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ArticleSeptember 24, 2018

Understanding Dissolution and Crystallization with Imaging: A Surface Point of View
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Dunja Novakovic*
Dunja Novakovic
Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5 E, 00014 Helsinki, Finland
*E-mail: [email protected]
More by Dunja Novakovic
http://orcid.org/0000-0003-2058-2194
Antti Isomäki
Antti Isomäki
Biomedicum Imaging Unit, Faculty of Medicine, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
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Bibi Pleunis
Bibi Pleunis
Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5 E, 00014 Helsinki, Finland
More by Bibi Pleunis
Sara J. Fraser-Miller
Sara J. Fraser-Miller
Dodd-Walls Center for Photonic and Quantum Technologies, Department of Chemistry, University of Otago, Dunedin 9016, New Zealand
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Leena Peltonen
Leena Peltonen
Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5 E, 00014 Helsinki, Finland
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Timo Laaksonen
Timo Laaksonen
Laboratory of Chemistry and Bioengineering, Tampere University of Technology, Korkeakoulunkatu 8, 33720 Tampere, Finland
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Clare J. Strachan
Clare J. Strachan
Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5 E, 00014 Helsinki, Finland
More by Clare J. Strachan
http://orcid.org/0000-0003-3134-8918

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Molecular Pharmaceutics

Cite this: Mol. Pharmaceutics 2018, 15, 11, 5361–5373

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https://doi.org/10.1021/acs.molpharmaceut.8b00840

Published September 24, 2018

Abstract

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The tendency for crystallization during storage and administration is the most considerable hurdle for poorly water-soluble drugs formulated in the amorphous form. There is a need to better detect often subtle and complex surface crystallization phenomena and understand their influence on the critical quality attribute of dissolution. In this study, the interplay between surface crystallization of the amorphous form during storage and dissolution testing, and its influence on dissolution behavior, is analyzed for the first time with multimodal nonlinear optical imaging (coherent anti-Stokes Raman scattering (CARS) and sum frequency generation (SFG)). Complementary analyses are provided with scanning electron microscopy, X-ray diffraction and infrared and Raman spectroscopies. Amorphous indomethacin tablets were prepared and subjected to two different storage conditions (30 °C/23% RH and 30 °C/75% RH) for various durations and then dissolution testing using a channel flow-through device. Trace levels of surface crystallinity previously imaged with nonlinear optics after 1 or 2 days of storage did not significantly decrease dissolution and supersaturation compared to the freshly prepared amorphous tablets while more extensive crystallization after longer storage times did. Multimodal nonlinear optical imaging of the tablet surfaces after 15 min of dissolution revealed complex crystallization behavior that was affected by both storage condition and time, with up to four crystalline polymorphs simultaneously observed. In addition to the well-known α- and γ-forms, the less reported metastable ε- and η-forms were also observed, with the ε-form being widely observed in samples that had retained significant surface amorphousness during storage. This form was also prepared in the pure form and further characterized. Overall, this study demonstrates the potential value of nonlinear optical imaging, together with more established solid-state analysis methods, to understand complex surface crystallization behavior and its influence on drug dissolution during the development of amorphous drugs and dosage forms.

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1. Introduction

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Conversion of the crystalline form of a drug into its amorphous form is one of the most promising enabling formulation approaches for the increasing number of poorly water-soluble drug molecules. The amorphous form, despite its thermodynamic physical instability and tendency for recrystallization, is often considered, as it offers a considerable solubility advantage over its crystalline counterpart.

In the early stages of amorphous drug development, solubility and dissolution are investigated. Experimentally, intrinsic dissolution tests ensure a constant surface area (1) and thus potentially enable the evaluation of solid-state effects, while the particle size effects are minimized. In addition to the conventional rotating disk apparatus, different flow-through and channel flow systems have been developed. Theoretically, the solubility and dissolution advantage of amorphous drugs can be calculated on the basis of thermal properties. The calculated increases in solubility and dissolution are generally higher than those experimentally obtained. (2) For instance, the experimentally determined solubility advantage of amorphous to crystalline γ-indomethacin is between 4.5 (2) and 4.9, (3) whereas the predicted ratio at 25 °C is between 25 and 104. (2) It is believed that the driving force for dissolution can be predicted fairly well based on the thermodynamic calculations and that the experimentally determined values are often underestimated. (2,3) One reason for underestimated experimental solubility and dissolution results is surface crystallization to less soluble forms during dissolution (solution-mediated or direct solid–solid). Furthermore, during administration, crystallization of the amorphous form can also occur and lead to insufficient concentration of dissolved drug molecules available for absorption and a consequent lack of therapeutic effect. For these reasons, it is important to detect and understand crystallization processes during dissolution testing.

Coupling solid-state analysis with dissolution testing can provide understanding of the surface solid-state phenomena affecting the dissolution process. Glancing angle X-ray diffraction (XRD) has been used to monitor surface crystallization after dissolution of partially amorphous indomethacin compacts as a function of tablet depth. (4) Imaging methods, such as polarized light microscopy (PLM) and ATR-FTIR spectroscopic imaging, (5) are also potentially attractive choices. However, the solid-state specificity of PLM is limited, and in the case of ATR-FTIR, the water complicates sampling and, depending on the selected region or peak of interest, can also interfere with analysis. (5) Due to its insensitivity to water, Raman spectroscopy has been used in situ to monitor solid-state changes occurring during dissolution. (6,7) However, conventional Raman systems, including with Raman probes, may not be sufficiently surface-specific to prevent the surface signal being overwhelmed by the signal from the core of the sample. (6,7) In the case of a very thin crystalline layer forming on the surface of the amorphous sample, even Raman microscopy cannot always detect surface crystallinity. (8) The relatively slow imaging speed of conventional Raman microscopy contributes to this challenge.

Nonlinear optical imaging, in particular involving coherent anti-Stokes Raman scattering (CARS) or sum frequency generation (SFG), is gaining interest in the solid-state analysis of pharmaceutics. (9) As well as offering rapid contactless sampling with submicron lateral resolution, nonlinear analytical methods are highly surface sensitive due to their being inherently confocal, with the signal being generated only in the focal volume of the overlapping lasers when phase matching criteria are fulfilled. CARS is orders of magnitude faster than conventional Raman microscopy (based on spontaneous Raman scattering) and has been used to image crystal phase transformations associated with the dissolution of pharmaceutical tablets, (10,11) in particular, solution-mediated hydrate formation. (12) Sum frequency generation (SFG), including second-harmonic generation (SHG), has proven powerful in detecting trace levels of crystallinity. (13−17) SFG can differentiate amorphous from crystalline forms (as long as the crystals are not centrosymmetric), as only noncentrosymmetric crystals can generate a bulk SFG signal. However, SFG alone cannot separate different crystals that belong to the same classification in terms of centrosymmetry (although the magnitude of the SFG signal may be different). Multimodal nonlinear imaging, in which two or more nonlinear optical techniques are combined, can provide more specific and reliable analysis when the amorphous form and multiple polymorphs are present. In our recent study, (18) the synergistic use of simultaneous CARS and SFG imaging allowed the distribution of the amorphous form and crystalline forms of the drug indomethacin to be imaged. The surface crystallization of the amorphous indomethacin tablets during storage was also imaged. (18) Briefly, the tablets stored at lower humidity crystallized predominately to the γ-indomethacin, whereas the tablets stored at higher humidity crystallized mostly to the α-form. Some small areas of the nondominant polymorph, not detected with ATR-FTIR or Raman spectroscopies, were also observed. Crystallization was also detected at an earlier stage with multimodal nonlinear optics than with ATR-FTIR and Raman spectroscopies.

Indomethacin is a widely studied drug with respect to its solid-state behavior and has been reported to exist in several polymorphic forms: α, β, γ, δ, ε, ζ, η, τ, as well as an unnamed form. (19−24) Some of these forms have only been observed in quite specific conditions; for example, the ζ- and η-forms were detected after exposure of amorphous particles to pH 1.2 buffer solution, while the τ form has been observed in semicrystalline dispersions. The β form was later confirmed to be a benzene solvate. (25) The crystal structures have been reported only for the α- and γ-polymorphs, although the powder XRD profiles for the other forms except ε have been published. The ε-form is less well-characterized than the other polymorphs due to stability-related measurement difficulties. (23) In addition to these crystalline forms, the amorphous form of indomethacin has been widely studied. Numerous studies have independently evaluated the dissolution (26−28) and storage-induced (29−31) solid-state transformations of the amorphous form of indomethacin. However, studies exploring the relationship between the partial (surface) crystallization induced by storage and dissolution behavior are limited. (32)

In this study, multimodal nonlinear imaging (CARS and SFG), together with XRD and ATR-FTIR spectroscopy, were utilized to investigate the relationship between surface crystallization of amorphous indomethacin tablets, during both storage and dissolution, and dissolution behavior. Of particular interest was whether very early stage crystallization during storage, as detected earlier with nonlinear imaging, (18) would affect surface crystallization during dissolution as well as dissolution behavior. The complex surface crystallization behavior of the freshly prepared and stored samples, including the simultaneous appearance of multiple solid-state forms and their distribution, was investigated.

2. Materials and Methods

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2.1. Sample Preparation

Amorphous indomethacin was prepared from the γ-form (Orion, Finland) by cooling the melt to room temperature. (33) Once solidified, the sample was kept in a desiccator with phosphorus pentoxide for 30 min, after which it was pulverized and compressed into tablets with a benchtop single punch press (Specac, UK). Flat-faced tablets were compressed with the same pressure of 1 ton and a dwell time of 30 s. The tablets weighed 300 ± 5 mg and had a diameter of 13 mm and a height of 2 mm. The same side of the tablet (upper side in the tablet press) was exposed to the dissolution medium and analyzed in all measurements. Freshly prepared amorphous indomethacin tablets were analyzed within a couple of hours and denoted as 0-day samples. To promote crystallization, the tablets were placed in open glass vials and stored at 30 °C at lower (23%) or higher (75%) relative humidity, obtained by using saturated salt solutions of potassium acetate and sodium chloride, respectively.

The γ-form (with a centrosymmetric P1̅ crystal structure) was used as received. The α-indomethacin form (with a noncentrosymmetric P2₁ crystal structure) was obtained by antisolvent precipitation with Milli-Q water from a warm ethanol solution prepared from γ-indomethacin. (25) The ε-form of indomethacin was prepared from a suspension of amorphous indomethacin in pH 6.8 phosphate buffer. (23,34) The δ-form was prepared from indomethacin methanolate. (22) Tablets composed of pure α-indomethacin were prepared in a similar manner as described for amorphous indomethacin. Attempts in making tablets composed from pure γ-indomethacin resulted in lamination and breakage in the dissolution cell sample cavity. Therefore, the initially amorphous tablets stored for 5 months at 30 °C/23% RH were used as pure γ-indomethacin tablets. Complete crystallization to the γ-indomethacin over a 5-month period was confirmed with XRD, differential scanning calorimetry (DSC), and FTIR.

2.2. Intrinsic Dissolution Testing

Freshly prepared amorphous tablets, as well as those stored for 1, 2, 7, or 22 days were subjected to dissolution testing in a custom-built channel flow system. The experimental setup was similar to that described by Peltonen et al. (35) The tablets were inserted in the cavity in the middle of the cell such that only one surface was flushed with fresh dissolution medium. Tablets and the cavity had a diameter of 13 mm and thus a constant surface area of 1.33 cm². The peristaltic pump (Watson Marlow 505U), channel flow cell, and reservoir with dissolution medium were connected with silicone tubing in an open loop manner. This ensured the constant availability of fresh buffer and maintenance of true sink conditions. The flow was kept constant at 9 mL/min. (36) This rate has earlier been found to simulate the (axial) velocity of the intestine best. (37) Solution samples were collected downstream every 30 s for the first 5 min and then in 1 min intervals until 30 min. The absorbance of unfiltered samples (33) was measured at 318 nm (1) with a 1600PC UV–Vis spectrophotometer (VWR, China). Every dissolution experiment was performed at least in triplicate. Phosphate buffer with a pH of 6.8 was used as the aqueous medium. A series of standard solutions of indomethacin in pH 6.8 phosphate buffer with concentrations ranging from 0.5 to 40 μg/mL was used to construct a calibration curve for quantification. As the tablets remained whole at the end of the experiment, the tablet surface exposed to the liquid medium could subsequently be further analyzed. All solid-state measurements on tablets subjected to dissolution testing were performed after 15 min of dissolution testing. Prior to solid-state analysis, the tablets’ surfaces were blotted with lens cleaning tissue paper and removed from the channel flow cell.

2.3. Scanning Electron Microscopy (SEM)

Surface sections of the tablets were mounted on double-sided carbon tape and sputter coated with platinum. The micrographs were obtained with a FEI Quanta 250 field emission gun SEM (FEI, Hillsboro, USA) microscope using a high vacuum and a voltage of 10 kV.

2.4. X-ray Diffractometry (XRD)

Diffractograms were collected in reflection mode using a Malvern Panalytical Empyrian (PANalytical B.V. Almelo, The Netherlands) instrument with Cu Kα₁ radiation (λ = 1.5406) and a divergence slit of 0.76 mm. The generator voltage was 45 kV, and the tube current 40 mA. Data were collected in a 2θ scan range of 5 to 50° with a step size of 0.013°. The tablets were rotated during the measurements.

2.5. Fourier Transform Infrared Spectroscopy (FTIR)

FTIR analysis was performed using a single-reflection MIRacle attenuated total reflectance (ATR) crystal (Pike Technologies, Wisconsin, USA) with a Vertex 70 spectrometer (Bruker Optics, Ettlingen, Germany). Measurements were collected using OPUS 5.5 (Bruker Optics, Ettlingen, Germany) software. Each spectrum consisted of an average of 256 scans with a spectral resolution of 4 cm^–1. The obtained spectra were standard normal variance (SNV) corrected prior to principal component analysis (PCA) in the spectral range of 1400–1800 cm^–1 using Simca software V10.5 (Umetrics, Umea, Sweden).

2.6. Multimodal Nonlinear Optical Imaging

Multimodal nonlinear imaging was performed with a Leica SP8 CARS microscope (Leica, Wetzlar, Germany). The CARS excitation source was a solid-state Nd:YVO₄ laser. The Stokes (fundamental) laser line at 1064.5 nm was temporally and spatially overlapped with the pump/probe beam. The wavelength of the pump line was tuned by an optical parametric oscillator (OPO). Combined incident beams were directed into an inverted microscope with an IR corrected 25×, 0.95 NA water immersion objective. The signal was collected in epi (backscattered) mode. For narrowband (single line) imaging and CARS spectral scans, photomultiplier tube (PMT) detectors were used, while for the second-order nonlinear spectra (including SFG), hybrid detectors (HyD) were used. Bright field images were collected in reflection mode using a 633 nm HeNe laser and PMT detector in the 623–643 nm range. The step size for the CARS spectral measurements was 1 nm (corresponding to a spectral resolution of approximately 12 cm^–1), whereas for the second-order spectral scans, the step size was 10 nm.

Three imaging modalities were used for the same field of view: (i) CARS spectral scans in the range of 1413–1800 cm^–1, (ii) second-order nonlinear spectral scans in the range of 400 to 700 nm, and (iii) a combination of narrowband CARS and SFG imaging. The combination images represent overlays of three channels: a single CARS line at 1701 cm^–1 in red (γ-indomethacin), a single CARS line at 1676 cm^–1 in blue (amorphous indomethacin), and a third channel representing the SFG signal (all noncentrosymmetric crystals). Potential two-photon excited fluorescence background signal interference in the narrowband images was minimized by subtracting the images obtained by one-laser excitation (pump laser only). Images represent the maximum projections of single-plane optical images at 2 μm steps in the z-direction. This step size was selected, as the instrument axial resolution is 2.5 μm. The total depth of the maximum projection images obtained in this manner was in the range of 20 to 52 μm. The lateral image size was 512 × 512 pixels covering a 465 × 465 μm area with images being collected with a line average of 4 and pixel dwell time of 1.2 μs. At least three different spots of each tablet were analyzed. To resolve SFG signal originating from different SFG-active polymorphs, the characteristic CARS peaks from the same regions were analyzed using Fiji ImageJ 1.51. False coloring (green and yellow) was assigned based on the relative intensity ratios of the CARS peaks at 1652 and 1676 cm^–1. The regions having SFG activity and a CARS peak at 1652 cm^–1 characteristic for α-indomethacin were colored green, while those having SFG activity and a CARS peak at 1676 cm^–1 characteristic for ε-indomethacin were colored yellow.

3. Results

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3.1. Dissolution Behavior

3.1.1. Pure Amorphous and Reference Crystalline Forms

As shown in Figure 1, the maximum dissolved concentration for the 0-day sample was reached after 2 min of dissolution testing and was around 12-fold higher than that of the reference γ-crystalline form of indomethacin, which stabilized at around 2 μg/mL. Supersaturation was followed by a concentration drop, indicating solution-mediated crystallization. The crystalline α-form exhibited a slightly increased concentration compared to the γ-form (around 3 μg/mL).

Figure 1. Dissolution profiles (drug release over time) for samples stored at (a) 30 °C/23% RH and (b) 30 °C/75% RH. Profiles of the pure amorphous tablet (day 0) and reference crystalline γ- and α-forms are shown for comparison. Profiles are generated with mean values of a minimum of three measurements. Error bars represent plus one standard deviation.

Crystallization on the surface of a dissolving tablet can increase the effective surface area available for dissolution. (38) Such an effect could be of greater influence for samples with higher levels of crystallization where the increase in surface area is greater. This can potentially explain why the dissolution profiles were not approaching those of the reference crystalline forms toward the end of the measurements. Another potential reason is that metastable polymorphs, more soluble than the α- or γ-forms, were crystallizing on the tablet surface.

3.1.2. Stored Samples

Amorphous indomethacin samples were kept in controlled storage conditions for 22 days, and their dissolution properties were periodically monitored. The largest differences between the samples in Figure 1 can be seen within the first 15 min. The maximum drug concentrations decreased upon increased storage time. At the beginning of the experiments, the dissolution profiles of the 1-day and 2-day samples were still largely similar to that of the freshly prepared tablets and faster than those of the samples stored for longer periods, although the 2-day sample stored at 30 °C/75% RH exhibited a slightly lower maximum concentration. The most pronounced effects of storage time and conditions can first be seen at 7 days of storage, when the maximum and subsequent concentrations were substantially lower. This was especially the case for tablets stored at 30 °C/23% RH, whose achieved concentrations were around two times lower than those of the tablets stored at 30 °C/75% RH. The dissolution profiles of the 22-day tablets stored at 30 °C/23% RH closely resembled those of the reference γ-form. The profiles of the 22-day tablets stored at 30 °C/75% RH were between or similar to those of the reference α- and γ-crystalline forms.

3.2. Visual Appearance

A change in surface color upon dissolution, indicating crystallization, was observed for many of the samples. This was visible especially when tablets were broken: a thin white layer that had formed on the surface exposed to the dissolution medium was clearly observed. The rest of the tablet remained yellow, which is characteristic of the amorphous form. A dissolution-induced change was less pronounced or not present for the samples stored for longer periods of time (7 and 22 days) at lower humidity, as they were already relatively white and presumably relatively crystalline throughout the tablet prior to dissolution testing.

3.3. Surface Morphology

The morphology of fresh and stored tablet surfaces after 15 min of dissolution testing was compared to the surfaces before dissolution testing using SEM (Figures 2 and 3). The surface of the freshly prepared tablet previously confirmed as amorphous was quite smooth. (18) Surfaces of tablets stored at 30 °C/23% RH prior to dissolution featured plate-like particles, and their surface coverage increased over time. The storage-induced changes in surface morphology were slower for the tablets stored at 30 °C/75% RH, and many observed particles on these tablets had needle-like morphology. (18)

Figure 2. SEM micrographs of an amorphous indomethacin tablet (day 0, first column) and tablets stored for 1, 2, 7, and 22 days (from left to right) at 30 °C/23% RH before dissolution testing (top row). SEM images of the tablets prepared and stored in the same manner after 15 min of intrinsic dissolution testing (bottom row).

