unit it is a significant gap in the development of continuous pharmaceutical manufg. processes for new active pharmaceutical ingredients (APIs). To move small-scale pharmaceutical isolation forward from traditional batch Nutsche filtration to continuous processing a continuous filter dryer prototype unit (CFD20) was developed in collaboration with Alconbury Weston Ltd. The performance of the prototype was evaluated by comparison with manual best practice exemplified using a modified Biotage VacMaster unit to gather data and process understanding for API filtration and washing. The ultimate objective was to link the chem. and phys. attributes of an API slurry with equipment and processing parameters to improve API isolation processes. Filtration performance was characterized by assessing filtrate flow rate by application of Darcy's law, the impact on product crystal size distribution and product purity were investigated using classical anal. methods. The overall performance of the 2 units was similar, showing that the prototype CFD20 can match best manual lab. practice for filtration and washing while allowing continuous processing and real-time data logging. This result is encouraging and the data gathered provides further insight to inform the development of CFD20.
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    Acevedo, D.; Jarmer, D. J.; Burcham, C. L.; Polster, C. S.; Nagy, Z. K. A Continuous Multi-Stage Mixed-Suspension Mixed-Product-Removal Crystallization System with Fines Dissolution. Chem. Eng. Res. Des. 2018, 135, 112– 120,  DOI: 10.1016/j.cherd.2018.05.029
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    A continuous multi-stage mixed-suspension mixed-product-removal crystallization system with fines dissolution
    Acevedo, David; Jarmer, Daniel J.; Burcham, Christopher L.; Polster, Christopher S.; Nagy, Zoltan K.
    Chemical Engineering Research and Design (2018), 135 (), 112-120CODEN: CERDEE; ISSN:1744-3563. (Elsevier B.V.)
    This work demonstrates how crystal particle size is affected by the addn. of fines dissoln. in a mixed suspension mixed product removal (MSMPR) cascade system. The cooling crystn. of paracetamol in water was used as a case study. Two MSMPR cascade configurations were evaluated: (i) nucleation-growth (NG), and (ii) nucleation-dissoln.-growth (NDG). Simulation results demonstrate that adding a dissoln. step in the MSMPR cascade configuration increases the av. product crystal size. Larger crystals and a narrower distribution were obtained due to the removal of fine crystals through the continuous process. However, a small decrease in the achievable yield was obsd. Exptl. results also showed a similar effect on the final mean size and CSD. The results demonstrate that a dissoln. stage can be optimized to increase the final crystal size and CSD by varying the dissoln. temp. to optimize the CSD with min. effect on the achievable yield.
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    Zhang, H.; Quon, J.; Alvarez, A. J.; Evans, J.; Myerson, A. S.; Trout, B. Development of Continuous Anti-Solvent/Cooling Crystallization Process Using Cascaded Mixed Suspension, Mixed Product Removal Crystallizers. Org. Process Res. Dev. 2012, 16 (5), 915– 924,  DOI: 10.1021/op2002886
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    Development of Continuous Anti-Solvent/Cooling Crystallization Process using Cascaded Mixed Suspension, Mixed Product Removal Crystallizers
    Zhang, Haitao; Quon, Justin; Alvarez, Alejandro J.; Evans, James; Myerson, Allan S.; Trout, Bernhardt
    Organic Process Research & Development (2012), 16 (5), 915-924CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    This paper describes a two-stage mixed-suspension, mixed-product removal (MSMPR) continuous crystn. developed for a pharmaceutical intermediate which uses anti-solvent and cooling to generate supersatn. The results indicate that the stage in which anti-solvent is added has a significant effect on the final crystal properties, while purity and yield were nearly identical. The population balance model was employed to det. growth and nucleation kinetics through parameter estn. With the incorporation of measured equil. distribution coeffs., the model was used to optimize crystal purity and yield of the product with respect to operating temp. and residence time.
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  143. 143
    Wierzbowska, B.; Hutnik, N.; Piotrowski, K.; Matynia, A. Continuous Mass Crystallization of Vitamin C in l-(+)-Ascorbic Acid–Ethanol–Water System: Size-Independent Growth Kinetic Model Approach. Cryst. Growth Des. 2011, 11 (5), 1557– 1565,  DOI: 10.1021/cg101521k
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    143
    Continuous Mass Crystallization of Vitamin C in L(+)-Ascorbic Acid-Ethanol-Water System: Size-Independent Growth Kinetic Model Approach
    Wierzbowska, Boguslawa; Hutnik, Nina; Piotrowski, Krzysztof; Matynia, Andrzej
    Crystal Growth & Design (2011), 11 (5), 1557-1565CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
    Exptl. results concerning continuous isohydrical drowning-out mass crystn. of vitamin C in an L(+)-ascorbic acid-ethanol-water system are presented. The process environment was created in a lab.-scale draft tube, mixed suspension mixed product removal (DT MSMPR) crystallizer with internal circulation of suspension. Assuming a const. feed concn. of ethanol (20 mass %), the feed concn. of vitamin C was changed within the 30-50 mass % range. The mean residence time of suspension in working vol. of a crystallizer was varied from 900 to 3600 s. Combinations of the presented above input process parameters resulted in a productivity 244-1692 kg/(m3 h) of crystal product, of mean size within 0.20-0.24 mm and of CV within the 50-60% range. The supersatn. level in mother soln. reached relatively high values (up to ca. 6.5 mass %), in particular at a short mean residence time of suspension (900 s). With this time elongation to 3600 s, the supersatn. level decreased, however, by ca. 40% (to 3.9 mass %). The simplest size-independent growth (SIG) kinetic model was adopted for nucleation ((3.3-27.8) × 107 1/(s m3)) and crystal growth ((1.6-6.9) × 10-8 m/s) rates estn. Kinetic relations and feedback between nucleation and crystals growth were identified and analyzed in detail.
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  144. 144
    Li, J.; Lai, T. C.; Trout, B. L.; Myerson, A. S. Continuous Crystallization of Cyclosporine: Effect of Operating Conditions on Yield and Purity. Cryst. Growth Des. 2017, 17 (3), 1000– 1007,  DOI: 10.1021/acs.cgd.6b01212
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    144
    Continuous Crystallization of Cyclosporine: Effect of Operating Conditions on Yield and Purity
    Li, Jicong; Lai, Tsai-ta C.; Trout, Bernhardt L.; Myerson, Allan S.
    Crystal Growth & Design (2017), 17 (3), 1000-1007CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
    A continuous crystn. process has potential advantages such as lower cost and improved flexibility in pharmaceutical prodn. when compared to batch crystn. In this work, multistage continuous cooling crystn. processes for cyclosporine were developed. The approach demonstrated that optimization of stage conditions can be used to improve yield and purity. For a multi-impurity system such as cyclosporine, the segregation of each impurity should be estd. sep. due to their different behaviors. The effective distribution coeffs. of the impurities were calcd. and related to the steady state mother liquor concns. A population balance and mass balance model including distribution coeffs. for impurities was used to est. max. yields and purities that could be obtained at various operating conditions. The results showed the limitation in yield and purity improvement using a mixed-suspension, mixed-product removal cascade. In addn., optimization along with economic anal. can aid in detg. operating conditions for a high yield with acceptable equipment and operation cost.
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  145. 145
    Yang, Y.; Song, L.; Gao, T.; Nagy, Z. K. Integrated Upstream and Downstream Application of Wet Milling with Continuous Mixed Suspension Mixed Product Removal Crystallization. Cryst. Growth Des. 2015, 15 (12), 5879– 5885,  DOI: 10.1021/acs.cgd.5b01290
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    145
    Integrated Upstream and Downstream Application of Wet Milling with Continuous Mixed Suspension Mixed Product Removal Crystallization
    Yang, Yang; Song, Liangcheng; Gao, Tianyue; Nagy, Zoltan K.
    Crystal Growth & Design (2015), 15 (12), 5879-5885CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
    The integration of rotor-stator wet mill and continuous mixed suspension mixed product removal crystallizer (MSMPRC) is studied in this work. The wet mill is applied in two different configurations: downstream in a recycle loop to continuously reduce particle size via controlled secondary nucleation and breakage and upstream as a high shear nucleator to continuously generate seed crystals in situ. These two novel approaches are compared to continuous MSMPRC without wet mill. In addn., the effects of wet mill operating conditions (i.e., tip speed, no. of turnover per residence time) on five important product and process qualities, including av. particle size, particle no., width of size distribution, yield, and startup duration are identified for both configurations. The paper demonstrates that desired av. crystal size, narrow size distribution, high yield, and very short startup duration can be achieved at the same time by applying the rotor-stator wet mill upstream as a continuous in situ high shear seed generator followed by continuous MSMPRC.
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  146. 146
    Hou, G.; Power, G.; Barrett, M.; Glennon, B.; Morris, G.; Zhao, Y. Development and Characterization of a Single Stage Mixed-Suspension, Mixed-Product-Removal Crystallization Process with a Novel Transfer Unit. Cryst. Growth Des. 2014, 14 (4), 1782– 1793,  DOI: 10.1021/cg401904a
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    146
    Development and Characterization of a Single Stage Mixed-Suspension, Mixed-Product-Removal Crystallization Process with a Novel Transfer Unit
    Hou, Guangyang; Power, Graham; Barrett, Mark; Glennon, Brian; Morris, Gary; Zhao, Yan
    Crystal Growth & Design (2014), 14 (4), 1782-1793CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
    A continuously operated single stage mixed-suspension, mixed-product-removal (MSMPR) crystallizer using intermittent withdrawal via a dip pipe with combined pressure/vacuum was successfully developed for the manuf. of active pharmaceutical ingredients. Approx. 5.8% of the total operating vol. was intermittently removed at a high velocity using vacuum. The transfer line was also periodically purged with nitrogen to ensure complete removal of residual solids. In situ process anal. technologies (focused beam reflective measurement (FBRM) and process video microscopy (PVM)) were successfully applied to monitor and characterize the MSMPR crystn. process. In this study, a cooling crystn. of paracetamol from an aq. iso-Pr alc. soln. was investigated. Exptl. results indicate that the crystn. system was able to operate without any clogging issues for over 10 residence times, before which the system had approached steady state. Three different start-up strategies for continuous crystn. were investigated, and the results indicate that the chord length distributions at steady state were the same for all cases. Also, starting the continuous operation from a satd. soln. that was seeded with product from a previous MSMPR run offered the quickest route to steady state. To better control and scale up the crystn. process, the nucleation and crystal growth kinetics of the model compd. were also detd. through use of the newly developed process. The growth rates were found to be size dependent, and an exponential three-parameter model was employed to characterize the size-dependent growth. It was seen that the crystal growth rate was extremely low and increased linearly with particle size when the particle size was below 10 μm. However, the growth rate increased dramatically with particle size when the particle size was between 10 and 1000 μm. The nucleation kinetics was correlated by the semiempirical equation BTOT = 1.11 × 1015MT0.98Gavg1.12. The orders of the total nucleation rate with respect to the magma d. and av. growth rate were 0.98 and 1.12, resp. Therefore, the effect of supersatn. (or residence time) and magma d. on the steady state crystal size was investigated.
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  147. 147
    Cui, Y.; O’Mahony, M.; Jaramillo, J. J.; Stelzer, T.; Myerson, A. S. Custom-Built Miniature Continuous Crystallization System with Pressure-Driven Suspension Transfer. Org. Process Res. Dev. 2016, 20 (7), 1276– 1282,  DOI: 10.1021/acs.oprd.6b00113
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    147
    Custom-Built Miniature Continuous Crystallization System with Pressure-Driven Suspension Transfer
    Cui, Yuqing; O'Mahony, Marcus; Jaramillo, Juan J.; Stelzer, Torsten; Myerson, Allan S.
    Organic Process Research & Development (2016), 20 (7), 1276-1282CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    At the bench scale, the transfer of solid-liq. streams between reaction vessels or crystallizers that operate continuously poses a significant problem. Reduced equipment size of pumps and valves (i.e., approaching that on the microfluidic scale) means even further reduced orifices in which suspensions must attempt to flow. It forces bridging of solids and leads to blockages in flow. This study presents a new pressure-driven flow crystallizer (PDFC) with a custom-built suspension transfer pumping system. In the system, a dip tube is used to carry suspension between crystallizers by controlling the pressure differences of the crystallizers. This novel system has a small footprint on the scale of similar benchtop flow synthesis systems and has been demonstrated to operate continuously with intermittent withdrawal for at least 24 h. The system accommodates both cooling and antisolvent crystn. It is compatible with a variety of solvents, can handle crystals with large and small aspect ratios, and can also handle a large range of crystal sizes and suspension d. The miniature design of the system requires as little as 0.36 psig (0.025 bar(g)) pressure to operate and a design equation can be used to guide the estn. of the min. pressure needed for the transfer of suspensions at larger scales.
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  148. 148
    Quon, J. L.; Zhang, H.; Alvarez, A.; Evans, J.; Myerson, A. S.; Trout, B. L. Continuous Crystallization of Aliskiren Hemifumarate. Cryst. Growth Des. 2012, 12 (6), 3036– 3044,  DOI: 10.1021/cg300253a
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    148
    Continuous Crystallization of Aliskiren Hemifumarate
    Quon, Justin L.; Zhang, Haitao; Alvarez, Alejandro; Evans, James; Myerson, Allan S.; Trout, Bernhardt L.
    Crystal Growth & Design (2012), 12 (6), 3036-3044CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
    Active ingredients in most pharmaceutical products are complex org. mols. that require crystn. as a purifn. and isolation step that results in a pure product at a high process yield. Knowledge of the operating conditions required to obtain crystals with the desired crystal shape, polymorph, and morphol. is crit. during process development. This paper describes a two-stage mixed suspension mixed product removal (MSMPR) continuous reactive crystn. procedure developed for Aliskiren hemifumarate. This process was able to crystallize Aliskiren hemifumarate at both high purity (> 99%) and high yield (> 92%). A model of the crystn. was developed through the simultaneous soln. of a population balance equation, kinetic expression for crystal growth and nucleation, and a mass balance. Exptl. data were fit to the model to obtain kinetic parameters for crystal growth and nucleation. After including equil. distribution coeff. data, the model was used to optimize crystal purity and yield of the product by adjusting the operating temp. and residence time. This process was integrated into an end-to-end continuous manufg. system developed at MIT.
