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Mechanistic Insights into Paracetamol Crystallization: Exploring Ultrasound and Hydrodynamic Cavitation with Quartz Crystal Microbalance Dissipation
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  • Madhumitha Dhanasekaran*
    Madhumitha Dhanasekaran
    Clean Energy Research Platform, Physical Sciences and Engineering (PSE) Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia
    *Email: [email protected]
    More by Madhumitha Dhanasekaran
    Orcidhttps://orcid.org/0000-0002-7318-8476
  • Varaha P. Sarvothaman*
    Varaha P. Sarvothaman
    Clean Energy Research Platform, Physical Sciences and Engineering (PSE) Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia
    *Email: [email protected]
    More by Varaha P. Sarvothaman
    Orcidhttps://orcid.org/0000-0001-7736-2227
  • Paolo Guida
    Paolo Guida
    Clean Energy Research Platform, Physical Sciences and Engineering (PSE) Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia
    More by Paolo Guida
    Orcidhttps://orcid.org/0000-0002-9805-9291
  • William L. Roberts
    William L. Roberts
    Clean Energy Research Platform, Physical Sciences and Engineering (PSE) Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia
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ACS Engineering Au

Cite this: ACS Eng. Au 2024, XXXX, XXX, XXX-XXX
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https://doi.org/10.1021/acsengineeringau.4c00036
Published December 4, 2024

© 2024 The Authors. Published by American Chemical Society. This publication is licensed under

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Abstract

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Crystallization is a crucial process in the purification of active pharmaceutical ingredients (APIs). Achieving controlled and efficient crystal formation is vital in successful production for industrial applications. This study investigates the crystallization of paracetamol using a model system, focusing on two techniques: ultrasound cavitation (UC) and hydrodynamic cavitation (HC). The role of cavitation in enhancing crystallization is well-established by using ultrasound. However, the crystallization process utilizing HC, especially in the absence of an antisolvent, is not investigated. A detailed investigation is still necessary to understand the nucleation process at the molecular level. This work primarily focuses on forming paracetamol crystals in an aqueous medium without the need for an antisolvent in HC. To address the nucleation study at the molecular level, the quartz crystal microbalance with dissipation (QCM-D) technique was employed to explore the nucleation kinetics of paracetamol crystallization while the solution is cooling. QCM-D allowed for real-time monitoring of mass changes and viscoelastic properties on the sensor surface, providing valuable insights into the adsorption, growth, and dissolution kinetics of paracetamol crystals under the influence of both cavitation techniques. The study revealed distinct crystallization behaviors depending on the type and intensity of cavitation, shedding light on the underlying mechanisms and potential implications for pharmaceutical manufacturing and formulation. These findings indicate that high-quality crystals can be produced using HC without the need for an antisolvent. This work highlights the significant potential for improving the efficiency and control of paracetamol crystallization and plays an important role in scaling up the crystallization process using HC.

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1. Introduction

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Crystallization is the process of formation of solid crystals from a homogeneous liquid phase. (1) This process is an important separation and purification process in chemical and pharmaceutical industries. (2,3) For the pharmaceutical industry, crystallization plays a crucial role in the manufacturing of solid oral dosage forms as the properties of the final product, such as tablets, are heavily influenced by the crystal characteristics of the active pharmaceutical ingredient (API). This process enables the selective production of a highly pure API, while also allowing for precise control over crystal size and morphology, which is essential for creating engineered products. Managing these crystal attributes is critical for subsequent processes including isolation, drying, and packaging. Additionally, controlling crystal properties impacts batch stability, shelf life, tableting, and ultimately the bioavailability and dissolution of the API in the body. As a result, there is growing interest in engineering the crystal habit of pharmaceutical compounds to optimize their shape, size, and surface area for improved bioavailability. (4)
The supersaturation of the solute is the driving force for crystal formation, and this can be achieved in different ways. The commercial methods used to achieve supersaturation is by variation of temperature or by the addition of an antisolvent. (5) As long as operating conditions like temperature, concentration, and pressure promote crystallization, this process continually occurs. Despite significant advancements in nucleation theories in recent years, the templating or specific ordering within the solid state during the nucleation process remains not fully understood. (6)
Solvent, temperature, and crystallization conditions have a major impact on the formation of a different form of the drug. Particular forms of a drug have different physicochemical properties, which have an important influence on how it is processed into a drug product. (7) There are three polymorphic forms of paracetamol; the common crystal form (form I, monoclinic), which is used in the pharmaceutical product, is thermodynamically stable, whereas forms II and III are metastable phases, which can undergo solid phase transitions. Form I is prepared in large quantities and described as plate-shaped. The tablets produced by form I have high capping tendency because of the stiff construction of the molecules inside the crystal. (8,9)
Table 1 shows some of the literature studies of the paracetamol crystallization methods and the techniques to monitor the nucleation point in the crystal. This importance is due to its significant advantages in facilitating process design and operation. Consequently, key phenomena in cooling crystallization, such as crystal nucleation, growth, and the metastable zone width, have been extensively studied. These phenomena play a key role in crystal size, distribution, habits, purity, and polymorphs. During the crystal formation, the rate of crystal growth depends on the rate at which crystal units arrive at the crystal surface, which is influenced by the intensity of local convection near the crystal. (1,11)
Table 1. Studies Using a Paracetamol Crystallization System
#crystallization Processtechnique usednucleation identification methodreference
1cooling crystallizationultrasound cavitationvisual observationenergy efficient crystallization of paracetamol using pulsed ultrasound (17)
2antisolvent crystallizationultrasound cavitationsonoluminescenceultrasound-assisted crystallization of paracetamol: crystal size distribution and polymorph control (15)
3cooling crystallizationultrasound cavitationvisually at saturation temperaturedetermination of the effect of the ultrasonic frequency on the cooling crystallization of paracetamol (20)
4suspension crystallizationultrasound cavitationvisual observation/precipitationthe effect of ultrasound on the crystallization of paracetamol in the presence of structurally similar impurities (16)
5antisolvent crystallizationmagnetic stirrervisual observation/precipitationan approach to engineer paracetamol crystals by antisolvent crystallization technique in the presence of various additives for direct compression (21)
6crystallization in supercooled liquidterahertz time domain spectroscopyphase change observation in spectracrystallization and phase changes in paracetamol from the amorphous solid to the liquid phase (22)
7cooling crystallizationconventional coolingFouriertransform - near infrared spectroscopy - change in spectrapolymorph transformation in paracetamol monitored by in-line NIR spectroscopy during a cooling crystallization process (23)
8antisolvent crystallizationhydrodynamic cavitationno information about nucleationantisolvent crystallization: particle size distribution with different devices (24)
9oscillatory flow mixingoscillatory baffled batch crystallizerin situ atomic force microscopy and optical microscopycrystallization of paracetamol under oscillatory flow mixing conditions (25)
10cooling crystallization with additivesconventional coolingno information about nucleationtailoring crystal size distributions for product performance, compaction of paracetamol (26)
Ultrasound is proven to influence the crystallization system in several ways, such as (1) reduced induction time, (2) reduced amount of antisolvent, (3) limiting the crystal size distribution, and (4) effects in polymorphism. (12) Using the cavitation phenomenon, ultrasound establishes its physical effects throughout the crystallization process. (13) Cavitational collapse induces shockwaves, high temperature and pressure, microjets, and improved mixing. (14) It is well established that the influence of ultrasound enhances the crystallization process. For example, Kaur Bhangu et al. and Nyugen et al. studied the antisolvent crystallization using ultrasound and the effect of ultrasound on paracetamol crystals, respectively. Their results suggest that the variations in the ultrasound conditions significantly show changes in the crystal size and induction time. (15,16) Also, Gielen et al. monitored the energy efficiency of paracetamol crystallization using pulsed ultrasound and found that the final particle size of paracetamol crystals is controlled in the batch setup without affecting the crystal shape. (17) Ultrasound-assisted crystallization is typically conducted in batch processes. However, to scale up crystallization for industrial applications, the hydrodynamic cavitation (HC) method is preferable to facilitate crystallization on a larger scale. (10)
This study explores the use of HC to enhance crystal formation without the need for an antisolvent, aiming for industrial applicability. Cavitational collapse in HC is similar to that of ultrasound cavitation (UC), initiating crystal formation. In HC, high-pressure fluid flows through a constriction (e.g., an orifice or venturi), leading to a local drop in the pressure. When the pressure drops below the vapor pressure of the solvent (water), microbubbles form (nucleation), which induces supersaturation of the solution, which upon cooling forms crystals. While both UC and HC have been investigated separately for crystallization processes in a study, they have not yet been applied simultaneously to a single protein or drug using the cooling crystallization technique without an antisolvent. Furthermore, the properties of crystals prepared by the HC technique for industrial applications remain underexplored and require further research. In this study, paracetamol has been crystallized using a cooling crystallization technique by employing UC and HC to enhance the crystal formation. Paracetamol (or acetaminophen) is specifically chosen due to its ease in availability, and it is the common drug widely used as over the counter analgesic and antipyretic. Paracetamol is known to have three polymorphs: stable form I (monoclinic), metastable form II (orthorhombic), and unstable form III. (18,19) One of the major issues in pharmaceutical crystallization processes is relatively poor reproducibility, which in this study was overcome using the UC and HC cavitation systems.
Even though crystallization studies have evolved over generations, the study of nucleation is still under investigation and is not completely understood. Understanding nucleation is crucial for optimizing crystallization processes in various industrial applications including pharmaceuticals, chemicals, and materials science. Control over nucleation can lead to better product quality, improved yield, and more efficient manufacturing processes. This paper addresses the nucleation induction time during the cooling process in UC- and HC-influenced paracetamol crystals to understand the nucleation kinetics in paracetamol crystals using the quartz crystal microbalance with dissipation (QCM-D) technique.
The QCM-D technique is a sensitive tool that employs the piezoelectric properties of quartz crystals to measure the attached mass on the electrode surface. QCM-D provides a real-time, label-free detection for molecular interactions and structural changes at surfaces, which makes it unique for nucleation studies. The molecular interactions at the surfaces can be studied in detail during the process of cooling, which is lacking in other methods. Also, this method has attracted significant attention due to its simple concept, low cost, easy portability, high sensitivity, and diverse applications in various fields.
QCM-D analyzes the change in frequency and dissipation from which the kinetics of change in mass with time is monitored. The minor change in mass allowed us to precisely mark the nucleation point at the molecular level. A change in the resonant frequency can be related to a change in the mass according to the Sauerbrey equation. (27) QCM-D can measure resonance at multiple overtones and track dissipation (or complex frequency) shifts, allowing it to assess the viscoelastic properties of deposited materials such as storage and loss moduli. This capability extends QCM beyond its traditional role as a simple gravimetric tool, enabling more comprehensive material analysis. The QCM-D technique has been employed in a wide range of research topics, for example, self-assembled monolayers, viscoelastic polymers, and adsorption of biological macromolecules (proteins and DNA) and is also employed in electrochemical reactions. (28−32) Due to the adaptability, consistency, and sensitivity for in situ sensing of small differences in the working environment around a quartz crystal sensor, this technique is used in a wide range of studies.
In this study, we use the QCM-D technique, known for its high sensitivity to mass variations (1.07 ng/Hz), to accurately analyze crystal nuclei formation at the molecular level in paracetamol crystallization. (33) Following UC and HC treatments, paracetamol solution were cooled at 1 °C/min to initiate crystallization, during which QCM-D responses were recorded to track both resonant frequency and dissipation. This enables us to calculate changes in the adsorbed mass on the sensor surface and pinpoint the nucleation induction point of the crystal. Our goal is to utilize QCM-D, to determine this nucleation point with precision, facilitated by UC and HC crystals. The findings from this study could aid in developing real-time monitoring systems for crystal formation and have potential applications across various crystallization methods.

2. Materials, Reactors, and Analytical Techniques Employed

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2.1. Materials

Paracetamol (Acetaminophen) was obtained from Apollo Scientific and used without further purification. 20 g L–1 solution of paracetamol was prepared in water (Milli-Q, resistance 18.2 MΩcm). The solution was heated to 80 °C under stirring while avoiding any evaporation to dissolve the solute completely. To confirm the solute dissolution, the solution was filtered over a 0.45 mm Millipore HAWP filter to remove any impurities, before transferring it to the experimental setup.