Figure 3. SEM micrographs of an amorphous indomethacin tablet (day 0, first column) and tablets stored for 1, 2, 7, and 22 days (from left to right) at 30 °C/75% RH before dissolution testing (top row). SEM images of the tablets prepared and stored in the same manner after 15 min of intrinsic dissolution testing (bottom row).

After 15 min of dissolution, the surface of the 0-day tablet had changed; crystal-like particles were observed in addition to smooth-looking areas. The 1-day samples after dissolution were similar to the freshly prepared samples after dissolution and also had some largely smooth regions. For both storage conditions, the 2-day samples had more needle-shaped particles after dissolution. The needles were usually 1–2 μm in size, with the largest observed needles being 40 μm long. The morphologies of the samples stored for the same times at different storage conditions after dissolution testing became strikingly different at day 7. The surfaces of tablets stored at 30 °C/23% RH was covered with plate-like particles, mostly 1–2 μm in size, with some up to about 5 μm. A few needle-shaped structures were also observed, but their number was considerably lower. In contrast, the surfaces of tablets stored at 30 °C/75% RH had many needle-like particles with some arranged in a spiral-like morphology (Figure 3, day 7 after dissolution). Most of the needles were between 5 and 10 μm long, although the largest was 100 μm in length. This difference for the two different storage conditions remained pronounced for the 22-day samples after dissolution. The largest observed plate-like particles for samples stored at lower humidity were 20 μm. Needle shaped particles for samples stored at higher humidity appeared more fused together over larger areas, and the majority of the individual particles were about 5 μm in length.

Crystals of γ-indomethacin generally have a plate-like morphology, whereas α-indomethacin crystals are needle-like with growth in the form of fibrous/spherulitic structures. (39) While the SEM images are suggestive of storage time- and condition-dependent crystallization for at least these two forms during dissolution, more specific solid-state analysis was performed with multimodal nonlinear optical imaging, together with XRD and ATR-FTIR spectroscopy.

3.4. Solid-State Analysis

Solid-state analysis was performed off-line by XRD, ATR-FTIR, and CARS/SFG upon 15 min of dissolution.

3.4.1. Freshly Prepared Amorphous Indomethacin (Day 0)

Prior to dissolution, the freshly prepared indomethacin tablet was amorphous according to XRD (Figure 4). Even though any potential remaining surface moisture after tablet blotting could partially attenuate the XRD signal, after 15 min of dissolution testing, we were able to see the appearance of two small diffraction peaks at 15.8 and 18.8° above the amorphous halo. This indicated partial crystallization. These two peaks did not correspond to those of previously published X-ray diffractograms of indomethacin polymorphs (α, γ, (19,25) δ, (22) ζ, η, (23) and τ (24)). The ε-form of indomethacin was also prepared in the present study, and its XRD pattern is presented and attributed to this form for the first time (Figure 4). The two peaks from the tablet after dissolution testing correspond to this diffraction pattern of the ε-form (marked in yellow in Figure 4). The diffractogram of the ε-form also had considerable similarity with the unnamed form of indomethacin reported by Lin. (21)

Figure 4. XRD diffractograms of tablets before and after 15 min of dissolution testing: (a) storage at 30 °C/23% RH and (b) storage at 30 °C/75% RH. Diffractograms of the α-, γ-, and ε-forms of indomethacin are shown for comparison, and some of their characteristic peaks are marked in green, red, and yellow, respectively. The ε-form was measured in transmission mode using a powder, while the α- and γ-forms were measured in reflection with tablets.

ATR-FTIR spectroscopy, which is more surface-specific than XRPD (sampling depth limited to approximately 1 to 2 μm) was also performed (Figure S1). Based on the PCA of the spectra (Figure 5), the same samples (after 15 min of dissolution testing) were most similar to the amorphous form even though their score values slightly approached that of the crystalline ε-form. This indicates some limited surface coverage with the ε-form.

Figure 5. PCA scores plot of the ATR-FTIR spectra of the amorphous (day 0) and all stored samples after 15 min of dissolution testing (a); loadings and reference IR spectra of different solid-state forms of indomethacin (b).

To obtain more precise information about the dissolution-induced surface distribution of the ε-form and any other potential minority species not detected with XRD and ATR-FTIR, multimodal nonlinear imaging was performed. No SFG or CARS signals indicative of crystallization were detected on the surface of the freshly prepared amorphous tablets prior to dissolution testing (Figures 6a and 7a), further confirming their amorphous nature. SFG has previously been shown to be very sensitive in detecting compression-induced crystallization to polymorphs with a noncentrosymmetric structure. (16) In contrast, signs of extensive crystallization after dissolution testing could be seen in a strong SFG signal (in yellow in Figures 6b and 7b). As these signals are only generated in the absence of centrosymmetry (amorphous forms do not fulfill this criterion but noncentrosymmetric crystals do), their presence was a definite sign of the initially amorphous tablet surface crystallizing during dissolution. The CARS spectral scans of the same area of view provided further insights into the polymorphism. The spectra from the SFG-active regions featured peaks at 1579, 1615, and 1676 cm^–1 (Figures 6d and 7d), which correspond to the reference CARS spectrum of the ε-form of indomethacin. No other minority species were detected.

Figure 6. CARS and SFG overlay images of samples stored at 30 °C/23% RH before (a) and after (b) 15 min of dissolution testing at pH 6.8. CARS spectra in the range of 1413–1800 cm^–1 from selected regions marked by arrows plotted with reference spectra of amorphous, ε-, and γ-indomethacin (c–e). Overlay images (a, b) represent overlays of three channels: single CARS line at 1701 cm^–1 in red (γ-indomethacin), single CARS line at 1676 cm^–1 in blue (amorphous indomethacin), and a third channel representing the SFG signal (all noncentrosymmetric crystals) in green and yellow. The separation between green and yellow regions is based on the intensity ratios of CARS peaks at 1652 and 1676 cm^–1 so that the regions having SFG activity and a CARS peak at 1652 cm^–1 are colored green (α-indomethacin), and the regions having SFG activity and a CARS peak at 1676 cm^–1 are colored yellow (ε-indomethacin). Panel (a) has been reprinted with permission from Novakovic et al. (18) Copyright 2017 American Chemical Society. am = amorphous.

Figure 7. CARS and SFG overlay images of samples stored at 30 °C/75% RH before (a) and after 15 min of dissolution testing at pH 6.8 (b). CARS spectra in the range of 1413–1800 cm^–1 from selected regions marked by arrows (c–f) plotted with reference spectra of amorphous, ε-, α-, and γ-indomethacin. Overlay images (a, b) represent overlays of three channels: single CARS line at 1701 cm^–1 in red (γ-indomethacin), single CARS line at 1676 cm^–1 in blue (amorphous indomethacin), and a third channel representing the SFG signal (all noncentrosymmetric crystals) in green and yellow. The separation between green and yellow regions is based on the intensity ratios of CARS peaks at 1652 and 1676 cm^–1 so that the regions having SFG activity and the CARS peak at 1652 cm^–1 are colored green (α-indomethacin), and the regions having SFG activity and CARS peak at 1676 cm^–1 are colored yellow (ε-indomethacin). Panel (a) has been reprinted with permission from Novakovic et al. (18) Copyright 2017 American Chemical Society. am = amorphous.

3.4.2. Tablets after Storage at Lower Humidity (30 °C/23% RH)

XRD analysis of the 1-day tablet stored at lower humidity prior to dissolution testing showed only an amorphous halo (Figure 4). After 15 min of dissolution, however, two small diffraction peaks (at 15.8 and 18.8° marked in yellow) above the amorphous halo could be observed. These peaks corresponded to the ε-form of indomethacin. For the 2-, 7-, and 22-day samples, almost no differences between the diffraction patterns for the corresponding before and after dissolution samples were observed. The 2-day samples exhibited an amorphous halo with some characteristic diffraction peaks of γ-indomethacin. The amorphous halo was not observable for the 7- and 22-day samples, with the diffractograms suggesting they were composed exclusively of γ-indomethacin already prior to dissolution.

The ATR-FTIR spectra of the tablet surfaces after storage at lower humidity (before dissolution) confirmed crystallization to the γ-form of indomethacin previously reported after 5 days of storage. (18) The ATR-FTIR spectra of the tablets upon dissolution were consistent with crystallization to the ε- and γ-forms observed with XRD (Figure S1). In the PCA scores plot (Figure 5), the post-dissolution tablets stored at lower humidity (marked with squares) gradually moved away from the amorphous and ε-forms and approached the γ-form as storage time increased. Thus, a post-dissolution trend from the ε- to γ-form as a function of storage time was observed.

Nonlinear optical imaging allowed a more detailed analysis of the surface crystallization behavior and distribution of the solid-state forms. Unlike for the freshly prepared samples, CARS spectra characteristic of γ-indomethacin were extracted from the images of all samples stored at lower humidity and the corresponding samples that underwent dissolution testing (Figure 6e). Thus, the spectra confirmed γ-indomethacin crystals after 15 min of dissolution as early as after 1 day of storage (Figure 6b), and a few γ crystals were also observed predissolution. (18) This crystallization to the γ-form at day 1, both with the pre and postdissolution samples, was not detectable with the XRD and ATR-FTIR setups used. The increase in the surface area covered with γ-indomethacin crystals (in red) can be seen in images of tablets stored for increasing amounts of time both before and after dissolution.

The presence of the SFG-active ε-form with characteristic CARS peaks at 1579, 1615, and 1676 cm^–1 (Figure 6d) was also observed for 1-day samples’ post-dissolution (but not before dissolution). Unlike XRD and ATR-FTIR, with which the ε-indomethacin was detected only at day 1 of post-dissolution, areas covered with the ε-form were observed with nonlinear imaging for all the samples stored at lower humidity (including 0-day) except for the 22-day sample. The areas covered with the ε-form post-dissolution decreased over storage time, while the γ-indomethacin coverage increased. Relatively large amorphous regions could still be seen on day 2, whereas from 7 days onward, they were notably decreased/absent.

Solid-state-specific visualization of tablet surfaces with nonlinear imaging in addition revealed some specific distribution patterns. This was most apparent with cracks present on the tablet surfaces at days 1 and 2—crystallization to the ε-form was concentrated in the vicinity of these cracks.

3.4.3. Tablets after Storage at Higher Humidity (30 °C/75% RH)

All samples stored at higher humidity, both before and after dissolution, were at least partially amorphous according to XRD (Figure 4). An amorphous halo characterized the 1-day sample both prior and subsequent to dissolution. The 2-, 7-, and 22-day samples had some γ-indomethacin diffraction peaks, while the 7- and 22-day samples also exhibited diffraction peaks characteristic of α-indomethacin.

Crystallization to the α-form of indomethacin after 22 days of storage at higher humidity (before dissolution) was confirmed with ATR-FTIR spectroscopy previously. (18) As can be seen from the PCA scores plot of the ATR-FTIR spectra, the 1-, 7-, and 22-day tablets stored at higher humidity that underwent dissolution testing (marked with circles in Figure 5) were mostly located between the reference solid-state forms of indomethacin, indicating that multiple forms were present simultaneously. The 2-day sample, however, was similar to ε-indomethacin.

Multiple polymorphs were simultaneously detected with multimodal CARS and SFG imaging. After storage and prior to dissolution, crystallization to α-indomethacin was predominantly observed at higher humidity. This was accompanied by some traces of the γ-form (Figure 7a). (18) Upon dissolution, in contrast to XRD and ATR-FTIR, crystallization was evident for the 1-day sample as seen by the strong SFG signals in yellow (Figure 7b). At days 1 and 2 after dissolution, the majority of the observed crystals (in yellow) were 2–3 μm in size. With the samples stored for 7 and 22 days after dissolution, the crystalline areas appeared slightly larger, with individual crystals (in green) equal to or exceeding 10 μm. The CARS spectra indicate that there were five solid-state forms after dissolution testing. Similar to the samples stored at lower humidity, the areas with characteristic CARS peaks at 1579, 1615, and 1676 cm^–1 and SFG activity assigned to the ε-indomethacin were observed for all the postdissolution samples stored at higher humidity except for day 22 (Figure 7d). CARS spectra of α-indomethacin were observed from 2 days of storage onward (Figure 7e). Traces of the α-form were also detected for the 1-day sample (Figure S2). The presence of γ-indomethacin was confirmed in all stored samples after dissolution testing (Figure 7f). Interestingly, the regions covered with the γ-form were largest after 22 days of storage. This finding is consistent with the XRD data, where the strong peaks of the γ-form were observed in addition to the less intense peaks corresponding to α-indomethacin (Figure 4b).

Areas having SFG activity and two strong sharp CARS peaks at 1591 and 1640 cm^–1 were clearly observed after dissolution only on day 7 (Figure S3). These areas were found only in traces. Based on the Raman spectra of indomethacin polymorphs available in the literature, (23,24) it is likely that this polymorph is the η-form (with benzoyl C═O stretching at 1642 cm^–1 in the Raman spectra (23)).

3.4.4. Reference Raman and CARS Spectra

For reference, CARS and Raman spectra of many of the different solid-state forms of indomethacin are provided. Figure 8 shows the CARS spectra of the γ-, α-, δ-, amorphous, ε-, and η-indomethacin forms as well as the Raman spectra of these forms plus the ζ-form. As the CARS and Raman spectral features arise from the same molecular vibrations, they are uniquely related to one another. (18,40) Carbonyl stretching of the carboxylic acid and benzoyl C═O groups of indomethacin feature solid-state-specific bands between 1500 and 1800 cm^–1. The CARS and Raman spectra for each solid-state form match one another. Detailed FTIR and Raman band assignments have been provided elsewhere. (23,41) The lower spectral resolution of the CARS spectra compared to the Raman spectra explains why some smaller peaks or shoulders visible in the Raman spectra disappear or are merged into larger peaks in the CARS spectra.

Figure 8. CARS (solid lines) and Raman (dotted lines) spectra of indomethacin solid-state forms. Raman spectra (except for the ε-form) are reproduced with permission from ref (23). The CARS spectral resolution is 12 cm^–1, while the Raman spectral resolution is 4 cm^–1. All CARS spectra are measured from the prepared reference forms, except for the spectrum of the η-form, which was recorded at the tablet surface. Polymorphs marked with asterisk are SFG-active.

4. Discussion

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The concentration versus time dissolution profiles for the freshly prepared amorphous samples show behavior typical of amorphous indomethacin with different stages able to be identified. (8,27) As the dissolution rate is directly proportional to the solubility of the drug (for a constant surface area), the solubility of the solid-state form at the surface of the compact dictates the release rate. Thus, after supersaturation is achieved and the solution-mediated crystallization covers the exposed tablet surface, the intrinsic dissolution rate decreased. (7) The relatively large variability between the replicates for partially amorphous samples as observed in this study has been observed before. (4) This has been attributed to the differences in tablet microstructure and preferred orientation effects. Batch-to-batch variation of dissolution behavior of an amorphous formulation of tacrolimus, due to different crystallization kinetics, has also been reported. (42)

The decrease in supersaturated concentrations of the stored samples compared to the pure amorphous indomethacin indicates that retardation of dissolution is induced by crystallization during storage. In our previous study, (18) early stage crystallization during storage was detected with nonlinear imaging already at days 1 and 2, which was at an earlier stage than with ATR-FTIR and Raman microscopy. Here, we have shown that this very early stage crystallization does not significantly affect the dissolution performance with these samples, as the final concentrations were similar for 0-, 1-, and 2-day samples at both storage conditions. Early stage crystallization could, however, be important and reduce drug dissolution in other samples or dissolution conditions, if these crystals were to act as seeds and promote solution-mediated growth of less soluble solid-state forms.

The crystallization of freshly prepared amorphous indomethacin upon dissolution has been quite extensively studied. Conversion to the α-polymorph during dissolution has previously been observed with Raman (26) and in situ Raman spectroscopy. (6,27) The α-form has been found to dominate in precipitates from supersaturated amorphous indomethacin solutions formed in ethanol/water at 37 °C observed by Sun et al., (43) while the γ-polymorph was observed with indomethacin/PVP solid dispersions in the same study. While studying the dissolution of quench-cooled amorphous indomethacin in water in a flow-through cell at room temperature, Greco and Bogner (8) detected three polymorphs with confocal Raman microscopy: the α- and γ-polymorphs as well as an unidentified form with a sharp peak at 1670 cm^–1. The form characterized by the peak at 1670 cm^–1 has also been observed with Raman spectroscopy mapping at different dissolution time points by Tres et al. (33) The peak was observed for extrudates of indomethacin with copovidone in a dissolution flow cell at 25 °C in pH 6.8 phosphate buffer. (33) While studying aqueous suspensions prepared with amorphous indomethacin at room temperature and a pH of 6.8, Surwase et al. (23) identified indirect conversion of amorphous indomethacin to the α-polymorph via the form they denoted as the ε-form (observed after 5 min) using ATR-FTIR spectroscopy. At a lower temperature (5 °C) at both pH 6.8 and 1.2, the α-form only became dominant after several sequential transformations involving the ε-, ζ-, and η-forms.

The results of the present study for day 0 are largely consistent with these studies. However, we observed surface crystallization only to the ε-form of indomethacin, most likely due to the earlier time point of dissolution (15 min) when solid-state analysis was performed. As confirmed by Surwase et al., (23) at pH 6.8 and room temperature (25 °C), the conversion of the amorphous to α-form can be via the metastable ε-polymorph. If the solid-state analysis in the present study had been performed at a later time point, it is likely that the α-form would have been predominantly observed.

The observed ε-form was prepared in pure form and further characterized in this study. Surwase et al. (23) and Koranne et al. (34) reported the IR spectra of the ε-polymorph. We believe that the Raman peak at around 1670 cm^–1 observed in earlier dissolution studies with amorphous indomethacin (8,33) was also due to formation of the ε-form. In the present study, this polymorph was confirmed by ATR-FTIR and further characterized by XRD, Raman, CARS, and SFG.

The storage time affected the crystallization and dissolution behavior at both studied storage conditions. The influence of crystallization to the γ-polymorph during storage at 25 °C/0% RH on dissolution was studied by Greco and Bogner. (8) The dissolution in water of amorphous indomethacin prepared by quench-cooling the melt and stored for 1 week resulted in the presence of three forms identified by confocal Raman microscopy: γ, the unidentified form with a peak at 1670 cm^–1 (which we attribute to the ε-form), and, at the end of experiments, the α-form. Samples having a higher percentage of crystallinity stored for 3 weeks showed two forms: γ and the form with the Raman peak at 1670 cm^–1, while the 6-week sample showed only the presence of the γ-form. Though the time scales and storage conditions are different, the findings exhibit the same trend as our observations at 30 °C/23% RH; the 1-day and 2-day samples had similar crystallization behavior to Greco and Bogner’s 1-week samples, and the 22-day samples corresponded to Greco and Bogner’s 6-week sample.

The solid-state results obtained with different analytical techniques are summarized in Table 1. Multiple polymorphs were detected simultaneously with all the used techniques. Of all the analytical techniques used, the combination of CARS and SFG proved to be the most potent in detecting especially the ε- and α-forms of indomethacin after dissolution. Furthermore, nonlinear imaging was especially capable of detecting multiple solid-state forms simultaneously including those present only in traces, including the η-form. For instance, the amorphous form together with four indomethacin polymorphs (ε, γ, α, η) were visualized on the surface of a 7-day tablet stored at 30 °C/75% RH after dissolution.