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  149. 149
    Alvarez, A. J.; Myerson, A. S. Continuous Plug Flow Crystallization of Pharmaceutical Compounds. Cryst. Growth Des. 2010, 10 (5), 2219– 2228,  DOI: 10.1021/cg901496s
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    149
    Continuous Plug Flow Crystallization of Pharmaceutical Compounds
    Alvarez, Alejandro J.; Myerson, Allan S.
    Crystal Growth & Design (2010), 10 (5), 2219-2228CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
    Crystn. processes in the pharmaceutical industry are usually designed to obtain crystals with controlled size, shape, purity, and polymorphic form. Knowledge of the process conditions required to fabricate crystals with controlled characteristics is crit. during process development. In this work, continuous crystn. of ketoconazole, flufenamic acid, and L-glutamic acid in a nonconventional plug flow crystallizer was investigated. Kenics type static mixers were used to promote homogeneous mixing of active pharmaceutical ingredient soln. and antisolvent. A strategy of multiple points of addn. of antisolvent along the crystallizer was evaluated to control the size of the crystals. Interestingly, it was found that crystal size can be increased or decreased with an increased no. of antisolvent addn. points, depending on the kinetics of the system. It was also found that smaller crystals with a narrower size distribution can be obtained with the static mixers. A model to describe the continuous crystn. process was developed through the simultaneous soln. of a population balance equation, kinetics expressions for crystal growth and nucleation, and a mass balance. The comparison of exptl. and calcd. values for crystal size distribution revealed that a growth rate dispersion model could describe accurately the continuous crystn. process. Collision of crystals with each other and with mixing elements inside the crystallizer may be the source of random fluctuation of the growth rate in the nonconventional plug flow crystallizer with static mixers.
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  150. 150
    Majumder, A.; Nagy, Z. K. Fines Removal in a Continuous Plug Flow Crystallizer by Optimal Spatial Temperature Profiles with Controlled Dissolution. AIChE J. 2013, 59 (12), 4582– 4594,  DOI: 10.1002/aic.14196
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    150
    Fines removal in a continuous plug flow crystallizer by optimal spatial temperature profiles with controlled dissolution
    Majumder, Aniruddha; Nagy, Zoltan K.
    AIChE Journal (2013), 59 (12), 4582-4594CODEN: AICEAC; ISSN:0001-1541. (John Wiley & Sons, Inc.)
    This work presents a systematic study for obtaining the optimal temp. profile in a continuous plug flow crystallizer (PFC). The proposed PFC consists of multiple segments where the temp. of each segment can be controlled individually. An optimization problem is formulated for a target crystal size distribution (without fines) with the temp. of the segments as decision variables. The results indicate that for the crystn. kinetics considered, dissoln. steps are necessary for the redn. of fines due to nucleation. A systematic study on the form of growth and dissoln. kinetics suggested that the key factor that dets. whether the dissoln. steps will be successful in reducing fines, without compromising the final size of the crystals from seed, is the size dependence of the growth and dissoln. kinetics. Best fines removal is achieved when the larger crystals grow faster than the smaller ones and the smaller crystals dissolve faster than the larger ones.
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    Furuta, M.; Mukai, K.; Cork, D.; Mae, K. Continuous Crystallization Using a Sonicated Tubular System for Controlling Particle Size in an API Manufacturing Process. Chem. Eng. Process. 2016, 102, 210– 218,  DOI: 10.1016/j.cep.2016.02.002
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    151
    Continuous crystallization using a sonicated tubular system for controlling particle size in an API manufacturing process
    Furuta, Masashi; Mukai, Kouji; Cork, David; Mae, Kazuhiro
    Chemical Engineering and Processing (2016), 102 (), 210-218CODEN: CENPEU; ISSN:0255-2701. (Elsevier B.V.)
    A pH swing crystn. that was very sensitive toward scale-up and required specific equipment due to the non-Newtonian characteristics of the fluid, has been investigated using continuous crystn. (CC) as a means to improve particle size control, scalability and potentially reduce manufg. cost. A sonicated tubular crystallizer was designed and shown to allow the pH swing crystn. to be operated robustly without blockage, to give a wide range of desired particle size. The results were compared with crystn. in a premixing semi-batch system and a simple addn. semi-batch system under similar conditions. Interestingly, it was found that the sonicated tubular system was the only one of the three systems that gave the desired control for small particle size (1-7 μm). Even though the productivity of the sonicated tubular crystallizer still needs to be increased to allow CC and numbering-up to become cost competitive with batch crystn., we have demonstrated the potential of continuous tubular crystn. as a useful alternative method to conventional batch operation.
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  152. 152
    Eder, R. J. P.; Schmitt, E. K.; Grill, J.; Radl, S.; Gruber-Woelfler, H.; Khinast, J. G. Seed Loading Effects on the Mean Crystal Size of Acetylsalicylic Acid in a Continuous-Flow Crystallization Device. Cryst. Res. Technol. 2011, 46 (3), 227– 237,  DOI: 10.1002/crat.201000634
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    Seed loading effects on the mean crystal size of acetylsalicylic acid in a continuous-flow crystallization device
    Eder, R. J. P.; Schmitt, E. K.; Grill, J.; Radl, S.; Gruber-Woelfler, H.; Khinast, J. G.
    Crystal Research and Technology (2011), 46 (3), 227-237CODEN: CRTEDF; ISSN:0232-1300. (Wiley-VCH Verlag GmbH & Co. KGaA)
    This study investigates the effects of seed loading on the mean crystal size of the model substance, acetylsalicylic acid, crystd. from ethanol in a continuously seeded tubular crystallizer. A hot, highly concd. ethanolic acetylsalicylic acid soln. was mixed with an acetylsalicylic acid-ethanol seed suspension. Subsequent cooling of the slurry in the tubing promoted supersatn. and hence crystal growth. The tubular shape of the 15 m-long crystallizer with an inner diam. of 2 mm enabled narrow residence time distributions of the crystals in the pipe and excellent temp. control in the radial direction and along the tubing. Crystals entering the crystallizer had both identical growth conditions in each section and about the same time for crystal growth. Narrow crystal size distributions were achieved with decreasing differences in the vol.-mean-diam. sizes of the seed and product crystals as seed loadings increased. Decreasing the seed size had a similar effect as increasing the seed loading, since in that case the same amt. of seed mass resulted in more individual seed particles. Altering the arrangement of the coiled crystallizer with respect to spatial directions (horizontal, vertical) did not lead to a significantly different outcome. All expts. produced considerably larger product crystals in comparison to the seeds despite relatively short crystn. times of less than 3 min. Moreover, product mass gains of a few hundred percent at a g/min-scale were achieved. Similarities in product crystal samples taken at different times at the outlet of the crystallizer showed that steady-state conditions were rapidly reached in the continuous flow crystn. device. (© 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim).
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    Eder, R. J. P.; Radl, S.; Schmitt, E.; Innerhofer, S.; Maier, M.; Gruber-Woelfler, H.; Khinast, J. G. Continuously Seeded, Continuously Operated Tubular Crystallizer for the Production of Active Pharmaceutical Ingredients. Cryst. Growth Des. 2010, 10 (5), 2247– 2257,  DOI: 10.1021/cg9015788
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    153
    Continuously Seeded, Continuously Operated Tubular Crystallizer for the Production of Active Pharmaceutical Ingredients
    Eder, Rafael J. P.; Radl, Stefan; Schmitt, Elisabeth; Innerhofer, Sabine; Maier, Markus; Gruber-Woelfler, Heidrun; Khinast, Johannes G.
    Crystal Growth & Design (2010), 10 (5), 2247-2257CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
    A continuously operated tubular crystallizer system with an inner diam. of 2.0 mm has been successfully operated. It allows the crystn. of active pharmaceutical ingredients (APIs) under controlled conditions. Acetylsalicylic acid (ASA) which was crystd. from ethanol (EtOH) was used as the model substance. An ethanolic suspension of ASA-seeds was fed into the tubular crystallizer system, where it was mixed with a slightly undersatd. ASA-EtOH soln. that was kept at an elevated temp. in its storage vessel. Supersatn. was created via cooling and the seeds grew to form the product crystals. This work mainly focuses on the proof-of-concept and on the impact of the flow rates on the product crystals and the crystal size distribution (CSD). All other parameters including concns., temps., and loading of seeds were kept const. Higher flow velocities generally resulted in reduced no. and vol. mean diams., due to reduced tendency of agglomeration and decreased time for crystal growth due to shorter residence times of the suspension in the tube. Generally, all expts. unmistakably led to shifting of vol. d. distributions toward significantly larger values for product crystals in comparison to the seeds and were capable of yielding product masses in a g/min scale.
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  154. 154
    McGlone, T.; Briggs, N. E. B.; Clark, C. A.; Brown, C. J.; Sefcik, J.; Florence, A. J. Oscillatory Flow Reactors (OFRs) for Continuous Manufacturing and Crystallization. Org. Process Res. Dev. 2015, 19 (9), 1186– 1202,  DOI: 10.1021/acs.oprd.5b00225
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    154
    Oscillatory Flow Reactors (OFRs) for Continuous Manufacturing and Crystallization
    McGlone, Thomas; Briggs, Naomi E. B.; Clark, Catriona A.; Brown, Cameron J.; Sefcik, Jan; Florence, Alastair J.
    Organic Process Research & Development (2015), 19 (9), 1186-1202CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    Continuous crystn. is an attractive approach for the delivery of consistent particles with specified crit. quality attributes (CQAs), which are attracting increased interest for the manuf. of high value materials, including fine chems. and pharmaceuticals. Oscillatory flow reactors (OFRs) offer a suitable platform to deliver consistent operating conditions under plug-flow operation while maintaining a controlled steady state. This review provides a brief overview of OFR technol. before outlining the operating principles and summarizing applications, emphasizing the use for controlled continuous crystn. While significant progress has been made to date, areas for further development are highlighted that will enhance the range of applications and ease of implementation of OFR technol. These depend on specific applications but include scale down, materials of construction suitable for chem. compatibility, encrustation mitigation, the enhancement of robust operation via automation, process anal. technol. (PAT), and real-time feedback control.
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  155. 155
    Pena, R.; Oliva, J. A.; Burcham, C. L.; Jarmer, D. J.; Nagy, Z. K. Process Intensification through Continuous Spherical Crystallization Using an Oscillatory Flow Baffled Crystallizer. Cryst. Growth Des. 2017, 17 (9), 4776– 4784,  DOI: 10.1021/acs.cgd.7b00731
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    155
    Process Intensification through Continuous Spherical Crystallization Using an Oscillatory Flow Baffled Crystallizer
    Pena, Ramon; Oliva, Joseph A.; Burcham, Christopher L.; Jarmer, Daniel J.; Nagy, Zoltan K.
    Crystal Growth & Design (2017), 17 (9), 4776-4784CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
    Drug substance purifn. by crystn. is a key interface in going from drug substance synthesis to final formulation and can often be a bottleneck in process efficiency. There has been increased importance in the development of continuous crystn. systems of active pharmaceutical ingredients to produce crystals with targeted phys. and biopharmaceutical properties. Continuous spherical crystn. (CSC) is a process intensification technique that can address many of the present flaws (e.g. size distribution, downstream processing efficiency) of traditional crystn. systems. In this study, a novel concept and method in the field of process intensification through continuous spherical crystn. is proposed. This study is based on performing crystn./spherical agglomeration in an oscillatory flow baffled crystallizer (OFBC). OFBCs are comparable to plug flow crystallizers (PFCs) in that they are both tubular crystallizers, however, the OFBC has periodically spaced orifice baffles with oscillatory motion overlapped on the net flow. Independent crystn. mechanisms can theor. be achieved through spatially distributed soln., solvent, anti-solvent, and bridging liq. addn.; offering more control of each mechanism. However, our studies showed that the OFBC allowed for spatially distributed addn. of solvents but achieving control of each mechanism individually was not attainable due to the back mixing of the system.
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  156. 156
    Liu, Y. C.; Dunn, D.; Lipari, M.; Barton, A.; Firth, P.; Speed, J.; Wood, D.; Nagy, Z. K. A Comparative Study of Continuous Operation between a Dynamic Baffle Crystallizer and a Stirred Tank Crystallizer. Chem. Eng. J. 2019, 367, 278– 294,  DOI: 10.1016/j.cej.2019.02.129
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    156
    A comparative study of continuous operation between a dynamic baffle crystallizer and a stirred tank crystallizer
    Liu, Yiqing Claire; Dunn, Davis; Lipari, Mary; Barton, Alastair; Firth, Paul; Speed, Jonathon; Wood, Dan; Nagy, Zoltan K.
    Chemical Engineering Journal (Amsterdam, Netherlands) (2019), 367 (), 278-294CODEN: CMEJAJ; ISSN:1385-8947. (Elsevier B.V.)
    Crystn., often as the final isolation and purifn. step in drug substance manufg., has substantial impact on downstream efficiency and final drug product quality. It is a crit. but challenging step in developing end-to-end continuous manufg., which has been identified as an emerging technol. in the pharmaceutical manufg. sector by the U.S. Food and Drug Administration (FDA). A traditional stirred tank crystallizer (STC) operated as a mixed-suspension-mixed-product-removal (MSMPR) system is a popular choice for continuous crystn. for its utilization of existing knowledge and equipment. However, there are disadvantages assocd. with agitational systems like the STC, such as poor local mixing and high shear rate. A com. dynamic baffle crystallizer (DBC) was studied here as an alternative unit operation. The DBC in this study consists of a jacketed glass vessel with dynamic 'donut' shaped baffles to provide oscillatory mixing to improve heat and mass transfer while exerting less shear. Our goal is to compare continuous operation performances in the DBC with the STC as MSMPR systems. First, residence time distribution (RTD) studies of both systems were performed considering single phase (liq. only) and two-phase (solid-liq.) operation. The RTD gives good insights into the mixing dynamics without computationally heavy fluid dynamic simulations. Continuous cooling crystn. of paracetamol was performed in the DBC and the STC. The DBC showed good potential to be used as an MSMPR system producing more uniform RTDs as well as higher quality crystn. products compared to a traditional STC.