2.2. Reactors Employed in the Study

2.2.1. Ultrasound Cavitation

The Hielscher UP400 St operating at a frequency of 24 kHz was used to introduce ultrasound into the solution containing paracetamol, the amplitude was set at 24.5 μm (100%), and the duty cycle was set at 1.0 (continuous mode of operation). The treatment consisted of 20 min of ultrasound application, the initial temperature of this operation was 18 °C, which was increased to 70 °C at the end of the treatment. After the application of ultrasound, the solution was left for cooling at a rate of 1 °C/min, and the temperature was monitored. The crystals were formed by this cooling process, and the formed crystals were filtered using a vacuum filtration technique and allowed to dry for a period of 2 h at 80 °C. The formed crystals were used further for characterization.

2.2.2. Hydrodynamic Cavitation

A vortex-diode based cavitation device (dt = 3 mm, nominal flow rate of 1 LPM) was procured from VIVIRA Process Technologies, India. In a vortex-diode based cavitation device, the phenomenon of cavitation is set up in its flow path. The fluid enters tangentially, creating a rotational flow that forms a free vortex. The free vortex induces a pressure drop as the liquid swirls within the vortex chamber. When the local pressure at the center of the vortex is less than the vapor pressure of liquid, cavities form and collapse, leading to cavitation (the geometry of this device is presented in Figure 1). An experimental setup similar to previous HC-based studies (34,35) was designed and operated. The HC loop employed a Grundfos PKm60 pump, and the frequency of the pump was manipulated by the use of a variable frequency drive. Other pipe fittings, such as ball valves and pressure gauges, were procured locally from Jeddah City, Saudi Arabia. The schematic of the HC reactor is presented in Figure 1. The operating pressure was chosen as ΔP = 200-kPag based on previous work. (36) The HC operation was performed for a duration of 10 min with temperature of this operation initially being 18 °C and increasing to 50 °C at the end of the treatment; no heat exchangers were used and the operation was a nonisothermal one.

Figure 1

Figure 1. Geometry of the vortex-based hydrodynamic reactor (Reproduced with permission from [37], Copyright [2019] [John Wiley and Sons], Simpson and Ranade (37)) and schematic of the experimental setup employed in this work.

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The crystals obtained from both methods were weighed to determine the crystallization yield. The yield was calculated using the following formula
Yield(%)=(MassoftheCrystalsobtainedInitialmassofthesubstance)×100
(1)

2.3. Analytical Techniques

2.3.1. Scanning Electron Micrographs

Scanning electron microscopy (SEM) was performed by using a field emission scanning electron microscope (Nova Nano SEM 630). The paracetamol crystals were mounted to the SEM stub and then coated with an Iridium prior to SEM observation.

2.3.2. Powder X-ray Diffraction Analysis

Powder X-ray diffraction (XRD) was analyzed for paracetamol crystals using a Bruker D2 Phaser X-ray Diffractometer for phase identification and crystallinity at room temperature. The diffractometer used Cu Kα radiation (λ = 1.54 Å) at an acceleration voltage of 30 kV and a current of 15 mA. The samples were scanned from 5 to 40° of 2θ with a step size of 0.01°.

2.3.3. Differential Scanning Calorimetry

The relative stability of paracetamol was analyzed using differential scanning calorimetry (DSC) (DSC-250 TA Instruments) by measuring the temperature and heat flows associated with paracetamol crystals. Using standard crucibles, a quantity of about 3 mg of paracetamol was measured and added. The measurements were performed under an inert nitrogen atmosphere to prevent potential oxidation. The heating–cooling–heating test was carried out using the following temperature program: heating samples at a rate of 10 °C/min from 25 to 200 °C, isotherm for 10 min, cooling at a rate 50 °C/min from 250 to 25 °C, isotherm for 10 min, and the second heating at a rate 10 °C/min to 200 °C.

2.3.4. Quartz Crystal Microbalance with Dissipation

QCM-D measurements were performed with a Q-sense analyzer (QE401, Biolin Scientific) by using gold-coated crystal sensors. The QCM-D crystal sensors were cleaned using acetone and ethanol and blow-dried using nitrogen. Cleaned substrates were used for further studies. The QCM-D response of the bare sensors was monitored in air as a control experiment. Injecting fluid into the chamber at a constant flow rate of 100 μL/min results in significant changes in the QCM-D signals. The resonance frequency and bandwidths have been collected for overtones, n, between 3 and 11, corresponding to frequencies between 15 and 55 MHz. Following the conventional methodology, the change in mass (Δm) was calculated using the Sauerbrey equation, which relates the changes in mass to the frequency differences, using one overtone (n).
Δm=−c.Δfn
(2)
where Δm is the change in mass, C mass sensitivity constant −17.7 ng/(cm2·Hz), Δf resonance frequency change, and n number of Harmonics.

3. Results and Discussion

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3.1. Crystallization Yield

During the crystallization process, after cavitation treatment (both in UC and HC methods), the solution is allowed to cool naturally, allowing time for crystal formation. The crystals were collected by filtration, dried, and weighed to calculate the yield using eq 1. Table 2 presents the yield details along with the initial mass and final mass obtained in the crystallization process. The yield was found to be 49.6% for crystals produced using the UC crystallization method and 72.5% for crystals produced using the HC crystallization method. The difference in yield percentage may be attributed to the varying volumes of liquid processed, as well as the differences in amplitude and frequency ranges utilized in the UC and HC methods. These crystals were further studied and characterized for purity.
Table 2. Paracetamol Crystal Yield Percentage Crystallized by UC and HC
initial mass of paracetamol (g)volume of liquid (mL)cavitation typemass of the crystal obtained (g)yield (%)
10500UC4.9649.6
452500HC7.2572.5

3.2. SEM Imaging

The SEM images of paracetamol crystals were taken. Figure 2a shows the crystals formed using UC, and Figure 2b shows the crystals formed by using HC. From these images, it is observed that the crystals formed using UC and HC have the consistent polymorph of the monoclinic I form. which is more stable. This agrees well with the reported crystal morphology. (4,38) The prismatic shape is maintained in both the experimental conditions; the only effect that is noticed in these two-preparation methods is the reduced particle size, which is clearly noticeable in SEM images. It can be observed that there are some small crystals that are visible and tend to stick to the larger crystals; these are produced due to the fragmentation process during the cavitation crystallization procedure. (39,40)

Figure 2

Figure 2. Paracetamol crystals induced by (a) UC-based processing and (b) HC-based processing.

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3.3. Powder X-ray Diffraction

Powder XRD analysis was performed to monitor the polymorphs of the crystal formed using UC and HC methods. The paracetamol crystals obtained from the two different cavitation methods have similar XRD patterns, as shown in Figure 3a,b, thus confirming the formation of the form 1 monoclinic crystal. The presence of sharp peaks indicates that the paracetamol crystals produced using these two cavitation methods have high crystallinity and have a well-ordered internal structure, which is similar to the conventional method of crystal formation. The prominent peaks at specific 2θ values, typically around 13°, 15°, 20°, and 23°, proves that the crystals belong to the form I polymorph. (41)

Figure 3

Figure 3. XRD results for (a) UC- and (b) HC-based processing.

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The UC-induced paracetamol crystals show significantly higher peak intensities than the HC sample. The higher intensities in the UC method are due to the larger or more uniformly oriented crystals; also, UC affects the nucleation and growth rates differently than HC. The difference in peak intensity between UC and HC suggests that the cavitation method influences certain aspects of crystal growth. Hence, the difference in relative intensities of the peaks is due to the different crystal preparation methods. In terms of peak position, the two XRD patterns agree well with those reported in the literature for paracetamol form I, confirming the crystal form and ensuring consistency with previously reported data. (42−44)

3.4. Differential Scanning Calorimetry

The DSC curves of paracetamol crystals produced using UC and HC are shown in Figure 4a,b, respectively. The DSC curves of paracetamol crystals prepared using UC and HC show a single endothermic peak at 170.9 and 171.4 °C, respectively, due to the melting of polymorphic form I (monoclinic), which is consistent with the literature. (45,46) The sharpness of the peak indicates a well-defined melting point, which is characteristic of a pure crystalline material. Also, the crystal produced using UC and HC does not significantly alter the crystalline structure of the paracetamol, which is also proven by powder XRD. Hence, UC and HC methods of producing paracetamol crystals provide a promising result by enhancing the growth rate compared to conventional methods of cooling crystallization, which will be very useful for industrial applications. (47)

Figure 4

Figure 4. DSC results for (a) UC- and (b) HC-based processing.

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3.5. QCM-D Results

After the application of UC and HC to paracetamol solutions, QCM-D measurements were recorded during the cooling phase to observe the onset of nucleation. The changes in frequency (Δf) and dissipation (ΔD) were tracked to monitor the crystallization process of paracetamol. (33,48) Using the Sauerbrey equation, the change in mass (Δm) was calculated to assess the nucleation kinetics, providing insights into the rate of mass accumulation and the formation of a crystalline structure over time. The paracetamol solution (20 g/L) was maintained at a temperature of 50 °C, the cooling rate was set at 1 °C/min when QCM-D measurements began, and Δf and Δm were monitored. As the solution cooled, Δf changed due to the viscosity shift.
During further cooling, as the viscosity increased, the mass on the QCM-D sensor gradually accumulated. In the initial phase, both Δf and Δm exhibited fluctuations, suggesting dynamic nucleation events with rapid adsorption on the sensor surface. Over time, these fluctuations decreased as mass accumulation became steadier, indicating the progressive growth of the crystal layer on the sensor. In samples influenced by ultrasound (UC), mass accumulation began immediately at 100 s (Figure 5a), with nucleation intensifying after 400 s, leading to rapid crystal formation. In contrast, for HC samples (Figure 5b), mass increase was more gradual, with nucleation beginning around 700 s and continuing up to 6000 s, where it reached a saturation point. (17) This gradual buildup in HC suggests that a stable, highly crystalline layer formed on the sensor surface over time.

Figure 5

Figure 5. QCM-D results for (a) UC- and (b) HC-based processing.

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The QCM-D results, based on induction time, indicate that even though the crystals formed by UC and HC have the same polymorph of form I, the nucleation starts at different time intervals, which is due to the power and cavitation intensities in UC and HC. Hence, it is important to note that the operating volumes and cavitational intensities of the two methods are different. The ultrasound setup had a smaller operating volume of 0.2 L (for QCM and 0.5 L for the yield calculation experiment), whereas HC used a 2.5 L volume. In the ultrasound system, cavitation is concentrated near the tip of the sonotrode, while in HC, it is distributed as the liquid exits the vortex reactor.
These presented results focused on comparing cavitation-induced crystallization in the absence of the antisolvent and evaluating the effectiveness of QCM-D for in situ monitoring of crystallization behavior. By analyzing the nucleation induction time and nucleation rates, further insights into the mechanical properties of the crystals, such as stiffness and damping, were gained. (49)

4. Conclusions

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The study conclusively demonstrates that both UC and HC significantly influence the crystallization dynamics of paracetamol with distinct effects on nucleation kinetics and crystal growth. Utilizing HC without the presence of an antisolvent provides a viable pathway for the crystallization process, facilitating the scalability for industrial applications. By employing the QCM-D technique, the research provides detailed, real-time insights into how different cavitational forces impact the adsorption, growth, and dissolution of paracetamol crystals. The findings highlight that the type and intensity of cavitation are critical factors in controlling the crystallization behavior, which can be leveraged to optimize pharmaceutical manufacturing processes. Ultimately, this study contributes to a deeper understanding of the cavitation phenomena, offering a pathway to enhance the efficiency and control of crystallization in the production of paracetamol and other crystalline compounds with potential applications in improving drug formulation and quality. Future studies could explore the use of multiple cavitation zones either through specialized sonotrode designs or by operating HC reactors with various other drugs. This approach demonstrates that the findings are not limited to paracetamol alone. Additionally, it could help accelerate cavitation-induced crystallization, facilitating scalability in pharmaceutical applications.

Author Information

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  • Corresponding Authors
  • Authors
    • Paolo Guida - Clean Energy Research Platform, Physical Sciences and Engineering (PSE) Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia;  Orcidhttps://orcid.org/0000-0002-9805-9291
    • William L. Roberts - Clean Energy Research Platform, Physical Sciences and Engineering (PSE) Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia
  • Author Contributions

    CRediT: Madhumitha Dhanasekaran conceptualization, investigation, methodology, writing - original draft; Varaha Prasad Sarvothaman formal analysis, methodology, validation, writing - review & editing; Paolo Guida supervision, validation, writing - review & editing; William L. Roberts conceptualization, supervision.

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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The authors would like to gratefully thank Professor Sahika Inal, Bioengineering Biological and Environmental Science and Engineering Division, KAUST, and Dr. Jokubas Surgailis for the use of the QCM-D technique used in this work. The authors would also like to thank the KAUST Core Laboratories for enabling the use of other analytical techniques used in this work.