Table 1. Overview of the Observed Solid-State Forms of Indomethacin before and after 15 min of Dissolution

sample	solid state forms
	XRD		ATR-FTIR^a		CARS/SFG
	before	after	before (18)	after	before (18)	after
Day 0	am^b	am, ε	am	am, ε (traces)	am	am, ε
30 °C/23% RH
Day 1	am	am, ε	am	am, ε (traces)	am, γ	am, ε, γ
Day 2	am, γ	am, γ	am, γ	γ	am, γ, α (traces)	am, ε, γ
Day 7	γ	γ	γ	γ	γ, α	ε, γ
Day 22	γ	γ	γ	γ	γ, α (traces)	γ
30 °C/75% RH
Day 1	am	am	am	am	am, α (traces)	am, ε, γ, α (traces)
Day 2	am, γ	am, γ, ε	am, γ	ε	am, α, γ (traces)	am, ε, γ, α
Day 7	am, γ, α	am, γ, α	am, γ	am, ε, γ	am, α, γ (traces)	am, ε, γ, α, η (traces)
Day 22	am, γ, α	am, γ, α	am, α	am, γ	am, α, γ (traces)	am, γ, α

^{^a}

Tentative assignments based on IR spectra and PCA.

^{^b}

am = amorphous.

Storage at higher humidity yielded a larger number of observed metastable forms upon dissolution. Surface crystallization in the solid state is now relatively well established. (18,30,44−46) In the current study, surface crystallization to the ε- and η-forms was observed only upon dissolution, indicating the process was solution-mediated.

SFG analysis revealed that, as well as the α-form, the ε-, η-, and δ-forms of indomethacin have noncentrosymmetric crystalline structures, based on their SFG activity. As the crystal structures of the ε-, η-, and δ-forms have not yet been solved, this provides at least some indication of their possible space groups. In addition to offering such solid-state structure information, multimodal nonlinear imaging involving both CARS and SFG provided greater confidence in resolving these polymorphs. SHG imaging has been used independently in stability and dissolution testing of amorphous drugs and their formulations (17,47) and was shown to have a large detection range, with a detection limit well-below that for routinely used methods such as DSC or XRPD. These studies however involved the crystallization of the amorphous form into one noncentrosymmetric (SHG-/SFG-active) crystalline form. Here, the SFG analysis is further enriched with vibrational spectroscopic characterization provided by CARS, which enabled identification of different crystal forms of indomethacin that could not have been resolved using SFG only.

The existence of different solid-state forms simultaneously makes some time points more difficult to interpret with the employed nonspatially resolved techniques of XRD and ATR-FTIR (combined with PCA). The XRD diffractograms and ATR-FTIR spectra (together with PCA scores) contain contributions from all present solid-state forms. The highly spatially resolved pixel-by-pixel nature of multimodal nonlinear imaging resulted in generally solid-state resolved signals, and minority polymorphs present were efficiently detected, in addition to the main polymorphic forms observed by XRD and ATR-FTIR.

The surface sensitivity of nonlinear optical imaging, combined with noncontact sampling, was important as highlighted by the samples stored at 30 °C/75% RH that exhibited dissolution-induced surface formation of the ε-form according to the nonlinear optical imaging results. This signal was not always apparent with XRD or ATR-FTIR spectroscopy. It is likely that the surface layer of these crystals could be so thin that the amorphous indomethacin signal from within the tablet overwhelmed the XRD signal, while the compression on the ATR-FTIR crystal may have been sufficient to induce disordering of the very thin layer of the highly metastable ε-form present.

The observed solid-state results postdissolution can also be compared with those in a study by Priemel at al., (32) where, after 45 min of dissolution in stimulated intestinal fluid without enzymes at pH 6.8 and temperature of 37 °C, the presence of the α- and γ-polymorphs was confirmed with ATR-FTIR, for both initially pure amorphous powders and samples stored for 5 days at the same storage conditions as in the present study (30 °C/23% RH). It is possible that since their solid-state analysis was performed at a later stage (45 min as opposed to 15 min in the present study), only the final prevailing polymorphs were present. However, as mentioned above, our results suggest that nonlinear imaging was more sensitive than the ATR-FTIR and could allow detection of the ε-form when ATR-FTIR or XRD may not.

The multimodal nonlinear imaging also provided other solid-state-specific information on distribution at the tablet surface that could not have been derived from the other characterization techniques used. Tablet cracks observed on days 1 and 2 with samples stored at 30 °C/23% RH upon dissolution typically contained crystals, as indicated by a SFG signal from these areas. Such surface irregularities or imperfections are typically places where the dissolution process is more rapid, which is why those areas are often referred to as “high energy spots”. Interestingly, the “crack-specific” crystallization was much less apparent in the samples stored at 30 °C/75% RH and may be due to a greater degree of relaxation in these regions when stored at the higher humidity.

The sample presentation during storage also appears to affect dissolution behavior. Priemel at el. (32) reported that the dissolution behavior of amorphous indomethacin particles stored at 30 °C/23% RH for 5 days was the same as that of the reference γ-form. Their study involved intrinsic dissolution experiments performed in simulated intestinal fluid without enzymes at pH 6.8 and with 0.05% of Tween 20. Their dissolution profiles corresponded to that of the γ-form already after 5 days, whereas in the present study at the same storage conditions, the dissolution profiles after 7 days approached that of the γ-form but were essentially the same as the γ-form only after 22 days of storage. In their study, individual particles were stored unlike the compressed tablets in this study. The greater overall surface area exposed to the environment during the storage in the study by Priemel et al. (32) may have affected the subsequently prepared tablet surface crystallinity prior to dissolution. This hypothesis could be tested with nonlinear imaging in the future.

Finally, it is interesting to note that in most of the samples, and in all those stored at higher humidity, multiple solid-state forms were simultaneously observed postdissolution, including two to four different polymorphs. This suggests that the transitions do not necessarily include only sequential transitions, as commonly reported with analytical techniques less efficient at detecting minority species. It is likely that heterogeneous sample characteristics (higher and lower energy amorphous regions on the tablet surfaces induced by particle compression into tablets) and dissolution conditions (different flow dynamics and local solution concentrations induced by surface roughness) contribute to this complex solid-state behavior. It is, however, also possible that the samples are exhibiting probabilistic crystallization behavior, in that more than one solid-state crystalline form may simultaneously crystallize in a single set of conditions.

5. Conclusions

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Simultaneous CARS and SFG imaging has been performed to elucidate complex solvent-mediated phase transformations on amorphous tablet surfaces upon dissolution as a function of storage time. SEM, XRD, and ATR-FTIR were used as complementary methods. Overall, multimodal nonlinear imaging proved to be more informative and sensitive than the other techniques used, with distributions of indomethacin polymorphs and the amorphous form efficiently imaged. In particular, the multimodal nonlinear imaging was better able to simultaneously detect multiple polymorphic forms, including those present in trace amounts. SFG also revealed which of the indomethacin polymorphs have noncentrosymmetric structures.

In particular, the recently reported ε-form of indomethacin was observed to form only upon exposure of the amorphous form to the dissolution media, in the early stages of storage at both storage conditions. This form was further characterized with XRD, Raman, and CARS and confirmed to have a noncentrosymmetric structure according to SFG.

It has earlier been established that surface crystallinity is generally more important than overall crystallinity when considering the relationship between crystallinity and the critical quality attribute, dissolution. Thus, multimodal nonlinear optical imaging is a suitable technique for understanding this relationship, especially when developing amorphous drugs and dosage forms. In this present study, very early stage crystallization observed with nonlinear imaging, but not detectable with the conventional solid-state analysis methods, did not have a significant effect on dissolution behavior. However, trace levels of crystallinity may be important in other samples, and multimodal nonlinear optical imaging combined with dissolution testing provides a means investigating such relationships.

Supporting Information

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.molpharmaceut.8b00840.

ATR-FTIR spectra of tablet surfaces after dissolution and additional CARS and SFG overlay images of tablets stored for 1 and 7 days at 30 °C/75% RH (PDF)

mp8b00840_si_001.pdf (696.06 kb)

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Author Information

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Corresponding Author
- Dunja Novakovic - Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5 E, 00014 Helsinki, Finland; http://orcid.org/0000-0003-2058-2194; Email: [email protected]
Authors
- Antti Isomäki - Biomedicum Imaging Unit, Faculty of Medicine, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
- Bibi Pleunis - Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5 E, 00014 Helsinki, Finland
- Sara J. Fraser-Miller - Dodd-Walls Center for Photonic and Quantum Technologies, Department of Chemistry, University of Otago, Dunedin 9016, New Zealand
- Leena Peltonen - Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5 E, 00014 Helsinki, Finland
- Timo Laaksonen - Laboratory of Chemistry and Bioengineering, Tampere University of Technology, Korkeakoulunkatu 8, 33720 Tampere, Finland
- Clare J. Strachan - Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5 E, 00014 Helsinki, Finland; http://orcid.org/0000-0003-3134-8918
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.
Notes
The authors declare no competing financial interest.

Acknowledgments

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Heikki Räikkönen from the University of Helsinki is gratefully acknowledged for his assistance with the XRD measurements. Marta Cristos from the The Complutense University of Madrid is acknowledged for her help in the initial intrinsic dissolution measurements and method setup. Jaana Koskela from the University of Helsinki is acknowledged for her help in preparing the δ-form of indomethacin. DN gratefully acknowledges the Doctoral Program in Drug Research funding provided by the University of Helsinki. CS acknowledges Business Finland, the Finnish Funding Agency for Innovation (project no. 1245/31/2015), the Academy of Finland (grant no. 289398), and the University of Helsinki for a three-year research project grant (2014–2016).

Abbreviations

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CARS	coherent anti-Stokes Raman scattering
SFG	sum frequency generation
SHG	second-harmonic generation
SEM	scanning electron microscopy
XRD	X-ray diffraction
PLM	polarized light microscopy
ATR-FTIR	attenuated total reflectance Fourier transform infrared spectroscopy
DSC	differential scanning calorimetry