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    McLachlan, H.; Ni, X.-W. On the Effect of Added Impurity on Crystal Purity of Urea in an Oscillatory Baffled Crystallizer and a Stirred Tank Crystallizer. J. Cryst. Growth 2016, 442, 81– 88,  DOI: 10.1016/j.jcrysgro.2016.03.001
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    On the effect of added impurity on crystal purity of urea in an oscillatory baffled crystallizer and a stirred tank crystallizer
    McLachlan, Hannah; Ni, Xiong-Wei
    Journal of Crystal Growth (2016), 442 (), 81-88CODEN: JCRGAE; ISSN:0022-0248. (Elsevier B.V.)
    Previous work has indicated that crystals produced in oscillatory baffled crystallizers (OBC) from a relatively 'pure' starting environment gave statistically higher purities than that in stirred tank crystallizers (STC) under comparable conditions. In this work, a known amt. of biuret (the impurity) was added to the 'pure' urea system and the results show that the OBC still produced higher purity crystals than the STC, although these purity values were statistically lower than from the 'pure' environment in both vessels. By evaluating crystn. rates of both urea and biuret, we noticed that these rates are higher in the STC than in the OBC, which would have led to small crystals in the former vessel. The CSD data however gave the opposite result where the CSD is wider with more, large crystals in the STC than in the OBC, in particular in the presence of added impurity. These larger crystals are likely formed due to agglomeration coupled with incorporation of impurity, which leads to a lower purity.
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    Ni, X.; Liao, A. Effects of Mixing, Seeding, Material of Baffles and Final Temperature on Solution Crystallization of l-Glutamic Acid in an Oscillatory Baffled Crystallizer. Chem. Eng. J. 2010, 156 (1), 226– 233,  DOI: 10.1016/j.cej.2009.10.045
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    158
    Effects of mixing, seeding, material of baffles and final temperature on solution crystallization of L-glutamic acid in an oscillatory baffled crystallizer
    Ni, Xiongwei; Liao, Anting
    Chemical Engineering Journal (Amsterdam, Netherlands) (2010), 156 (1), 226-233CODEN: CMEJAJ; ISSN:1385-8947. (Elsevier B.V.)
    In this paper, we report the effects of mixing intensity, seeding, compn. of baffle material and final temp. on meta-stable zone width (MSZW) and crystal polymorph in soln. crystn. of an industrially important compd., -glutamic acid, in an oscillatory baffled crystallizer (OBC). The results show that the MSZW decreases with increasing of mixing; meta-stable α crystals are transformed into stable β crystals with enhanced mixing intensity. Seeding meta-stable α crystals in operational conditions that promote β crystals leads to the formation of α crystals allowing co-existence of both forms; while seeding stable β crystals in conditions that favor α form allow β crystals prevailing in all conditions. Smoother surface of baffle material in OBC exhibits larger MSZW and favors meta-stable crystals, while rougher surface has smaller MSZW with stable crystals dominating. The meta-stable crystals gradually change into the stable form when final cooling temp. is closer to its nucleation temp. The outcomes from this work indicate that by controlling process parameters desirable crystal polymorph can be obtained in the OBC.
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    Acevedo, D.; Yang, X.; Liu, Y. C.; O’Connor, T. F.; Koswara, A.; Nagy, Z. K.; Madurawe, R.; Cruz, C. N. Encrustation in Continuous Pharmaceutical Crystallization Processes—A Review. Org. Process Res. Dev. 2019, 23 (6), 1134– 1142,  DOI: 10.1021/acs.oprd.9b00072
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    Encrustation in Continuous Pharmaceutical Crystallization Processes-A Review
    Acevedo, David; Yang, Xiaochuan; Liu, Yiqing C.; O'Connor, Thomas F.; Koswara, Andy; Nagy, Zoltan K.; Madurawe, Rapti; Cruz, Celia N.
    Organic Process Research & Development (2019), 23 (6), 1134-1142CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    Encrustation is a risk factor that can cause product and process failure in continuous crystn. processes. Mitigation, prevention, and control of encrustation have been extensively researched. Various risk mitigation strategies proposed in the literature, such as coating of crystallizer walls, use of additives to control encrustation kinetics, and periodic steady-state operation show promising results in delaying or preventing encrustation. Because of the increased interest in the use of continuous crystn. in industrial applications, it is important to understand this risk factor further. This review presents recent developments on dynamic models, mechanisms, and risk factors for encrustation in continuous crystn. processes. Various design and control strategies to mitigate the encrustation risk are also summarized. Appropriate control strategies should be implemented during continuous crystn. to avoid the impact of encrustation on drug substance quality.
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    Koswara, A.; Nagy, Z. K. Anti-Fouling Control of Plug-Flow Crystallization via Heating and Cooling Cycle. IFAC-PapersOnLine 2015, 48 (8), 193– 198,  DOI: 10.1016/j.ifacol.2015.08.180
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    Reynolds, T.; Boychyn, M.; Sanderson, T.; Bulmer, M.; More, J.; Hoare, M. Scale-down of Continuous Filtration for Rapid Bioprocess Design: Recovery and Dewatering of Protein Precipitate Suspensions. Biotechnol. Bioeng. 2003, 83 (4), 454– 464,  DOI: 10.1002/bit.10687
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    Scale-down of continuous filtration for rapid bioprocess design: Recovery and dewatering of protein precipitate suspensions
    Reynolds, T.; Boychyn, M.; Sanderson, T.; Bulmer, M.; More, J.; Hoare, M.
    Biotechnology and Bioengineering (2003), 83 (4), 454-464CODEN: BIBIAU; ISSN:0006-3592. (John Wiley & Sons, Inc.)
    The early specification of bioprocesses often has to be achieved with small (tens of milliliters) quantities of process material. If extensive process discovery is to be avoided at pilot or industrial scale, it is necessary that scale-down methods be created that not only examine the conditions of process stages but also allows prodn. of realistic output streams (i.e., streams truly representative of the large scale). These output streams can then be used in the development of subsequent purifn. operations. The traditional approach to predicting filtration operations is via a bench-scale pressure filter using const. pressure tests to examine the effect of pressure on the filtrate flux rate and filter cake dewatering. Interpretation of the results into cake resistance at unit applied pressure (α0) and compressibility (n) is used to predict the pressure profile required to maintain the filtrate flux rate at a const. predetd. value. This article reports on the operation of a continuous mode lab. filter in such a way as to prep. filter cakes and filtrate similar to what may be achieved at the industrial scale. Anal. of the filtration rate profile indicated the filter cake to have changing properties (compressibility) with time. Using the insight gained from the new scale-down methodol. gave predictions of the flux profile in a pilot-scale candle filter superior to those obtained from the traditional batch filter used for lab. development.
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    Foley, G. A Review of Factors Affecting Filter Cake Properties in Dead-End Microfiltration of Microbial Suspensions. J. Membr. Sci. 2006, 274 (1–2), 38– 46,  DOI: 10.1016/j.memsci.2005.12.008
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    A review. Dead-end microfiltration of microbial suspensions is reviewed with particular emphasis on the factors affecting the specific cake resistance. The effects of cell size and shape, cell surface properties (including charge), ionic environment, fermn. medium components and ageing effects are reviewed in detail. The measurement of specific resistance and correlation of cake compressibility data is described and current understanding of the underlying mechanisms of cake compression is discussed. Factors affecting the packing arrangement of cells in filter cakes are also reviewed and discussed in the context of the Carman-Kozeny equation.
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    de Castro, M. D. L.; Priego-Capote, F. Continuous Filtration as a Separation Technique. Trends Anal. Chem. 2008, 27 (2), 101– 107,  DOI: 10.1016/j.trac.2007.11.006
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    Arunkumar, A.; Singh, N.; Peck, M.; Borys, M. C.; Li, Z. J. Investigation of Single-Pass Tangential Flow Filtration (SPTFF) as an Inline Concentration Step for Cell Culture Harvest. J. Membr. Sci. 2017, 524, 20– 32,  DOI: 10.1016/j.memsci.2016.11.007
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    Investigation of single-pass tangential flow filtration (SPTFF) as an inline concentration step for cell culture harvest
    Arunkumar, Abhiram; Singh, Nripen; Peck, Michael; Borys, Michael C.; Li, Zheng Jian
    Journal of Membrane Science (2017), 524 (), 20-32CODEN: JMESDO; ISSN:0376-7388. (Elsevier B.V.)
    This work examd. the use of single-pass tangential flow filtration (SPTFF) to conc. cell culture harvest. Conventional tangential flow filtration (TFF) is routinely used in biotechnol. and related industries to conc. protein solns. and exchange them into the final formulation buffer. However, several pump passes and a recirculation skid are required to achieve the target concn. in conventional TFF. Thus, it is impractical to implement TFF for inline concn. of protein solns. during the manuf. of biol. products. New developments in the biotechnol. industry have focused on using ultrafiltration in a single pump pass (also known as SPTFF) to conc. protein solns. in a single pump pass as an inline concn. step. There is thus a potential utility for this technol. to overcome manufg. bottlenecks. While there is limited work in literature describing the use of SPTFF for concn. of in-process protein pools, no work has been reported on the use of SPTFF for concn. of cell culture harvest and the challenges faced in this situation. This work examines the utility of using a 30 kDa ultrafiltration membrane in the SPTFF mode to conc. cell culture harvest for six different biol. assets in order to det. its feasibility over a wide range of biol. cell culture harvest streams. Cell culture harvest provided unique challenges to SPTFF that were overcome using a synthetic adsorptive hybrid filter technol. In particular, the hydraulic conditions necessary to achieve a targeted concn. factor varied from lot-to-lot for the same mol. This caused difficulty in implementing a given set of operating conditions for the same mol. because of process instability. To address these challenges, we used high capacity adsorptive filters that effectively reduced both particulates and sol. contaminants during primary recovery to improve the SPTFF performance. The adsorptive filter mainly removed process related impurities, specifically HCP and DNA that prematurely fouled the ultrafiltration membrane and changed the capacity of SPTFF. The adsorptive filter also eradicated cell-culture lot-to-lot performance variability with SPTFF by offering a relative std. deviation of <10%. The use of SPTFF by simultaneously coupling the clarification with the concn. was successfully demonstrated. This is the first work to report the use of SPTFF to conc. cell culture harvest for six different biol. assets, overcoming challenges using adsorptive filtration, and demonstrate debottlenecking for manufg.
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    Song, L.; Elimelech, M. Theory of Concentration Polarization in Crossflow Filtration. J. Chem. Soc., Faraday Trans. 1995, 91 (19), 3389,  DOI: 10.1039/ft9959103389
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    A novel theory was developed for concn. polarization of non-interacting particles in crossflow-filtration systems. This theory reveals that the extent of concn. polarization, as well as the behavior of the permeate flux, are characterized by an important dimensionless filtration no. (NF = 4πap3ΔP/3kT). There is a crit. value of NF for a given suspension and operational conditions. When NF is smaller than the crit. value, a polarization layer exists directly over the membrane surface and the wall particle concn. is detd. by the pressure and temp. At higher NF, a cake layer of retained particles forms between the polarization layer and the membrane surface. Math. models were constructed for both cases and anal. solns. for the permeate flux were derived. An increase in permeate flux with increasing pressure was predicted for all operating conditions.
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    Gursch, J.; Hohl, R.; Toschkoff, G.; Dujmovic, D.; Brozio, J.; Krumme, M.; Rasenack, N.; Khinast, J. Continuous Processing of Active Pharmaceutical Ingredients Suspensions via Dynamic Cross-Flow Filtration. J. Pharm. Sci. 2015, 104 (10), 3481– 3489,  DOI: 10.1002/jps.24562
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    Continuous Processing of Active Pharmaceutical Ingredients Suspensions via Dynamic Cross-Flow Filtration
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    Journal of Pharmaceutical Sciences (2015), 104 (10), 3481-3489CODEN: JPMSAE; ISSN:0022-3549. (John Wiley & Sons, Inc.)
    Over the last years, continuous manufg. has created significant interest in the pharmaceutical industry. Continuous filtration at low flow rates and high solid loadings poses, however, a significant challenge. A com. available, continuously operating, dynamic cross-flow filtration device (CFF) is tested and characterized. It is shown that the CFF is a highly suitable technol. for continuous filtration. For all tested model active pharmaceutical ingredients, a material-specific strictly linear relationship between feed and permeate rate is identified. Moreover, for each tested substance, a const. concn. factor is reached. A one-parameter model based on a linear equation is suitable to fully describe the CFF filtration performance. This rather unexpected finding and the concn. polarization layer buildup is analyzed and a basic model to describe the obsd. filtration behavior is developed. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Assocn. J Pharm Sci.
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    Gursch, J.; Hohl, R.; Dujmovic, D.; Brozio, J.; Krumme, M.; Rasenack, N.; Khinast, J. Dynamic Cross-Flow Filtration: Enhanced Continuous Small-Scale Solid-Liquid Separation. Drug Dev. Ind. Pharm. 2016, 42 (6), 977– 984,  DOI: 10.3109/03639045.2015.1100200
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    Dynamic cross-flow filtration: enhanced continuous small-scale solid-liquid separation
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    Drug Development and Industrial Pharmacy (2016), 42 (6), 977-984CODEN: DDIPD8; ISSN:0363-9045. (Taylor & Francis Ltd.)
    In a previous study, a small-scale dynamic filtration device (SFD) was analyzed and the basic mechanisms governing the filtration process were characterized. The present work aims at improving the device's performance in terms of actual prodn. Various operation modes were tested in order to increase permeate flow and concn. factors (CF), while maintaining a fully continuous prodn. mode. Both, a vacuum-enhanced and a pulsating operation mode, proved to be superior to the currently implemented open-operation mode. For example, for lactose, an increase of the CF could be achieved from 1.7 in open mode to 7.6 in pulsating operation mode. The investigated operation strategy enables process control systems to rapidly react to fluctuating feeds that may occur due to changes in upstream manufg. steps. As a result, not only filtration performance in terms of permeate rate but also process flexibility can be significantly increased. Overall, vacuum-enhanced operation was shown to be most promising for integration into an industrial environment. The option to elevate achievable concn. factors, ease of flow monitoring as well as the ability to react to changes in the feed conditions allow for effective and efficient continuous small-scale filtration.
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    Kossik, J. Operation of a Disposable Rotary Drum Filter. In AIChE Annual Meeting, Pharmaceutical & Biotechnology Pilot Plants; 2001.