References

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    Chadha, R.; Gupta, S.; Shukla, G. Crystal habit, characterization and pharmacological activity of various crystal forms of arteether. Acta Pharm. Sin. B 2011, 1 (2), 129– 135,  DOI: 10.1016/j.apsb.2011.06.010
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    Krycer, I.; Pope, D. G.; Hersey, J. A. The prediction of paracetamol capping tendencies. J. Pharm. Pharmacol. 1982, 34 (12), 802– 804,  DOI: 10.1111/j.2042-7158.1982.tb06229.x
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    Bauer, J.; Spanton, S.; Henry, R.; Quick, J.; Dziki, W.; Porter, W.; Morris, J. Ritonavir: an extraordinary example of conformational polymorphism. Pharm. Res. 2001, 18, 859– 866,  DOI: 10.1023/A:1011052932607
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    Ritonavir: an extraordinary example of conformational polymorphism
    Bauer, John; Spanton, Stephen; Henry, Rodger; Quick, John; Dziki, Walter; Porter, William; Morris, John
    Pharmaceutical Research (2001), 18 (6), 859-866CODEN: PHREEB; ISSN:0724-8741. (Kluwer Academic/Plenum Publishers)
    Purpose. In the summer of 1998, Norvir semi-solid capsules supplies were threatened as a result of a new much less sol. crystal form of ritonavir. This report provides characterization of the 2 polymorphs and the structures and hydrogen bonding network for each form. Methods. Ritonavir polymorphism was investigated by solid state spectroscopy and microscopy techniques including solid state NMR, near-IR Spectroscopy, powder x-ray Diffraction and single crystal x-ray. A sensitive seed detection test was developed. Results. Ritonavir polymorphs were thoroughly characterized and the structures detd. An unusual conformation was found for form II that results in a strong hydrogen bonding network. A possible mechanism for heterogeneous nucleation of form II was investigated. Conclusions. Ritonavir exhibited conformational polymorphism with two unique crystal lattices having significantly different soly. properties. Although the polymorph (form II) corresponding to the "cis" conformation is a more stable packing arrangement, nucleation, even in the presence of form II seeds, is energetically unfavored except in highly supersatd. solns. The coincidence of a highly supersatd. soln. and a probable heterogeneous nucleation by a degrdn. product resulted in the sudden appearance of the more stable form II polymorph.
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    Astier, J.-P.; Veesler, S. Using Temperature To Crystallize Proteins: A Mini-Review. Cryst. Growth Des. 2008, 8 (12), 4215– 4219,  DOI: 10.1021/cg800665b
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    Using Temperature To Crystallize Proteins: A Mini-Review
    Astier, Jean-Pierre; Veesler, Stephane
    Crystal Growth & Design (2008), 8 (12), 4215-4219CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
    A review. The aim of this overview is to provide biocrystallographs that intend to tackle crystn. with practical examples of the effect of temp. on protein phase sepn. and crystn. Crystn. involves two sep. processes: nucleation and growth, which are rarely completely unconnected. Here, the authors give four concrete examples illustrating how temp. can be used to crystallize proteins. The authors describe the nucleation of a new phase, solid or liq. and the growth and transformation of existing crystals obtained by seeding or primary or secondary nucleation. The advantages of temp. as a crystn. parameter are const. compn., ease of control and monitoring and reversibility.
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    Nývlt, J. Design of batch crystallizers. In Industrial Crystallization; Springer, 1976; pp 335– 342.
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    McCausland, L. J.; Cains, P. W.; Martin, P. D. Use the power of sonocrystallization for improved properties. Chem. Eng. Prog. 2001, 97 (7), 56– 61
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    Use the power of sonocrystallization for improved properties
    McCausland, Linda J.; Cains, Peter W.; Martin, Peter D.
    Chemical Engineering Progress (2001), 97 (7), 56-61CODEN: CEPRA8; ISSN:0360-7275. (American Institute of Chemical Engineers)
    A review, with 8 refs., of the title subject, including ultrasonic cavitation, cavitation and nucleation, modification and control of properties, ultrasonic equipment, scaled-up units, and large-scale batch crystn.
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    Prasad, R.; Dalvi, S. V. Sonocrystallization: Monitoring and controlling crystallization using ultrasound. Chem. Eng. Sci. 2020, 226, 115911,  DOI: 10.1016/j.ces.2020.115911
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    Sonocrystallization: Monitoring and controlling crystallization using ultrasound
    Prasad, Rupanjali; Dalvi, Sameer V.
    Chemical Engineering Science (2020), 226 (), 115911CODEN: CESCAC; ISSN:0009-2509. (Elsevier Ltd.)
    A review. Crystn. is an extensively used unit operation for prodn. of solid forms of inorg. and org. compds., pharmaceuticals, cosmetics, and polymers etc. However, the stochastic nature of crystn. makes it difficult to control the product characteristics such as crystal size, size distribution, morphol., polymorphism, and chirality. Use of ultrasound has been shown to greatly influence crystn. and help in gaining control over product characteristics. Ultrasonic waves generate cavitation in the soln. resulting in enhanced micromixing, increased mass transfer rates and uniform supersatn. which then lowers induction time, reduces metastable zone width, increases nucleation rates and narrows down particle size and size distribution. This review attempts to present a coherent understanding of the mechanism of sonocrystn. Further, a newly emerging field of ultrasonic spectroscopy, which is relatively unexplored but holds a tremendous potential for online monitoring of crystn., has also been discussed.
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    Leighton, T. The Acoustic Bubble; Academic Press, 2012.
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    Kaur Bhangu, S.; Ashokkumar, M.; Lee, J. Ultrasound assisted crystallization of paracetamol: crystal size distribution and polymorph control. Cryst. Growth Des. 2016, 16 (4), 1934– 1941,  DOI: 10.1021/acs.cgd.5b01470
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    Ultrasound Assisted Crystallization of Paracetamol: Crystal Size Distribution and Polymorph Control
    Kaur Bhangu, Sukhvir; Ashokkumar, Muthupandian; Lee, Judy
    Crystal Growth & Design (2016), 16 (4), 1934-1941CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
    Antisolvent crystn. of paracetamol was conducted using ultrasound. The effect of various ultrasonic frequencies and power on the mean crystal size, crystal size distribution, induction time, and type of polymorph obtained was studied. Multibubble sonoluminescence intensity was used to correlate the crystn. results with cavitation activity. Results showed that under optimum conditions ultrasound can significantly (i) reduce the mean crystal size from 170 to 13 μm, (ii) lower the induction time from 360 to 30 s, and (iii) narrow the size distribution. A close assocn. between cavitation activity and rate of nucleation was obsd. In addn., crystn. under sonication led to the formation of not only monoclinic polymorph (form I) but also orthorhombic polymorph (form II) of paracetamol, which is otherwise difficult to obtain in the absence of ultrasound.
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  16. 16
    Nguyen, T. T. H.; Khan, A.; Bruce, L. M.; Forbes, C.; O’Leary, R. L.; Price, C. J. The effect of ultrasound on the crystallisation of paracetamol in the presence of structurally similar impurities. Crystals 2017, 7 (10), 294,  DOI: 10.3390/cryst7100294
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    Gielen, B.; Kusters, P.; Jordens, J.; Thomassen, L. C. J.; Van Gerven, T.; Braeken, L. Energy efficient crystallization of paracetamol using pulsed ultrasound. Chem. Eng. Process. 2017, 114, 55– 66,  DOI: 10.1016/j.cep.2017.01.001
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    Energy efficient crystallization of paracetamol using pulsed ultrasound
    Gielen, Bjorn; Kusters, Piet; Jordens, Jeroen; Thomassen, Leen C. J.; Van Gerven, Tom; Braeken, Leen
    Chemical Engineering and Processing (2017), 114 (), 55-66CODEN: CENPEU; ISSN:0255-2701. (Elsevier B.V.)
    This work studies the use of pulsed ultrasound during cooling crystn. of paracetamol. The effect of the pulse time on the nucleation temp., crystal size and shape was evaluated and compared to silent conditions and continuous sonication. Most work is performed in a batch crystallizer, though some preliminary data in a recirculation configuration is also provided. In both setups, the nucleation temp. increased by at least 8 °C when ultrasound was applied compared to the non-sonicated case. When ultrasound is switched on more than 10% of the time, a similar nucleation temp. as with continuous treatment is obtained. At this minimal pulse setting, a bubble population, consisting of both oscillating and dissolving bubbles, is present in the vessel at all times. The pulse threshold can be validated using bubble dissoln. calcns., and its existence leads to a vast redn. in ultrasonic energy consumption compared to continuous sonication. Finally, this work shows that the final particle size of paracetamol can be controlled in the batch setup by the pulse conditions, without affecting the crystal shape. The recirculation system shows a similar response, although further validation is recommended.
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    Di Martino, P.; Conflant, P.; Drache, M.; Huvenne, J. P.; Guyot-Hermann, A. M. Preparation and physical characterization of forms II and III of paracetamol. J. Therm. Anal. Calorim. 1997, 48, 447– 458,  DOI: 10.1007/BF01979491
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    Wang, I. C.; Lee, M. J.; Seo, D. Y.; Lee, H. E.; Choi, Y.; Kim, W. S.; Kim, C. S.; Jeong, M. Y.; Choi, G. J. Polymorph transformation in paracetamol monitored by in-line NIR spectroscopy during a cooling crystallization process. AAPS PharmSciTech 2011, 12 (2), 764– 770,  DOI: 10.1208/s12249-011-9642-x
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    19
    Polymorph Transformation in Paracetamol Monitored by In-line NIR Spectroscopy During a Cooling Crystallization Process
    Wang, In-Chun; Lee, Min-Jeong; Seo, Da-Young; Lee, Hea-Eun; Choi, Yongsun; Kim, Woo-Sik; Kim, Chang-Sam; Jeong, Myung-Yung; Choi, Guang Jin
    AAPS PharmSciTech (2011), 12 (2), 764-770CODEN: AAPHFZ; ISSN:1530-9932. (Springer)
    The reliable in-line monitoring of pharmaceutical processes has been regarded as a key tool toward the full implementation of process anal. technol. In this study, near-IR (NIR) spectroscopy was examd. for use as an in-line monitoring method of the paracetamol cooling crystn. process. The drug powder was dissolved in ethanol-based cosolvent at 60° and was cooled by 1° min for crystn. NIR spectra acquired by in-line measurement were interpreted by principal component anal. combined with off-line characterizations via x-ray diffraction, optical microscopy, and transmission electron microscopy. The whole crystn. process appeared to take place in three steps. A metastable form II polymorph of paracetamol was formed and transformed into the stable form I polymorph on the way to the growth of pure form I by cooling crystn. These observations are consistent with a previous focused beam reflectance method-based study (Barthe et al., Cryst Growth Des 8:3316-3322, 2008).
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    Jordens, J.; Gielen, B.; Braeken, L.; Van Gerven, T. Determination of the effect of the ultrasonic frequency on the cooling crystallization of paracetamol. Chem. Eng. Process. 2014, 84, 38– 44,  DOI: 10.1016/j.cep.2014.01.006
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    Determination of the effect of the ultrasonic frequency on the cooling crystallization of paracetamol
    Jordens, Jeroen; Gielen, Bjorn; Braeken, Leen; Van Gerven, Tom
    Chemical Engineering and Processing (2014), 84 (), 38-44CODEN: CENPEU; ISSN:0255-2701. (Elsevier B.V.)
    This paper presents a study on the effect of ultrasonic frequency on both the nucleation and the degrdn. of paracetamol under sonication. The effect of ultrasonic irradn. was investigated for frequencies ranging from 41 to 1140 kHz. The results obtained in this paper show that the lower ultrasonic frequencies are preferable, both to enhance the nucleation rate and to limit degrdn. A redn. of the metastable zone width was obsd. in all expts. when applying ultrasound. The highest redn. was achieved at a frequency of 41 kHz and a decrease of the redn. was obsd. with increasing ultrasonic frequencies. Degrdn. was limited at a frequency of 41 kHz, while significantly higher levels of degrdn. are obsd. at higher frequencies. Radical formation seems to be the main degrdn. mechanism for all frequencies.
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  21. 21
    Kaialy, W.; Larhrib, H.; Chikwanha, B.; Shojaee, S.; Nokhodchi, A. An approach to engineer paracetamol crystals by antisolvent crystallization technique in presence of various additives for direct compression. Int. J. Pharm. 2014, 464 (1–2), 53– 64,  DOI: 10.1016/j.ijpharm.2014.01.026
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    21
    An approach to engineer paracetamol crystals by antisolvent crystallization technique in presence of various additives for direct compression
    Kaialy, Waseem; Larhrib, Hassan; Chikwanha, Brian; Shojaee, Saeed; Nokhodchi, Ali
    International Journal of Pharmaceutics (Amsterdam, Netherlands) (2014), 464 (1-2), 53-64CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
    Paracetamol is a popular over-the-counter analgesic and a challenging model drug due to its poor technol. and biopharmaceutical properties such as flowability, compressibility, compactibility and wettability. This work was aimed to alter the crystal habit of paracetamol from elongated to polyhedral-angular via particle engineering while maintaining the stable polymorphic form (form I: monoclinic form). The engineered paracetamol crystals obtained in the present investigation showed better technol. and biopharmaceutical properties in comparison to the com. paracetamol. Engineered paracetamol crystals were obtained using antisolvent crystn. technique in the presence of various concns. (0.1, 0.5 and 1%, wt./wt.) of additives, namely, polyvinyl alc. (PVA), Avicel PH 102 (microcryst. cellulose), Brij 58, methylcellulose (MC) and polyethylene glycol having different mol. wts. (PEGs 1500, 6000 and 8000). Paracetamols crystd. in the presence of Avicel (or phys. mixed with Avicel), Brij 58 and PEG 6000 demonstrated the best compactibility over a range of compaction pressures. Brij-crystd. paracetamol provided the fastest dissoln. rate among all the paracetamol batches. Paracetamols crystd. in the presence of PVA or Avicel, or phys. mixed with Avicel demonstrated a reduced degree of crystallinity in comparison to the other paracetamols. This study showed that the type, the grade and the concn. of additives could influence the phys. stability such as flow, crystallinity and polymorphic transformation of paracetamol, the technol. and biopharmaceutical properties of paracetamol. Stable polymorphic form of paracetamol with optimal tableting characteristics can be achieved through particle engineering.
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    Sibik, J.; Sargent, M. J.; Franklin, M.; Zeitler, J. A. Crystallization and phase changes in paracetamol from the amorphous solid to the liquid phase. Mol. Pharmaceutics 2014, 11 (4), 1326– 1334,  DOI: 10.1021/mp400768m
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    Crystallization and Phase Changes in Paracetamol from the Amorphous Solid to the Liquid Phase
    Sibik, Juraj; Sargent, Michael J.; Franklin, Miriam; Zeitler, J. Axel
    Molecular Pharmaceutics (2014), 11 (4), 1326-1334CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
    For the case of paracetamol, we show how terahertz time-domain spectroscopy can be used to characterize the solid and liq. phase dynamics. Heating of supercooled amorphous paracetamol from 295 K in a covered sample under vacuum leads to its crystn. at 330 K. First, form III is formed followed by the transformation of form III to form II at 375 K, to form I at 405 K, and finally melting is obsd. around 455 K. We discuss the difference between the featureless spectra of the supercooled liq. and its liq. melt. Lastly, we studied the onset of crystn. from the supercooled liq. in detail and quantified its kinetics based on the Avrami-Erofeev model. We detd. an effective rate const. of k = 0.056 min-1 with a corresponding onset of crystn. at T = 329.5 K for a heating rate of 0.4 K min-1.