References

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Greco, Kristyn; Bogner, Robin
Molecular Pharmaceutics (2010), 7 (5), 1406-1418CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
The crystn. of amorphous drugs during dissoln. is a type of soln. mediated phase transformation that can reduce the bioavailability enhancement one hoped to gain from the amorphous state. The goal of this study was to explore the effects of processing on the dissoln. performance of amorphous indomethacin. The amorphous solids were prepd. by four techniques, quench cooling the melted solid, cryogrinding γ indomethacin amorphous for 1 or 3 h and quench cooling the solid followed by 1 h of cryogrinding. Dissoln. results assessed in a flow-through intrinsic dissoln. app. reveal decreases in the dissoln. rate of amorphous indomethacin during the exptl. time frame indicating that a soln. mediated phase transformation has occurred. The amorphous solids prepd. by melt quenching and melt quenching followed by cryogrinding showed a significant dissoln. rate advantage over the γ form of indomethacin. In contrast, indomethacin that was cryoground amorphous for 1 or 3 h did not show any dissoln. rate advantage over the cryst. material. Transformation was confirmed by in situ Raman microscopy and polarized light microscopy with differences seen in the nature of the crystals apparent on the surface of the dissolving solid. A portion of the melt quenched amorphous sample was annealed at 25°C and 0% relative humidity to induce partial crystn. of γ indomethacin. As crystallinity increased, the dissoln. rate decreased. The transformation time of partially amorphous indomethacin was not dependent on the level of crystallinity present, indicating only a small fraction of cryst. material needs to be present to affect the kinetics of crystn. The soln. mediated phase transformation of amorphous indomethacin is affected by the processing method even though all solids were confirmed amorphous by polarized light microscopy and X-ray diffraction. Dissoln. may distinguish differences in amorphous solids that other methods cannot discern.
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Schmitt, P. D. Recent advances in nonlinear optical analyses of pharmaceutical materials in the solid state. Mol. Pharmaceutics 2017, 14 (3), 555– 565, DOI: 10.1021/acs.molpharmaceut.6b00809
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Recent Advances in Nonlinear Optical Analyses of Pharmaceutical Materials in the Solid State
Schmitt, Paul D.
Molecular Pharmaceutics (2017), 14 (3), 555-565CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
A review. The past decade has seen an increase in the use of nonlinear optical (NLO) techniques such as second harmonic generation, coherent antistokes Raman scattering, stimulated Raman scattering, and two-photon fluorescence for the solid-state characterization of pharmaceutical materials. These combined techniques offer several advantages (e.g., speed, selectivity, quantitation) of potential interest to the pharmaceutical community, as decreased characterization times in formulation development and testing could help decrease the time required to bring new, higher quality drugs to market. The large body of literature recently published in this field merits a review. Literature will be discussed in order of drug development, starting with applications in initial therapeutic mol. crystn. and polymorphic anal., followed by final dosage form characterization, and ending with drug product performance testing.
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Windbergs, M.; Jurna, M.; Offerhaus, H. L.; Herek, J. L.; Kleinebudde, P.; Strachan, C. J. Chemical imaging of oral solid dosage forms and changes upon dissolution using coherent anti-Stokes Raman scattering microscopy. Anal. Chem. 2009, 81 (6), 2085– 2091, DOI: 10.1021/ac8020856
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Chemical imaging of oral solid dosage forms and changes upon dissolution using coherent anti-Stokes Raman scattering microscopy
Windbergs, Maike; Jurna, Martin; Offerhaus, Herman L.; Herek, Jennifer L.; Kleinebudde, Peter; Strachan, Clare J.
Analytical Chemistry (Washington, DC, United States) (2009), 81 (6), 2085-2091CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
Dissoln. testing is a crucial part of pharmaceutical dosage form investigations and is generally performed by analyzing the concn. of the released drug in a defined vol. of flowing dissoln. medium. As solid-state properties of the components affect dissoln. behavior to a large and sometimes even unpredictable extent there is a strong need for monitoring and esp. visualizing solid-state properties during dissoln. testing. In this study coherent anti-Stokes Raman scattering (CARS) microscopy was used to visualize the solid-state properties of lipid-based oral dosage forms contg. the model drug theophylline anhydrate during dissoln. in real time. The drug release from the dosage form matrix was monitored with a spatial resoln. of about 1.5 μm. In addn., as theophylline anhydrate tends to form the less sol. monohydrate during dissoln., CARS microscopy allowed the solid-state transformation of the drug to be spatially visualized. The results obtained by CARS microscopy revealed that the method used to combine lipid and active ingredient into a sustained release dosage form can influence the physicochem. behavior of the drug during dissoln. In this case, formation of theophylline monohydrate on the surface was visualized during dissoln. with tablets compressed from powd. mixts. but not with solid lipid extrudates.
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Jurna, M.; Windbergs, M.; Strachan, C. J.; Hartsuiker, L.; Otto, C.; Kleinebudde, P.; Herek, J. L.; Offerhaus, H. L. Coherent anti-Stokes Raman scattering microscopy to monitor drug dissolution in different oral pharmaceutical tablets. J. Innovative Opt. Health Sci. 2009, 2 (1), 37– 43, DOI: 10.1142/S1793545809000322
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Fussell, A.; Garbacik, E.; Offerhaus, H.; Kleinebudde, P.; Strachan, C. In situ dissolution analysis using coherent anti-Stokes Raman scattering (CARS) and hyperspectral CARS microscopy. Eur. J. Pharm. Biopharm. 2013, 85 (3, Part B), 1141– 1147, DOI: 10.1016/j.ejpb.2013.08.012
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In situ dissolution analysis using coherent anti-Stokes Raman scattering (CARS) and hyperspectral CARS microscopy
Fussell, Andrew; Garbacik, Erik; Offerhaus, Herman; Kleinebudde, Peter; Strachan, Clare
European Journal of Pharmaceutics and Biopharmaceutics (2013), 85 (3PB), 1141-1147CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)
The solid-state form of an active pharmaceutical ingredient (API) in an oral dosage form plays an important role in detg. the dissoln. rate of the API. As the solid-state form can change during dissoln., there is a need to monitor the oral dosage form during dissoln. testing. Coherent anti-Stokes Raman scattering (CARS) microscopy provides rapid, spectrally selective imaging to monitor the oral dosage form during dissoln. In this study, in situ CARS microscopy was combined with inline UV absorption spectroscopy to monitor the solid-state change in oral dosage forms contg. theophylline anhydrate undergoing dissoln. and to correlate the solid-state change with a change in dissoln. rate. The results from in situ CARS microscopy showed that theophylline anhydrate converted to theophylline monohydrate during dissoln. resulting in a redn. in the dissoln. rate. The addn. of Me cellulose to the dissoln. medium was found to delay the theophylline monohydrate growth and changed the morphol. of the monohydrate. The net effect was an increased dissoln. rate for theophylline anhydrate. Our results show that in situ CARS microscopy combined with inline UV absorption spectroscopy is capable of monitoring oral dosage forms undergoing dissoln. and correlating changes in solid-state form with changes in dissoln. rate.
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Kestur, U. S.; Wanapun, D.; Toth, S. J.; Wegiel, L. A.; Simpson, G. J.; Taylor, L. S. Nonlinear optical imaging for sensitive detection of crystals in bulk amorphous powders. J. Pharm. Sci. 2012, 101 (11), 4201– 4213, DOI: 10.1002/jps.23280
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Nonlinear optical imaging for sensitive detection of crystals in bulk amorphous powders
Kestur, Umesh S.; Wanapun, Duangporn; Toth, Scott J.; Wegiel, Lindsay A.; Simpson, Garth J.; Taylor, Lynne S.
Journal of Pharmaceutical Sciences (2012), 101 (11), 4201-4213CODEN: JPMSAE; ISSN:0022-3549. (John Wiley & Sons, Inc.)
The primary aim of this study was to evaluate the utility of second-order nonlinear imaging of chiral crystals (SONICC) to quantify crystallinity in drug-polymer blends, including solid dispersions. Second harmonic generation (SHG) can potentially exhibit scaling with crystallinity between linear and quadratic depending on the nature of the source, and thus, it is important to det. the response of pharmaceutical powders. Phys. mixts. contg. different proportions of cryst. naproxen and hydroxyl Pr Me cellulose acetate succinate (HPMCAS) were prepd. by blending and a dispersion was produced by solvent evapn. A custom-built SONICC instrument was used to characterize the SHG intensity as a function of the cryst. drug fraction in the various samples. Powder X-ray diffraction (PXRD) and Raman spectroscopy were used as complementary methods known to exhibit linear scaling. SONICC was able to detect cryst. drug even in the presence of 99.9 wt % HPMCAS in the binary mixts. The calibration curve revealed a linear dynamic range with a R2 value of 0.99 spanning the range from 0.1 to 100 wt % naproxen with a root mean square error of prediction of 2.7%. Using the calibration curve, the errors in the validation samples were in the range of 5%-10%. Anal. of a 75 wt % HPMCAS-naproxen solid dispersion with SONICC revealed the presence of crystallites at an earlier time point than could be detected with PXRD and Raman spectroscopy. In addn., results from the crystn. kinetics expt. using SONICC were in good agreement with Raman spectroscopy and PXRD. In conclusion, SONICC has been found to be a sensitive technique for detecting low levels (0.1% or lower) of crystallinity, even in the presence of large quantities of a polymer. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Assocn. J Pharm Sci.
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Wanapun, D.; Kestur, U. S.; Kissick, D. J.; Simpson, G. J.; Taylor, L. S. Selective detection and quantitation of organic molecule crystallization by second harmonic generation microscopy. Anal. Chem. 2010, 82 (13), 5425– 5432, DOI: 10.1021/ac100564f
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Selective Detection and Quantitation of Organic Molecule Crystallization by Second Harmonic Generation Microscopy
Wanapun, Duangporn; Kestur, Umesh S.; Kissick, David J.; Simpson, Garth J.; Taylor, Lynne S.
Analytical Chemistry (Washington, DC, United States) (2010), 82 (13), 5425-5432CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
Second order nonlinear optical imaging of chiral crystals (SONICC) was applied to selectively detect crystal formation at early stages and characterize the kinetics of nucleation and growth. SONICC relies on second harmonic generation (SHG), a nonlinear optical effect that only arises from noncentosym. ordered domain structures, which include crystals of chiral mols. The model systems studied include pharmaceutically relevant compds.: griseofulvin and chlorpropamide. SONICC demonstrates low detection limits producing an 8 order of magnitude improvement relative to macroscopic av. techniques and 5 order of magnitude improvement relative to optical microscopy. SONICC was also applied to examine the kinetics of crystn. in amorphous griseofulvin. The results show that SONICC enables simultaneous monitoring of individual crystal growth, nucleation rate, and macroscopic crystn. kinetics.
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Schmitt, P. D.; Trasi, N. S.; Taylor, L. S.; Simpson, G. J. Finding the needle in the haystack: Characterization of trace crystallinity in a commercial formulation of paclitaxel protein-bound particles by Raman spectroscopy enabled by second harmonic generation microscopy. Mol. Pharmaceutics 2015, 12 (7), 2378– 2383, DOI: 10.1021/acs.molpharmaceut.5b00065
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Finding the Needle in the Haystack: Characterization of Trace Crystallinity in a Commercial Formulation of Paclitaxel Protein-Bound Particles by Raman Spectroscopy Enabled by Second Harmonic Generation Microscopy
Schmitt, Paul D.; Trasi, Niraj S.; Taylor, Lynne S.; Simpson, Garth J.
Molecular Pharmaceutics (2015), 12 (7), 2378-2383CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
Second harmonic generation (SHG) microscopy was used to rapidly identify regions of interest for localized confocal Raman spectroscopy measurements in order to quantify crystallinity within lyophilized Abraxane powder (protein bound paclitaxel for injectable suspension). Water insol. noncentrosym. cryst. particles ranging from ∼1 to 120 μm were identified by SHG, with wide variability in crystal size and frequency obsd. between several batches of Abraxane. By targeting the Raman anal. to these localized regions identified by SHG, the required measurement time was decreased over 2 orders of magnitude, from 8 h to 2 s. Exptl. Raman spectra of SHG active domains in Abraxane were in good agreement with exptl. spectra of pure cryst. paclitaxel. These collective results are consistent with up to 30% of the active ingredient being present as poorly sol. cryst. particulates in some batches of Abraxane.
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Mah, P. T.; Novakovic, D.; Saarinen, J.; Van Landeghem, S.; Peltonen, L.; Laaksonen, T.; Isomäki, A.; Strachan, C. J. Elucidation of compression-induced surface crystallization in amorphous tablets using sum frequency generation (SFG) microscopy. Pharm. Res. 2017, 34 (5), 957– 970, DOI: 10.1007/s11095-016-2046-6
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Song, Z.; Sarkar, S.; Vogt, A. D.; Danzer, G. D.; Smith, C. J.; Gualtieri, E. J.; Simpson, G. J. Kinetic modeling of accelerated stability testing enabled by second harmonic generation microscopy. Anal. Chem. 2018, 90 (7), 4406– 4413, DOI: 10.1021/acs.analchem.7b04260
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Kinetic Modeling of Accelerated Stability Testing Enabled by Second Harmonic Generation Microscopy
Song, Zhengtian; Sarkar, Sreya; Vogt, Andrew D.; Danzer, Gerald D.; Smith, Casey J.; Gualtieri, Ellen J.; Simpson, Garth J.
Analytical Chemistry (Washington, DC, United States) (2018), 90 (7), 4406-4413CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
The low limits of detection afforded by second harmonic generation (SHG) microscopy coupled with image anal. algorithms enabled quant. modeling of the temp.-dependent crystn. of active pharmaceutical ingredients (APIs) within amorphous solid dispersions (ASDs). ASDs, in which an API is maintained in an amorphous state within a polymer matrix, are finding increasing use to address soly. limitations of small-mol. APIs. Extensive stability testing is typically performed for ASD characterization, the time frame for which is often dictated by the earliest detectable onset of crystal formation. Here a study of accelerated stability testing on ritonavir, a human immunodeficiency virus (HIV) protease inhibitor, has been conducted. Under the condition for accelerated stability testing at 50 °C/75%RH and 40 °C/75%RH, ritonavir crystn. kinetics from amorphous solid dispersions were monitored by SHG microscopy. SHG microscopy coupled by image anal. yielded limits of detection for ritonavir crystals as low as 10 ppm, which is about 2 orders of magnitude lower than other methods currently available for crystallinity detection in ASDs. The four decade dynamic range of SHG microscopy enabled quant. modeling with an established (JMAK) kinetic model. From the SHG images, nucleation and crystal growth rates were independently detd.
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Novakovic, D.; Saarinen, J.; Rojalin, T.; Antikainen, O.; Fraser-Miller, S. J.; Laaksonen, T.; Peltonen, L.; Isomäki, A.; Strachan, C. J. Multimodal nonlinear optical imaging for sensitive detection of multiple pharmaceutical solid-state forms and surface transformations. Anal. Chem. 2017, 89 (21), 11460– 11467, DOI: 10.1021/acs.analchem.7b02639
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Multimodal Nonlinear Optical Imaging for Sensitive Detection of Multiple Pharmaceutical Solid-State Forms and Surface Transformations
Novakovic, Dunja; Saarinen, Jukka; Rojalin, Tatu; Antikainen, Osmo; Fraser-Miller, Sara J.; Laaksonen, Timo; Peltonen, Leena; Isomaki, Antti; Strachan, Clare J.
Analytical Chemistry (Washington, DC, United States) (2017), 89 (21), 11460-11467CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
Two nonlinear imaging modalities, coherent anti-Stokes Raman scattering (CARS) and sum-frequency generation (SFG), were successfully combined for sensitive multimodal imaging of multiple solid-state forms and their changes on drug tablet surfaces. Two imaging approaches were used and compared: (i) hyperspectral CARS combined with principal component anal. (PCA) and SFG imaging and (ii) simultaneous narrowband CARS and SFG imaging. Three different solid-state forms of indomethacin-the cryst. gamma and alpha forms, as well as the amorphous form-were clearly distinguished using both approaches. Simultaneous narrowband CARS and SFG imaging was faster, but hyperspectral CARS and SFG imaging has the potential to be applied to a wider variety of more complex samples. These methodologies were further used to follow crystn. of indomethacin on tablet surfaces under two storage conditions: 30 °C/23% RH and 30 °C/75% RH. Imaging with (sub)micron resoln. showed that the approach allowed detection of very early stage surface crystn. The surfaces progressively crystd. to predominantly (but not exclusively) the gamma form at lower humidity and the alpha form at higher humidity. Overall, this study suggests that multimodal nonlinear imaging is a highly sensitive, solid-state (and chem.) specific, rapid, and versatile imaging technique for understanding and hence controlling (surface) solid-state forms and their complex changes in pharmaceuticals.
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Yamamoto, H. 1-Acyl-indoles. II. A new syntheses of 1-(p-chlorobenzoyl)-5-methoxy-3-indolylacetic acid and its polymorphism. Chem. Pharm. Bull. 1968, 16 (1), 17– 19, DOI: 10.1248/cpb.16.17
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1-Acyl-indoles. II. A new syntheses of 1-(ion-chlorobenzoyl)-5-methoxy-3-indolylacetic acid and its polymorphism
Yamamoto, Hisao
Chemical & Pharmaceutical Bulletin (1968), 16 (1), 17-19CODEN: CPBTAL; ISSN:0009-2363.
1-(p-Chlorobenzoyl)-2-methyl-5-methoxy-3-indolylacetic acid, a potent antiinflammatory drug, was directly prepd. from N-(p-chlorobenzoyl)-p-methoxyphenyl-hydrazine-HCl and levulinic acid in excellent yield by the new method. The recrystn. of 1-(p-chlorobenzoyl)-2-methyl-5-methoxy-3-indolylacetic acid from solvents gave crystals of polymorphism -α, β, and γ-types.
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Borka, L. The Polymorphism of indomethacin. New modifications, their melting behavior and solubility. Acta Pharm. Suec. 1974, 11 (3), 295– 303
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Lin, S. Y. Isolation and solid-state characteristics of a new crystal form of indomethacin. J. Pharm. Sci. 1992, 81 (6), 572– 576, DOI: 10.1002/jps.2600810622
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Isolation and solid-state characteristics of a new crystal form of indomethacin
Lin, Shan Yang
Journal of Pharmaceutical Sciences (1992), 81 (6), 572-6CODEN: JPMSAE; ISSN:0022-3549.
A new polymorphic crystal form of indomethacin was pptd. from an aq. soln. of indomethacin and β-cyclodextrin by titrn. with a 0.5N HCl aq. soln. Three polymorphs (α, β, and γ forms) and a new crystal form were differentiated with thermal anal., IR spectroscopy, powder x-ray diffractometry, TLC, elemental anal., and Fourier-transform IR (FTIR) spectroscopy with a newly developed FTIR microscope equipped with a thermal analyzer. The new crystal polymorph of indomethacin exhibited endo- and exothermic peaks near 102.8 and 104.1°, resp., because of phase transition without wt. loss, followed by 2 addnl. endothermic peaks at 151 and 158.9°, because of fusion. The differential scanning calorimetry-FTIR system can be used to examine the correlation between structural change of C:O stretching bands of this new polymorph and its thermal response. The new crystal form contained some γ-form crystals, detd. with an FTIR microscope equipped with a mapping option. Solid-state 13C-NMR spectra of the polymorphs of indomethacin were also examd.
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Crowley, K. J.; Zografi, G. Cryogenic grinding of indomethacin polymorphs and solvates: Assessment of amorphous phase formation and amorphous phase physical stability. J. Pharm. Sci. 2002, 91 (2), 492– 507, DOI: 10.1002/jps.10028
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Cryogenic grinding of indomethacin polymorphs and solvates: assessment of amorphous phase formation and amorphous phase physical stability
Crowley, Kieran J.; Zografi, George
Journal of Pharmaceutical Sciences (2002), 91 (2), 492-507CODEN: JPMSAE; ISSN:0022-3549. (Wiley-Liss, Inc.)
The effect of cryogenic grinding on five crystal forms of indomethacin (IMC) was investigated with particular interest in the formation of amorphous phase. Powder x-ray diffraction (PXRD) and differential scanning calorimetry (DSC) demonstrated that amorphous phase formation took place for all three polymorphs (γ, α, and δ) and one solvate (IMC methanolate). In the latter case, a postgrinding drying stage was needed to remove desolvated methanol from the ground amorphous product because methanol destabilized amorphous IMC presumably via a plasticizing effect. The crystal structure of another solvate, IMC t-butanolate, was unaffected by grinding, indicating that amorphous phase formation on grinding does not occur in all cases. Ground amorphous materials possessed similar glass transition temps. but significant differences in phys. stability as assessed by both isothermal and nonisothermal crystn. It is argued that phys. factors, namely residual crystal phase and sp. surface area, det. the isothermal and nonisothermal crystn. behavior of ground amorphous samples as opposed to intrinsic differences in the structure of the amorphous phase.
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Surwase, S. A.; Boetker, J. P.; Saville, D.; Boyd, B. J.; Gordon, K. C.; Peltonen, L.; Strachan, C. J. Indomethacin: New polymorphs of an old drug. Mol. Pharmaceutics 2013, 10 (12), 4472– 4480, DOI: 10.1021/mp400299a
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Indomethacin: New Polymorphs of an Old Drug
Surwase, Sachin A.; Boetker, Johan P.; Saville, Dorothy; Boyd, Ben J.; Gordon, Keith C.; Peltonen, Leena; Strachan, Clare J.
Molecular Pharmaceutics (2013), 10 (12), 4472-4480CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
This study reports the appearance and characterization of multiple new polymorphic forms of indomethacin. Considering the interest in amorphous suspensions for toxicol. studies of poorly water-sol. drugs, we sought to investigate the crystn. behavior of amorphous indomethacin in aq. suspension. Specifically, the effect of pH and temp. on crystn. behavior was studied. Quench cooled amorphous powder was added to buffered media at different pH values (1.2, 4.5, and 6.8) at 5 and 25 °C. Both the solid and the soln. were analyzed at different time points up to 24 h. Attenuated total reflection Fourier transform IR (ATR-FTIR) spectroscopy (with principal component anal.) was used to study solid-phase transformations and UV spectroscopy used to probe soln. concn. The crystn. onset time decreased and rate of crystn. increased with increasing pH and temp. Diverse polymorphic forms were obsd., with three new forms being identified; these were named ε, ζ, and η. At 25 °C, the amorphous form recrystd. directly to the α form, except at pH 6.8, where it initially converted briefly into the ε form. At 5 °C, all three new polymorphic forms were obsd. sequentially in the order ε, ζ, and then η, with the no. of these forms obsd. increasing sequentially with decreasing pH. The three new forms exhibited distinct X-ray powder diffraction (XPRD), differential scanning calorimetry (DSC), and FTIR and Raman spectroscopy profiles. The soln. concn. profiles suggest that the relative phys. stabilities of the polymorphs at 5 °C from lowest to highest is ε < ζ < η < α. The appearance of new polymorphs in this study suggests that amorphous suspensions are worth considering when performing polymorphic screening studies.