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    Hohmann, L.; Löbnitz, L.; Menke, C.; Santhirakumaran, B.; Stier, P.; Stenger, F.; Dufour, F.; Wiese, G.; zur Horst-Meyer, S.; Kusserow, B.; Zang, W.; Nirschl, H.; Kockmann, N. Continuous Downstream Processing of Amino Acids in a Modular Miniplant. Chem. Eng. Technol. 2018, 41 (6), 1152– 1164,  DOI: 10.1002/ceat.201700657
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    Continuous downstream processing of amino acids in a modular miniplant
    Hohmann, Lukas; Loebnitz, Lisa; Menke, Christina; Santhirakumaran, Bavatharani; Stier, Patrick; Stenger, Frank; Dufour, Fabrice; Wiese, Georg; zur Horst-Meyer, Santer; Kusserow, Burkhard; Zang, Werner; Nirschl, Hermann; Kockmann, Norbert
    Chemical Engineering & Technology (2018), 41 (6), 1152-1164CODEN: CETEER; ISSN:1521-4125. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Global competition leads to a need for a fast time to market and increased resource efficiency. Continuous processing, module-based plant design, and multipurpose equipment are recently discussed approaches for the fine-chem. industry. As a representative, the downstream process of amino acid prodn. is discussed herein. A conventional batch procedure was transferred to a continuous process and realized in a modular miniplant, which comprised of evapn. in a wiped-film evaporator, seeded cooling crystn. in a coiled tubular crystallizer, and solid/liq. sepn. on a vacuum belt filter. The operations were realized on-skid with individual automation systems and integrated sensors. L-Alanine was successfully processed in steady-state operation.
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    Wong, S. Y.; Chen, J.; Forte, L. E.; Myerson, A. S. Compact Crystallization, Filtration, and Drying for the Production of Active Pharmaceutical Ingredients. Org. Process Res. Dev. 2013, 17 (4), 684– 692,  DOI: 10.1021/op400011s
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    Compact Crystallization, Filtration, and Drying for the Production of Active Pharmaceutical Ingredients
    Wong, Shin Yee; Chen, Jie; Forte, Laura E.; Myerson, Allan S.
    Organic Process Research & Development (2013), 17 (4), 684-692CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    With the growing problem of drug shortages worldwide, a soln. could be a centralized compact pharmaceutical manufg. platform that produces API and finished drug product. In this paper, the development of a combined crystn., hybrid filtration-drying-dissoln. app. to be used in such a compact platform is discussed. Expts. were conducted to evaluate each unit operation. Crystn. expts. using a conventional stirred tank and the newly designed scraped surface crystallizer demonstrated the advantages of the new design in terms of crystn. rates, yields and the ease of automation. Postcrystn. operations were operated stepwise using the custom hybrid device that delivered satisfactory results for each operation, e.g. after filtration, Fluoxetine HCl was dried in less than 20 min, with 99% yield after dissoln. in the liq. excipient.
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    Wong, S. Y.; Tatusko, A. P.; Trout, B. L.; Myerson, A. S. Development of Continuous Crystallization Processes Using a Single-Stage Mixed-Suspension, Mixed-Product Removal Crystallizer with Recycle. Cryst. Growth Des. 2012, 12 (11), 5701– 5707,  DOI: 10.1021/cg301221q
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    Development of Continuous Crystallization Processes Using a Single-Stage Mixed-Suspension, Mixed-Product Removal Crystallizer with Recycle
    Wong, Shin Yee; Tatusko, Adam P.; Trout, Bernhardt L.; Myerson, Allan S.
    Crystal Growth & Design (2012), 12 (11), 5701-5707CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
    An ideal pharmaceutical crystn. process produces a pure product at a high yield while minimizing energy input, the process equipment footprint, and its complexity. A good candidate for such a process is a single-stage mixed-suspension, mixed-product removal (MSMPR) crystallizer with recycle (SMR) system, where the characteristics of the refined crystal are controlled by the crystn. conditions of the MSMPR and the yield is manipulated by the recycle ratio. In this study, two continuous SMR systems, for the cooling crystn. of cyclosporine and the antisolvent-cooling crystn. of deferasirox, were developed. Both systems were designed to maintain the desired operating conditions inside the MSMPR crystallizer. For cooling crystn., the recycle stream was concd. via vacuum evapn. For antisolvent-cooling crystn., the desired solvent to antisolvent ratio was maintained by controlling the flow rates of feed, antisolvent, and recycle streams. The max. exptl. yield and purity of the crystals were detd. as 91.8 and 94.3%, resp. (for cyclosporine) and 89.1% with 0.2 ppm impurity A, resp. (for deferasirox). For cyclosporine, this yield is 5.5% higher than that of a multistage MSMPR with a recycle system. Addnl., the SMR system is relatively simple, having a lower operational demand, in terms of space and no. of unit operations required.
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    Ferguson, S.; Ortner, F.; Quon, J.; Peeva, L.; Livingston, A.; Trout, B. L.; Myerson, A. S. Use of Continuous MSMPR Crystallization with Integrated Nanofiltration Membrane Recycle for Enhanced Yield and Purity in API Crystallization. Cryst. Growth Des. 2014, 14 (2), 617– 627,  DOI: 10.1021/cg401491y
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    Use of Continuous MSMPR Crystallization with Integrated Nanofiltration Membrane Recycle for Enhanced Yield and Purity in API Crystallization
    Ferguson, Steven; Ortner, Franziska; Quon, Justin; Peeva, Ludmila; Livingston, Andrew; Trout, Bernhardt L.; Myerson, Allan S.
    Crystal Growth & Design (2014), 14 (2), 617-627CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
    If continuous processing is to be employed in pharmaceutical prodn., it is essential that continuous crystn. techniques can meet the purity and yield achievable in current batch crystn. processes. Recycling of mother liquor in steady state MSMPR crystns. allows the yield in the equiv. equil. batch process to be met or exceeded. However, the extent to which yield can be increased is limited by the buildup of impurities within the system. In this study, an org. solvent nanofiltration membrane was used to preferentially conc. an API (deferasirox, M.W. = 373 Da) and purge the limiting impurity 4-hydrazinobenzoic acid (MW = 152 Da) from the mother liquor recycle stream in a mixed solvent (THF:ethanol) antisolvent (water) system. Incorporation of the membrane recycle allowed yields of 98.0% and 98.7% to be achieved. This compares to the following: a control MSMPR run without a membrane (70.3%), an equiv. batch process (89.2%), and the current com. batch process (92%). Comparable product impurity levels were measured for the following: the MSMPR membrane recycle expts. (0.15 ppm and 0.22 ppm), the MSMPR control (0.13 ppm), and batch (0.32 ppm) control expts. All processes met the regulatory specifications of a max. of 3 ppm of the impurity 4-hydrainobenzoic acid.
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  177. 177
    Acevedo, D.; Peña, R.; Yang, Y.; Barton, A.; Firth, P.; Nagy, Z. K. Evaluation of Mixed Suspension Mixed Product Removal Crystallization Processes Coupled with a Continuous Filtration System. Chem. Eng. Process. 2016, 108, 212– 219,  DOI: 10.1016/j.cep.2016.08.006
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    177
    Evaluation of mixed suspension mixed product removal crystallization processes coupled with a continuous filtration system
    Acevedo, David; Pena, Ramon; Yang, Yang; Barton, Alastair; Firth, Paul; Nagy, Zoltan K.
    Chemical Engineering and Processing (2016), 108 (), 212-219CODEN: CENPEU; ISSN:0255-2701. (Elsevier B.V.)
    As the pharmaceutical industry evolves and goes through the paradigm shift from batch to continuous manufg., innovative processes need to be developed to replace unit operations that have historically been batch operations. This requires innovation in the continuous crystn. field of study as well as innovation in downstream processes (e.g. filtration, drying, milling, and granulation). Herein a novel and com. available continuous filter carousel (CFC) system was assessed for its feasibility of continuous filtration while coupled with a continuous mixed suspension mixed product removal (MSMPR) crystallizer. The filtration system was assessed using two different crystn. systems (i.e. cooling and antisolvent) with significantly different kinetics and morphologies to assess the robustness of the integrated platform. With proper optimization of the various filtration parameters for the different crystn. systems a controlled state of operation was achieved in each case. The crystal product from the CFC system shows good consistency with the crystals in the slurry in the MSMPR. Moisture content and productivity of the filtration system were reported and show dependency on crystal properties. The CFC system was equipped with solvent vessels that aided the continuous filtration by acting as a wash or a clean-in-place solvent, preventing or removing filter clogging, resp.
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  178. 178
    Liu, Y. C.; Domokos, A.; Coleman, S.; Firth, P.; Nagy, Z. K. Development of Continuous Filtration in a Novel Continuous Filtration Carousel Integrated with Continuous Crystallization. Org. Process Res. Dev. 2019, 23 (12), 2655– 2665,  DOI: 10.1021/acs.oprd.9b00342
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    178
    Development of Continuous Filtration in a Novel Continuous Filtration Carousel Integrated with Continuous Crystallization
    Liu, Yiqing C.; Domokos, Andras; Coleman, Simon; Firth, Paul; Nagy, Zoltan K.
    Organic Process Research & Development (2019), 23 (12), 2655-2665CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    Pharmaceutical manufg. has been largely carried out in batch mode, which has disadvantages such as batch-to-batch variations and difficult scale-up. As a result, the pharmaceutical industry is going through the paradigm shift to continuous manufg. Many unit operations have been studied for continuous operation; however, the bottleneck largely lies in drug substance isolation processes, such as crystn. and filtration. Herein a novel com. continuous filtration unit, the continuous filtration carousel (CFC), coupled with an innovative continuous crystn. system, the oscillatory baffle reactor (OBR), was studied to construct a truly continuous drug substance sepn. step where supersatd. soln. was continuously crystd. and filtered to produce solid products without a hold-up tank. Two compds. were studied to evaluate the CFC performance: paracetamol and benzoic acid. Standalone filtration expts. were performed first to examine the operating parameters of the CFC from which an optimal set of operating parameters was chosen for the integration of continuous filtration and crystn. Successful integration of continuous crystn. and filtration of paracetamol and benzoic acid was demonstrated where dry uniform paracetamol crystals were obtained while benzoic acid products were high in moisture content. Implementing drying functionality in the filter chamber can improve its performance. In hopes to expedite the application of continuous filtration in the pharmaceutical industry, a risk consideration discussion is given to identify and organize potential risk factors assocd. with continuous filtration.
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  179. 179
    Capellades, G.; Neurohr, C.; Azad, M.; Brancazio, D.; Rapp, K.; Hammersmith, G.; Myerson, A. S. A Compact Device for the Integrated Filtration, Drying, and Mechanical Processing of Active Pharmaceutical Ingredients. J. Pharm. Sci. 2020, 109 (3), 1365– 1372,  DOI: 10.1016/j.xphs.2019.12.011
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    179
    A Compact Device for the Integrated Filtration, Drying, and Mechanical Processing of Active Pharmaceutical Ingredients
    Capellades Gerard; Neurohr Clemence; Azad Mohammad; Brancazio David; Rapp Kersten; Hammersmith Gregory; Myerson Allan S
    Journal of pharmaceutical sciences (2020), 109 (3), 1365-1372 ISSN:.
    Recent changes in the pharmaceutical sector call for the development of novel manufacturing approaches to reduce costs and improve control over product quality. In this area, the development of compact, plug-and-play devices that fit in a continuous manufacturing system has gained interest in recent years. Most Nutsche filters offer a versatile solution as compact filtration and drying devices. However, conventional drying processes tend to generate a large amount of lumps, usually requiring further mechanical processing of the isolated drug substance before it can be formulated. In this work, we present a compact, automatable filtration device that takes advantage of a unique impeller design and in situ measurements of the drying heat duty to integrate mechanical processing into the drying step. By preventing the formation of dry lumps during drug substance drying, and breaking needle-like crystals through the developed agitation program, the resulting powder can be directly used for tablet formulation. This device, designed to fit in a compact continuous manufacturing module, has the potential to reduce manufacturing costs and footprint, while allowing for the low-shear mechanical processing of heat-sensitive compounds.
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    Nagy, B.; Szilágyi, B.; Domokos, A.; Tacsi, K.; Pataki, H.; Marosi, G.; Kristóf Nagy, Z.; Nagy, Z. K. Modeling of Pharmaceutical Filtration and Continuous Integrated Crystallization-Filtration Processes. Chem. Eng. J. 2020, 127566,  DOI: 10.1016/j.cej.2020.127566
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    Pernenkil, L.; Cooney, C. L. A Review on the Continuous Blending of Powders. Chem. Eng. Sci. 2006, 61 (2), 720– 742,  DOI: 10.1016/j.ces.2005.06.016
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    Berthiaux, H.; Marikh, K.; Gatumel, C. Continuous Mixing of Powder Mixtures with Pharmaceutical Process Constraints. Chem. Eng. Process. 2008, 47 (12), 2315– 2322,  DOI: 10.1016/j.cep.2008.01.009
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    Continuous mixing of powder mixtures with pharmaceutical process constraints
    Berthiaux, Henri; Marikh, Khadija; Gatumel, Cendrine
    Chemical Engineering and Processing (2008), 47 (12), 2315-2322CODEN: CENPEU; ISSN:0255-2701. (Elsevier B.V.)
    While it would provide many advantages from many aspects, the application of continuous mixing processes to the pharmaceutical field is still in its infancy. In this paper the authors report results concerning the continuous mixing of 9 ingredients (including 3 actives) that constitute a current drug. The authors examine these results in the light of different pharmaceutical process constraints, such as mixt. quality control, time-stability of this quality, sensitivity of the process to perturbations. The app. is a pilot plant Gericke GCM 500 continuous mixer with 3 loss-in-wt. feeders. A specific exptl. protocol is developed to det. the homogeneity of the mixts. at the outlet of the mixer. The homogeneity of the mixts. is examd. through industrial stds. that would allow the product to be released on the market. The steady-state operation is first reported on, and it is demonstrated that a very acceptable mixt. can be produced under certain conditions, with excellent time stability. The response of the mixer to filling sequences of 2 crit. feeders is also quantified in terms of mixt. homogeneity. It is found that it may be preferable to stop the process during these periods.