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  23. 23
    Wang, I.-C.; Lee, M.-J.; Seo, D.-Y.; Lee, H.-E.; Choi, Y.; Kim, W.-S.; Kim, C.-S.; Jeong, M.-Y.; Choi, G. J. Polymorph transformation in paracetamol monitored by in-line NIR spectroscopy during a cooling crystallization process. AAPS PharmSciTech 2011, 12, 764– 770,  DOI: 10.1208/s12249-011-9642-x
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    23
    Polymorph Transformation in Paracetamol Monitored by In-line NIR Spectroscopy During a Cooling Crystallization Process
    Wang, In-Chun; Lee, Min-Jeong; Seo, Da-Young; Lee, Hea-Eun; Choi, Yongsun; Kim, Woo-Sik; Kim, Chang-Sam; Jeong, Myung-Yung; Choi, Guang Jin
    AAPS PharmSciTech (2011), 12 (2), 764-770CODEN: AAPHFZ; ISSN:1530-9932. (Springer)
    The reliable in-line monitoring of pharmaceutical processes has been regarded as a key tool toward the full implementation of process anal. technol. In this study, near-IR (NIR) spectroscopy was examd. for use as an in-line monitoring method of the paracetamol cooling crystn. process. The drug powder was dissolved in ethanol-based cosolvent at 60° and was cooled by 1° min for crystn. NIR spectra acquired by in-line measurement were interpreted by principal component anal. combined with off-line characterizations via x-ray diffraction, optical microscopy, and transmission electron microscopy. The whole crystn. process appeared to take place in three steps. A metastable form II polymorph of paracetamol was formed and transformed into the stable form I polymorph on the way to the growth of pure form I by cooling crystn. These observations are consistent with a previous focused beam reflectance method-based study (Barthe et al., Cryst Growth Des 8:3316-3322, 2008).
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    Madane, K.; Ranade, V. V. Anti-solvent crystallization: Particle size distribution with different devices. Chem. Eng. J. 2022, 446, 137235,  DOI: 10.1016/j.cej.2022.137235
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    Anti-solvent crystallization particle size distribution with different devices
    Madane, Ketan; Ranade, Vivek V.
    Chemical Engineering Journal (Amsterdam, Netherlands) (2022), 446 (Part_3), 137235CODEN: CMEJAJ; ISSN:1385-8947. (Elsevier B.V.)
    Particle size distribution (PSD) is one of the crit. attributes of crystals. PSD not only influences downstream processes but also controls final product performance in crystn. In this work, we have used the model system of methanol-water-paracetamol for carrying out anti-solvent crystn. to produce paracetamol crystals. With ref. to a base case of anti-solvent crystn. in a stirred tank, we have used three devices connected to the stirred tank with an external loop with full recycling. A peristaltic pump was used to circulate the contents of the stirred tank in an external loop comprising a simple tube, a fluidic oscillator (FO), and a vortex diode (VD). Anti-solvent was introduced at a point lying between the pump and these three devices to understand the influence of these devices on mixing and potential particle breakage. The PSD of crystals obtained with these three devices are compared with that of the base case for one supersatn. ratio (SSR = 1.63). The results indicated the potential of manipulating the PSD of crystals with a strategy of using fluidic devices in an external loop. The overall arrangement can be potentially extended to continuous crystn.
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    Chew, C. M.; Ristic, R. I.; Dennehy, R. D.; De Yoreo, J. J. Crystallization of paracetamol under oscillatory flow mixing conditions. Cryst. Growth Des. 2004, 4 (5), 1045– 1052,  DOI: 10.1021/cg049913l
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    Crystallization of Paracetamol under Oscillatory Flow Mixing Conditions
    Chew, Chun M.; Ristic, Radoljub I.; Dennehy, Robert D.; De Yoreo, James J.
    Crystal Growth & Design (2004), 4 (5), 1045-1052CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
    There has been an increasing effort in designing pharmaceutical particles with controllable properties (quality) such as chem. purity, morphol., size distribution, surface characteristics, and microstrain content. In this paper, we explore the feasibility of oscillatory flow mixing (OFM) in improving the quality of pharmaceutical ppts., using paracetamol (4-acetamidophenol) as a model system. In-situ at. force microscopy (AFM) and optical microscopy were applied to observe the growth of {110} faces of single paracetamol crystals. These studies showed that (a) the bunching and macrostep formation occur at all values of supersatn.; and (b) the oscillation of soln. with respect to the growing interface and its relative velocity are the crit. parameters for the minimization of the interfacial instabilities, and in turn, for maintaining structural quality. These findings were tested in a conventional impeller driven batch crystallizer (IDBC) and in an oscillatory baffled batch crystallizer (OBBC), in which, apart from hydrodynamics, all external conditions such as initial supersatn. and crystn. temp. were kept const. The phys. properties (the quality) of the ppts. were characterized by low angle laser light scattering (LALLS), SEM, and x-ray powder diffraction (XRPD), resp. The anal. of obtained results and their comparison for these two types of mixing shows clearly that particles pptd. in OBBC are of significantly higher quality than those produced in IDBC. A computational fluid dynamics (CFD) software package, Fluent 5, was used to model dynamical fluid patterns in both crystallizers.
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    Keshavarz, L.; Pishnamazi, M.; Khandavilli, U. B. R.; Shirazian, S.; Collins, M. N.; Walker, G. M.; Frawley, P. J. Tailoring crystal size distributions for product performance, compaction of paracetamol. Arabian J. Chem. 2021, 14 (4), 103089,  DOI: 10.1016/j.arabjc.2021.103089
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    Sauerbrey, G. Verwendung von Schwingquarzen zur Wägung dünner Schichten und zur Mikrowägung. Z. Phys. 1959, 155 (2), 206– 222,  DOI: 10.1007/BF01337937
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    The use of quartz oscillators for weighing thin layers and for microweighing
    Sauerbrey, Gunther
    Zeitschrift fuer Physik (1959), 155 (), 206-22CODEN: ZEPYAA; ISSN:0044-3328.
    The frequency of a quartz plate is altered if a layer of foreign material is deposited on the quartz, e.g. by evapn. Since changes in frequency can be measured very accurately, the phenomenon can be used for weighing thin layers. The change in frequency is proportional to the d. of the foreign layer and the proportionality const. can be calcd. from the characteristic frequency of the quartz plate. The accuracy of the method is limited by the temp. variation of the characteristic frequency of the quartz oscillator. For a temp. fluctuation of 1° the accuracy is ±4.10-9 g./cm. This corresponds to a mean thickness of the layer of 0.4 A. at a d. of 1 g./cc. The method can also be used for direct microweighing, e.g. by evapg. a drop of a soln. on the quartz plate.
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    Janshoff, A.; Galla, H. J.; Steinem, C. Piezoelectric mass-sensing devices as biosensors-an alternative to optical biosensors?. Angew. Chem., Int. Ed. 2000, 39 (22), 4004– 4032,  DOI: 10.1002/1521-3773(20001117)39:22<4004::AID-ANIE4004>3.0.CO;2-2
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    Piezoelectric mass-sensing devices as biosensors-an alternative to optical biosensors?
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    A review with 194 refs. on piezoelec. biosensors as an alternative to optical biosensors. In the early days of electronic communication-as a result of the limited no. of quartz resonators available-frequency adjustment was accomplished by a pencil mark depositing a foreign mass layer on the crystal. In 1959, Sauerbrey showed that the shift in resonance frequency of thickness-shear-mode resonators is proportional to the deposited mass. This was the starting point for the development of a new generation of piezoelec. mass-sensitive devices. However, it was the development of new powerful oscillator circuits that were capable of operating thickness shear mode resonators in fluids that enabled this technique to be introduced into bioanalytic applications. In the last decade adsorption of biomols. on functionalized surfaces turned in to one of the paramount applications of piezoelec. transducers. These applications include the study of the interaction of DNA and RNA with complementary strands, specific recognition of protein ligands by immobilized receptors, the detection of virus capsids, bacteria, mammalian cells, and last but not least the development of complete immunosensors. Piezoelec. transducers allow a label-free detection of mols.; they are more than mere mass sensors since the sensor response is also influenced by interfacial phenomena, viscoelastic properties of the adhered biomaterial, surface charges of adsorbed mols., and surface roughness. These new insights have recently been used to investigate the adhesion of cells, liposomes, and proteins onto surfaces, thus allowing the detn. of the morphol. changes of cells as a response to pharmacol. substances and changes in the water content of biopolymers without employing labor-intense techniques. However, the future will show whether the quartz-crystal microbalance will assert itself against established label-free sensor devices such as surface plasmon resonance spectroscopy and interferometry.
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    Modelling of vortex based hydrodynamic cavitation reactors
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    Chemical Engineering Journal (Amsterdam, Netherlands) (2019), 377 (), 119639CODEN: CMEJAJ; ISSN:1385-8947. (Elsevier B.V.)
    Vortex based hydrodynamic cavitation reactors offer various advantages like early inception, less erosion and higher cavitational yield. No systematic modeling efforts have been reported to interpret the cavitation performance of these vortex based devices for cavitation. It is essential to develop a modeling framework for describing performance of cavitation reactors. We have addressed this need in the present work. A comprehensive modeling framework comprising three layers: per - pass performance models (overall process), computational fluid dynamics models (flow on reactor scale) and cavity dynamics models (cavity scale) is developed. The approach and computational models were evaluated using the exptl. data on treatment of acetone-contaminated water. The presented models were successful in describing the exptl. data using initial cavity size as an adjustable parameter. Efforts were made to quantify optimum operating conditions and scale-up. The developed approach, models and results will provide useful design guidelines for pollutant degrdn. using vortex based cavitation reactors. It will also provide a sound and useful basis for comprehensive multi-scale modeling of hydrodynamic cavitation reactors.
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    Ranade, V. V.; Prasad Sarvothaman, V.; Simpson, A.; Nagarajan, S. Scale-up of vortex based hydrodynamic cavitation devices: A case of degradation of di-chloro aniline in water. Ultrason. Sonochem. 2021, 70, 105295,  DOI: 10.1016/j.ultsonch.2020.105295
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    Scale-up of vortex based hydrodynamic cavitation devices: A case of degradation of di-chloro aniline in water
    Ranade, Vivek V.; Prasad Sarvothaman, Varaha; Simpson, Alister; Nagarajan, Sanjay
    Ultrasonics Sonochemistry (2021), 70 (), 105295CODEN: ULSOER; ISSN:1350-4177. (Elsevier B.V.)
    Hydrodynamic cavitation (HC) is being increasingly used in a wide range of applications. Unlike ultrasonic cavitation, HC is scalable and has been used at large scale industrial applications. However, no information about influence of scale on performance of HC is available in the open literature. In this work, we present for the first time, exptl. data on use of HC for degrdn. of complex org. pollutants in water on four different scales (∼200 times scale-up in terms of capacity). Vortex based HC devices offer various advantages like early inception, high cavitational yield and significantly lower propensity to clogging and erosion. We have used vortex based HC devices in this work. 2,4 dichloroaniline (DCA) - an arom. compd. with multiple functional groups was considered as a model pollutant. Degrdn. of DCA in water was performed using vortex-based HC devices with characteristic throat dimension, dt as 3, 6, 12 and 38 mm with scale-up of almost 200 time based on the flow rates (1.3 to 247 LPM). Considering the exptl. constraints on operating the largest scale HC device, the exptl. data is presented here at only one value of pressure drop across HC device (280 kPa). A previously used per-pass degrdn. model was extended to describe the exptl. data for the pollutant used in this study and a generalized form is presented. The degrdn. performance was found to decrease with increase in the scale and then plateaus. Appropriate correlation was developed based on the exptl. data. The developed approach and presented results provide a sound basis and a data set for further development of comprehensive multi-scale modeling of HC devices.
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    Ultrasound-assisted crystn. (sonocrystn.) was used to prep. a mixt. of nano- and micrometer-sized crystals of the monoclinic form of paracetamol-a widely used analgesic known for its particularly problematic mech. behavior under compression (i.e. poor tabletability). The nano- and micrometer-sized crystals yielded a powder which exhibits elastic moduli and bulk cohesions that are significantly higher than those obsd. in samples consisting of macrometer-sized crystals, thus leading to enhanced tabletability without the use of excipients, particle coating, salt, or cocrystal formation. Exptl. compaction and finite element anal. were utilized to rationalize the significantly improved compaction behavior of the monoclinic form of paracetamol.
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    Model for Interpreting Surface Crystallization Using Quartz Crystal Microbalance: Theory and Experiments
    Lapidot, Tomer; Sedransk Campbell, Kyra L.; Heng, Jerry Y. Y.
    Analytical Chemistry (Washington, DC, United States) (2016), 88 (9), 4886-4893CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    Surface crystn. of calcium sulfate was investigated using a dissipation crystal quartz microbalance (QCM-D) together with microscopy to understand the mech. property changes occurring during the growth process. The use of optical microscopy and SEM revealed that needle-shaped crystals grow as clusters on the QCM sensor's surface, not in uniform layers. As crystn. growth progressed, QCM-D revealed inversions between neg. and pos. frequency shifts. This behavior, a function of the growth of crystals in clusters, is not adequately predicted by existing models. As such, a new mass-to-frequency conversion model is proposed herein to explain the obsd. frequency inversions. This model is derived from a lumped element approach with point-contact loading and Mason equiv. circuit theory. Critically, the phys. phenomena occurring form the basis of the model, particularly addressing the three sources of impedance. When a crystal nucleates and grows, its inertial impedance is considered along with a Kelvin-Voigt link with a hydration layer. A comparison between the proposed model and exptl. data, of both frequency and dissipation data for the first four harmonics, shows good agreement for the supersaturations (S = C/C*) of S = 3.75, S = 3.48, and S = 3.22. Addnl., significant improvements over existing models for the case of surface crystn. are obsd. The proposed model was therefore able to explain that frequency inversions are caused by a shift from inertia-dominated to elastic-dominated impedance, occurring as a result of crystal growth. Using the nucleation induction time and nucleation rates, detd. with imaging, an addnl. understanding of the crystals' mech. properties (stiffness and dampening) was obtained.
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  • Abstract