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Van Duong, T.; Ludeker, D.; Van Bockstal, P. J.; De Beer, T.; Van Humbeeck, J.; Van den Mooter, G. Polymorphism of indomethacin in semicrystalline dispersions: Formation, transformation, and segregation. Mol. Pharmaceutics 2018, 15 (3), 1037– 1051, DOI: 10.1021/acs.molpharmaceut.7b00930
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Polymorphism of Indomethacin in Semicrystalline Dispersions: Formation, Transformation, and Segregation
Van Duong, Tu; Ludeker, David; Van Bockstal, Pieter-Jan; De Beer, Thomas; Van Humbeeck, Jan; Van den Mooter, Guy
Molecular Pharmaceutics (2018), 15 (3), 1037-1051CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
The crystn. of metastable crystal polymorphs in polymer matrixes has been extensively reported in literature as a possible approach to enhance the soly. of poorly water-sol. drug compds., yet no clarification of the mechanism of the polymorph formation has been proposed. The current work aims to elucidate the polymorphism behavior of the model compd. indomethacin as well as the mechanism of polymorph selection of drugs in semicryst. systems. Indomethacin crystd. as either the α- or τ-form, a new metastable form, or a mixt. of the two polymorphs in dispersions contg. different drug loadings in polyethylene glycol, poloxamer, or Gelucire as the result of the variation in the mobility of drug mols. As a general rule, low mol. mobility of the amorphous drug favors the crystn. into thermodynamically stable forms whereas metastable cryst. polymorphs are preferred when the mol. mobility of the drug is sufficiently high. This rule provides insight into the polymorph selection of numerous active pharmaceutical ingredients in semicryst. dispersions and can be used as a guide for polymorphic screening from melt crystn. by tuning the mobility of drug mols. In addn., the drug crystd. faster while the polymer crystd. slower as the drug-loading increased with the maxima of drug crystn. rate in 70% indomethacin dispersion. Increasing the drug content in solid dispersions reduced the τ to α polymorphic transition rate, except for when the more stable form was initially dominant. The segregation of τ and α polymorphs as well as the polymorphic transformation during storage led to the inherent inhomogeneity of the semicryst. dispersions. This study highlights and expands our understanding about the complex crystn. behavior of semicryst. systems and is crucial for prepn. of solid dispersions with reproducible and consistent physicochem. properties and pharmaceutical performance.
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Kaneniwa, N.; Otsuka, M.; Hayashi, T. Physicochemical characterization of indomethacin polymorphs and the transformation kinetics in ethanol. Chem. Pharm. Bull. 1985, 33 (8), 3447– 3455, DOI: 10.1248/cpb.33.3447
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Physicochemical characterization of indomethacin polymorphs and the transformation kinetics in ethanol
Kaneniwa, Nobuyoshi; Otsuka, Makoto; Hayashi, Tetsuo
Chemical & Pharmaceutical Bulletin (1985), 33 (8), 3447-55CODEN: CPBTAL; ISSN:0009-2363.
Methods for the prepn. of polymorphs of indomethacin (IMC) (I) [53-86-1] were studied to obtain the pure polymorphs. The physicochem. properties of IMC polymorphs were measured by using x-ray diffraction anal. IR spectroscopy, DTA DSC, and 2 polymorphs (α and γ forms) and 1 benzene solvate (β form) were identified. The pure α form was obtained when distd. water at room temp. was poured into an EtOH [64-17-5] soln. of IMC at ∼80°, and the pptd. crystals were filtered and dried. The pure β and γ forms were obtained by recrystn. from benzene and Et2O, resp., at room temp. The m.ps. of the α and γ forms were 148 and 154°, resp., and their heats of fusion were 7.49 and 8.64 kcal/mol, resp., as detd. by DSC. A mixt. of α and γ forms was obtained by the method previously reported for α form prepn. (recrystn. method), since the pure α form was transformed to the γ form in EtOH at room temp. The transformation of α form to γ form in EtOH was analyzed by the kinetic method using 9 kinds of kinetic models. The transformation followed kinetics corresponding to 2-dimensional growth of nuclei (Avrami equation), and the activation energy was 14.2 kcal/mol from the Arrhenius plot. The solubilities of the α and γ forms in distd. water were 0.87 and 0.69 mg/100 mL, resp.
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Karmwar, P.; Graeser, K.; Gordon, K. C.; Strachan, C. J.; Rades, T. Effect of different preparation methods on the dissolution behaviour of amorphous indomethacin. Eur. J. Pharm. Biopharm. 2012, 80 (2), 459– 464, DOI: 10.1016/j.ejpb.2011.10.006
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Effect of different preparation methods on the dissolution behaviour of amorphous indomethacin
Karmwar, Pranav; Graeser, Kirsten; Gordon, Keith C.; Strachan, Clare J.; Rades, Thomas
European Journal of Pharmaceutics and Biopharmaceutics (2012), 80 (2), 459-464CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)
The aim of this study was to investigate whether amorphous indomethacin samples prepd. using different preparative techniques and processing parameters exhibit different structural and thermodn. characteristics and whether these differences can be correlated to their dissoln. behavior. Samples were prepd. either by cooling the drug melt at different cooling rates or by cryo-milling the drug for different milling times. The resulting amorphous materials were characterized using X-ray diffraction, Raman spectroscopy and polarising light microscopy. All samples were entirely X-ray amorphous, except for the sample cryo-milled for 15 min, which exhibited residual crystallinity. The shape of the halos in the diffractograms, however, varied depending on the prepn. method and processing parameters, suggesting structural variations in the near order of the mols. between the prepd. amorphous forms. This finding was supported by principal component anal. of the Raman spectra, as the samples clustered in the scores plot according to processing parameters for both of the preparative methods used. When investigating the dissoln. behavior, the samples cooled at different cooling rates showed no significant differences in their dissoln. profiles and dissoln. rates (≈0.55 μg/mL/cm2). In contrast, for cryo-milled samples, dissoln. rate depended on the milling time, with samples milled for 120, 180 and 240 min, showing significantly increased dissoln. rates of 0.28, 0.48 and 0.59 μg/mL/cm2, resp., when compared to cryst. indomethacin (≈0.06 and 0.05 μg/mL/cm2 for α and γ-indomethacin, resp.). The milling processes appear to continue to affect the degree of disorder in the solid material, enhancing its dissoln. rate, although all samples milled for >30 min were X-ray amorphous. Thus, choosing the right prepn. technique and parameters for prepg. amorphous solids is crit. for producing materials with enhanced dissoln. profiles.
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Alonzo, D. E.; Zhang, G. G. Z.; Zhou, D.; Gao, Y.; Taylor, L. S. Understanding the behavior of amorphous pharmaceutical systems during dissolution. Pharm. Res. 2010, 27 (4), 608– 618, DOI: 10.1007/s11095-009-0021-1
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Understanding the Behavior of Amorphous Pharmaceutical Systems during Dissolution
Alonzo, David E.; Zhang, Geoff G. Z.; Zhou, Deliang; Gao, Yi; Taylor, Lynne S.
Pharmaceutical Research (2010), 27 (4), 608-618CODEN: PHREEB; ISSN:0724-8741. (Springer)
Purpose: To investigate the underlying phys. processes taking place during dissoln. of amorphous pharmaceuticals and correlate them to the obsd. soln. concn.-time profiles. Felodipine and indomethacin were used as model hydrophobic compds. Concn.-time profiles were monitored during dissoln. of the model amorphous compds. using in situ fiber-optic UV spectroscopy. Crystn. of the solid exposed to an aq. environment was monitored using Raman spectroscopy and/or powder x-ray diffraction. Polarized light microscopy was used to provide qual. information about crystn. processes. For felodipine, a small extent of supersatn. was generated via dissoln. at 25°C but not at 37°C. The amorphous solid was found to crystallize rapidly at both temps. upon exposure to the dissoln. medium. Addn. of low concns. of polymers to the dissoln. medium was found to delay crystn. of the amorphous solid, leading to the generation of supersatd. solns. Amorphous indomethacin did not crystallize as readily in an aq. environment; hence, dissoln. resulted in supersatd. solns. However, crystn. from these supersatd. solns. was rapid. Polymeric additives were able to retard crystn. from supersatd. solns. of both indomethacin and felodipine for up to 4 h. The dissoln. advantage of amorphous solids can be negated either by crystn. of the amorphous solid on contact with the dissoln. medium or through rapid crystn. of the supersatd. soln. Polymeric additives can potentially retard both of these crystn. routes, leading to the generation of supersatd. solns. that can persist for biol. relevant timeframes.
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Mah, P. T.; Peltonen, L.; Novakovic, D.; Rades, T.; Strachan, C. J.; Laaksonen, T. The effect of surfactants on the dissolution behavior of amorphous formulations. Eur. J. Pharm. Biopharm. 2016, 103, 13– 22, DOI: 10.1016/j.ejpb.2016.03.007
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The effect of surfactants on the dissolution behavior of amorphous formulations
Mah, Pei T.; Peltonen, Leena; Novakovic, Dunja; Rades, Thomas; Strachan, Clare J.; Laaksonen, Timo
European Journal of Pharmaceutics and Biopharmaceutics (2016), 103 (), 13-22CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)
The optimal design of oral amorphous formulations benefits from the use of excipients to maintain drug supersatn. and thus ensures adequate absorption during intestinal transit. The use of surfactants for the maintenance of supersatn. in amorphous formulations has not been investigated in detail. The main aim of this study was to investigate the effect of surfactant on the dissoln. behavior of neat amorphous drug and binary polymer based solid dispersion. Indomethacin was used as the model drug and the surfactants studied were polysorbate 80 and poloxamer 407. The presence of surfactants (alone or in combination with polymers) in the buffer was detrimental to the dissoln. of neat amorphous indomethacin, suggesting that the surfactants promoted the crystn. of neat amorphous indomethacin. In contrast, the presence of surfactants (0.01% w/v) in the buffer resulted in a significant improvement on the dissoln. behavior of binary polymer based solid dispersion. Incorporating the surfactant to the formulation to form ternary solid dispersion adversely affected the dissoln. behavior. In conclusion, the use of surfactants (as wetting or solubilization agents) in dissoln. studies of neat amorphous drugs requires prudent consideration. The design of amorphous formulations with optimal dissoln. performance requires the appropriate selection of a combination of excipients and consideration of the method of introducing the excipients.
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Karmwar, P.; Graeser, K.; Gordon, K. C.; Strachan, C. J.; Rades, T. Investigation of properties and recrystallisation behaviour of amorphous indomethacin samples prepared by different methods. Int. J. Pharm. 2011, 417 (1–2), 94– 100, DOI: 10.1016/j.ijpharm.2010.12.019
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Investigation of properties and recrystallisation behaviour of amorphous indomethacin samples prepared by different methods
Karmwar, Pranav; Graeser, Kirsten; Gordon, Keith C.; Strachan, Clare J.; Rades, Thomas
International Journal of Pharmaceutics (2011), 417 (1-2), 94-100CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
The aim of this study was to investigate if amorphous indomethacin samples, prepd. using different prepn. methods, exhibit different structural and kinetic characteristics and if these differences can be correlated to their phys. stability (time to crystn.). Samples were prepd. by melt quenching, spray drying, ball milling, and cryo-milling. The resulting amorphous materials were characterized using X-ray diffraction, Raman spectroscopy and differential scanning calorimetry. All freshly prepd. samples were completely X-ray amorphous (with a halo being the only feature in the diffractograms). The shape of the halos in the diffractograms, however, varied depending on the prepn. method, suggesting structural variations in the near order of the mols. between the differently prepd. amorphous forms. Principal component anal. of the Raman spectra of the various amorphous forms revealed that the samples clustered in the scores plot according to prepn. method, again suggesting structural differences due to prepn. method. The range of vibrations assocd. with the largest spectral differences in the loadings plot showed that these differences were due to a range of mol. conformations and intermol. interactions. The ranking of the samples with respect to stability was: quench cooled amorphous samples > cryo-milled (α-form) > spray dried > ball milled (α-form) > ball milled (γ-form) = cryo-milled (γ-form). This ranking was not correlated with the diffractogram shapes or sample distribution in the scores plot of the Raman spectra, suggesting that phys. stability was not directly affected by structural variation in the samples. However, ranking of stability of the differently prepd. amorphous forms of the drug could be predicted by detg. the relaxation time values, for all amorphous samples. The relaxation times, calcd. by using the Adam Gibbs and Kohlrausch-Williams-Watts equations, were in accordance with the exptl. detd. stability order. This study showed that correlation of phys. stability with calcd. relaxation time is possible for the same amorphous systems prepd. by different methods. This could aid in selecting the most appropriate prepn. techniques in situations where there are a variety of suitable methods.
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Wu, T.; Yu, L. Surface crystallization of indomethacin below Tg. Pharm. Res. 2006, 23 (10), 2350– 2355, DOI: 10.1007/s11095-006-9023-4
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Surface Crystallization of Indomethacin Below Glass Transition Temperature
Wu, Tian; Yu, Lian
Pharmaceutical Research (2006), 23 (10), 2350-2355CODEN: PHREEB; ISSN:0724-8741. (Springer)
Purpose. To study the surface crystn. of indomethacin (IMC) below T g and its effects on the kinetics of overall crystn. Methods. Crystal growth rates in liq. layers formed between microscope cover glasses were measured with the top cover glass in place and removed. Polymorphs were identified by powder x-ray diffraction, Raman microscopy, and melting-point detn. by hot-stage microscopy. Surface crystals were identified by scratching the sample surface, by cutting the sample to expose its interior, and by analyzing the intensity of x-ray diffraction. Amorphous IMC particles of different sizes were stored at 40° (T g-2°) and analyzed at different times by differential scanning calorimetry to obtain the kinetics of crystn. Results. Crystal growth of IMC below T g at the free surface was approx. two orders of magnitude faster than that in the bulk, resulting in a surface layer of crystals around a slower-crystg. interior. Surface crystn. yielded mainly the γ polymorph. Amorphous IMC powders showed rapid initial crystn. at 40°, but the crystn. abruptly slowed down at "satn. levels" below 100%; the larger the particles, the lower the "satn. level." Conclusion. The faster surface crystn. of IMC than the bulk crystn. leads to unusual crystn. kinetics wherein a rapid initial increase of crystallinity is followed by an abrupt slowdown of crystn. Surface crystn. should be distinguished from bulk crystn. in modeling and controlling the crystn. of amorphous solids.
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Andronis, V.; Yoshioka, M.; Zografi, G. Effects of sorbed water on the crystallization of indomethacin from the amorphous state. J. Pharm. Sci. 1997, 86 (3), 346– 351, DOI: 10.1021/js9602711
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Effects of Sorbed Water on the Crystallization of Indomethacin from the Amorphous State
Andronis, Vlassios; Yoshioka, Minoru; Zografi, George
Journal of Pharmaceutical Sciences (1997), 86 (3), 346-351CODEN: JPMSAE; ISSN:0022-3549. (American Chemical Society)
The water sorption isotherm and the crystn. rates for amorphous indomethacin were detd. at 30° as a function of relative humidity (RH), along with the effects of water content on the glass transition temp. (Tg). Below 43% RH, only the stable γ crystal form appears, whereas at higher RH, only the metastable α crystal form appears. The tendency for the α crystals to form at higher RH is consistent with the Ostwald step rule. The crystn. rate of the α form continuously increased with increasing RH due to increasing mol. mobility. The crystn. mechanism of the γ form changed from surface-initiated to bulk-initiated crystn. at 21% RH, and although crystn. rates of the γ form increased with increasing RH in both cases, they were higher when crystn. was surface-initiated. The complex crystn. behavior of the γ form is explained by the higher water content and mol. mobility of the surface relative to the bulk and the general effect of water on α or γ crystal form selection as described by the Ostwald step rule.
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Priemel, P. A.; Grohganz, H.; Gordon, K. C.; Rades, T.; Strachan, C. J. The impact of surface- and nano-crystallisation on the detected amorphous content and the dissolution behaviour of amorphous indomethacin. Eur. J. Pharm. Biopharm. 2012, 82 (1), 187– 193, DOI: 10.1016/j.ejpb.2012.05.012
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The impact of surface- and nano-crystallisation on the detected amorphous content and the dissolution behaviour of amorphous indomethacin
Priemel, P. A.; Grohganz, H.; Gordon, K. C.; Rades, T.; Strachan, C. J.
European Journal of Pharmaceutics and Biopharmaceutics (2012), 82 (1), 187-193CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)
The crystallinity and phys. stability of amorphous drugs has previously been studied using different anal. techniques. However, the effect of the measurement method on obsd. crystallinity and its importance for crit. quality attributes, such as dissoln., has not yet been widely investigated.The aim of this study was to (i) qual. analyze and understand the recrystn. behavior of amorphous indomethacin during storage, (ii) quantify the amorphous content during storage with complementary anal. techniques and (iii) investigate the relationship between obsd. recrystn. behavior and dissoln. behavior.Quench cooled indomethacin was stored and the samples were visualized by SEM to gain spatially resolved information about the recrystn. behavior. Crystn. was quantified by Fourier transform attenuated total reflectance IR (FT-ATR-IR) spectroscopy, differential scanning calorimetry and X-ray powder diffraction.These techniques resulted in different obsd. recrystn. profiles. The physicochem. phenomena detected and sampling geometry for each technique together with the sample recrystg. from the surface and appearance of nano-crystals were used to explain the differences.The dissoln. behavior at the obsd. recrystn. endpoints for the different anal. techniques revealed that FT-ATR-IR spectroscopy predicted the changes in dissoln. behavior due to crystn. best.
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Tres, F.; Treacher, K.; Booth, J.; Hughes, L. P.; Wren, S. A. C.; Aylott, J. W.; Burley, J. C. Indomethacin-Kollidon VA64 extrudates: A mechanistic study of pH-dependent controlled release. Mol. Pharmaceutics 2016, 13 (3), 1166– 1175, DOI: 10.1021/acs.molpharmaceut.5b00979
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Indomethacin-Kollidon VA64 Extrudates: A Mechanistic Study of pH-Dependent Controlled Release
Tres, Francesco; Treacher, Kevin; Booth, Jonathan; Hughes, Leslie P.; Wren, Stephen A. C.; Aylott, Jonathan W.; Burley, Jonathan C.
Molecular Pharmaceutics (2016), 13 (3), 1166-1175CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
Because of its weakly acidic nature (pKa of 4.5), indomethacin presents an aq. soly. that significantly increases when changing from acidic to neutral/alk. pH (1.5 μg/mL at pH 1.2 and 105.2 μg/mL at pH 7.4). We have therefore investigated the impact of the dissoln. medium pH on the dissoln. performance of indomethacin:Kollidon VA64 extrudates. The impact of the drug loading on the dissoln. properties of these systems was also examd. (5%, 15%, 30%, 50%, 70%, and 90% drug loading). Time-resolved Raman spectroscopy along with in-line UV-vis spectrophotometry was employed to directly relate changes in dissoln. behavior to physicochem. changes that occur to the extrudate during the test. The dissoln. tests were performed in pH 2 HCl (to mimic the stomach conditions), and this was then switched during the expt. to pH 6.8 phosphate buffer (to simulate the poststomach conditions). The rotating disk dissoln. rate test was also used to simultaneously measure the dissoln. rate of both the drug and the polymer. We found that in pH 2 HCl buffer, for the 15% or higher drug-loaded extrudates, Kollidon VA64 preferentially dissolves from the exterior of the compact leaving an amorphous drug-rich hydrophobic shell, which, similarly to an enteric coating, inhibits the drug release. The in situ formation of an enteric coating has been previously hypothesized, and this has been the first time that is directly obsd. in a pH-variable dissoln. test. The dissoln. medium switch to pH 6.8 phosphate buffer, due to the large increase of the aq. soly. of indomethacin at this pH, leads to rapid dissoln. of the material forming the coating and therefore total drug release. In contrast, the 5% extrudate is fully hydrated and quickly dissolves at low pH pointing to a dissoln. performance dependent on highly water-sol. Kollidon VA64.
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Koranne, S.; Thakral, S.; Suryanarayanan, R. Effect of formulation and process parameters on the disproportionation of indomethacin sodium in buffered lyophilized formulations. Pharm. Res. 2018, 35 (11), 214, DOI: 10.1007/s11095-018-2499-x
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Peltonen, L.; Liljeroth, P.; Heikkilä, T.; Kontturi, K.; Hirvonen, J. Dissolution testing of acetylsalicylic acid by a channel flow method—correlation to USP basket and intrinsic dissolution methods. Eur. J. Pharm. Sci. 2003, 19 (5), 395– 401, DOI: 10.1016/S0928-0987(03)00140-4
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Dissolution testing of acetylsalicylic acid by a channel flow method-correlation to USP basket and intrinsic dissolution methods
Peltonen, Leena; Liljeroth, Peter; Heikkila, Tiina; Kontturi, Kyosti; Hirvonen, Jouni
European Journal of Pharmaceutical Sciences (2003), 19 (5), 395-401CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)