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    Williams, J. C. Continuous Mixing of Solids. A Review. Powder Technol. 1976, 15 (2), 237– 243,  DOI: 10.1016/0032-5910(76)80052-6
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    Osorio, J. G.; Vanarase, A. U.; Romañach, R. J.; Muzzio, F. J. Continuous Powder Mixing. In Pharmaceutical Blending and Mixing; John Wiley & Sons, Ltd: Chichester, UK, 2015; pp 101– 127.  DOI: 10.1002/9781118682692.ch6 .
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    Ierapetritou, M.; Muzzio, F.; Reklaitis, G. Perspectives on the Continuous Manufacturing of Powder-Based Pharmaceutical Processes. AIChE J. 2016, 62 (6), 1846– 1862,  DOI: 10.1002/aic.15210
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    Perspectives on the continuous manufacturing of powder-based pharmaceutical processes
    Ierapetritou, Marianthi; Muzzio, Fernando; Reklaitis, Gintaras
    AIChE Journal (2016), 62 (6), 1846-1862CODEN: AICEAC; ISSN:0001-1541. (John Wiley & Sons, Inc.)
    There is no expanded citation for this reference.
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    Vanarase, A. U.; Muzzio, F. J. Effect of Operating Conditions and Design Parameters in a Continuous Powder Mixer. Powder Technol. 2011, 208 (1), 26– 36,  DOI: 10.1016/j.powtec.2010.11.038
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    Effect of operating conditions and design parameters in a continuous powder mixer
    Vanarase, Aditya U.; Muzzio, Fernando J.
    Powder Technology (2011), 208 (1), 26-36CODEN: POTEBX; ISSN:0032-5910. (Elsevier B.V.)
    An exptl. investigation was carried out to study the mixing performance and flow behavior in a continuous powder mixer for a typical pharmaceutical mixt. Blender performance, characterized by the relative std. deviation (RSD) of compn. of blend samples taken at the blender discharge and by the variance redn. ratio (VRR) of the blender, was measured as a function of impeller rotation rate, flow rate and blade configuration. The flow behavior in the continuous mixer was characterized using the residence time distribution (RTD) and powder hold-up measurements. To quantify the strain applied to the powder in the blender, the no. of blade passes experienced by the powder in the blender was calcd. using the residence time measurements. The relation between different exptl. parameters and mean residence time and mean centered variance was examd. The mixing performance was largely dominated by the material properties of the mixt., which had a larger effect than the ingredient flow rate variability contributed by the feeders. Holdup was strongly dependent on impeller rotation rate; as impeller rotation rate increased, holdup (and therefore, residence time) decreased sharply. As a result, intermediate rotation rates showed the best mixing performance. Blade configuration affected performance as well; blade patterns where some of the blades push the powder backwards improved the mixing performance.
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    Osorio, J. G.; Muzzio, F. J. Effects of Processing Parameters and Blade Patterns on Continuous Pharmaceutical Powder Mixing. Chem. Eng. Process. 2016, 109, 59– 67,  DOI: 10.1016/j.cep.2016.07.012
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    187
    Effects of processing parameters and blade patterns on continuous pharmaceutical powder mixing
    Osorio, Juan G.; Muzzio, Fernando J.
    Chemical Engineering and Processing (2016), 109 (), 59-67CODEN: CENPEU; ISSN:0255-2701. (Elsevier B.V.)
    The present study summarizes the exptl. characterization of a new continuous powder mixer(GCG-70 by Glatt)using common pharmaceutical ingredients. The powder hold-up and residence time distribution were used to characterize the bulk behavior of the mixer as a function of impeller rotational speed, total throughput(mass flow rate)and blade configuration. The relative std. deviation(RSD), calcd. from samples taken at the outlet of the blender, was used to characterize its mixing performance. The hold-up and the mean residence time decreased with increasing impeller rotational speed. The mean centered variance and the no. of blade passes increased with increasing impeller rotational speed. The effect of the blade configuration on the mixing dynamics diminished as the rotation rate increased. The hold-up and mean residence time were sensitive enough to demonstrate the effects of blade configurations. The mixing performance, depending on the processing parameters, was found to be between 5% and 10% RSD for 5% wt./wt. active pharmaceutical ingredient(API), and <3% for 30% wt./wt. API. These results showed improvements in the mixing performance when compared to studies of other continuous mixers using similar materials and anal. techniques for quantification.
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  188. 188
    Burcham, C. L.; Florence, A. J.; Johnson, M. D. Continuous Manufacturing in Pharmaceutical Process Development and Manufacturing. Annu. Rev. Chem. Biomol. Eng. 2018, 9 (1), 253– 281,  DOI: 10.1146/annurev-chembioeng-060817-084355
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    188
    Continuous Manufacturing in Pharmaceutical Process Development and Manufacturing
    Burcham Christopher L; Johnson Martin D; Florence Alastair J
    Annual review of chemical and biomolecular engineering (2018), 9 (), 253-281 ISSN:.
    The pharmaceutical industry has found new applications for the use of continuous processing for the manufacture of new therapies currently in development. The transformation has been encouraged by regulatory bodies as well as driven by cost reduction, decreased development cycles, access to new chemistries not practical in batch, improved safety, flexible manufacturing platforms, and improved product quality assurance. The transformation from batch to continuous manufacturing processing is the focus of this review. The review is limited to small, chemically synthesized organic molecules and encompasses the manufacture of both active pharmaceutical ingredients (APIs) and the subsequent drug product. Continuous drug product is currently used in approved processes. A few examples of production of APIs under current good manufacturing practice conditions using continuous processing steps have been published in the past five years, but they are lagging behind continuous drug product with respect to regulatory filings.
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  189. 189
    Järvinen, M. A.; Paaso, J.; Paavola, M.; Leiviskä, K.; Juuti, M.; Muzzio, F.; Järvinen, K. Continuous Direct Tablet Compression: Effects of Impeller Rotation Rate, Total Feed Rate and Drug Content on the Tablet Properties and Drug Release. Drug Dev. Ind. Pharm. 2013, 39 (11), 1802– 1808,  DOI: 10.3109/03639045.2012.738681
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    189
    Continuous direct tablet compression: effects of impeller rotation rate, total feed rate and drug content on the tablet properties and drug release
    Jarvinen Maiju A; Paaso Janne; Paavola Marko; Leiviska Kauko; Juuti Mikko; Muzzio Fernando; Jarvinen Kristiina
    Drug development and industrial pharmacy (2013), 39 (11), 1802-8 ISSN:.
    CONTEXT: Continuous processing is becoming popular in the pharmaceutical industry for its cost and quality advantages. OBJECTIVE: This study evaluated the mechanical properties, uniformity of dosage units and drug release from the tablets prepared by continuous direct compression process. MATERIALS AND METHODS: The tablet formulations consisted of acetaminophen (3-30% (w/w)) pre-blended with 0.25% (w/w) colloidal silicon dioxide, microcrystalline cellulose (69-96% (w/w)) and magnesium stearate (1% (w/w)). The continuous tableting line consisted of three loss-in-weight feeders and a convective continuous mixer and a rotary tablet press. The process continued for 8 min and steady state was reached within 5 min. The effects of acetaminophen content, impeller rotation rate (39-254 rpm) and total feed rate (15 and 20 kg/h) on tablet properties were examined. RESULTS AND DISCUSSION: All the tablets complied with the friability requirements of European Pharmacopoeia and rapidly released acetaminophen. However, the relative standard deviation of acetaminophen content (10% (w/w)) increased with an increase in impeller rotation rate at a constant total feed rate (20 kg/h). A compression force of 12 kN tended to result in greater tablet hardness and subsequently a slower initial acetaminophen release from tablets when compared with those made with the compression force of about 8 kN. CONCLUSIONS: In conclusion, tablets could be successfully prepared by a continuous direct compression process and process conditions affected to some extent tablet properties.
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  190. 190
    Wagner, B.; Brinz, T.; Otterbach, S.; Khinast, J. Rapid Automated Process Development of a Continuous Capsule-Filling Process. Int. J. Pharm. 2018, 546 (1–2), 154– 165,  DOI: 10.1016/j.ijpharm.2018.05.009
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    190
    Rapid automated process development of a continuous capsule-filling process
    Wagner, Bernhard; Brinz, Thomas; Otterbach, Stephanie; Khinast, Johannes
    International Journal of Pharmaceutics (Amsterdam, Netherlands) (2018), 546 (1-2), 154-165CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
    This paper introduces a rapid automated process-development approach for a continuous capsule-filling process. In our proposed method, both the material attributes and the crit. process parameters were varied to understand and to optimize the overall process. Using our approach a statistical process model can be generated with unprecedented speed (2 days), which is the prerequisite for effectively developing and operating continuous process platforms. In a first set of expts. a process model was developed using different mixt. compns. of ascorbic acid, lactose and magnesium stearate while changing simultaneously the crit. process parameters of the capsule filler (speed, pressure, immersion depth and powder bed height). Targets of the model were the mean fill wt. and the relative std. deviation of the produced capsules. In a second exptl. set the model was tested, i.e., the goal was to predict the behavior of the system at different set points in order to predict wt. and relative std. deviation for predefined targets. Predictions were very good, thus validating our approach. The combination of the rapid automated process development approach and the continuous capsule-filling process resulted in a new strategy for the development and manuf. of pharmaceutical dosage forms.
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    Chattoraj, S.; Sun, C. C. Crystal and Particle Engineering Strategies for Improving Powder Compression and Flow Properties to Enable Continuous Tablet Manufacturing by Direct Compression. J. Pharm. Sci. 2018, 107 (4), 968– 974,  DOI: 10.1016/j.xphs.2017.11.023
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    191
    Crystal and Particle Engineering Strategies for Improving Powder Compression and Flow Properties to Enable Continuous Tablet Manufacturing by Direct Compression
    Chattoraj, Sayantan; Sun, Changquan Calvin
    Journal of Pharmaceutical Sciences (Philadelphia, PA, United States) (2018), 107 (4), 968-974CODEN: JPMSAE; ISSN:0022-3549. (Elsevier Inc.)
    Continuous manufg. of tablets has many advantages, including batch size flexibility, demand-adaptive scale up or scale down, consistent product quality, small operational foot print, and increased manufg. efficiency. Simplicity makes direct compression the most suitable process for continuous tablet manufg. However, deficiencies in powder flow and compression of active pharmaceutical ingredients (APIs) limit the range of drug loading that can routinely be considered for direct compression. For the widespread adoption of continuous direct compression, effective API engineering strategies to address power flow and compression problems are needed. Appropriate implementation of these strategies would facilitate the design of high-quality robust drug products, as stipulated by the Quality-by-Design framework. Here, several crystal and particle engineering strategies for improving powder flow and compression properties are summarized. The focus is on the underlying materials science, which is the foundation for effective API engineering to enable successful continuous manufg. by the direct compression process.
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  192. 192
    Ervasti, T.; Simonaho, S.-P.; Ketolainen, J.; Forsberg, P.; Fransson, M.; Wikström, H.; Folestad, S.; Lakio, S.; Tajarobi, P.; Abrahmsén-Alami, S. Continuous Manufacturing of Extended Release Tablets via Powder Mixing and Direct Compression. Int. J. Pharm. 2015, 495 (1), 290– 301,  DOI: 10.1016/j.ijpharm.2015.08.077
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    192
    Continuous manufacturing of extended release tablets via powder mixing and direct compression
    Ervasti, Tuomas; Simonaho, Simo-Pekka; Ketolainen, Jarkko; Forsberg, Peter; Fransson, Magnus; Wikstrom, Hakan; Folestad, Staffan; Lakio, Satu; Tajarobi, Pirjo; Abrahmsen-Alami, Susanna
    International Journal of Pharmaceutics (Amsterdam, Netherlands) (2015), 495 (1), 290-301CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
    The aim of the current work was to explore continuous dry powder mixing and direct compression for manufg. of extended release (ER) matrix tablets. The study was span out with a challenging formulation design comprising ibuprofen compns. with varying particle size and a relatively low amt. of the matrix former hydroxypropyl methylcellulose (HPMC). Std. grade HPMC (CR) was compared to a recently developed direct compressible grade (DC2). The work demonstrate that ER tablets with desired quality attributes could be manufd. via integrated continuous mixing and direct compression. The most robust tablet quality (wt., assay, tensile strength) was obtained using high mixer speed and large particle size ibuprofen and HPMC DC2 due to good powder flow. At low mixer speed it was more difficult to achieve high quality low dose tablets. Notably, with HPMC DC2 the processing conditions had a significant effect on drug release. Longer processing time and/or faster mixer speed was needed to achieve robust release with compns. contg. DC2 compared with those contg. CR. This work confirms the importance of balancing process parameters and material properties to find consistent product quality. Also, adaptive control is proven a pivotal means for control of continuous manufg. systems.
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  193. 193
    Simonaho, S.-P.; Ketolainen, J.; Ervasti, T.; Toiviainen, M.; Korhonen, O. Continuous Manufacturing of Tablets with PROMIS-Line — Introduction and Case Studies from Continuous Feeding, Blending and Tableting. Eur. J. Pharm. Sci. 2016, 90, 38– 46,  DOI: 10.1016/j.ejps.2016.02.006
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    Continuous manufacturing of tablets with PROMIS-line - Introduction and case studies from continuous feeding, blending and tableting
    Simonaho, Simo-Pekka; Ketolainen, Jarkko; Ervasti, Tuomas; Toiviainen, Maunu; Korhonen, Ossi
    European Journal of Pharmaceutical Sciences (2016), 90 (), 38-46CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)
    Drug manufg. technol. is in the midst of modernization and continuous manufg. of drug products is esp. the focus of great interest. The adoption of new manufg. approaches requires extensive cooperation between industry, regulatory bodies, academics and equipment manufacturers. In this paper we introduce PROMIS-line which is a continuous tableting line built at the University of Eastern Finland, School of Pharmacy, PROMIS-center. PROMIS-line is modular and tablets can be produced via dry granulation or direct compression. In three case studies, continuous feeding, blending and tablet performance is studied to illustrate some basic features of PROMIS-line. In conclusion, the PROMIS-line is an excellent tool for studying the fundamentals of continuous manufg. of tablets.