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    Figure 1

    Figure 1. Geometry of the vortex-based hydrodynamic reactor (Reproduced with permission from [37], Copyright [2019] [John Wiley and Sons], Simpson and Ranade (37)) and schematic of the experimental setup employed in this work.

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    Figure 2

    Figure 2. Paracetamol crystals induced by (a) UC-based processing and (b) HC-based processing.

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    Figure 3

    Figure 3. XRD results for (a) UC- and (b) HC-based processing.

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    Figure 4

    Figure 4. DSC results for (a) UC- and (b) HC-based processing.

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    Figure 5

    Figure 5. QCM-D results for (a) UC- and (b) HC-based processing.

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  • References

    This article references 49 other publications.

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      The pos. influence of ultrasound (US) on crystn. processes is shown by the dramatic redn. of the induction period, supersatn. conditions and metastable zone width. Manipulation of this influence can be achieved by changing US-related variables such as frequency, intensity, power and even geometrical characteristics of the ultrasonic device (e.g. horn type size). The vol. of the sonicated soln. and irradn. time are also variables to be optimized in a case-by-case basis as the mechanisms of US action on crystn. remain to be established. Nevertheless, the results obtained so far make foreseeable that crystal size distribution, and even crystal shape, can be tailored' by appropriate selection of the sonication conditions.
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    4. 4
      Keshavarz, L.; Pishnamazi, M.; Rao Khandavilli, U. B.; Shirazian, S.; Collins, M. N.; Walker, G. M.; Frawley, P. J. Tailoring crystal size distributions for product performance, compaction of paracetamol. Arabian J. Chem. 2021, 14 (4), 103089,  DOI: 10.1016/j.arabjc.2021.103089
      There is no corresponding record for this reference.
    5. 5
      Nalajala, V. S.; Moholkar, V. S. Investigations in the physical mechanism of sonocrystallization. Ultrason. Sonochem. 2011, 18 (1), 345– 355,  DOI: 10.1016/j.ultsonch.2010.06.016
      There is no corresponding record for this reference.
    6. 6
      Oxtoby, D. W. Crystal nucleation in simple and complex fluids. Philos. Trans. R. Soc., A 2003, 361 (1804), 419– 428,  DOI: 10.1098/rsta.2002.1145
      There is no corresponding record for this reference.
    7. 7
      Chadha, R.; Gupta, S.; Shukla, G. Crystal habit, characterization and pharmacological activity of various crystal forms of arteether. Acta Pharm. Sin. B 2011, 1 (2), 129– 135,  DOI: 10.1016/j.apsb.2011.06.010
      There is no corresponding record for this reference.
    8. 8
      Krycer, I.; Pope, D. G.; Hersey, J. A. The prediction of paracetamol capping tendencies. J. Pharm. Pharmacol. 1982, 34 (12), 802– 804,  DOI: 10.1111/j.2042-7158.1982.tb06229.x
      There is no corresponding record for this reference.
    9. 9
      Bauer, J.; Spanton, S.; Henry, R.; Quick, J.; Dziki, W.; Porter, W.; Morris, J. Ritonavir: an extraordinary example of conformational polymorphism. Pharm. Res. 2001, 18, 859– 866,  DOI: 10.1023/A:1011052932607
      9
      Ritonavir: an extraordinary example of conformational polymorphism
      Bauer, John; Spanton, Stephen; Henry, Rodger; Quick, John; Dziki, Walter; Porter, William; Morris, John
      Pharmaceutical Research (2001), 18 (6), 859-866CODEN: PHREEB; ISSN:0724-8741. (Kluwer Academic/Plenum Publishers)
      Purpose. In the summer of 1998, Norvir semi-solid capsules supplies were threatened as a result of a new much less sol. crystal form of ritonavir. This report provides characterization of the 2 polymorphs and the structures and hydrogen bonding network for each form. Methods. Ritonavir polymorphism was investigated by solid state spectroscopy and microscopy techniques including solid state NMR, near-IR Spectroscopy, powder x-ray Diffraction and single crystal x-ray. A sensitive seed detection test was developed. Results. Ritonavir polymorphs were thoroughly characterized and the structures detd. An unusual conformation was found for form II that results in a strong hydrogen bonding network. A possible mechanism for heterogeneous nucleation of form II was investigated. Conclusions. Ritonavir exhibited conformational polymorphism with two unique crystal lattices having significantly different soly. properties. Although the polymorph (form II) corresponding to the "cis" conformation is a more stable packing arrangement, nucleation, even in the presence of form II seeds, is energetically unfavored except in highly supersatd. solns. The coincidence of a highly supersatd. soln. and a probable heterogeneous nucleation by a degrdn. product resulted in the sudden appearance of the more stable form II polymorph.
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    10. 10
      Astier, J.-P.; Veesler, S. Using Temperature To Crystallize Proteins: A Mini-Review. Cryst. Growth Des. 2008, 8 (12), 4215– 4219,  DOI: 10.1021/cg800665b
      10
      Using Temperature To Crystallize Proteins: A Mini-Review
      Astier, Jean-Pierre; Veesler, Stephane
      Crystal Growth & Design (2008), 8 (12), 4215-4219CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
      A review. The aim of this overview is to provide biocrystallographs that intend to tackle crystn. with practical examples of the effect of temp. on protein phase sepn. and crystn. Crystn. involves two sep. processes: nucleation and growth, which are rarely completely unconnected. Here, the authors give four concrete examples illustrating how temp. can be used to crystallize proteins. The authors describe the nucleation of a new phase, solid or liq. and the growth and transformation of existing crystals obtained by seeding or primary or secondary nucleation. The advantages of temp. as a crystn. parameter are const. compn., ease of control and monitoring and reversibility.
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    11. 11
      Nývlt, J. Design of batch crystallizers. In Industrial Crystallization; Springer, 1976; pp 335– 342.
      There is no corresponding record for this reference.
    12. 12
      McCausland, L. J.; Cains, P. W.; Martin, P. D. Use the power of sonocrystallization for improved properties. Chem. Eng. Prog. 2001, 97 (7), 56– 61
      12
      Use the power of sonocrystallization for improved properties
      McCausland, Linda J.; Cains, Peter W.; Martin, Peter D.
      Chemical Engineering Progress (2001), 97 (7), 56-61CODEN: CEPRA8; ISSN:0360-7275. (American Institute of Chemical Engineers)
      A review, with 8 refs., of the title subject, including ultrasonic cavitation, cavitation and nucleation, modification and control of properties, ultrasonic equipment, scaled-up units, and large-scale batch crystn.
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    13. 13
      Prasad, R.; Dalvi, S. V. Sonocrystallization: Monitoring and controlling crystallization using ultrasound. Chem. Eng. Sci. 2020, 226, 115911,  DOI: 10.1016/j.ces.2020.115911
      13
      Sonocrystallization: Monitoring and controlling crystallization using ultrasound
      Prasad, Rupanjali; Dalvi, Sameer V.
      Chemical Engineering Science (2020), 226 (), 115911CODEN: CESCAC; ISSN:0009-2509. (Elsevier Ltd.)
      A review. Crystn. is an extensively used unit operation for prodn. of solid forms of inorg. and org. compds., pharmaceuticals, cosmetics, and polymers etc. However, the stochastic nature of crystn. makes it difficult to control the product characteristics such as crystal size, size distribution, morphol., polymorphism, and chirality. Use of ultrasound has been shown to greatly influence crystn. and help in gaining control over product characteristics. Ultrasonic waves generate cavitation in the soln. resulting in enhanced micromixing, increased mass transfer rates and uniform supersatn. which then lowers induction time, reduces metastable zone width, increases nucleation rates and narrows down particle size and size distribution. This review attempts to present a coherent understanding of the mechanism of sonocrystn. Further, a newly emerging field of ultrasonic spectroscopy, which is relatively unexplored but holds a tremendous potential for online monitoring of crystn., has also been discussed.
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    14. 14
      Leighton, T. The Acoustic Bubble; Academic Press, 2012.
      There is no corresponding record for this reference.
    15. 15
      Kaur Bhangu, S.; Ashokkumar, M.; Lee, J. Ultrasound assisted crystallization of paracetamol: crystal size distribution and polymorph control. Cryst. Growth Des. 2016, 16 (4), 1934– 1941,  DOI: 10.1021/acs.cgd.5b01470
      15
      Ultrasound Assisted Crystallization of Paracetamol: Crystal Size Distribution and Polymorph Control
      Kaur Bhangu, Sukhvir; Ashokkumar, Muthupandian; Lee, Judy
      Crystal Growth & Design (2016), 16 (4), 1934-1941CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
      Antisolvent crystn. of paracetamol was conducted using ultrasound. The effect of various ultrasonic frequencies and power on the mean crystal size, crystal size distribution, induction time, and type of polymorph obtained was studied. Multibubble sonoluminescence intensity was used to correlate the crystn. results with cavitation activity. Results showed that under optimum conditions ultrasound can significantly (i) reduce the mean crystal size from 170 to 13 μm, (ii) lower the induction time from 360 to 30 s, and (iii) narrow the size distribution. A close assocn. between cavitation activity and rate of nucleation was obsd. In addn., crystn. under sonication led to the formation of not only monoclinic polymorph (form I) but also orthorhombic polymorph (form II) of paracetamol, which is otherwise difficult to obtain in the absence of ultrasound.
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    16. 16
      Nguyen, T. T. H.; Khan, A.; Bruce, L. M.; Forbes, C.; O’Leary, R. L.; Price, C. J. The effect of ultrasound on the crystallisation of paracetamol in the presence of structurally similar impurities. Crystals 2017, 7 (10), 294,  DOI: 10.3390/cryst7100294
      There is no corresponding record for this reference.
    17. 17
      Gielen, B.; Kusters, P.; Jordens, J.; Thomassen, L. C. J.; Van Gerven, T.; Braeken, L. Energy efficient crystallization of paracetamol using pulsed ultrasound. Chem. Eng. Process. 2017, 114, 55– 66,  DOI: 10.1016/j.cep.2017.01.001
      17
      Energy efficient crystallization of paracetamol using pulsed ultrasound
      Gielen, Bjorn; Kusters, Piet; Jordens, Jeroen; Thomassen, Leen C. J.; Van Gerven, Tom; Braeken, Leen
      Chemical Engineering and Processing (2017), 114 (), 55-66CODEN: CENPEU; ISSN:0255-2701. (Elsevier B.V.)
      This work studies the use of pulsed ultrasound during cooling crystn. of paracetamol. The effect of the pulse time on the nucleation temp., crystal size and shape was evaluated and compared to silent conditions and continuous sonication. Most work is performed in a batch crystallizer, though some preliminary data in a recirculation configuration is also provided. In both setups, the nucleation temp. increased by at least 8 °C when ultrasound was applied compared to the non-sonicated case. When ultrasound is switched on more than 10% of the time, a similar nucleation temp. as with continuous treatment is obtained. At this minimal pulse setting, a bubble population, consisting of both oscillating and dissolving bubbles, is present in the vessel at all times. The pulse threshold can be validated using bubble dissoln. calcns., and its existence leads to a vast redn. in ultrasonic energy consumption compared to continuous sonication. Finally, this work shows that the final particle size of paracetamol can be controlled in the batch setup by the pulse conditions, without affecting the crystal shape. The recirculation system shows a similar response, although further validation is recommended.