A new modification of the channel flow dissoln. method is introduced together with the theor. basis to ext. the soly. and mass transfer parameters from the dissoln. expts. Correlation of drug dissoln. profiles in the channel flow app. was evaluated with respect to USP basket and intrinsic dissoln. methods at pH 1.2 or 6.8. Acetylsalicylic acid (ASA) was studied as a pure drug substance and as three simple tablet compns. with microcryst. cellulose (MCC) and/or lactose as excipients. The channel flow measurements of 100% ASA tablets correlated well with the results of intrinsic dissoln. tests. In the channel flow method as well as in the USP basket method the release of ASA was fastest from the tablet compns. contg. lactose, while the slowest dissoln. rate was obsd. with the compn. contg. MCC as the only excipient. As presumed, the dissoln. rate of the weak acid was decreased as the pH of the medium was lowered, which was clearly confirmed also by the three dissoln. methods. MCC forms matrix tablets and in the USP basket method the dissoln. profiles followed square root of time kinetics indicating that diffusion was the rate-controlling step of ASA dissoln. Also the channel flow results indicated that the dissoln. Of ASA was controlled by mass transfer. The swelling behavior of the tablets is different in the channel flow method as compared to the basket method: only one tablet surface is exposed to the dissoln. medium in the channel flow system. The contact between the tablet surface and the dissoln. medium is more similar between the channel flow and intrinsic dissoln. methods.
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Sarnes, A.; Østergaard, J.; Jensen, S. S.; Aaltonen, J.; Rantanen, J.; Hirvonen, J.; Peltonen, L. Dissolution study of nanocrystal powders of a poorly soluble drug by UV imaging and channel flow methods. Eur. J. Pharm. Sci. 2013, 50 (3), 511– 519, DOI: 10.1016/j.ejps.2013.08.030
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Dissolution study of nanocrystal powders of a poorly soluble drug by UV imaging and channel flow methods
Sarnes, Annika; Oestergaard, Jesper; Jensen, Sabrine Smedegaard; Aaltonen, Jaakko; Rantanen, Jukka; Hirvonen, Jouni; Peltonen, Leena
European Journal of Pharmaceutical Sciences (2013), 50 (3-4), 511-519CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)
Application of drug nanocrystals provides advantageous options for the pharmaceutical formulation development of poorly sol. drugs. The objective of this study was to investigate the dissoln. behavior improving effects of differently sized nanocrystals of a poorly sol. model drug, indomethacin. Nanocrystal suspensions were prepd. using a top-down wet milling technique with three stabilizers: poloxamer F68, poloxamer F127 and polysorbate 80. The dissoln. of the differently sized indomethacin nanocrystals were investigated using a channel flow dissoln. method and by UV imaging. Unmilled bulk indomethacin and phys. mixts. were used as refs. According to both the dissoln. methods, the dissoln. properties of indomethacin were improved by the particle size redn. UV imaging was used for the first time as a dissoln. testing method for fast dissolving nanoscale material. The technique provided new information about the concn. of the dissolved drug next to the sample surface; with the smallest nanocrystals (580 nm) the indomethacin concn. next to the particle surface exceeded five-fold the thermodn. satd. indomethacin soln. concn. Thus the soly. improvement itself, not only the increased surface area for dissoln., may have an important role in the higher dissoln. rates of nanocrystal formulations. Poloxamer F68 was the most optimal stabilizer in the prepn. of the indomethacin nanocrystal suspensions and in the soly. and dissoln. enhancement as well.
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Sunesen, V. H.; Pedersen, B. L.; Kristensen, H. G.; Müllertz, A. In vivo in vitro correlations for a poorly soluble drug, danazol, using the flow-through dissolution method with biorelevant dissolution media. Eur. J. Pharm. Sci. 2005, 24 (4), 305– 313, DOI: 10.1016/j.ejps.2004.11.007
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In vivo in vitro correlations for a poorly soluble drug, danazol, using the flow-through dissolution method with biorelevant dissolution media
Sunesen, Vibeke Hougaard; Pedersen, Betty Lomstein; Kristensen, Henning Gjelstrup; Muellertz, Anette
European Journal of Pharmaceutical Sciences (2005), 24 (4), 305-313CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)
The purpose of the study was to design dissoln. tests that were able to distinguish between the behavior of danazol under fasted and fed conditions, by biorelevant media. In vitro dissoln. of 100 mg danazol capsules was performed using the flow-through dissoln. method. Flow rates were 8, 16 or 32 mL/min, corresponding to total vols. dissoln. medium of 960, 1920 and 3840 mL, resp. The media used contained bile salt and phospholipid levels relevant for either fasted or fed conditions in vivo. Crude and inexpensive bile components, Porcine Bile Ext. and soybean phospholipids, were used as the bile source. The effect of adding different concns. and molar ratios of monoglycerides and fatty acids to the fed state media was investigated. In vivo release profiles under fasted and fed conditions were obtained from a previous study by deconvolution [Sunesen, V.H., Vedelsdal, R., Kristensen, H.G., Christrup, L., Muellertz, A. 2005]. Effect of liq. vol. and food intake on the abs. bioavailability of danazol, a poorly sol. drug, [Eur. J. Pharm. Sci. 24, 297-303]. In the fasted state, the physiol. most relevant correlation with in vivo results was achieved with a medium contg. 6.3 mM bile salts and 1.25 mM phospholipids (8 mL/min). A medium contg. 18.8 mM bile salts, 3.75 mM phospholipids, 4.0 mM monoglycerides and 30 mM fatty acids (8 mL/min) gave the closest correlation with fed state in vivo results. By using the flow-through dissoln. method it was possible to obtain correlations with in vivo release of danazol under fasted and fed conditions. Both hydrodynamics and medium compn. were important for the dissoln. of danazol. In the fed state an IVIVC could only be obtained by including monoglycerides and fatty acids in the medium.
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Greco, K.; Bogner, R. Solution-mediated phase transformation: Significance during dissolution and implications for bioavailability. J. Pharm. Sci. 2012, 101 (9), 2996– 3018, DOI: 10.1002/jps.23025
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Solution-mediated phase transformation: Significance during dissolution and implications for bioavailability
Greco, Kristyn; Bogner, Robin
Journal of Pharmaceutical Sciences (2012), 101 (9), 2996-3018CODEN: JPMSAE; ISSN:0022-3549. (John Wiley & Sons, Inc.)
A review. Soly. improvement of poorly sol. drug compds. is a key approach to ensuring the successful development of many new drugs. Methods used to improve the soly. of drug compds. include forming a salt, cocrystal, or amorphous solid. These methods of improving soly. can often lead to a phenomenon called soln.-mediated phase transformation, a phase change that is facilitated through exposure to soln. Soln.-mediated phase transformation occurs in three steps: dissoln. to create a supersatd. soln. followed by nucleation of less sol. phase and the growth of that phase. When the growth of the less sol. phase occurs on the surface of the metastable solid, this phenomenon can cause a marked decrease in dissoln. rate during in vitro dissoln. evaluation, and ultimately in vivo. Therefore, transformation to a less sol. solid during dissoln. is an important aspect to consider when evaluating approaches to increase the soly. of a poorly sol. drug. Identification of soln.-mediated phase transformation during dissoln. is reviewed for powder dissoln., rotating disk method, and channel flow-through app. Types of soln.-mediated phase transformation are described in this report, including those involving salts, polymorphs, amorphous solids, and cocrystals. Many exptl. examples are provided. Evidence of potential soln.-mediated phase transformation in vivo is discussed to better understand the relationship between in vitro dissoln. evaluation and in vivo performance. © 2011 Wiley Periodicals, Inc. and the American Pharmacists Assocn. J Pharm Sci.
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Slavin, P. A.; Sheen, D. B.; Shepherd, E. E. A.; Sherwood, J. N.; Feeder, N.; Docherty, R.; Milojevic, S. Morphological evaluation of the γ-polymorph of indomethacin. J. Cryst. Growth 2002, 237–239, 300– 305, DOI: 10.1016/S0022-0248(01)01924-8
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Morphological evaluation of the γ-polymorph of indomethacin
Slavin, Paul A.; Sheen, David B.; Shepherd, Evelyn E. A.; Sherwood, John N.; Feeder, Neil; Docherty, Robert; Milojevic, Snezena
Journal of Crystal Growth (2002), 237-239 (Pt. 1), 300-305CODEN: JCRGAE; ISSN:0022-0248. (Elsevier Science B.V.)
A study was made of the polymorphic nature of crystals of the pharmaceutical indomethacin grown from a wide range of solvents and from the melt. In most solvents, growth at high supersaturations yielded either a 1:0.5 solvated form (approx.) or the α-polymorph. At low supersaturations the γ-polymorph was commonly produced. Solns. in MeOH and tBuOH yielded a 1:1 solvate. The morphol. of the γ-form showed no variation with solvent type but changed with supersatn. in a manner consistent with a differential variation in growth rates of the faces. This lack of solvent influence was confirmed by the fact that a similar morphol. resulted on growth from the melt. Morphol. predictions were carried out for the γ-polymorph and these show good agreement with exptl. observations.
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Hartshorn, C. M.; Lee, Y. J.; Camp, C. H.; Liu, Z.; Heddleston, J.; Canfield, N.; Rhodes, T. A.; Hight Walker, A. R.; Marsac, P. J.; Cicerone, M. T. Multicomponent chemical imaging of pharmaceutical solid dosage forms with broadband CARS microscopy. Anal. Chem. 2013, 85 (17), 8102– 8111, DOI: 10.1021/ac400671p
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Taylor, L. S.; Zografi, G. Spectroscopic characterization of interactions between PVP and indomethacin in amorphous molecular dispersions. Pharm. Res. 1997, 14 (12), 1691– 1698, DOI: 10.1023/A:1012167410376
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Spectroscopic characterization of interactions between PVP and indomethacin in amorphous molecular dispersions
Taylor, Lynne S.; Zografi, George
Pharmaceutical Research (1997), 14 (12), 1691-1698CODEN: PHREEB; ISSN:0724-8741. (Plenum Publishing Corp.)
The mol. structure of indomethacin-PVP amorphous solid dispersions was studied and specific interactions between the components was identified using vibrational spectroscopy. Solid dispersions of PVP and indomethacin were prepd. using a solvent evapn. technique and IR and FT-Raman spectra were obtained. A comparison of the carbonyl stretching region of γ indomethacin, known to form carboxylic acid dimers, with that of amorphous indomethacin indicated that the amorphous phase exists predominantly as dimers. The hydrogen bonding of α indomethacin is not as dimers. Addn. of PVP to amorphous indomethacin increased the intensity of the IR band assigned to non-hydrogen bonded carbonyl. Concomitantly, the PVP carbonyl stretch appeared at a lower wavenumber indicating hydrogen bonding. Model solvent systems aided spectral interpretation. The magnitude of the spectral changes were comparable for an indomethacin-PVP solid dispersion and a soln. of indomethacin in methylpyrrolidone at the same wt. percent. Indomethacin interacts with PVP in solid dispersions through hydrogen bonds formed between the drug hydroxyl and polymer carbonyl resulting in disruption of indomethacin dimers. PVP may influence the crystn. kinetics by preventing the self assocn. of indomethacin mols. The similarity of results for solid dispersions and solns. emphasizes the "soln." nature of this binary amorphous state.
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Trasi, N. S.; Purohit, H. S.; Taylor, L. S. Evaluation of the crystallization tendency of commercially available amorphous tacrolimus formulations exposed to different stress conditions. Pharm. Res. 2017, 34 (10), 2142– 2155, DOI: 10.1007/s11095-017-2221-4
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Evaluation of the Crystallization Tendency of Commercially Available Amorphous Tacrolimus Formulations Exposed to Different Stress Conditions
Trasi, Niraj S.; Purohit, Hitesh S.; Taylor, Lynne S.
Pharmaceutical Research (2017), 34 (10), 2142-2155CODEN: PHREEB; ISSN:0724-8741. (Springer)
Tacrolimus, an immunosuppressant, is a poorly water sol. compd. whereby the com. available capsule formulations contain the drug in amorphous form. The goal of this study was to evaluate the robustness of the innovator product and five generic formulations to crystn. following storage at stress conditions. Methods: Products were purchased from a pharmacy and stored at 40/75% relative humidity (RH), open dish conditions. Crystallinity was detd. using x-ray diffraction. The quantity of the ingredients in the formulations were detd. using different approaches and the various factors that might cause instability in the formulations were studied. Results: After 4 wk of open dish storage at 40/75% RH, one of the generic formulations showed evidence of tacrolimus crystn. Further investigations revealed batch-to-batch variations in crystn. tendency with the extent of crystallinity varying between 50 and 100% for different batches. Crystn. was also obsd. at lower storage temps. (30) when the RH was maintained at 75%. It was found that crystn. could be induced in a model formulation by wet granulating an ethanolic soln. of the drug with lactose and drying at 60-70 followed by exposure to stress conditions. Conclusions: It seems probable that the generic that was susceptible to crystn. contains amorphous drug phys. mixed with polymeric excipients, rather than as an amorphous solid dispersion. This study highlights the importance of considering the manufg. process on the stability of the resultant amorphous product.
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Sun, D. D.; Lee, P. I. Evolution of supersaturation of amorphous pharmaceuticals: The effect of rate of supersaturation generation. Mol. Pharmaceutics 2013, 10 (11), 4330– 4346, DOI: 10.1021/mp400439q
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Evolution of Supersaturation of Amorphous Pharmaceuticals: The Effect of Rate of Supersaturation Generation
Sun, Dajun D.; Lee, Ping I.
Molecular Pharmaceutics (2013), 10 (11), 4330-4346CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
The combination of a rapidly dissolving and supersaturating spring with a pptn. retarding parachute has often been pursued as an effective formulation strategy for amorphous solid dispersions (ASDs) to enhance the rate and extent of oral absorption. However, the interplay between these two rate processes in achieving and maintaining supersatn. remains inadequately understood, and the effect of rate of supersatn. buildup on the overall time evolution of supersatn. during the dissoln. of amorphous solids has not been explored. The objective of this study is to investigate the effect of supersatn. generation rate on the resulting kinetic soly. profiles of amorphous pharmaceuticals and to delineate the evolution of supersatn. from a mechanistic viewpoint. Exptl. concn.-time curves under varying rates of supersatn. generation and recrystn. for model drugs, indomethacin (IND), naproxen (NAP) and piroxicam (PIR), were generated from infusing dissolved drug (e.g., in ethanol) into the dissoln. medium and compared with that predicted from a comprehensive mechanistic model based on the classical nucleation theory taking into account both the particle growth and ripening processes. In the absence of any dissolved polymer to inhibit drug pptn., both our exptl. and predicted results show that the max. achievable supersatn. (i.e., kinetic soly.) of the amorphous solids increases, the time to reach max. decreases, and the rate of concn. decline in the de-supersatn. phase increases, with increasing rate of supersatn. generation (i.e., dissoln. rate). Our mechanistic model also predicts the existence of an optimal supersatn. rate which maximizes the area under the curve (AUC) of the kinetic soly. concn.-time profile, which agrees well with exptl. data. In the presence of a dissolved polymer from ASD dissoln., these obsd. trends also hold true except the de-supersatn. phase is more extended due to the crystn. inhibition effect. Since the obsd. kinetic soly. of nonequil. amorphous solids depends on the rate of supersatn. generation, our results also highlight the underlying difficulty in detg. a reproducible soly. advantage for amorphous solids.
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Zhu, L.; Wong, L.; Yu, L. Surface-enhanced crystallization of amorphous nifedipine. Mol. Pharmaceutics 2008, 5 (6), 921– 926, DOI: 10.1021/mp8000638
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Surface-Enhanced Crystallization of Amorphous Nifedipine
Zhu, Lei; Wong, Letitia; Yu, Lian
Molecular Pharmaceutics (2008), 5 (6), 921-926CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
Amorphous solids are generally more sol. and faster dissolving than their cryst. counterparts, a property useful for delivering poorly sol. drugs. Amorphous drugs must be stable against crystn., for crystn. negates their advantages. Recent studies found that crystal growth in amorphous indomethacin is orders of magnitude faster at the free surface than through the bulk and this surface-enhanced crystn. can be inhibited by an ultrathin coating. Herein, we report a second system that exhibits the same phenomena. Crystal growth at the free surface of amorphous nifedipine (NIF) was at least 1 order of magnitude faster than that through the bulk below the glass transition temp. Tg (42 °C). A thin coating of gold (10 nm) reduced the surface crystal growth rate to the bulk crystal growth rate. Surface-enhanced crystal growth was more pronounced near and below Tg than substantially above Tg, which suggests that this growth mode is more important for the glassy state. Our results support the view that a thin layer of mols. near the surface have higher mobility than the bulk mols. and can enable faster crystal growth. The higher mobility of surface mols. and the resulting fast crystal growth can be suppressed by an ultrathin coating.
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Hasebe, M.; Musumeci, D.; Yu, L. Fast surface crystallization of molecular glasses: creation of depletion zones by surface diffusion and crystallization flux. J. Phys. Chem. B 2015, 119 (7), 3304– 3311, DOI: 10.1021/jp512400c
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Fast Surface Crystallization of Molecular Glasses: Creation of Depletion Zones by Surface Diffusion and Crystallization Flux
Hasebe, Mariko; Musumeci, Daniele; Yu, Lian
Journal of Physical Chemistry B (2015), 119 (7), 3304-3311CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
Mol. glasses can grow crystals much faster at the free surface than in the interior. A property of this process is the creation of depressed grooves or depletion zones around the crystals on the initially flat amorphous surface. With SEM and at. force microscopy, the authors studied this phenomenon in indomethacin (IMC), which crystallizes in two polymorphs (α and γ) of different morphologies. The obsd. depletion zones are well reproduced by the known coeffs. of surface diffusion and the velocities of crystal growth. At the slow-growing flanks of needle-like α-IMC crystals, depletion zones widen and deepen over time according to the expected kinetics for surface diffusion responding to a crystn. flux. Before fast-advancing growth fronts, depletion zones have less time to develop; their steady-state dimensions agree with the same model revised for a moving phase boundary. These results support the view that surface diffusion enables fast surface crystal growth on mol. glasses. The authors' finding helps understand crystal growth in thin films in which the formation of deep depletion zones can cause dewetting and alter growth kinetics.
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Zhu, L.; Jona, J.; Nagapudi, K.; Wu, T. Fast surface crystallization of amorphous griseofulvin below Tg. Pharm. Res. 2010, 27 (8), 1558– 1567, DOI: 10.1007/s11095-010-0140-8
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Fast Surface Crystallization of Amorphous Griseofulvin Below Tg
Zhu, Lei; Jona, Janan; Nagapudi, Karthik; Wu, Tian
Pharmaceutical Research (2010), 27 (8), 1558-1567CODEN: PHREEB; ISSN:0724-8741. (Springer)
To study crystal growth rates of amorphous griseofulvin (GSF) below its glass transition temp. (Tg) and the effect of surface crystn. on the overall crystn. kinetics of amorphous GSF. Amorphous GSF was generated by melt quenching. Surface and bulk crystal growth rates were detd. using polarized light microscope. X-ray powder diffraction (XRPD) and Raman microscopy were used to identify the polymorph of the crystals. Crystn. kinetics of amorphous GSF powder stored at 40° (Tg-48°) and room temp. (Tg-66°) was monitored using XRPD. Results: Crystal growth at the surface of amorphous GSF is 10- to 100-fold faster than that in the bulk. The surface crystal growth can be suppressed by an ultrathin gold coating. Below Tg, the crystn. of amorphous GSF powder was biphasic with a rapid initial crystn. stage dominated by the surface crystn. and a slow or suspended late stage controlled by the bulk crystn. GSF exhibits the fastest surface crystn. kinetics among the known amorphous pharmaceutical solids. Well below Tg, surface crystn. dominated the overall crystn. kinetics of amorphous GSF powder. Thus, surface crystn. should be distinguished from bulk crystn. in studying, modeling and controlling the crystn. of amorphous solids.
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Elkhabaz, A.; Sarkar, S.; Dinh, J. K.; Simpson, G. J.; Taylor, L. S. Variation in supersaturation and phase behavior of ezetimibe amorphous solid dispersions upon dissolution in different biorelevant media. Mol. Pharmaceutics 2018, 15 (1), 193– 206, DOI: 10.1021/acs.molpharmaceut.7b00814
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Variation in Supersaturation and Phase Behavior of Ezetimibe Amorphous Solid Dispersions upon Dissolution in Different Biorelevant Media
Elkhabaz, Ahmed; Sarkar, Sreya; Dinh, Janny K.; Simpson, Garth J.; Taylor, Lynne S.
Molecular Pharmaceutics (2018), 15 (1), 193-206CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
The delivery of poorly water-sol. drugs using amorphous solid dispersions (ASDs) has been widely acknowledged as a promising strategy for enhancing oral bioavailability. Upon dissoln., ASDs have accelerated dissoln. rates and yield supersatd. solns. leading to higher apparent solubilities. Understanding the complex phase behavior of ASDs during dissoln. is crucial for developing an effective formulation. Since the absorption of a lipophilic, high permeability drug is detd. primarily by the intraluminal dissoln. process and the final concn. achieved, there is a need for evaluation in biorelevant dissoln. media that simulate both fasting and fed gastrointestinal states. In this study, using ezetimibe as a model drug, three different ASDs were prepd. using poly(acrylic acid) (PAA), polyvinylpyrrolidone (PVP), and hydroxypropyl methylcellulose acetyl succinate (HPMC-AS). Dissoln. of ASDs was carried out in sodium phosphate buffer, fed-state simulated intestinal fluid (FeSSIF), and Ensure Plus to evaluate the impact of different dissoln. media on release profile, supersatn., and phase behavior. The supersatn. level and crystn. kinetics varied among the dispersions and were found to be highly dependent on the medium employed. The presence of solubilizing additives in biorelevant media greatly affected the generation and stabilization of supersatd. solns. Second harmonic generation microscopy was found to enable the detection of crystals in all media including the highly turbid Ensure Plus system. In conclusion, it is important to evaluate the impact of complex biorelevant media on the dissoln. performance of ASDs to better design supersaturating formulations for oral delivery.
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Published September 24, 2018