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    Van Snick, B.; Holman, J.; Cunningham, C.; Kumar, A.; Vercruysse, J.; De Beer, T.; Remon, J. P.; Vervaet, C. Continuous Direct Compression as Manufacturing Platform for Sustained Release Tablets. Int. J. Pharm. 2017, 519 (1–2), 390– 407,  DOI: 10.1016/j.ijpharm.2017.01.010
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    194
    Continuous direct compression as manufacturing platform for sustained release tablets
    Van Snick, B.; Holman, J.; Cunningham, C.; Kumar, A.; Vercruysse, J.; De Beer, T.; Remon, J. P.; Vervaet, C.
    International Journal of Pharmaceutics (Amsterdam, Netherlands) (2017), 519 (1-2), 390-407CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
    This study presents a framework for process and product development on a continuous direct compression manufg. platform. A challenging sustained release formulation with high content of a poorly flowing low d. drug was selected. Two HPMC grades were evaluated as matrix former: std. Methocel CR and directly compressible Methocel DC2. The feeding behavior of each formulation component was investigated by deriving feed factor profiles. The max. feed factor was used to est. the drive command and depended strongly upon the d. of the material. Furthermore, the shape of the feed factor profile allowed definition of a customized refill regime for each material. Inline NIRs was used to est. the residence time distribution (RTD) in the mixer and monitor blend uniformity. Tablet content and wt. variability were detd. as addnl. measures of mixing performance. For Methocel CR, the best axial mixing (i.e. feeder fluctuation dampening) was achieved when an impeller with high no. of radial mixing blades operated at low speed. However, the variability in tablet wt. and content uniformity deteriorated under this condition. One can therefore conclude that balancing axial mixing with tablet quality is crit. for Methocel CR. However, reformulating with the direct compressible Methocel DC2 as matrix former improved tablet quality vastly. Furthermore, both process and product were significantly more robust to changes in process and design variables. This observation underpins the importance of flowability during continuous blending and die-filling. At the compaction stage, blends with Methocel CR showed better tabletability driven by a higher compressibility as the smaller CR particles have a higher bonding area. However, tablets of similar strength were achieved using Methocel DC2 by targeting equal porosity. Compaction pressure impacted tablet properties and dissoln. Hence controlling thickness during continuous manufg. of sustained release tablets was crucial to ensure reproducible dissoln.
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    Azad, M. A.; Osorio, J. G.; Brancazio, D.; Hammersmith, G.; Klee, D. M.; Rapp, K.; Myerson, A. A Compact, Portable, Re-Configurable, and Automated System for on-Demand Pharmaceutical Tablet Manufacturing. Int. J. Pharm. 2018, 539 (1–2), 157– 164,  DOI: 10.1016/j.ijpharm.2018.01.027
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    A compact, portable, re-configurable, and automated system for on-demand pharmaceutical tablet manufacturing
    Azad, Mohammad A.; Osorio, Juan G.; Brancazio, David; Hammersmith, Gregory; Klee, David M.; Rapp, Kersten; Myerson, Allan
    International Journal of Pharmaceutics (Amsterdam, Netherlands) (2018), 539 (1-2), 157-164CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
    Due to the complex nature of the pharmaceutical supply chain, the industry faces several major challenges when it comes to ensuring an adequate supply of quality drug products. These challenges are not only the causes of supply chain disruptions and financial loss, but can also prevent underserved and remote areas from receiving life-saving drugs. As a preliminary demonstration to mitigate all these challenges, at MIT we have developed active pharmaceutical ingredients manufg. in a miniature platform. However, manufg. of final oral solid dosage as tablets from drug substances had not been demonstrated. In this study, a compact, portable, re-configurable, and automated tablet manufg. system, roughly the size of a North American household oven, [72.4 cm (length) × 53.3 cm (width) × 134.6 cm (height)] was designed, built and demonstrated. This miniature system is able to manuf. on-demand tablets from drug crystals on a scale of hundreds to thousands per day. Ibuprofen and Diazepam, each having different drug loading, were manufd. using this miniature system and meet U. S. Pharmacopeia stds. We foresee this flexible, miniature, plug-and-play pharmaceutical solids dosage manufg. system advancing on-demand ready-to-use pharmaceuticals enabling future treatment of human diseases at the point-of-care.
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  196. 196
    Azad, M. A.; Osorio, J. G.; Wang, A.; Klee, D. M.; Eccles, M. E.; Grela, E.; Sloan, R.; Hammersmith, G.; Rapp, K.; Brancazio, D.; Myerson, A. S. On-Demand Manufacturing of Direct Compressible Tablets: Can Formulation Be Simplified?. Pharm. Res. 2019, 36 (12), 167,  DOI: 10.1007/s11095-019-2716-2
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    196
    On-Demand Manufacturing of Direct Compressible Tablets: Can Formulation Be Simplified?
    Azad Mohammad A; Osorio Juan G; Wang Allison; Klee David M; Eccles Mary E; Grela Erin; Sloan Rebecca; Hammersmith Gregory; Rapp Kersten; Brancazio David; Myerson Allan S; Azad Mohammad A; Osorio Juan G; Hammersmith Gregory
    Pharmaceutical research (2019), 36 (12), 167 ISSN:.
    PURPOSE: Oral direct compressible tablets are the most frequently used drug products. Manufacturing of tablets requires design and development of formulations, which need a number of excipients. The choice of excipients depends on the concentration, manufacturability, stability, and bioavailability of the active pharmaceutical ingredients (APIs). At MIT, we developed a miniature platform for on-demand manufacturing of direct compressible tablets. This study investigated how formulations could be simplified to use a small number of excipients for a number of different API's in which long term stability is not required. METHOD: Direct compressible tablets of five pharmaceutical drugs, Diazepam, Diphenhydramine HCl, Doxycycline Monohydrate, Ibuprofen, and Ciprofloxacin HCl, with different drug loadings, were made using direct compression in an automated small scale system.. The critical quality attributes (CQA) of the tablets were assessed for the quality standards set by the United States Pharmacopeia (USP). RESULTS: This miniature system can manufacture tablets - on-demand from crystalline API using the minimum number of excipients required for drug product performance. All drug tablets met USP quality standards after manufacturing and after 2 weeks of accelerated stability test, except for slightly lower drug release for Ibuprofen. CONCLUSIONS: On-demand tablets manufacturing where there is no need for long term stability using a flexible, miniature, automated (integrated) system will simplify pharmaceutical formulation design compared to traditional formulations. This advancement will offer substantial economic benefits by decreasing product time-to-market and enhancing quality.
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  197. 197
    Asachi, M.; Nourafkan, E.; Hassanpour, A. A Review of Current Techniques for the Evaluation of Powder Mixing. Adv. Powder Technol. 2018, 29 (7), 1525– 1549,  DOI: 10.1016/j.apt.2018.03.031
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    197
    A review of current techniques for the evaluation of powder mixing
    Asachi, Maryam; Nourafkan, Ehsan; Hassanpour, Ali
    Advanced Powder Technology (2018), 29 (7), 1525-1549CODEN: APTEEE; ISSN:0921-8831. (Elsevier B.V.)
    Blending a mixt. of powders to a homogeneous system is a crucial step in many manufg. processes. To achieve a high quality of the end product, powder mixts. should be made with high content uniformity. For instance, producing uniform tablets depends on the homogeneous dispersion of active pharmaceutical ingredient (API), often in low level quantities, into excipients. To control the uniformity of a powder mixt., the first required step is to est. the powder content information during blending. There are several powder homogeneity evaluation techniques which differ in accuracy, fundamental basis, cost and operating conditions. In this article, emerging techniques for the anal. of powder content and powder blend uniformity, are explained and compared. The advantages and drawbacks of all the techniques are reviewed to help the readers to select the appropriate equipment for the powder mixing evaluation. In addn., the paper highlights the recent innovative online measurement techniques used for the non-invasive evaluation of the mixing performance.
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    Nagy, B.; Farkas, A.; Borbás, E.; Vass, P.; Nagy, Z. K.; Marosi, G. Raman Spectroscopy for Process Analytical Technologies of Pharmaceutical Secondary Manufacturing. AAPS PharmSciTech 2019, 20 (1), 1,  DOI: 10.1208/s12249-018-1201-2
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    Raman Spectroscopy for Process Analytical Technologies of Pharmaceutical Secondary Manufacturing
    Nagy, Brigitta; Farkas, Attila; Borbas, Eniko; Vass, Panna; Nagy, Zsombor Kristof; Marosi, Gyorgy
    AAPS PharmSciTech (2019), 20 (1), 1-16CODEN: AAPHFZ; ISSN:1530-9932. (Springer)
    As the process anal. technol. (PAT) mindset is progressively introduced and adopted by the pharmaceutical companies, there is an increasing demand for effective and versatile real-time analyzers to address the quality assurance challenges of drug manufg. In the last decades, Raman spectroscopy has emerged as one of the most promising tools for non-destructive and fast characterization of the pharmaceutical processes. This review summarizes the achieved results of the real-time application of Raman spectroscopy in the field of the secondary manufg. of pharmaceutical solid dosage forms, covering the most common secondary process steps of a tablet prodn. line. In addn., the feasibility of Raman spectroscopy for real-time control is critically reviewed, and challenges and possible approaches to moving from real-time monitoring to process anal. controlled technologies (PACT) are discussed.
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    Bowler, A. L.; Bakalis, S.; Watson, N. J. A Review of In-Line and on-Line Measurement Techniques to Monitor Industrial Mixing Processes. Chem. Eng. Res. Des. 2020, 153, 463– 495,  DOI: 10.1016/j.cherd.2019.10.045
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    A review of in-line and on-line measurement techniques to monitor industrial mixing processes
    Bowler, Alexander Lewis; Bakalis, Serafim; Watson, Nicholas James
    Chemical Engineering Research and Design (2020), 153 (), 463-495CODEN: CERDEE; ISSN:1744-3563. (Elsevier B.V.)
    Mixing is a ubiquitous operation in process engineering. It is not only used for combining materials, but also for promoting heat and mass transfer, increasing aeration, suspending solids, and modifying material structure. Measurement techniques have the potential to optimize industrial mixing processes and improve product quality by monitoring crit. process parameters. Real-time sensing techniques that do not require manual material sampling are of particular interest owing to their automatic data acquisition capability. This makes them suitable for use in control systems for process automation and eventually as connected sensors in Industry 4.0. This review article focuses on these measurement techniques, defined as in- and online, along with their capability for implementation in industrial processes. The applications reviewed include liq.-liq., gas-liq., solid-liq., solid-gas-liq., in addn. to solids blending. A technique selection section discussing the decision-making process when choosing a sensor and a summary table including the advantages, disadvantages, applications and limitations of each technique are provided. The article concludes by discussing the future of monitoring techniques for mixing processes.
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    Crouter, A.; Briens, L. Methods to Assess Mixing of Pharmaceutical Powders. AAPS PharmSciTech 2019, 20 (2), 84,  DOI: 10.1208/s12249-018-1286-7
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    200
    Methods to Assess Mixing of Pharmaceutical Powders
    Crouter, Allison; Briens, Lauren
    AAPS PharmSciTech (2019), 20 (2), 84CODEN: AAPHFZ; ISSN:1530-9932. (Springer)
    The pharmaceutical manufg. process consists of several steps, each of which must be monitored and controlled to ensure quality stds. are met. The level of blending has an impact on the final product quality; therefore, it is important to be able to monitor blending progress and identify an end-point. Currently, the pharmaceutical industry assesses blend content and uniformity through the extn. of samples using thief probes followed by anal. methods, such as spectroscopy, to det. the sample compn. The development of process anal. technologies (PAT) can improve product monitoring with the aim of increasing efficiency, product quality and consistency, and creating a better understanding of the manufg. process. Ideally, these are inline methods to remove issues related to extractive sampling and allow direct monitoring of the system using various sensors. Many technologies have been investigated, including spectroscopic techniques such as near-IR spectroscopy, velocimetric techniques that may use tracers, tomog. techniques, and acoustic emissions monitoring. While some techniques have demonstrated potential, many have significant disadvantages including the need for equipment modification, specific requirements of the material, expensive equipment, extensive anal., the location of the probes may be crit. and/or invasive, and lastly, the technique may only be applicable to the development phase. Both the advantages and disadvantages of the technologies should be considered in application to a specific system.
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  201. 201
    Nagy, B.; Farkas, A.; Gyürkés, M.; Komaromy-Hiller, S.; Démuth, B.; Szabó, B.; Nusser, D.; Borbás, E.; Marosi, G.; Nagy, Z. K. In-Line Raman Spectroscopic Monitoring and Feedback Control of a Continuous Twin-Screw Pharmaceutical Powder Blending and Tableting Process. Int. J. Pharm. 2017, 530 (1–2), 21– 29,  DOI: 10.1016/j.ijpharm.2017.07.041
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    In-line Raman spectroscopic monitoring and feedback control of a continuous twin-screw pharmaceutical powder blending and tableting process
    Nagy, Brigitta; Farkas, Attila; Gyurkes, Martin; Komaromy-Hiller, Szofia; Demuth, Balazs; Szabo, Bence; Nusser, David; Borbas, Eniko; Marosi, Gyorgy; Nagy, Zsombor Kristof
    International Journal of Pharmaceutics (Amsterdam, Netherlands) (2017), 530 (1-2), 21-29CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
    The integration of Process Anal. Technol. (PAT) initiative into the continuous prodn. of pharmaceuticals is indispensable for reliable prodn. The present paper reports the implementation of in-line Raman spectroscopy in a continuous blending and tableting process of a three-component model pharmaceutical system, contg. caffeine as model active pharmaceutical ingredient (API), glucose as model excipient and magnesium stearate as lubricant. The real-time anal. of API content, blend homogeneity, and tablet content uniformity was performed using a Partial Least Squares (PLS) quant. method. The in-line Raman spectroscopic monitoring showed that the continuous blender was capable of producing blends with high homogeneity, and technol. malfunctions can be detected by the proposed PAT method. The Raman spectroscopy-based feedback control of the API feeder was also established, creating a 'Process Anal. Controlled Technol.' (PACT), which guarantees the required API content in the produced blend. This is, to the best of the authors' knowledge, the first ever application of Raman-spectroscopy in continuous blending and the first Raman-based feedback control in the formulation technol. of solid pharmaceuticals.