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    18. 18
      Di Martino, P.; Conflant, P.; Drache, M.; Huvenne, J. P.; Guyot-Hermann, A. M. Preparation and physical characterization of forms II and III of paracetamol. J. Therm. Anal. Calorim. 1997, 48, 447– 458,  DOI: 10.1007/BF01979491
      There is no corresponding record for this reference.
    19. 19
      Wang, I. C.; Lee, M. J.; Seo, D. Y.; Lee, H. E.; Choi, Y.; Kim, W. S.; Kim, C. S.; Jeong, M. Y.; Choi, G. J. Polymorph transformation in paracetamol monitored by in-line NIR spectroscopy during a cooling crystallization process. AAPS PharmSciTech 2011, 12 (2), 764– 770,  DOI: 10.1208/s12249-011-9642-x
      19
      Polymorph Transformation in Paracetamol Monitored by In-line NIR Spectroscopy During a Cooling Crystallization Process
      Wang, In-Chun; Lee, Min-Jeong; Seo, Da-Young; Lee, Hea-Eun; Choi, Yongsun; Kim, Woo-Sik; Kim, Chang-Sam; Jeong, Myung-Yung; Choi, Guang Jin
      AAPS PharmSciTech (2011), 12 (2), 764-770CODEN: AAPHFZ; ISSN:1530-9932. (Springer)
      The reliable in-line monitoring of pharmaceutical processes has been regarded as a key tool toward the full implementation of process anal. technol. In this study, near-IR (NIR) spectroscopy was examd. for use as an in-line monitoring method of the paracetamol cooling crystn. process. The drug powder was dissolved in ethanol-based cosolvent at 60° and was cooled by 1° min for crystn. NIR spectra acquired by in-line measurement were interpreted by principal component anal. combined with off-line characterizations via x-ray diffraction, optical microscopy, and transmission electron microscopy. The whole crystn. process appeared to take place in three steps. A metastable form II polymorph of paracetamol was formed and transformed into the stable form I polymorph on the way to the growth of pure form I by cooling crystn. These observations are consistent with a previous focused beam reflectance method-based study (Barthe et al., Cryst Growth Des 8:3316-3322, 2008).
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    20. 20
      Jordens, J.; Gielen, B.; Braeken, L.; Van Gerven, T. Determination of the effect of the ultrasonic frequency on the cooling crystallization of paracetamol. Chem. Eng. Process. 2014, 84, 38– 44,  DOI: 10.1016/j.cep.2014.01.006
      20
      Determination of the effect of the ultrasonic frequency on the cooling crystallization of paracetamol
      Jordens, Jeroen; Gielen, Bjorn; Braeken, Leen; Van Gerven, Tom
      Chemical Engineering and Processing (2014), 84 (), 38-44CODEN: CENPEU; ISSN:0255-2701. (Elsevier B.V.)
      This paper presents a study on the effect of ultrasonic frequency on both the nucleation and the degrdn. of paracetamol under sonication. The effect of ultrasonic irradn. was investigated for frequencies ranging from 41 to 1140 kHz. The results obtained in this paper show that the lower ultrasonic frequencies are preferable, both to enhance the nucleation rate and to limit degrdn. A redn. of the metastable zone width was obsd. in all expts. when applying ultrasound. The highest redn. was achieved at a frequency of 41 kHz and a decrease of the redn. was obsd. with increasing ultrasonic frequencies. Degrdn. was limited at a frequency of 41 kHz, while significantly higher levels of degrdn. are obsd. at higher frequencies. Radical formation seems to be the main degrdn. mechanism for all frequencies.
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    21. 21
      Kaialy, W.; Larhrib, H.; Chikwanha, B.; Shojaee, S.; Nokhodchi, A. An approach to engineer paracetamol crystals by antisolvent crystallization technique in presence of various additives for direct compression. Int. J. Pharm. 2014, 464 (1–2), 53– 64,  DOI: 10.1016/j.ijpharm.2014.01.026
      21
      An approach to engineer paracetamol crystals by antisolvent crystallization technique in presence of various additives for direct compression
      Kaialy, Waseem; Larhrib, Hassan; Chikwanha, Brian; Shojaee, Saeed; Nokhodchi, Ali
      International Journal of Pharmaceutics (Amsterdam, Netherlands) (2014), 464 (1-2), 53-64CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
      Paracetamol is a popular over-the-counter analgesic and a challenging model drug due to its poor technol. and biopharmaceutical properties such as flowability, compressibility, compactibility and wettability. This work was aimed to alter the crystal habit of paracetamol from elongated to polyhedral-angular via particle engineering while maintaining the stable polymorphic form (form I: monoclinic form). The engineered paracetamol crystals obtained in the present investigation showed better technol. and biopharmaceutical properties in comparison to the com. paracetamol. Engineered paracetamol crystals were obtained using antisolvent crystn. technique in the presence of various concns. (0.1, 0.5 and 1%, wt./wt.) of additives, namely, polyvinyl alc. (PVA), Avicel PH 102 (microcryst. cellulose), Brij 58, methylcellulose (MC) and polyethylene glycol having different mol. wts. (PEGs 1500, 6000 and 8000). Paracetamols crystd. in the presence of Avicel (or phys. mixed with Avicel), Brij 58 and PEG 6000 demonstrated the best compactibility over a range of compaction pressures. Brij-crystd. paracetamol provided the fastest dissoln. rate among all the paracetamol batches. Paracetamols crystd. in the presence of PVA or Avicel, or phys. mixed with Avicel demonstrated a reduced degree of crystallinity in comparison to the other paracetamols. This study showed that the type, the grade and the concn. of additives could influence the phys. stability such as flow, crystallinity and polymorphic transformation of paracetamol, the technol. and biopharmaceutical properties of paracetamol. Stable polymorphic form of paracetamol with optimal tableting characteristics can be achieved through particle engineering.
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    22. 22
      Sibik, J.; Sargent, M. J.; Franklin, M.; Zeitler, J. A. Crystallization and phase changes in paracetamol from the amorphous solid to the liquid phase. Mol. Pharmaceutics 2014, 11 (4), 1326– 1334,  DOI: 10.1021/mp400768m
      22
      Crystallization and Phase Changes in Paracetamol from the Amorphous Solid to the Liquid Phase
      Sibik, Juraj; Sargent, Michael J.; Franklin, Miriam; Zeitler, J. Axel
      Molecular Pharmaceutics (2014), 11 (4), 1326-1334CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      For the case of paracetamol, we show how terahertz time-domain spectroscopy can be used to characterize the solid and liq. phase dynamics. Heating of supercooled amorphous paracetamol from 295 K in a covered sample under vacuum leads to its crystn. at 330 K. First, form III is formed followed by the transformation of form III to form II at 375 K, to form I at 405 K, and finally melting is obsd. around 455 K. We discuss the difference between the featureless spectra of the supercooled liq. and its liq. melt. Lastly, we studied the onset of crystn. from the supercooled liq. in detail and quantified its kinetics based on the Avrami-Erofeev model. We detd. an effective rate const. of k = 0.056 min-1 with a corresponding onset of crystn. at T = 329.5 K for a heating rate of 0.4 K min-1.
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    23. 23
      Wang, I.-C.; Lee, M.-J.; Seo, D.-Y.; Lee, H.-E.; Choi, Y.; Kim, W.-S.; Kim, C.-S.; Jeong, M.-Y.; Choi, G. J. Polymorph transformation in paracetamol monitored by in-line NIR spectroscopy during a cooling crystallization process. AAPS PharmSciTech 2011, 12, 764– 770,  DOI: 10.1208/s12249-011-9642-x
      23
      Polymorph Transformation in Paracetamol Monitored by In-line NIR Spectroscopy During a Cooling Crystallization Process
      Wang, In-Chun; Lee, Min-Jeong; Seo, Da-Young; Lee, Hea-Eun; Choi, Yongsun; Kim, Woo-Sik; Kim, Chang-Sam; Jeong, Myung-Yung; Choi, Guang Jin
      AAPS PharmSciTech (2011), 12 (2), 764-770CODEN: AAPHFZ; ISSN:1530-9932. (Springer)
      The reliable in-line monitoring of pharmaceutical processes has been regarded as a key tool toward the full implementation of process anal. technol. In this study, near-IR (NIR) spectroscopy was examd. for use as an in-line monitoring method of the paracetamol cooling crystn. process. The drug powder was dissolved in ethanol-based cosolvent at 60° and was cooled by 1° min for crystn. NIR spectra acquired by in-line measurement were interpreted by principal component anal. combined with off-line characterizations via x-ray diffraction, optical microscopy, and transmission electron microscopy. The whole crystn. process appeared to take place in three steps. A metastable form II polymorph of paracetamol was formed and transformed into the stable form I polymorph on the way to the growth of pure form I by cooling crystn. These observations are consistent with a previous focused beam reflectance method-based study (Barthe et al., Cryst Growth Des 8:3316-3322, 2008).
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    24. 24
      Madane, K.; Ranade, V. V. Anti-solvent crystallization: Particle size distribution with different devices. Chem. Eng. J. 2022, 446, 137235,  DOI: 10.1016/j.cej.2022.137235
      24
      Anti-solvent crystallization particle size distribution with different devices
      Madane, Ketan; Ranade, Vivek V.
      Chemical Engineering Journal (Amsterdam, Netherlands) (2022), 446 (Part_3), 137235CODEN: CMEJAJ; ISSN:1385-8947. (Elsevier B.V.)
      Particle size distribution (PSD) is one of the crit. attributes of crystals. PSD not only influences downstream processes but also controls final product performance in crystn. In this work, we have used the model system of methanol-water-paracetamol for carrying out anti-solvent crystn. to produce paracetamol crystals. With ref. to a base case of anti-solvent crystn. in a stirred tank, we have used three devices connected to the stirred tank with an external loop with full recycling. A peristaltic pump was used to circulate the contents of the stirred tank in an external loop comprising a simple tube, a fluidic oscillator (FO), and a vortex diode (VD). Anti-solvent was introduced at a point lying between the pump and these three devices to understand the influence of these devices on mixing and potential particle breakage. The PSD of crystals obtained with these three devices are compared with that of the base case for one supersatn. ratio (SSR = 1.63). The results indicated the potential of manipulating the PSD of crystals with a strategy of using fluidic devices in an external loop. The overall arrangement can be potentially extended to continuous crystn.
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    25. 25
      Chew, C. M.; Ristic, R. I.; Dennehy, R. D.; De Yoreo, J. J. Crystallization of paracetamol under oscillatory flow mixing conditions. Cryst. Growth Des. 2004, 4 (5), 1045– 1052,  DOI: 10.1021/cg049913l
      25
      Crystallization of Paracetamol under Oscillatory Flow Mixing Conditions
      Chew, Chun M.; Ristic, Radoljub I.; Dennehy, Robert D.; De Yoreo, James J.
      Crystal Growth & Design (2004), 4 (5), 1045-1052CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
      There has been an increasing effort in designing pharmaceutical particles with controllable properties (quality) such as chem. purity, morphol., size distribution, surface characteristics, and microstrain content. In this paper, we explore the feasibility of oscillatory flow mixing (OFM) in improving the quality of pharmaceutical ppts., using paracetamol (4-acetamidophenol) as a model system. In-situ at. force microscopy (AFM) and optical microscopy were applied to observe the growth of {110} faces of single paracetamol crystals. These studies showed that (a) the bunching and macrostep formation occur at all values of supersatn.; and (b) the oscillation of soln. with respect to the growing interface and its relative velocity are the crit. parameters for the minimization of the interfacial instabilities, and in turn, for maintaining structural quality. These findings were tested in a conventional impeller driven batch crystallizer (IDBC) and in an oscillatory baffled batch crystallizer (OBBC), in which, apart from hydrodynamics, all external conditions such as initial supersatn. and crystn. temp. were kept const. The phys. properties (the quality) of the ppts. were characterized by low angle laser light scattering (LALLS), SEM, and x-ray powder diffraction (XRPD), resp. The anal. of obtained results and their comparison for these two types of mixing shows clearly that particles pptd. in OBBC are of significantly higher quality than those produced in IDBC. A computational fluid dynamics (CFD) software package, Fluent 5, was used to model dynamical fluid patterns in both crystallizers.