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Abstract
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Figure 1
Figure 1. Dissolution profiles (drug release over time) for samples stored at (a) 30 °C/23% RH and (b) 30 °C/75% RH. Profiles of the pure amorphous tablet (day 0) and reference crystalline γ- and α-forms are shown for comparison. Profiles are generated with mean values of a minimum of three measurements. Error bars represent plus one standard deviation.
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Figure 2
Figure 2. SEM micrographs of an amorphous indomethacin tablet (day 0, first column) and tablets stored for 1, 2, 7, and 22 days (from left to right) at 30 °C/23% RH before dissolution testing (top row). SEM images of the tablets prepared and stored in the same manner after 15 min of intrinsic dissolution testing (bottom row).
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Figure 3
Figure 3. SEM micrographs of an amorphous indomethacin tablet (day 0, first column) and tablets stored for 1, 2, 7, and 22 days (from left to right) at 30 °C/75% RH before dissolution testing (top row). SEM images of the tablets prepared and stored in the same manner after 15 min of intrinsic dissolution testing (bottom row).
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Figure 4
Figure 4. XRD diffractograms of tablets before and after 15 min of dissolution testing: (a) storage at 30 °C/23% RH and (b) storage at 30 °C/75% RH. Diffractograms of the α-, γ-, and ε-forms of indomethacin are shown for comparison, and some of their characteristic peaks are marked in green, red, and yellow, respectively. The ε-form was measured in transmission mode using a powder, while the α- and γ-forms were measured in reflection with tablets.
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Figure 5
Figure 5. PCA scores plot of the ATR-FTIR spectra of the amorphous (day 0) and all stored samples after 15 min of dissolution testing (a); loadings and reference IR spectra of different solid-state forms of indomethacin (b).
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Figure 6
Figure 6. CARS and SFG overlay images of samples stored at 30 °C/23% RH before (a) and after (b) 15 min of dissolution testing at pH 6.8. CARS spectra in the range of 1413–1800 cm^–1 from selected regions marked by arrows plotted with reference spectra of amorphous, ε-, and γ-indomethacin (c–e). Overlay images (a, b) represent overlays of three channels: single CARS line at 1701 cm^–1 in red (γ-indomethacin), single CARS line at 1676 cm^–1 in blue (amorphous indomethacin), and a third channel representing the SFG signal (all noncentrosymmetric crystals) in green and yellow. The separation between green and yellow regions is based on the intensity ratios of CARS peaks at 1652 and 1676 cm^–1 so that the regions having SFG activity and a CARS peak at 1652 cm^–1 are colored green (α-indomethacin), and the regions having SFG activity and a CARS peak at 1676 cm^–1 are colored yellow (ε-indomethacin). Panel (a) has been reprinted with permission from Novakovic et al. (18) Copyright 2017 American Chemical Society. am = amorphous.
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Figure 7
Figure 7. CARS and SFG overlay images of samples stored at 30 °C/75% RH before (a) and after 15 min of dissolution testing at pH 6.8 (b). CARS spectra in the range of 1413–1800 cm^–1 from selected regions marked by arrows (c–f) plotted with reference spectra of amorphous, ε-, α-, and γ-indomethacin. Overlay images (a, b) represent overlays of three channels: single CARS line at 1701 cm^–1 in red (γ-indomethacin), single CARS line at 1676 cm^–1 in blue (amorphous indomethacin), and a third channel representing the SFG signal (all noncentrosymmetric crystals) in green and yellow. The separation between green and yellow regions is based on the intensity ratios of CARS peaks at 1652 and 1676 cm^–1 so that the regions having SFG activity and the CARS peak at 1652 cm^–1 are colored green (α-indomethacin), and the regions having SFG activity and CARS peak at 1676 cm^–1 are colored yellow (ε-indomethacin). Panel (a) has been reprinted with permission from Novakovic et al. (18) Copyright 2017 American Chemical Society. am = amorphous.
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Figure 8
Figure 8. CARS (solid lines) and Raman (dotted lines) spectra of indomethacin solid-state forms. Raman spectra (except for the ε-form) are reproduced with permission from ref (23). The CARS spectral resolution is 12 cm^–1, while the Raman spectral resolution is 4 cm^–1. All CARS spectra are measured from the prepared reference forms, except for the spectrum of the η-form, which was recorded at the tablet surface. Polymorphs marked with asterisk are SFG-active.
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References
This article references 47 other publications.
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  What is the true solubility advantage for amorphous pharmaceuticals?
  Hancock, Bruno C.; Parks, Michael
  Pharmaceutical Research (2000), 17 (4), 397-404CODEN: PHREEB; ISSN:0724-8741. (Kluwer Academic/Plenum Publishers)
  In order to evaluate the magnitude of the soly. advantage for amorphous pharmaceutical materials when compared to their cryst. counterparts, the thermal properties of several drugs in their amorphous and cryst. states were detd. using differential scanning calorimetry. From these properties the soly. advantage for the amorphous form was predicted as a function of temp. using a simple thermodn. anal. These predictions were compared to the results of exptl. measurements of the aq. solubilities of the amorphous and cryst. forms of the drugs at several temps. By treating each amorphous drug as either an equil. supercooled liq. or a pseudo-equil. glass, the soly. advantage compared to the most stable cryst. form was predicted to be between 10 and 1600 fold. The measured soly. advantage was usually considerably less than this, and for one compd. studied in detail its temp. dependence was also less than predicted. It was calcd. that even for partially amorphous materials the apparent soly. enhancement (theor. or measured) is likely to influence in-vitro and in-vivo dissoln. behavior. Amorphous pharmaceuticals are markedly more sol. than their cryst. counterparts, however, their exptl. soly. advantage is typically less than that predicted from simple thermodn. considerations. This appears to be the result of difficulties in detg. the soly. of amorphous materials under true equil. conditions. Simple thermodn. predictions can provide a useful indication of the theor. max. soly. advantage for amorphous pharmaceuticals, which directly reflects the driving force for their initial dissoln.
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  Solubility advantage of amorphous pharmaceuticals: I. A thermodynamic analysis
  Murdande, Sharad B.; Pikal, Michael J.; Shanker, Ravi M.; Bogner, Robin H.
  Journal of Pharmaceutical Sciences (2010), 99 (3), 1254-1264CODEN: JPMSAE; ISSN:0022-3549. (Wiley-Liss, Inc.)
  In recent years there has been growing interest in advancing amorphous pharmaceuticals as an approach for achieving adequate soly. Due to difficulties in the exptl. measurement of soly., a reliable est. of the soly. enhancement ratio of an amorphous form of a drug relative to its cryst. counterpart would be highly useful. We have developed a rigorous thermodn. approach to est. enhancement in soly. that can be achieved by conversion of a cryst. form to the amorphous form. We rigorously treat the three factors that contribute to differences in soly. between amorphous and cryst. forms. First, we calc. the free energy difference between amorphous and cryst. forms from thermal properties measured by modulated differential scanning calorimetry (MDSC). Secondly, since an amorphous solute can absorb significant amts. of water, which reduces its activity and soly., a correction is made using water sorption isotherm data and the Gibbs-Duhem equation. Next, a correction is made for differences in the degree of ionization due to differences in solubilities of the two forms. Utilizing this approach the theor. estd. soly. enhancement ratio of 7.0 for indomethacin (amorphous/γ-crystal) was found to be in close agreement with the exptl. detd. ratio of 4.9. © 2009 Wiley-Liss, Inc. and the American Pharmacists Assocn. J Pharm Sci 99: 1254-1264, 2010.
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  Debnath, S.; Predecki, P.; Suryanarayanan, R. Use of glancing angle x-ray powder diffractometry to depth-profile phase transformations during dissolution of indomethacin and theophylline tablets. Pharm. Res. 2004, 21 (1), 149– 159, DOI: 10.1023/B:PHAM.0000012163.89163.f8
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  Ewing, A. V.; Clarke, G. S.; Kazarian, S. G. Stability of indomethacin with relevance to the release from amorphous solid dispersions studied with ATR-FTIR spectroscopic imaging. Eur. J. Pharm. Sci. 2014, 60, 64– 71, DOI: 10.1016/j.ejps.2014.05.001
  5
  Stability of indomethacin with relevance to the release from amorphous solid dispersions studied with ATR-FTIR spectroscopic imaging
  Ewing, Andrew V.; Clarke, Graham S.; Kazarian, Sergei G.
  European Journal of Pharmaceutical Sciences (2014), 60 (), 64-71CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)
  This work presents the use of attenuated total reflection Fourier transform IR (ATR-FTIR) spectroscopy and spectroscopic imaging to study the stability and dissoln. behavior of amorphous solid dispersions (ASDs). ASDs are employed to improve the bioavailability of drugs which are poorly sol. in aq. solns. Selecting the appropriate polymeric excipients for use in pharmaceutical tablets is crucial to control drug stability and subsequent release. In this study, indomethacin was used as a model poorly-aq. sol. drug since the amorphous-form has improved dissoln. properties over its cryst. forms. ASDs of indomethacin/polyethylene glycol (PEG) and indomethacin/hydroxypropyl methylcellulose (HPMC) in a 1:3 wt ratio were compared. Firstly, ATR-FTIR spectroscopy was employed to monitor the stability of indomethacin in the ASDs over 96 h. While the indomethacin/HPMC ASD showed the ability to maintain the amorphous indomethacin form for longer periods of time, ATR-FTIR spectra revealed that indomethacin in the drug/PEG ASD crystd. to the stable γ-form, via the α-form. Secondly, ATR-FTIR spectroscopic imaging was used to study the dissoln. of ASD tablets in a phosphate buffer (pH 7.5). Crystn. of amorphous indomethacin was characterized in the spectra collected during the dissoln. of the indomethacin/PEG ASD which consequently hindered release into the surrounding soln. In contrast, release of amorphous indomethacin was more effective from HPMC.
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6. 6
  Savolainen, M.; Kogermann, K.; Heinz, A.; Aaltonen, J.; Peltonen, L.; Strachan, C.; Yliruusi, J. Better understanding of dissolution behaviour of amorphous drugs by in situ solid-state analysis using Raman spectroscopy. Eur. J. Pharm. Biopharm. 2009, 71 (1), 71– 79, DOI: 10.1016/j.ejpb.2008.06.001
  6
  Better understanding of dissolution behaviour of amorphous drugs by in situ solid-state analysis using Raman spectroscopy
  Savolainen, M.; Kogermann, K.; Heinz, A.; Aaltonen, J.; Peltonen, L.; Strachan, C.; Yliruusi, J.
  European Journal of Pharmaceutics and Biopharmaceutics (2009), 71 (1), 71-79CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)
  Amorphous drugs have a higher kinetic soly. and dissoln. rate than their cryst. counterparts. However, this advantage is lost if the amorphous form converts to the stable cryst. form during the dissoln. as the dissoln. rate will gradually change to that of the cryst. form. The purpose of this study was to use in situ Raman spectroscopy in combination with either partial least squares discriminant anal. (PLS-DA) or partial least squares (PLS) regression anal. to monitor as well as quantify the solid-phase transitions that take place during the dissoln. of two amorphous drugs, indomethacin (IMC) and carbamazepine (CBZ). The dissoln. rate was higher from amorphous IMC compared to the cryst. α- and γ-forms. However, the dissoln. rate started to slow down during the expt. In situ Raman anal. verified that at that time point the sample started to crystallize to the α-form. Amorphous CBZ instantly started to crystallize upon contact with the dissoln. medium. The transition from the amorphous form to CBZ dihydrate appears to go through the anhydrate form I. Based on the PLS anal. the amt. of form I formed in the sample during the dissoln. affected the dissoln. rate. Raman spectroscopy combined with PLS-DA was also more sensitive to the solid-state changes than X-ray powder diffraction (XRPD) and was able to detect changes in the solid-state that could not be detected with XRPD.
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7. 7
  Aaltonen, J.; Heinänen, P.; Peltonen, L.; Kortejärvi, H.; Tanninen, V. P.; Christiansen, L.; Hirvonen, J.; Yliruusi, J.; Rantanen, J. In situ measurement of solvent-mediated phase transformations during dissolution testing. J. Pharm. Sci. 2006, 95 (12), 2730– 2737, DOI: 10.1002/jps.20725
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8. 8
  Greco, K.; Bogner, R. Crystallization of amorphous indomethacin during dissolution: Effect of processing and annealing. Mol. Pharmaceutics 2010, 7 (5), 1406– 1418, DOI: 10.1021/mp1000197
  8
  Crystallization of Amorphous Indomethacin during Dissolution: Effect of Processing and Annealing
  Greco, Kristyn; Bogner, Robin
  Molecular Pharmaceutics (2010), 7 (5), 1406-1418CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
  The crystn. of amorphous drugs during dissoln. is a type of soln. mediated phase transformation that can reduce the bioavailability enhancement one hoped to gain from the amorphous state. The goal of this study was to explore the effects of processing on the dissoln. performance of amorphous indomethacin. The amorphous solids were prepd. by four techniques, quench cooling the melted solid, cryogrinding γ indomethacin amorphous for 1 or 3 h and quench cooling the solid followed by 1 h of cryogrinding. Dissoln. results assessed in a flow-through intrinsic dissoln. app. reveal decreases in the dissoln. rate of amorphous indomethacin during the exptl. time frame indicating that a soln. mediated phase transformation has occurred. The amorphous solids prepd. by melt quenching and melt quenching followed by cryogrinding showed a significant dissoln. rate advantage over the γ form of indomethacin. In contrast, indomethacin that was cryoground amorphous for 1 or 3 h did not show any dissoln. rate advantage over the cryst. material. Transformation was confirmed by in situ Raman microscopy and polarized light microscopy with differences seen in the nature of the crystals apparent on the surface of the dissolving solid. A portion of the melt quenched amorphous sample was annealed at 25°C and 0% relative humidity to induce partial crystn. of γ indomethacin. As crystallinity increased, the dissoln. rate decreased. The transformation time of partially amorphous indomethacin was not dependent on the level of crystallinity present, indicating only a small fraction of cryst. material needs to be present to affect the kinetics of crystn. The soln. mediated phase transformation of amorphous indomethacin is affected by the processing method even though all solids were confirmed amorphous by polarized light microscopy and X-ray diffraction. Dissoln. may distinguish differences in amorphous solids that other methods cannot discern.
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9. 9
  Schmitt, P. D. Recent advances in nonlinear optical analyses of pharmaceutical materials in the solid state. Mol. Pharmaceutics 2017, 14 (3), 555– 565, DOI: 10.1021/acs.molpharmaceut.6b00809
  9
  Recent Advances in Nonlinear Optical Analyses of Pharmaceutical Materials in the Solid State
  Schmitt, Paul D.
  Molecular Pharmaceutics (2017), 14 (3), 555-565CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
  A review. The past decade has seen an increase in the use of nonlinear optical (NLO) techniques such as second harmonic generation, coherent antistokes Raman scattering, stimulated Raman scattering, and two-photon fluorescence for the solid-state characterization of pharmaceutical materials. These combined techniques offer several advantages (e.g., speed, selectivity, quantitation) of potential interest to the pharmaceutical community, as decreased characterization times in formulation development and testing could help decrease the time required to bring new, higher quality drugs to market. The large body of literature recently published in this field merits a review. Literature will be discussed in order of drug development, starting with applications in initial therapeutic mol. crystn. and polymorphic anal., followed by final dosage form characterization, and ending with drug product performance testing.
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10. 10
  Windbergs, M.; Jurna, M.; Offerhaus, H. L.; Herek, J. L.; Kleinebudde, P.; Strachan, C. J. Chemical imaging of oral solid dosage forms and changes upon dissolution using coherent anti-Stokes Raman scattering microscopy. Anal. Chem. 2009, 81 (6), 2085– 2091, DOI: 10.1021/ac8020856
  10
  Chemical imaging of oral solid dosage forms and changes upon dissolution using coherent anti-Stokes Raman scattering microscopy
  Windbergs, Maike; Jurna, Martin; Offerhaus, Herman L.; Herek, Jennifer L.; Kleinebudde, Peter; Strachan, Clare J.
  Analytical Chemistry (Washington, DC, United States) (2009), 81 (6), 2085-2091CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
  Dissoln. testing is a crucial part of pharmaceutical dosage form investigations and is generally performed by analyzing the concn. of the released drug in a defined vol. of flowing dissoln. medium. As solid-state properties of the components affect dissoln. behavior to a large and sometimes even unpredictable extent there is a strong need for monitoring and esp. visualizing solid-state properties during dissoln. testing. In this study coherent anti-Stokes Raman scattering (CARS) microscopy was used to visualize the solid-state properties of lipid-based oral dosage forms contg. the model drug theophylline anhydrate during dissoln. in real time. The drug release from the dosage form matrix was monitored with a spatial resoln. of about 1.5 μm. In addn., as theophylline anhydrate tends to form the less sol. monohydrate during dissoln., CARS microscopy allowed the solid-state transformation of the drug to be spatially visualized. The results obtained by CARS microscopy revealed that the method used to combine lipid and active ingredient into a sustained release dosage form can influence the physicochem. behavior of the drug during dissoln. In this case, formation of theophylline monohydrate on the surface was visualized during dissoln. with tablets compressed from powd. mixts. but not with solid lipid extrudates.
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11. 11
  Jurna, M.; Windbergs, M.; Strachan, C. J.; Hartsuiker, L.; Otto, C.; Kleinebudde, P.; Herek, J. L.; Offerhaus, H. L. Coherent anti-Stokes Raman scattering microscopy to monitor drug dissolution in different oral pharmaceutical tablets. J. Innovative Opt. Health Sci. 2009, 2 (1), 37– 43, DOI: 10.1142/S1793545809000322
  There is no corresponding record for this reference.
12. 12
  Fussell, A.; Garbacik, E.; Offerhaus, H.; Kleinebudde, P.; Strachan, C. In situ dissolution analysis using coherent anti-Stokes Raman scattering (CARS) and hyperspectral CARS microscopy. Eur. J. Pharm. Biopharm. 2013, 85 (3, Part B), 1141– 1147, DOI: 10.1016/j.ejpb.2013.08.012
  12
  In situ dissolution analysis using coherent anti-Stokes Raman scattering (CARS) and hyperspectral CARS microscopy
  Fussell, Andrew; Garbacik, Erik; Offerhaus, Herman; Kleinebudde, Peter; Strachan, Clare
  European Journal of Pharmaceutics and Biopharmaceutics (2013), 85 (3PB), 1141-1147CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)
  The solid-state form of an active pharmaceutical ingredient (API) in an oral dosage form plays an important role in detg. the dissoln. rate of the API. As the solid-state form can change during dissoln., there is a need to monitor the oral dosage form during dissoln. testing. Coherent anti-Stokes Raman scattering (CARS) microscopy provides rapid, spectrally selective imaging to monitor the oral dosage form during dissoln. In this study, in situ CARS microscopy was combined with inline UV absorption spectroscopy to monitor the solid-state change in oral dosage forms contg. theophylline anhydrate undergoing dissoln. and to correlate the solid-state change with a change in dissoln. rate. The results from in situ CARS microscopy showed that theophylline anhydrate converted to theophylline monohydrate during dissoln. resulting in a redn. in the dissoln. rate. The addn. of Me cellulose to the dissoln. medium was found to delay the theophylline monohydrate growth and changed the morphol. of the monohydrate. The net effect was an increased dissoln. rate for theophylline anhydrate. Our results show that in situ CARS microscopy combined with inline UV absorption spectroscopy is capable of monitoring oral dosage forms undergoing dissoln. and correlating changes in solid-state form with changes in dissoln. rate.
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13. 13
  Kestur, U. S.; Wanapun, D.; Toth, S. J.; Wegiel, L. A.; Simpson, G. J.; Taylor, L. S. Nonlinear optical imaging for sensitive detection of crystals in bulk amorphous powders. J. Pharm. Sci. 2012, 101 (11), 4201– 4213, DOI: 10.1002/jps.23280
  13
  Nonlinear optical imaging for sensitive detection of crystals in bulk amorphous powders
  Kestur, Umesh S.; Wanapun, Duangporn; Toth, Scott J.; Wegiel, Lindsay A.; Simpson, Garth J.; Taylor, Lynne S.
  Journal of Pharmaceutical Sciences (2012), 101 (11), 4201-4213CODEN: JPMSAE; ISSN:0022-3549. (John Wiley & Sons, Inc.)