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  202. 202
    Palmer, J.; Reynolds, G. K.; Tahir, F.; Yadav, I. K.; Meehan, E.; Holman, J.; Bajwa, G. Mapping Key Process Parameters to the Performance of a Continuous Dry Powder Blender in a Continuous Direct Compression System. Powder Technol. 2020, 362, 659– 670,  DOI: 10.1016/j.powtec.2019.12.028
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    Mapping key process parameters to the performance of a continuous dry powder blender in a continuous direct compression system
    Palmer, John; Reynolds, Gavin K.; Tahir, Furqan; Yadav, Indrajeetsinh K.; Meehan, Elizabeth; Holman, James; Bajwa, Gurjit
    Powder Technology (2020), 362 (), 659-670CODEN: POTEBX; ISSN:0032-5910. (Elsevier B.V.)
    This work aims to expand the typical raw material attributes that can successfully be processed on a continuous direct compression line with a particular focus on the continuous dry powder blender. Three grades of Acetaminophen were investigated as model active pharmaceutical ingredients and chosen to span a broad range of material attributes wider than what would normally be considered for a direct compression process. An exptl. design was set-up for each grade of Acetaminophen to investigate the effect of throughput, impeller speed and impeller configuration on the crit. process responses and attributes. The strain experienced by the in-process material was found crit. to improve content uniformity. The impeller speed and design can be optimized at a given throughput to obtain a strain which would deliver the required content homogeneity. The content uniformity of the final tablets can be modelled as a function of the strain using an exponential decay model.
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    Fonteyne, M.; Vercruysse, J.; De Leersnyder, F.; Van Snick, B.; Vervaet, C.; Remon, J. P.; De Beer, T. Process Analytical Technology for Continuous Manufacturing of Solid-Dosage Forms. TrAC, Trends Anal. Chem. 2015, 67, 159– 166,  DOI: 10.1016/j.trac.2015.01.011
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    Process Analytical Technology for continuous manufacturing of solid-dosage forms
    Fonteyne, Margot; Vercruysse, Jurgen; De Leersnyder, Fien; Van Snick, Bernd; Vervaet, Chris; Remon, Jean Paul; De Beer, Thomas
    TrAC, Trends in Analytical Chemistry (2015), 67 (), 159-166CODEN: TTAEDJ; ISSN:0165-9936. (Elsevier B. V.)
    A review. Currently, pharmaceutical prodn. is making the switch from batch processing towards continuous processing. The quality of intermediate and end products produced by batch processes is assured by off-line testing. It is obvious that off-line tests in anal. labs. cancel out the advantages of continuous processing, so the crit. quality attributes of continuously produced pharmaceuticals need to be monitored in real time. In 2004, the US Food and Drug Administration launched the process anal. technol. (PAT) concept to stimulate the pharmaceutical industry to change from off-line to real-time quality testing. This review explores the implementation of PAT tools within continuous pharmaceutical processes (i.e., blending, spray drying, roller compaction, twin-screw granulation and compression), focusing on both opportunities and challenges.
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    Fonteyne, M.; Vercruysse, J.; De Leersnyder, F.; Besseling, R.; Gerich, A.; Oostra, W.; Remon, J. P.; Vervaet, C.; De Beer, T. Blend Uniformity Evaluation during Continuous Mixing in a Twin Screw Granulator by In-Line NIR Using a Moving F-Test. Anal. Chim. Acta 2016, 935, 213– 223,  DOI: 10.1016/j.aca.2016.07.020
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    Blend uniformity evaluation during continuous mixing in a twin screw granulator by in-line NIR using a moving F-test
    Fonteyne, Margot; Vercruysse, Jurgen; De Leersnyder, Fien; Besseling, Rut; Gerich, Ad; Oostra, Wim; Remon, Jean Paul; Vervaet, Chris; De Beer, Thomas
    Analytica Chimica Acta (2016), 935 (), 213-223CODEN: ACACAM; ISSN:0003-2670. (Elsevier B.V.)
    This study focuses on the twin screw granulator of a continuous from-powder-to-tablet prodn. line. Whereas powder dosing into the granulation unit is possible from a container of preblended material, a truly continuous process uses several feeders (each one dosing an individual ingredient) and relies on a continuous blending step prior to granulation. The aim of the current study was to investigate the in-line blending capacity of this twin screw granulator, equipped with conveying elements only. The feasibility of in-line NIR (SentroPAT, Sentronic GmbH, Dresden, Germany) spectroscopy for evaluating the blend uniformity of powders after the granulator was tested. Anhyd. theophylline was used as a tracer mol. and was blended with lactose monohydrate. Theophylline and lactose were both fed from a different feeder into the twin screw granulator barrel. Both homogeneous mixts. and mixing expts. with induced errors were investigated. The in-line spectroscopic analyses showed that the twin screw granulator is a useful tool for in-line blending in different conditions. The blend homogeneity was evaluated by means of a novel statistical method being the moving F-test method in which the variance between two blocks of collected NIR spectra is evaluated. The α- and β-error of the moving F-test are controlled by using the appropriate block size of spectra. The moving F-test method showed to be an appropriate calibration and maintenance free method for blend homogeneity evaluation during continuous mixing.
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    Vanarase, A. U.; Alcalà, M.; Jerez Rozo, J. I.; Muzzio, F. J.; Romañach, R. J. Real-Time Monitoring of Drug Concentration in a Continuous Powder Mixing Process Using NIR Spectroscopy. Chem. Eng. Sci. 2010, 65 (21), 5728– 5733,  DOI: 10.1016/j.ces.2010.01.036
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    Real-time monitoring of drug concentration in a continuous powder mixing process using NIR spectroscopy
    Vanarase, Aditya U.; Alcala, Manel; Jerez Rozo, Jackeline I.; Muzzio, Fernando J.; Romanach, Rodolfo J.
    Chemical Engineering Science (2010), 65 (21), 5728-5733CODEN: CESCAC; ISSN:0009-2509. (Elsevier Ltd.)
    A non-destructive NIR spectroscopic method was used to acquire online spectra of a continuous mixing process, and evaluate the performance of this novel system. Partial least squares (PLS) calibration models were developed and used for real-time detn. of active ingredient concn. on the blends produced with a continuous mixer. The NIR method was developed for concns. ranging from 0 to 15% (wt./wt.) of acetaminophen (APAP), the active pharmaceutical ingredient used in the expts. The calibration model's overall accuracy was 0.41% (wt./wt.), and estd. through the root mean square error of cross validation (RMSECV) for samples predicted using leave-class-out cross validation. In this cross validation, each concn. was defined as a class, and when a sample of a specific concn. was predicted all samples of that concn. were left out of the calibration model. The precision of the calibration model was also estd. at various concn. levels, to facilitate the differentiation between the variation in drug concn. due to the anal. method's measurement uncertainty and the variation in the drug distribution throughout the powder blend. The results obtained are very promising since in 3 of the 5 powder mixes, the variation in the drug concn. in the powder blends was similar to that of the anal. method indicating a high degree of blend homogeneity.
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    Sierra-Vega, N. O.; Román-Ospino, A.; Scicolone, J.; Muzzio, F. J.; Romañach, R. J.; Méndez, R. Assessment of Blend Uniformity in a Continuous Tablet Manufacturing Process. Int. J. Pharm. 2019, 560, 322– 333,  DOI: 10.1016/j.ijpharm.2019.01.073
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    206
    Assessment of blend uniformity in a continuous tablet manufacturing process
    Sierra-Vega, Nobel O.; Roman-Ospino, Andres; Scicolone, James; Muzzio, Fernando J.; Romanach, Rodolfo J.; Mendez, Rafael
    International Journal of Pharmaceutics (Amsterdam, Netherlands) (2019), 560 (), 322-333CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
    Blend uniformity was monitored throughout a continuous manufg. (CM) process by near IR (NIR) spectroscopic measurements of flowing blends and compared to the drug concn. in the tablets. The NIR spectra were obtained through the chute after the blender and within the feed frame, while transmission spectra were obtained for the tablets. The CM process was performed with semi-fine acetaminophen blends at 10.0% (wt./wt.). The blender was operated at 250 RPM, for best performance, and 106 and 495 rpm where a lower mixing efficiency was expected. The variation in blender RPM increased the variation in drug concn. at the chute but not at the feed frame. Statistical results show that the drug concn. of tablets can be predicted, with great accuracy, from blends within the feed frame. This study demonstrated a mixing effect within the feed frame, which contribute to a 60% decrease in the relative std. deviation of the drug concn., when compared to the chute. Variog. anal. showed that the min. sampling and anal. error was five times less in the feed frame than the chute. This study demonstrates that the feed frame is an ideal location for monitoring the drug concn. of powder blends for CM processes.
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    Van Snick, B.; Holman, J.; Vanhoorne, V.; Kumar, A.; De Beer, T.; Remon, J. P.; Vervaet, C. Development of a Continuous Direct Compression Platform for Low-Dose Drug Products. Int. J. Pharm. 2017, 529 (1–2), 329– 346,  DOI: 10.1016/j.ijpharm.2017.07.003
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    Development of a continuous direct compression platform for low-dose drug products
    Van Snick, B.; Holman, J.; Vanhoorne, V.; Kumar, A.; De Beer, T.; Remon, J. P.; Vervaet, C.
    International Journal of Pharmaceutics (Amsterdam, Netherlands) (2017), 529 (1-2), 329-346CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
    In this work a continuous direct compression process was developed for a low-dosed drug product. Each unit operation of the GEA CDC-50 system was thoroughly investigated. This paper aimed to tackle the macroscopic and microscopic blend uniformity challenges inherently assocd. with continuous direct compression of cohesive and agglomerated APIs formulated at low dose. D., compressibility and flow were identified as key material properties at the feeding stage. The screw speed coupled with powder flow regulated the gravimetric feeding performance. The impact of process and design variables was elucidated at the blending stage. The impeller configuration (no. and pattern of radial mixing blades) and speed were key variables to steer the residence time distribution at the blending stage. An impeller configuration with distributed radial mixing blades could sufficiently filter the steady state feeding variability at low mixer speed, but exerted limited strain and shear on the blend. Hence micro-agglomerates persisted through the blending process and occasionally resulted in super potent tablets. Therefore, a new configuration was evaluated with more radial mixing blades centered on the impeller. This configuration resulted in a long mixing time at high tip speed which induced a maximized strain and shear. Consequently, excellent uniformity of the blend and tablets at macroscopic and microscopic level was achieved. Besides, this impeller improved robustness towards feeding disturbances, changes in process settings and variable blend properties. Next, it was demonstrated that the lubrication step requires crit. attention during the design of the equipment, formulation and process. This study provided abundant evidence that an optimized continuous direct compression process allows direct compression of challenging low-dose drug products.
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    Grymonpré, W.; Blahova Prudilova, B.; Vanhoorne, V.; Van Snick, B.; Detobel, F.; Remon, J. P.; De Beer, T.; Vervaet, C. Downscaling of the Tableting Process: Feasibility of Miniaturized Forced Feeders on a High-Speed Rotary Tablet Press. Int. J. Pharm. 2018, 550 (1–2), 477– 485,  DOI: 10.1016/j.ijpharm.2018.09.006
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    Downscaling of the tableting process: Feasibility of miniaturized forced feeders on a high-speed rotary tablet press
    Grymonpre, W.; Blahova Prudilova, B.; Vanhoorne, V.; Van Snick, B.; Detobel, F.; Remon, J. P.; De Beer, T.; Vervaet, C.
    International Journal of Pharmaceutics (Amsterdam, Netherlands) (2018), 550 (1-2), 477-485CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
    With the current transformation of the pharmaceutical industry towards continuous manufg., there is an inherent need to embrace this concept already during the early stages of drug formulation. Therefore, this research paper investigated the feasibility of using miniaturized forced feeders on a high-speed rotary tablet press with the intention of downscaling the tableting process. Forced feeders with a reduced vol. (up to 46% compared to the conventional two-compartment forced feeder) were designed by either sealing one compartment (i.e. R&D1) or lowering of the compartment height (i.e. R&D2). These feed frame designs were thoroughly analyzed in combination with two paddle types over a wide range of process-settings (i.e. tableting speed, paddle speed, direction of paddle rotation, overfill-level). A poorly flowing model powder (i.e. MCC 101) was deliberately selected as challenging formulation. Empirical modeling of feed frame R&D1 revealed a pos. impact on the die-filling variability when the radial curved cuboid paddles rotated in counterclockwise direction at high paddle speed. Moreover, a strong resemblance between the R&D2 feed frame and the conventional forced feeder was obsd. during multivariate data anal., indicating that this miniaturized type could be used during downscaling studies of the conventional tableting process. The potential of this forced feeder was acknowledged by the similar trends in die-filling variability with respect to varying process settings, when a design-of-expts. (DOE) was performing including feed frame type as a qual. factor. Overall, it was concluded that both types of miniaturized forced feeders can be used on a high-speed rotary tablet press when lower material consumption rates are desired while the R&D2 feed frame bears the highest predictability regarding the die-filling uniformity in the conventional larger two-compartment forced feeder.
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  209. 209
    Matsunami, K.; Nagato, T.; Hasegawa, K.; Sugiyama, H. A Large-Scale Experimental Comparison of Batch and Continuous Technologies in Pharmaceutical Tablet Manufacturing Using Ethenzamide. Int. J. Pharm. 2019, 559, 210– 219,  DOI: 10.1016/j.ijpharm.2019.01.028
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    209
    A large-scale experimental comparison of batch and continuous technologies in pharmaceutical tablet manufacturing using ethenzamide
    Matsunami, Kensaku; Nagato, Takuya; Hasegawa, Koji; Sugiyama, Hirokazu
    International Journal of Pharmaceutics (Amsterdam, Netherlands) (2019), 559 (), 210-219CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
    This paper compares batch and continuous technologies in terms of product quality and process performance in pharmaceutical tablet manufg. using ethenzamide as the active pharmaceutical ingredient. Batch and continuous processes using wet granulation were investigated by performing expts. on the scale of 5 and up to 100 kg/lot, using the same raw materials. Three technologies were tested and compared: (i) batch technol. using fluidized bed granulation, (ii) batch technol. using high shear granulation, (iii) continuous technol. using high shear granulation. In the full-scale expt., in all three technologies including continuous technol., the quality of the tablets fulfilled the target values regarding hardness, active pharmaceutical ingredient content, and dissoln. The granules produced by different technologies, however, presented varying attributes regarding granule size distribution, loose bulk d., or scanning electron microscope images. The process performance, more specifically the yield, was slightly better for batch technologies than for the continuous technol., mainly due to losses in the start-up operation. Notably, this study has shown that continuous technol., which is generally believed to not entail scale-up procedures, could in fact, require parameter adjustment for prolonged operation. The results provided suggestions for improvements to implement large-scale continuous technologies in the pharmaceutical industry.