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    26. 26
      Keshavarz, L.; Pishnamazi, M.; Khandavilli, U. B. R.; Shirazian, S.; Collins, M. N.; Walker, G. M.; Frawley, P. J. Tailoring crystal size distributions for product performance, compaction of paracetamol. Arabian J. Chem. 2021, 14 (4), 103089,  DOI: 10.1016/j.arabjc.2021.103089
      There is no corresponding record for this reference.
    27. 27
      Sauerbrey, G. Verwendung von Schwingquarzen zur Wägung dünner Schichten und zur Mikrowägung. Z. Phys. 1959, 155 (2), 206– 222,  DOI: 10.1007/BF01337937
      27
      The use of quartz oscillators for weighing thin layers and for microweighing
      Sauerbrey, Gunther
      Zeitschrift fuer Physik (1959), 155 (), 206-22CODEN: ZEPYAA; ISSN:0044-3328.
      The frequency of a quartz plate is altered if a layer of foreign material is deposited on the quartz, e.g. by evapn. Since changes in frequency can be measured very accurately, the phenomenon can be used for weighing thin layers. The change in frequency is proportional to the d. of the foreign layer and the proportionality const. can be calcd. from the characteristic frequency of the quartz plate. The accuracy of the method is limited by the temp. variation of the characteristic frequency of the quartz oscillator. For a temp. fluctuation of 1° the accuracy is ±4.10-9 g./cm. This corresponds to a mean thickness of the layer of 0.4 A. at a d. of 1 g./cc. The method can also be used for direct microweighing, e.g. by evapg. a drop of a soln. on the quartz plate.
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    28. 28
      Janshoff, A.; Galla, H. J.; Steinem, C. Piezoelectric mass-sensing devices as biosensors-an alternative to optical biosensors?. Angew. Chem., Int. Ed. 2000, 39 (22), 4004– 4032,  DOI: 10.1002/1521-3773(20001117)39:22<4004::AID-ANIE4004>3.0.CO;2-2
      28
      Piezoelectric mass-sensing devices as biosensors-an alternative to optical biosensors?
      Janshoff, Andreas; Galla, Hans-Joachim; Steinem, Claudia
      Angewandte Chemie, International Edition (2000), 39 (22), 4004-4032CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH)
      A review with 194 refs. on piezoelec. biosensors as an alternative to optical biosensors. In the early days of electronic communication-as a result of the limited no. of quartz resonators available-frequency adjustment was accomplished by a pencil mark depositing a foreign mass layer on the crystal. In 1959, Sauerbrey showed that the shift in resonance frequency of thickness-shear-mode resonators is proportional to the deposited mass. This was the starting point for the development of a new generation of piezoelec. mass-sensitive devices. However, it was the development of new powerful oscillator circuits that were capable of operating thickness shear mode resonators in fluids that enabled this technique to be introduced into bioanalytic applications. In the last decade adsorption of biomols. on functionalized surfaces turned in to one of the paramount applications of piezoelec. transducers. These applications include the study of the interaction of DNA and RNA with complementary strands, specific recognition of protein ligands by immobilized receptors, the detection of virus capsids, bacteria, mammalian cells, and last but not least the development of complete immunosensors. Piezoelec. transducers allow a label-free detection of mols.; they are more than mere mass sensors since the sensor response is also influenced by interfacial phenomena, viscoelastic properties of the adhered biomaterial, surface charges of adsorbed mols., and surface roughness. These new insights have recently been used to investigate the adhesion of cells, liposomes, and proteins onto surfaces, thus allowing the detn. of the morphol. changes of cells as a response to pharmacol. substances and changes in the water content of biopolymers without employing labor-intense techniques. However, the future will show whether the quartz-crystal microbalance will assert itself against established label-free sensor devices such as surface plasmon resonance spectroscopy and interferometry.
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    29. 29
      Xiang, C.; Xie, Q.; Hu, J.; Yao, S. Studies on electrochemical copolymerization of aniline with o-phenylenediamine and degradation of the resultant copolymers via electrochemical quartz crystal microbalance and scanning electrochemical microscope. Synth. Met. 2006, 156 (5–6), 444– 453,  DOI: 10.1016/j.synthmet.2006.01.010
      There is no corresponding record for this reference.
    30. 30
      Snook, G. A.; Chen, G. Z. The measurement of specific capacitances of conducting polymers using the quartz crystal microbalance. J. Electroanal. Chem. 2008, 612 (1), 140– 146,  DOI: 10.1016/j.jelechem.2007.08.024
      There is no corresponding record for this reference.
    31. 31
      Madhumitha, D.; Dhathathreyan, A. Interaction of Myoglobin colloids with BSA in solution: Insights into complex formation and elastic compliance. Int. J. Biol. Macromol. 2017, 105, 1259– 1268,  DOI: 10.1016/j.ijbiomac.2017.07.157
      There is no corresponding record for this reference.
    32. 32
      Dhanasekaran, M.; Jaganathan, M.; Dhathathreyan, A. Colloids versus solution state adsorption of proteins: Interaction of Myoglobin with supported lipid bilayers. Int. J. Biol. Macromol. 2018, 114, 434– 440,  DOI: 10.1016/j.ijbiomac.2018.03.078
      There is no corresponding record for this reference.
    33. 33
      Liu, L.-S.; Kim, J.-M.; Kim, W.-S. Quartz Crystal Microbalance Technique for in Situ Analysis of Supersaturation in Cooling Crystallization. Anal. Chem. 2016, 88 (11), 5718– 5724,  DOI: 10.1021/acs.analchem.5b04609
      There is no corresponding record for this reference.
    34. 34
      Sarvothaman, V. P.; Velisoju, V. K.; Subburaj, J.; Panithasan, M. S.; Kulkarni, S. R.; Castaño, P.; Turner, J.; Guida, P.; Roberts, W. L.; Nagarajan, S. Is cavitation a truly sensible choice for intensifying photocatalytic oxidation processes?–Implications on phenol degradation using ZnO photocatalysts. Ultrason. Sonochem. 2023, 99, 106548,  DOI: 10.1016/j.ultsonch.2023.106548
      There is no corresponding record for this reference.
    35. 35
      Sarvothaman, V. P.; Simpson, A. T.; Ranade, V. V. Modelling of vortex based hydrodynamic cavitation reactors. Chem. Eng. J. 2019, 377, 119639,  DOI: 10.1016/j.cej.2018.08.025
      35
      Modelling of vortex based hydrodynamic cavitation reactors
      Sarvothaman, Varaha Prasad; Simpson, Alister Thomas; Ranade, Vivek Vinayak
      Chemical Engineering Journal (Amsterdam, Netherlands) (2019), 377 (), 119639CODEN: CMEJAJ; ISSN:1385-8947. (Elsevier B.V.)
      Vortex based hydrodynamic cavitation reactors offer various advantages like early inception, less erosion and higher cavitational yield. No systematic modeling efforts have been reported to interpret the cavitation performance of these vortex based devices for cavitation. It is essential to develop a modeling framework for describing performance of cavitation reactors. We have addressed this need in the present work. A comprehensive modeling framework comprising three layers: per - pass performance models (overall process), computational fluid dynamics models (flow on reactor scale) and cavity dynamics models (cavity scale) is developed. The approach and computational models were evaluated using the exptl. data on treatment of acetone-contaminated water. The presented models were successful in describing the exptl. data using initial cavity size as an adjustable parameter. Efforts were made to quantify optimum operating conditions and scale-up. The developed approach, models and results will provide useful design guidelines for pollutant degrdn. using vortex based cavitation reactors. It will also provide a sound and useful basis for comprehensive multi-scale modeling of hydrodynamic cavitation reactors.
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    36. 36
      Ranade, V. V.; Prasad Sarvothaman, V.; Simpson, A.; Nagarajan, S. Scale-up of vortex based hydrodynamic cavitation devices: A case of degradation of di-chloro aniline in water. Ultrason. Sonochem. 2021, 70, 105295,  DOI: 10.1016/j.ultsonch.2020.105295
      36
      Scale-up of vortex based hydrodynamic cavitation devices: A case of degradation of di-chloro aniline in water
      Ranade, Vivek V.; Prasad Sarvothaman, Varaha; Simpson, Alister; Nagarajan, Sanjay
      Ultrasonics Sonochemistry (2021), 70 (), 105295CODEN: ULSOER; ISSN:1350-4177. (Elsevier B.V.)
      Hydrodynamic cavitation (HC) is being increasingly used in a wide range of applications. Unlike ultrasonic cavitation, HC is scalable and has been used at large scale industrial applications. However, no information about influence of scale on performance of HC is available in the open literature. In this work, we present for the first time, exptl. data on use of HC for degrdn. of complex org. pollutants in water on four different scales (∼200 times scale-up in terms of capacity). Vortex based HC devices offer various advantages like early inception, high cavitational yield and significantly lower propensity to clogging and erosion. We have used vortex based HC devices in this work. 2,4 dichloroaniline (DCA) - an arom. compd. with multiple functional groups was considered as a model pollutant. Degrdn. of DCA in water was performed using vortex-based HC devices with characteristic throat dimension, dt as 3, 6, 12 and 38 mm with scale-up of almost 200 time based on the flow rates (1.3 to 247 LPM). Considering the exptl. constraints on operating the largest scale HC device, the exptl. data is presented here at only one value of pressure drop across HC device (280 kPa). A previously used per-pass degrdn. model was extended to describe the exptl. data for the pollutant used in this study and a generalized form is presented. The degrdn. performance was found to decrease with increase in the scale and then plateaus. Appropriate correlation was developed based on the exptl. data. The developed approach and presented results provide a sound basis and a data set for further development of comprehensive multi-scale modeling of HC devices.
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    37. 37
      Simpson, A.; Ranade, V. V. Flow characteristics of vortex based cavitation devices: Computational investigation on influence of operating parameters and scale. AIChE J. 2019, 65 (9), e16675  DOI: 10.1002/aic.16675
      There is no corresponding record for this reference.
    38. 38
      Bučar, D.-K.; Elliott, J. A.; Eddleston, M. D.; Cockcroft, J. K.; Jones, W. Sonocrystallization Yields Monoclinic Paracetamol with Significantly Improved Compaction Behavior. Angew. Chem., Int. Ed. 2015, 54 (1), 249– 253,  DOI: 10.1002/anie.201408894
      38
      Sonocrystallization Yields Monoclinic Paracetamol with Significantly Improved Compaction Behavior
      Bucar, Dejan-Kresimir; Elliott, James A.; Eddleston, Mark D.; Cockcroft, Jeremy K.; Jones, William
      Angewandte Chemie, International Edition (2015), 54 (1), 249-253CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Ultrasound-assisted crystn. (sonocrystn.) was used to prep. a mixt. of nano- and micrometer-sized crystals of the monoclinic form of paracetamol-a widely used analgesic known for its particularly problematic mech. behavior under compression (i.e. poor tabletability). The nano- and micrometer-sized crystals yielded a powder which exhibits elastic moduli and bulk cohesions that are significantly higher than those obsd. in samples consisting of macrometer-sized crystals, thus leading to enhanced tabletability without the use of excipients, particle coating, salt, or cocrystal formation. Exptl. compaction and finite element anal. were utilized to rationalize the significantly improved compaction behavior of the monoclinic form of paracetamol.
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    39. 39
      Kim, H. N.; Suslick, K. S. The Effects of Ultrasound on Crystals: Sonocrystallization and Sonofragmentation. Crystals 2018, 8 (7), 280,  DOI: 10.3390/cryst8070280
      39
      The effects of ultrasound on crystals: sonocrystallization and sonofragmentation
      Kim, Hyo Na; Suslick, Kenneth S.
      Crystals (2018), 8 (7), 280/1-280/20CODEN: CRYSBC; ISSN:2073-4352. (MDPI AG)
      A review. When ultrasound is applied to a soln. for crystn., it can affect the properties of the cryst. products significantly. Ultrasonic irradn. decreases the induction time and metastable zone and increases the nucleation rate. Due to these effects, it generally yields smaller crystals with a narrower size distribution when compared with conventional crystns. Also, ultrasonic irradn. can cause fragmentation of existing crystals which is caused by crystal collisions or sonofragmentation. The effect of various exptl. parameters and empirical products of sonocrystn. have been reported, but the mechanisms of sonocrystn. and sonofragmentation have not been confirmed clearly. In this review, we build upon previous studies and highlight the effects of ultrasound on the crystn. of org. mols. In addn., recent work on sonofragmentation of mol. and ionic crystals is discussed.
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    40. 40
      Gielen, B.; Claes, T.; Janssens, J.; Jordens, J.; Thomassen, L. C. J.; Gerven, T. V.; Braeken, L. Particle Size Control during Ultrasonic Cooling Crystallization of Paracetamol. Chem. Eng. Technol. 2017, 40, 1300– 1308,  DOI: 10.1002/ceat.201600647
      40
      Particle Size Control during Ultrasonic Cooling Crystallization of Paracetamol
      Gielen, Bjorn; Claes, Thomas; Janssens, Jonas; Jordens, Jeroen; Thomassen, Leen C. J.; Van Gerven, Tom; Braeken, Leen
      Chemical Engineering & Technology (2017), 40 (7), 1300-1308CODEN: CETEER; ISSN:1521-4125. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The effect of ultrasound on the crystal size during cooling crystn. of paracetamol was investigated. Sonication was enabled in three distinct stages to define the operating guidelines for crystal size control. In addn., it was identified whether size redn. results from a higher amt. of nuclei upon primary nucleation or from enhanced secondary nucleation. The results show that tuning of the ultrasonic power d. and exposure time after nucleation results in crystal sizes between 70 and 140 μm. In contrast, the use of ultrasound before nucleation does not affect the size, indicating enhanced secondary nucleation as the main mechanism. Finally, sonication after complete desupersatn. reduces the crystal size by about 30 μm but causes surface erosion.
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    41. 41
      Kachrimanis, K.; Braun, D. E.; Griesser, U. J. Quantitative analysis of paracetamol polymorphs in powder mixtures by FT-Raman spectroscopy and PLS regression. J. Pharm. Biomed. Anal. 2007, 43 (2), 407– 412,  DOI: 10.1016/j.jpba.2006.07.032
      There is no corresponding record for this reference.
    42. 42
      Yamamura, S.; Momose, Y. Characterization of monoclinic crystals in tablets by pattern-fitting procedure using X-ray powder diffraction data. Int. J. Pharm. 2003, 259 (1), 27– 37,  DOI: 10.1016/S0378-5173(03)00206-0
      There is no corresponding record for this reference.
    43. 43
      Shtukenberg, A. G.; Tan, M.; Vogt-Maranto, L.; Chan, E. J.; Xu, W.; Yang, J.; Tuckerman, M. E.; Hu, C. T.; Kahr, B. Melt Crystallization for Paracetamol Polymorphism. Cryst. Growth Des. 2019, 19 (7), 4070– 4080,  DOI: 10.1021/acs.cgd.9b00473
      43
      Melt Crystallization for Paracetamol Polymorphism
      Shtukenberg, Alexander G.; Tan, Melissa; Vogt-Maranto, Leslie; Chan, Eric J.; Xu, Wenqian; Yang, Jingxiang; Tuckerman, Mark E.; Hu, Chunhua T.; Kahr, Bart
      Crystal Growth & Design (2019), 19 (7), 4070-4080CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
      Trimorphic paracetamol, one of the most commonly used analgesic and antipyretic drugs, has been a model system for studying transformations among phases of mol. cryst. materials. During crystn. from the melt and the glass above 0, three new polymorphs of paracetamol (N-acetyl-para-aminophenol or acetaminophen) were discovered, doubling the no. of known ambient forms. The crystal structure of one new form was solved using a combination of powder x-ray diffraction and computational techniques. Growth kinetics became anomalous near the glass transition: as temp. decreased, growth rate increased; this rare and poorly understood phenomenon is commonly identified as the glass-to-crystal (GC) growth mode. In addn., two polymorphs displayed optical evidence of helicoidal morphologies, a characteristic of at least 25% of mol. crystals, that has been resistant to a universal explanation.
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    44. 44
      Oloyede, O. O.; Alabi, Z. O.; Akinyemi, A. O.; Oyelere, S. F.; Oluseye, A. B.; Owoyemi, B. C. D. Comparative evaluation of acetaminophen form (I) in commercialized paracetamol brands. Sci. Afr. 2023, 19, e01537  DOI: 10.1016/j.sciaf.2022.e01537
      There is no corresponding record for this reference.
    45. 45
      Giordano, F.; Rossi, A.; Bettini, R.; Savioli, A.; Gazzaniga, A.; Novák, C. S. Thermal behavior of paracetamol-polymeric excipients mixtures. J. Therm. Anal. Calorim. 2002, 68 (2), 575– 590,  DOI: 10.1023/A:1016004206043
      45
      Thermal Behavior of Paracetamol-Polymeric Excipients Mixtures
      Giordano, F.; Rossi, A.; Bettini, R.; Savioli, A.; Gazzaniga, A.; Novak, Cs.
      Journal of Thermal Analysis and Calorimetry (2002), 68 (2), 575-590CODEN: JTACF7; ISSN:1418-2874. (Kluwer Academic Publishers)
      The thermal behavior of binary mixts. of paracetamol and a polymeric excipient (microcryst. cellulose, hydroxypropylmethylcellulose and cross-linked poly(vinylpyrrolidone)) was investigated. The phys. mixts., ranging from 50 to 90% by mass of drug, were submitted to a heating-cooling-heating program in the 35-180° temp. range. Solid-state anal. was performed by means of differential scanning calorimetry (DSC), hot stage microscopy (HSM), micro-Fourier transformed IR spectroscopy (MFTIR), and SEM. The polymeric excipients were found to address in a reproducible manner the recrystn. of molten paracetamol within the binary mixt. into Form II or Form III. The degree of crystallinity of paracetamol in the binary mixts., evaluated from fusion enthalpies during the first and second heating scans, was influenced by the compn. of the mixt., the nature of the excipient and the thermal history. In particular, DSC on mixts. with cross-linked poly(vinylpyrrolidone) and hydroxypropylmethylcellulose with drug contents below 65 and 75%, resp., evidenced the presence only of amorphous paracetamol after the cooling phase. Microcryst. cellulose was very effective in directing the recrystn. of molten paracetamol as Form II.
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    46. 46
      Klímová, K.; Leitner, J. DSC study and phase diagrams calculation of binary systems of paracetamol. Thermochim. Acta 2012, 550, 59– 64,  DOI: 10.1016/j.tca.2012.09.024
      46
      DSC study and phase diagrams calculation of binary systems of paracetamol
      Klimova, K.; Leitner, J.
      Thermochimica Acta (2012), 550 (), 59-64CODEN: THACAS; ISSN:0040-6031. (Elsevier B.V.)
      The study reports a DSC investigation of solid-liq. equil. in three binary mixts. of paracetamol, namely with caffeine, ascorbic acid and citric acid. All these systems reveal simple eutectic behavior and eutectic temps. and temps. of liquidus were detd. Further, assessed eutectic and liquidus temps. together with data for pure components were used for evaluation of parameters of the Redlich-Kister equation for the excess Gibbs energy of binary melts. Finally, binary T-x phase diagrams of the above mentioned systems were calcd. using the FactSage software.
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    47. 47
      Sacchetti, M. Thermodynamic Analysis of DSC Data for Acetaminophen Polymorphs. J. Therm. Anal. Calorim. 2001, 63, 345– 350,  DOI: 10.1023/A:1010180123331
      47
      Thermodynamic analysis of DSC data for acetaminophen polymorphs
      Sacchetti, M.
      Journal of Thermal Analysis and Calorimetry (2001), 63 (2), 345-350CODEN: JTACF7; ISSN:1418-2874. (Kluwer Academic Publishers)
      This article provides a thermodn. anal. of DSC data for acetaminophen polymorphic forms I and II by measurement of heat capacity. Form I has lower heat capacity and free energy and hence better stability than Form II down to at least -30°. The transition temp. below which Form II becomes more stable was < -120°. Form I is more stable than Form II as a consequence of its higher entropy, since its crystallog. packing arrangement is of larger energy.
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    48. 48
      Liu, L.-S.; Kim, J.-M.; Chang, S.-M.; Choi, G.-J.; Kim, W.-S. Quartz Crystal Microbalance Technique for Analysis of Cooling Crystallization. Anal. Chem. 2013, 85, 4790– 4796,  DOI: 10.1021/ac400585c
      There is no corresponding record for this reference.
    49. 49
      Lapidot, T.; Sedransk Campbell, K. L.; Heng, J. Y. Y. Model for Interpreting Surface Crystallization Using Quartz Crystal Microbalance: Theory and Experiments. Anal. Chem. 2016, 88 (9), 4886– 4893,  DOI: 10.1021/acs.analchem.6b00713
      49
      Model for Interpreting Surface Crystallization Using Quartz Crystal Microbalance: Theory and Experiments
      Lapidot, Tomer; Sedransk Campbell, Kyra L.; Heng, Jerry Y. Y.
      Analytical Chemistry (Washington, DC, United States) (2016), 88 (9), 4886-4893CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      Surface crystn. of calcium sulfate was investigated using a dissipation crystal quartz microbalance (QCM-D) together with microscopy to understand the mech. property changes occurring during the growth process. The use of optical microscopy and SEM revealed that needle-shaped crystals grow as clusters on the QCM sensor's surface, not in uniform layers. As crystn. growth progressed, QCM-D revealed inversions between neg. and pos. frequency shifts. This behavior, a function of the growth of crystals in clusters, is not adequately predicted by existing models. As such, a new mass-to-frequency conversion model is proposed herein to explain the obsd. frequency inversions. This model is derived from a lumped element approach with point-contact loading and Mason equiv. circuit theory. Critically, the phys. phenomena occurring form the basis of the model, particularly addressing the three sources of impedance. When a crystal nucleates and grows, its inertial impedance is considered along with a Kelvin-Voigt link with a hydration layer. A comparison between the proposed model and exptl. data, of both frequency and dissipation data for the first four harmonics, shows good agreement for the supersaturations (S = C/C*) of S = 3.75, S = 3.48, and S = 3.22. Addnl., significant improvements over existing models for the case of surface crystn. are obsd. The proposed model was therefore able to explain that frequency inversions are caused by a shift from inertia-dominated to elastic-dominated impedance, occurring as a result of crystal growth. Using the nucleation induction time and nucleation rates, detd. with imaging, an addnl. understanding of the crystals' mech. properties (stiffness and dampening) was obtained.
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