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  210. 210
    Järvinen, K.; Hoehe, W.; Järvinen, M.; Poutiainen, S.; Juuti, M.; Borchert, S. In-Line Monitoring of the Drug Content of Powder Mixtures and Tablets by near-Infrared Spectroscopy during the Continuous Direct Compression Tableting Process. Eur. J. Pharm. Sci. 2013, 48 (4–5), 680– 688,  DOI: 10.1016/j.ejps.2012.12.032
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    210
    In-line monitoring of the drug content of powder mixtures and tablets by near-infrared spectroscopy during the continuous direct compression tableting process
    Jarvinen, Kristiina; Hoehe, Wolfgang; Jarvinen, Maiju; Poutiainen, Sami; Juuti, Mikko; Borchert, Sven
    European Journal of Pharmaceutical Sciences (2013), 48 (4-5), 680-688CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)
    Continuous manufg. methods offer economic and quality advantages when compared with batch manufg. methods. In continuous manufg., one requires real time assurance of quality of product via the implementation of PAT tools. This study focuses on an in-line near-IR (NIR) spectroscopic method for detg. the drug content of powder mixts. and tablets during a continuous tableting process. Tablets consisting of acetaminophen (20-30%), lactose (69.07-78.93%) and magnesium stearate (0.93-1.07%) were prepd. in a continuous direct compression line that consisted of 2 loss-in-wt. feeders, one for acetaminophen and one for premixed lactose and magnesium stearate, and a continuous mixer followed by a rotary tablet press. NIR spectroscopy was applied to the continuous mixer and tablet press to perform a 100% product check at full tableting speed. The UV-spectrophotometric method was used as an off-line ref. method to det. the acetaminophen content in the samples. The powder mixt. and tablet samples were taken during the process for the calibration of continuous mixer and tablet press, resp. For the continuous mixer, model creation with the PLS method yielded R-Square and RMSEC (root mean square error of calibration) values of 0.975% and 0.56%, resp. For the tablet press, the corresponding R-Square and RMSEC values were 0.943% and 0.75%, resp. A test run demonstrated good predictability in the estn. of the API content in the powder mixts. and tablets during the continuous tableting process. For the continuous mixer and tablet press, the RMSEP (root mean square error of prediction) values were 0.96% and 1.37%, resp. This study demonstrates that an NIR instrument capable of fast spectra acquisition can be a valuable tool for the in-line monitoring of the continuous mixing and tableting processes.
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  211. 211
    Nagy, Z. K.; Balogh, A.; Vajna, B.; Farkas, A.; Patyi, G.; Kramarics, Á.; Marosi, G. Comparison of Electrospun and Extruded Soluplus®-Based Solid Dosage Forms of Improved Dissolution. J. Pharm. Sci. 2012, 101 (1), 322– 332,  DOI: 10.1002/jps.22731
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    211
    Comparison of electrospun and extruded Soluplus-based solid dosage forms of improved dissolution
    Nagy, Zsombor K.; Balogh, Attila; Vajna, Balazs; Farkas, Attila; Patyi, Gergo; Kramarics, Aron; Marosi, Gyoergy
    Journal of Pharmaceutical Sciences (2012), 101 (1), 322-332CODEN: JPMSAE; ISSN:0022-3549. (Wiley-Liss, Inc.)
    Electrospinning (ES) and extrusion of a poorly water-sol. active pharmaceutical ingredient were used to improve its dissoln., which is a major challenge in the field of pharmaceutical technol. Spironolactone was applied as model drug and recently developed polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus) was used as carrier matrix and solubilizer. ES of the polymer matrix from ethanol soln. was optimized at first without spironolactone and then the cosoln. of the drug and the carrier was used for forming electrospun fibers. It resulted in real solid soln. due to its very efficient amorphization effect. On the contrary, a low amt. of cryst. spironolactone appeared in the extrudates according to Raman microscopy, X-ray diffraction (XRD), SEM and energy-dispersive spectrometry (EDS). Raman microspectrometry had the lowest detection limit of spironolactone crystals compared with XRD and differential scanning calorimetry. Both ES and extrusion techniques resulted in significantly improved dissoln. Electrospun ultrafine fibers increased the dissoln. more effectively, owing to the formed solid soln. and huge surface. The developed continuous technologies demonstrate great potential to tackle the challenge of inadequate dissoln. of poorly water-sol. drugs in several cases. © 2011 Wiley-Liss, Inc. and the American Pharmacists Assocn. J Pharm Sci.
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  212. 212
    Szabo, E.; Demuth, B.; Nagy, B.; Molnar, K.; Farkas, A.; Szabo, B.; Balogh, A.; Hirsch, E.; Nagy, B.; Marosi, G.; Nagy, Z. K. Scaled-up Preparation of Drug-Loaded Electrospun Polymer Fibres and Investigation of Their Continuous Processing to Tablet Form. eXPRESS Polym. Lett. 2018, 12 (5), 436– 451,  DOI: 10.3144/expresspolymlett.2018.37
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    212
    Scaled-up preparation of drug-loaded electrospun polymer fibres and investigation of their continuous processing to tablet form
    Szabo, E.; Demuth, B.; Nagy, B.; Molnar, K.; Farkas, A.; Szabo, B.; Balogh, A.; Hirsch, E.; Marosi, G.; Nagy, Z. K.
    eXPRESS Polymer Letters (2018), 12 (5), 436-451CODEN: PLOEAK; ISSN:1788-618X. (Budapest University of Technology and Economics, Dep. of Polymer Engineering)
    Polymer-based electrospun amorphous solid dispersions (ASDs) were prepd. and investigated from pharmaceutical application point of view. Spironolactone (SPIR) was used as model drug mixed in various concns. with polymers suitable for fiber formation, such as vinylpyrrolidone-vinyl acetate copolymer, polyvinylpyrrolidone K30 and hydroxypropyl methylcellulose. Single needle electrospinning was applied at first for screening the compn. of the prepd. ASDs. Scaling-up the selected polymer-drug combination was accomplished by high speed electrospinning, the productivity of which enabled investigation of downstream processing to generate tablet formulation. The steps of a potential continuous prodn. line (fiber collection, grinding, feeding and tableting) proved to be feasible with the electrospun ASD without any sign of crystn. If cryst. drug was added into the ASD contg. tablets as impurity strictly monotonous decrease of drug dissoln. was obsd. in the function of the cryst. drug content. The capabilities of the non-destructive Raman and near-IR spectroscopies, as fast quality assurance tools, were compared to each other in quantifying of cryst. SPIR content in the prepd. tablets.
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  213. 213
    Szabó, E.; Démuth, B.; Galata, D. L.; Vass, P.; Hirsch, E.; Csontos, I.; Marosi, G.; Nagy, Z. K. Continuous Formulation Approaches of Amorphous Solid Dispersions: Significance of Powder Flow Properties and Feeding Performance. Pharmaceutics 2019, 11 (12), 654,  DOI: 10.3390/pharmaceutics11120654
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    213
    Continuous formulation approaches of amorphous solid dispersions: significance of powder flow properties and feeding performance
    Szabo, Edina; Demuth, Balazs; Galata, Dorian Laszlo; Vass, Panna; Hirsch, Edit; Csontos, Istvan; Marosi, Gyorgy; Nagy, Zsombor K.
    Pharmaceutics (2019), 11 (12), 654CODEN: PHARK5; ISSN:1999-4923. (MDPI AG)
    Prepn. and formulation of amorphous solid dispersions (ASDs) are becoming more and more popular in the pharmaceutical field because the dissoln. of poorly water-sol. drugs can be effectively improved this way, which can lead to increased bioavailability in many cases. During downstream processing of ASDs, technologists need to keep in mind both traditional challenges and the newest trends. In the last decade, the pharmaceutical industry began to display considerable interest in continuous processing, which can be explained with their potential advantages such as smaller footprint, easier scale-up, and more consistent product, better quality and quality assurance. Continuous downstream processing of drug-loaded ASDs opens new ways for automatic operation. Therefore, the formulation of poorly water-sol. drugs may be more effective and safe. However, developments can be challenging due to the poor flowability and feeding properties of ASDs. Consequently, this review pays special attention to these characteristics since the feeding of the components greatly influences the content uniformity in the final dosage form. The main purpose of this paper is to summarize the most important steps of the possible ASD-based continuous downstream processes in order to give a clear overview of current course lines and future perspectives.
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  214. 214
    Kalivoda, A.; Fischbach, M.; Kleinebudde, P. Application of Mixtures of Polymeric Carriers for Dissolution Enhancement of Fenofibrate Using Hot-Melt Extrusion. Int. J. Pharm. 2012, 429 (1–2), 58– 68,  DOI: 10.1016/j.ijpharm.2012.03.009
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    214
    Application of mixtures of polymeric carriers for dissolution enhancement of fenofibrate using hot-melt extrusion
    Kalivoda, Adela; Fischbach, Matthias; Kleinebudde, Peter
    International Journal of Pharmaceutics (Amsterdam, Netherlands) (2012), 429 (1-2), 58-68CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
    Hot-melt extrusion was applied to improve dissoln. behavior of poorly sol. model drug fenofibrate. Blends of polymers were used as carrier: copovidone (COP), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer (PVCL-PVAc-PEG) and hypromellose 2910/5 (HPMC). The ratio of fenofibrate to COP remained constantly 1 + 3 (weighted parts) with varying amts. of PVCL-PVAc-PEG and HPMC. Solid state of fenofibrate was characterized by X-ray diffractometry and differential scanning calorimetry. Dissoln. performance was compared to marketed formulations Lipidil and Lipidil-Ter. Stability studies were conducted at 25 °C/60%rH. The dissoln. rate from extrudates was significantly increased when compared to pure fenofibrate powder or phys. mixt. of the components. A supersatn. of 7.6-12.1 was reached with the pelletized extrudates. All extrudates were superior to marketed formulations. No recrystn. was obsd. after 26 wk of storage for fenofibrate-COP extrudates 1 + 3 (weighted parts) with or without polymeric additives. Even so, both degree and duration of supersatn. decreased with increasing storage periods with the exception of fenofibrate-HPMC extrudates. Of particular interest is the finding that by adding polymers with differing release characteristics to the drug-carrier mixt., the dissoln. performance of hot-melt extruded solid dosage forms can be readily adapted to meet specific requirements.
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  215. 215
    Gryczke, A.; Schminke, S.; Maniruzzaman, M.; Beck, J.; Douroumis, D. Development and Evaluation of Orally Disintegrating Tablets (ODTs) Containing Ibuprofen Granules Prepared by Hot Melt Extrusion. Colloids Surf., B 2011, 86 (2), 275– 284,  DOI: 10.1016/j.colsurfb.2011.04.007
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    215
    Development and evaluation of orally disintegrating tablets (ODTs) containing Ibuprofen granules prepared by hot melt extrusion
    Gryczke, Andreas; Schminke, Silke; Maniruzzaman, Mohammed; Beck, Julien; Douroumis, Dennis
    Colloids and Surfaces, B: Biointerfaces (2011), 86 (2), 275-284CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier B.V.)
    In the current study ibuprofen was embedded in a methacrylate copolymer (Eudragit EPO) matrix to produce solid dispersions by hot-melt extrusion (HME) processing. The obtained granules were incorporated in orally disintegrating tablets (ODTs). The tablets were developed by varying the ratio of superdisintegrants such as sodium croscarmellose and crosslinked polyvinylpyrrolidone grades while a direct compression process was used to compress the ODTs under various compaction forces to optimize tablet robustness. The properties of the compressed tablets which included porosity, hardness, friability and dissoln. profiles were further evaluated and compared with Nurofen Meltlet ODTs. The taste and sensory evaluation in human volunteers demonstrated excellence in masking the bitter active and improved tablet palatability.
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  216. 216
    Baronsky-Probst, J.; Möltgen, C.-V.; Kessler, W.; Kessler, R. W. Process Design and Control of a Twin Screw Hot Melt Extrusion for Continuous Pharmaceutical Tamper-Resistant Tablet Production. Eur. J. Pharm. Sci. 2016, 87, 14– 21,  DOI: 10.1016/j.ejps.2015.09.010
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    216
    Process design and control of a twin screw hot melt extrusion for continuous pharmaceutical tamper-resistant tablet production
    Baronsky-Probst, J.; Moeltgen, C.-V.; Kessler, W.; Kessler, R. W.
    European Journal of Pharmaceutical Sciences (2016), 87 (), 14-21CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)
    Hot melt extrusion (HME) is a well-known process within the plastic and food industries that has been utilized for the past several decades and is increasingly accepted by the pharmaceutical industry for continuous manufg. For tamper-resistant formulations of e.g. opioids, HME is the most efficient prodn. technique. The focus of this study is thus to evaluate the manufacturability of the HME process for tamper-resistant formulations. Parameters such as the specific mech. energy (SME), as well as the melt pressure and its std. deviation, are important and will be discussed in this study. In the first step, the existing process data are analyzed by means of multivariate data anal. Key crit. process parameters such as feed rate, screw speed, and the concn. of the API in the polymers are identified, and crit. quality parameters of the tablet are defined. In the second step, a relationship between the crit. material, product and process quality attributes are established by means of Design of Expts. (DoEs). The resulting SME and the temp. at the die are essential data points needed to indirectly qualify the degrdn. of the API, which should be minimal. NIR-spectroscopy is used to monitor the material during the extrusion process. In contrast to most applications in which the probe is directly integrated into the die, the optical sensor is integrated into the cooling line of the strands. This saves costs in the probe design and maintenance and increases the robustness of the chemometric models. Finally, a process measurement system is installed to monitor and control all of the crit. attributes in real-time by means of first princip