  The primary aim of this study was to evaluate the utility of second-order nonlinear imaging of chiral crystals (SONICC) to quantify crystallinity in drug-polymer blends, including solid dispersions. Second harmonic generation (SHG) can potentially exhibit scaling with crystallinity between linear and quadratic depending on the nature of the source, and thus, it is important to det. the response of pharmaceutical powders. Phys. mixts. contg. different proportions of cryst. naproxen and hydroxyl Pr Me cellulose acetate succinate (HPMCAS) were prepd. by blending and a dispersion was produced by solvent evapn. A custom-built SONICC instrument was used to characterize the SHG intensity as a function of the cryst. drug fraction in the various samples. Powder X-ray diffraction (PXRD) and Raman spectroscopy were used as complementary methods known to exhibit linear scaling. SONICC was able to detect cryst. drug even in the presence of 99.9 wt % HPMCAS in the binary mixts. The calibration curve revealed a linear dynamic range with a R2 value of 0.99 spanning the range from 0.1 to 100 wt % naproxen with a root mean square error of prediction of 2.7%. Using the calibration curve, the errors in the validation samples were in the range of 5%-10%. Anal. of a 75 wt % HPMCAS-naproxen solid dispersion with SONICC revealed the presence of crystallites at an earlier time point than could be detected with PXRD and Raman spectroscopy. In addn., results from the crystn. kinetics expt. using SONICC were in good agreement with Raman spectroscopy and PXRD. In conclusion, SONICC has been found to be a sensitive technique for detecting low levels (0.1% or lower) of crystallinity, even in the presence of large quantities of a polymer. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Assocn. J Pharm Sci.
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14. 14
  Wanapun, D.; Kestur, U. S.; Kissick, D. J.; Simpson, G. J.; Taylor, L. S. Selective detection and quantitation of organic molecule crystallization by second harmonic generation microscopy. Anal. Chem. 2010, 82 (13), 5425– 5432, DOI: 10.1021/ac100564f
  14
  Selective Detection and Quantitation of Organic Molecule Crystallization by Second Harmonic Generation Microscopy
  Wanapun, Duangporn; Kestur, Umesh S.; Kissick, David J.; Simpson, Garth J.; Taylor, Lynne S.
  Analytical Chemistry (Washington, DC, United States) (2010), 82 (13), 5425-5432CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
  Second order nonlinear optical imaging of chiral crystals (SONICC) was applied to selectively detect crystal formation at early stages and characterize the kinetics of nucleation and growth. SONICC relies on second harmonic generation (SHG), a nonlinear optical effect that only arises from noncentosym. ordered domain structures, which include crystals of chiral mols. The model systems studied include pharmaceutically relevant compds.: griseofulvin and chlorpropamide. SONICC demonstrates low detection limits producing an 8 order of magnitude improvement relative to macroscopic av. techniques and 5 order of magnitude improvement relative to optical microscopy. SONICC was also applied to examine the kinetics of crystn. in amorphous griseofulvin. The results show that SONICC enables simultaneous monitoring of individual crystal growth, nucleation rate, and macroscopic crystn. kinetics.
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15. 15
  Schmitt, P. D.; Trasi, N. S.; Taylor, L. S.; Simpson, G. J. Finding the needle in the haystack: Characterization of trace crystallinity in a commercial formulation of paclitaxel protein-bound particles by Raman spectroscopy enabled by second harmonic generation microscopy. Mol. Pharmaceutics 2015, 12 (7), 2378– 2383, DOI: 10.1021/acs.molpharmaceut.5b00065
  15
  Finding the Needle in the Haystack: Characterization of Trace Crystallinity in a Commercial Formulation of Paclitaxel Protein-Bound Particles by Raman Spectroscopy Enabled by Second Harmonic Generation Microscopy
  Schmitt, Paul D.; Trasi, Niraj S.; Taylor, Lynne S.; Simpson, Garth J.
  Molecular Pharmaceutics (2015), 12 (7), 2378-2383CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
  Second harmonic generation (SHG) microscopy was used to rapidly identify regions of interest for localized confocal Raman spectroscopy measurements in order to quantify crystallinity within lyophilized Abraxane powder (protein bound paclitaxel for injectable suspension). Water insol. noncentrosym. cryst. particles ranging from ∼1 to 120 μm were identified by SHG, with wide variability in crystal size and frequency obsd. between several batches of Abraxane. By targeting the Raman anal. to these localized regions identified by SHG, the required measurement time was decreased over 2 orders of magnitude, from 8 h to 2 s. Exptl. Raman spectra of SHG active domains in Abraxane were in good agreement with exptl. spectra of pure cryst. paclitaxel. These collective results are consistent with up to 30% of the active ingredient being present as poorly sol. cryst. particulates in some batches of Abraxane.
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16. 16
  Mah, P. T.; Novakovic, D.; Saarinen, J.; Van Landeghem, S.; Peltonen, L.; Laaksonen, T.; Isomäki, A.; Strachan, C. J. Elucidation of compression-induced surface crystallization in amorphous tablets using sum frequency generation (SFG) microscopy. Pharm. Res. 2017, 34 (5), 957– 970, DOI: 10.1007/s11095-016-2046-6
  There is no corresponding record for this reference.
17. 17
  Song, Z.; Sarkar, S.; Vogt, A. D.; Danzer, G. D.; Smith, C. J.; Gualtieri, E. J.; Simpson, G. J. Kinetic modeling of accelerated stability testing enabled by second harmonic generation microscopy. Anal. Chem. 2018, 90 (7), 4406– 4413, DOI: 10.1021/acs.analchem.7b04260
  17
  Kinetic Modeling of Accelerated Stability Testing Enabled by Second Harmonic Generation Microscopy
  Song, Zhengtian; Sarkar, Sreya; Vogt, Andrew D.; Danzer, Gerald D.; Smith, Casey J.; Gualtieri, Ellen J.; Simpson, Garth J.
  Analytical Chemistry (Washington, DC, United States) (2018), 90 (7), 4406-4413CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
  The low limits of detection afforded by second harmonic generation (SHG) microscopy coupled with image anal. algorithms enabled quant. modeling of the temp.-dependent crystn. of active pharmaceutical ingredients (APIs) within amorphous solid dispersions (ASDs). ASDs, in which an API is maintained in an amorphous state within a polymer matrix, are finding increasing use to address soly. limitations of small-mol. APIs. Extensive stability testing is typically performed for ASD characterization, the time frame for which is often dictated by the earliest detectable onset of crystal formation. Here a study of accelerated stability testing on ritonavir, a human immunodeficiency virus (HIV) protease inhibitor, has been conducted. Under the condition for accelerated stability testing at 50 °C/75%RH and 40 °C/75%RH, ritonavir crystn. kinetics from amorphous solid dispersions were monitored by SHG microscopy. SHG microscopy coupled by image anal. yielded limits of detection for ritonavir crystals as low as 10 ppm, which is about 2 orders of magnitude lower than other methods currently available for crystallinity detection in ASDs. The four decade dynamic range of SHG microscopy enabled quant. modeling with an established (JMAK) kinetic model. From the SHG images, nucleation and crystal growth rates were independently detd.
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18. 18
  Novakovic, D.; Saarinen, J.; Rojalin, T.; Antikainen, O.; Fraser-Miller, S. J.; Laaksonen, T.; Peltonen, L.; Isomäki, A.; Strachan, C. J. Multimodal nonlinear optical imaging for sensitive detection of multiple pharmaceutical solid-state forms and surface transformations. Anal. Chem. 2017, 89 (21), 11460– 11467, DOI: 10.1021/acs.analchem.7b02639
  18
  Multimodal Nonlinear Optical Imaging for Sensitive Detection of Multiple Pharmaceutical Solid-State Forms and Surface Transformations
  Novakovic, Dunja; Saarinen, Jukka; Rojalin, Tatu; Antikainen, Osmo; Fraser-Miller, Sara J.; Laaksonen, Timo; Peltonen, Leena; Isomaki, Antti; Strachan, Clare J.
  Analytical Chemistry (Washington, DC, United States) (2017), 89 (21), 11460-11467CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
  Two nonlinear imaging modalities, coherent anti-Stokes Raman scattering (CARS) and sum-frequency generation (SFG), were successfully combined for sensitive multimodal imaging of multiple solid-state forms and their changes on drug tablet surfaces. Two imaging approaches were used and compared: (i) hyperspectral CARS combined with principal component anal. (PCA) and SFG imaging and (ii) simultaneous narrowband CARS and SFG imaging. Three different solid-state forms of indomethacin-the cryst. gamma and alpha forms, as well as the amorphous form-were clearly distinguished using both approaches. Simultaneous narrowband CARS and SFG imaging was faster, but hyperspectral CARS and SFG imaging has the potential to be applied to a wider variety of more complex samples. These methodologies were further used to follow crystn. of indomethacin on tablet surfaces under two storage conditions: 30 °C/23% RH and 30 °C/75% RH. Imaging with (sub)micron resoln. showed that the approach allowed detection of very early stage surface crystn. The surfaces progressively crystd. to predominantly (but not exclusively) the gamma form at lower humidity and the alpha form at higher humidity. Overall, this study suggests that multimodal nonlinear imaging is a highly sensitive, solid-state (and chem.) specific, rapid, and versatile imaging technique for understanding and hence controlling (surface) solid-state forms and their complex changes in pharmaceuticals.
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19. 19
  Yamamoto, H. 1-Acyl-indoles. II. A new syntheses of 1-(p-chlorobenzoyl)-5-methoxy-3-indolylacetic acid and its polymorphism. Chem. Pharm. Bull. 1968, 16 (1), 17– 19, DOI: 10.1248/cpb.16.17
  19
  1-Acyl-indoles. II. A new syntheses of 1-(ion-chlorobenzoyl)-5-methoxy-3-indolylacetic acid and its polymorphism
  Yamamoto, Hisao
  Chemical & Pharmaceutical Bulletin (1968), 16 (1), 17-19CODEN: CPBTAL; ISSN:0009-2363.
  1-(p-Chlorobenzoyl)-2-methyl-5-methoxy-3-indolylacetic acid, a potent antiinflammatory drug, was directly prepd. from N-(p-chlorobenzoyl)-p-methoxyphenyl-hydrazine-HCl and levulinic acid in excellent yield by the new method. The recrystn. of 1-(p-chlorobenzoyl)-2-methyl-5-methoxy-3-indolylacetic acid from solvents gave crystals of polymorphism -α, β, and γ-types.
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20. 20
  Borka, L. The Polymorphism of indomethacin. New modifications, their melting behavior and solubility. Acta Pharm. Suec. 1974, 11 (3), 295– 303
  There is no corresponding record for this reference.
21. 21
  Lin, S. Y. Isolation and solid-state characteristics of a new crystal form of indomethacin. J. Pharm. Sci. 1992, 81 (6), 572– 576, DOI: 10.1002/jps.2600810622
  21
  Isolation and solid-state characteristics of a new crystal form of indomethacin
  Lin, Shan Yang
  Journal of Pharmaceutical Sciences (1992), 81 (6), 572-6CODEN: JPMSAE; ISSN:0022-3549.
  A new polymorphic crystal form of indomethacin was pptd. from an aq. soln. of indomethacin and β-cyclodextrin by titrn. with a 0.5N HCl aq. soln. Three polymorphs (α, β, and γ forms) and a new crystal form were differentiated with thermal anal., IR spectroscopy, powder x-ray diffractometry, TLC, elemental anal., and Fourier-transform IR (FTIR) spectroscopy with a newly developed FTIR microscope equipped with a thermal analyzer. The new crystal polymorph of indomethacin exhibited endo- and exothermic peaks near 102.8 and 104.1°, resp., because of phase transition without wt. loss, followed by 2 addnl. endothermic peaks at 151 and 158.9°, because of fusion. The differential scanning calorimetry-FTIR system can be used to examine the correlation between structural change of C:O stretching bands of this new polymorph and its thermal response. The new crystal form contained some γ-form crystals, detd. with an FTIR microscope equipped with a mapping option. Solid-state 13C-NMR spectra of the polymorphs of indomethacin were also examd.
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22. 22
  Crowley, K. J.; Zografi, G. Cryogenic grinding of indomethacin polymorphs and solvates: Assessment of amorphous phase formation and amorphous phase physical stability. J. Pharm. Sci. 2002, 91 (2), 492– 507, DOI: 10.1002/jps.10028
  22
  Cryogenic grinding of indomethacin polymorphs and solvates: assessment of amorphous phase formation and amorphous phase physical stability
  Crowley, Kieran J.; Zografi, George
  Journal of Pharmaceutical Sciences (2002), 91 (2), 492-507CODEN: JPMSAE; ISSN:0022-3549. (Wiley-Liss, Inc.)
  The effect of cryogenic grinding on five crystal forms of indomethacin (IMC) was investigated with particular interest in the formation of amorphous phase. Powder x-ray diffraction (PXRD) and differential scanning calorimetry (DSC) demonstrated that amorphous phase formation took place for all three polymorphs (γ, α, and δ) and one solvate (IMC methanolate). In the latter case, a postgrinding drying stage was needed to remove desolvated methanol from the ground amorphous product because methanol destabilized amorphous IMC presumably via a plasticizing effect. The crystal structure of another solvate, IMC t-butanolate, was unaffected by grinding, indicating that amorphous phase formation on grinding does not occur in all cases. Ground amorphous materials possessed similar glass transition temps. but significant differences in phys. stability as assessed by both isothermal and nonisothermal crystn. It is argued that phys. factors, namely residual crystal phase and sp. surface area, det. the isothermal and nonisothermal crystn. behavior of ground amorphous samples as opposed to intrinsic differences in the structure of the amorphous phase.
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23. 23
  Surwase, S. A.; Boetker, J. P.; Saville, D.; Boyd, B. J.; Gordon, K. C.; Peltonen, L.; Strachan, C. J. Indomethacin: New polymorphs of an old drug. Mol. Pharmaceutics 2013, 10 (12), 4472– 4480, DOI: 10.1021/mp400299a
  23
  Indomethacin: New Polymorphs of an Old Drug
  Surwase, Sachin A.; Boetker, Johan P.; Saville, Dorothy; Boyd, Ben J.; Gordon, Keith C.; Peltonen, Leena; Strachan, Clare J.
  Molecular Pharmaceutics (2013), 10 (12), 4472-4480CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
  This study reports the appearance and characterization of multiple new polymorphic forms of indomethacin. Considering the interest in amorphous suspensions for toxicol. studies of poorly water-sol. drugs, we sought to investigate the crystn. behavior of amorphous indomethacin in aq. suspension. Specifically, the effect of pH and temp. on crystn. behavior was studied. Quench cooled amorphous powder was added to buffered media at different pH values (1.2, 4.5, and 6.8) at 5 and 25 °C. Both the solid and the soln. were analyzed at different time points up to 24 h. Attenuated total reflection Fourier transform IR (ATR-FTIR) spectroscopy (with principal component anal.) was used to study solid-phase transformations and UV spectroscopy used to probe soln. concn. The crystn. onset time decreased and rate of crystn. increased with increasing pH and temp. Diverse polymorphic forms were obsd., with three new forms being identified; these were named ε, ζ, and η. At 25 °C, the amorphous form recrystd. directly to the α form, except at pH 6.8, where it initially converted briefly into the ε form. At 5 °C, all three new polymorphic forms were obsd. sequentially in the order ε, ζ, and then η, with the no. of these forms obsd. increasing sequentially with decreasing pH. The three new forms exhibited distinct X-ray powder diffraction (XPRD), differential scanning calorimetry (DSC), and FTIR and Raman spectroscopy profiles. The soln. concn. profiles suggest that the relative phys. stabilities of the polymorphs at 5 °C from lowest to highest is ε < ζ < η < α. The appearance of new polymorphs in this study suggests that amorphous suspensions are worth considering when performing polymorphic screening studies.
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24. 24
  Van Duong, T.; Ludeker, D.; Van Bockstal, P. J.; De Beer, T.; Van Humbeeck, J.; Van den Mooter, G. Polymorphism of indomethacin in semicrystalline dispersions: Formation, transformation, and segregation. Mol. Pharmaceutics 2018, 15 (3), 1037– 1051, DOI: 10.1021/acs.molpharmaceut.7b00930
  24
  Polymorphism of Indomethacin in Semicrystalline Dispersions: Formation, Transformation, and Segregation
  Van Duong, Tu; Ludeker, David; Van Bockstal, Pieter-Jan; De Beer, Thomas; Van Humbeeck, Jan; Van den Mooter, Guy
  Molecular Pharmaceutics (2018), 15 (3), 1037-1051CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
  The crystn. of metastable crystal polymorphs in polymer matrixes has been extensively reported in literature as a possible approach to enhance the soly. of poorly water-sol. drug compds., yet no clarification of the mechanism of the polymorph formation has been proposed. The current work aims to elucidate the polymorphism behavior of the model compd. indomethacin as well as the mechanism of polymorph selection of drugs in semicryst. systems. Indomethacin crystd. as either the α- or τ-form, a new metastable form, or a mixt. of the two polymorphs in dispersions contg. different drug loadings in polyethylene glycol, poloxamer, or Gelucire as the result of the variation in the mobility of drug mols. As a general rule, low mol. mobility of the amorphous drug favors the crystn. into thermodynamically stable forms whereas metastable cryst. polymorphs are preferred when the mol. mobility of the drug is sufficiently high. This rule provides insight into the polymorph selection of numerous active pharmaceutical ingredients in semicryst. dispersions and can be used as a guide for polymorphic screening from melt crystn. by tuning the mobility of drug mols. In addn., the drug crystd. faster while the polymer crystd. slower as the drug-loading increased with the maxima of drug crystn. rate in 70% indomethacin dispersion. Increasing the drug content in solid dispersions reduced the τ to α polymorphic transition rate, except for when the more stable form was initially dominant. The segregation of τ and α polymorphs as well as the polymorphic transformation during storage led to the inherent inhomogeneity of the semicryst. dispersions. This study highlights and expands our understanding about the complex crystn. behavior of semicryst. systems and is crucial for prepn. of solid dispersions with reproducible and consistent physicochem. properties and pharmaceutical performance.
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25. 25
  Kaneniwa, N.; Otsuka, M.; Hayashi, T. Physicochemical characterization of indomethacin polymorphs and the transformation kinetics in ethanol. Chem. Pharm. Bull. 1985, 33 (8), 3447– 3455, DOI: 10.1248/cpb.33.3447
  25
  Physicochemical characterization of indomethacin polymorphs and the transformation kinetics in ethanol
  Kaneniwa, Nobuyoshi; Otsuka, Makoto; Hayashi, Tetsuo
  Chemical & Pharmaceutical Bulletin (1985), 33 (8), 3447-55CODEN: CPBTAL; ISSN:0009-2363.
  Methods for the prepn. of polymorphs of indomethacin (IMC) (I) [53-86-1] were studied to obtain the pure polymorphs. The physicochem. properties of IMC polymorphs were measured by using x-ray diffraction anal. IR spectroscopy, DTA DSC, and 2 polymorphs (α and γ forms) and 1 benzene solvate (β form) were identified. The pure α form was obtained when distd. water at room temp. was poured into an EtOH [64-17-5] soln. of IMC at ∼80°, and the pptd. crystals were filtered and dried. The pure β and γ forms were obtained by recrystn. from benzene and Et2O, resp., at room temp. The m.ps. of the α and γ forms were 148 and 154°, resp., and their heats of fusion were 7.49 and 8.64 kcal/mol, resp., as detd. by DSC. A mixt. of α and γ forms was obtained by the method previously reported for α form prepn. (recrystn. method), since the pure α form was transformed to the γ form in EtOH at room temp. The transformation of α form to γ form in EtOH was analyzed by the kinetic method using 9 kinds of kinetic models. The transformation followed kinetics corresponding to 2-dimensional growth of nuclei (Avrami equation), and the activation energy was 14.2 kcal/mol from the Arrhenius plot. The solubilities of the α and γ forms in distd. water were 0.87 and 0.69 mg/100 mL, resp.
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26. 26
  Karmwar, P.; Graeser, K.; Gordon, K. C.; Strachan, C. J.; Rades, T. Effect of different preparation methods on the dissolution behaviour of amorphous indomethacin. Eur. J. Pharm. Biopharm. 2012, 80 (2), 459– 464, DOI: 10.1016/j.ejpb.2011.10.006
  26
  Effect of different preparation methods on the dissolution behaviour of amorphous indomethacin
  Karmwar, Pranav; Graeser, Kirsten; Gordon, Keith C.; Strachan, Clare J.; Rades, Thomas
  European Journal of Pharmaceutics and Biopharmaceutics (2012), 80 (2), 459-464CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)
  The aim of this study was to investigate whether amorphous indomethacin samples prepd. using different preparative techniques and processing parameters exhibit different structural and thermodn. characteristics and whether these differences can be correlated to their dissoln. behavior. Samples were prepd. either by cooling the drug melt at different cooling rates or by cryo-milling the drug for different milling times. The resulting amorphous materials were characterized using X-ray diffraction, Raman spectroscopy and polarising light microscopy. All samples were entirely X-ray amorphous, except for the sample cryo-milled for 15 min, which exhibited residual crystallinity. The shape of the halos in the diffractograms, however, varied depending on the prepn. method and processing parameters, suggesting structural variations in the near order of the mols. between the prepd. amorphous forms. This finding was supported by principal component anal. of the Raman spectra, as the samples clustered in the scores plot according to processing parameters for both of the preparative methods used. When investigating the dissoln. behavior, the samples cooled at different cooling rates showed no significant differences in their dissoln. profiles and dissoln. rates (≈0.55 μg/mL/cm2). In contrast, for cryo-milled samples, dissoln. rate depended on the milling time, with samples milled for 120, 180 and 240 min, showing significantly increased dissoln. rates of 0.28, 0.48 and 0.59 μg/mL/cm2, resp., when compared to cryst. indomethacin (≈0.06 and 0.05 μg/mL/cm2 for α and γ-indomethacin, resp.). The milling processes appear to continue to affect the degree of disorder in the solid material, enhancing its dissoln. rate, although all samples milled for >30 min were X-ray amorphous. Thus, choosing the right prepn. technique and parameters for prepg. amorphous solids is crit. for producing materials with enhanced dissoln. profiles.
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27. 27
  Alonzo, D. E.; Zhang, G. G. Z.; Zhou, D.; Gao, Y.; Taylor, L. S. Understanding the behavior of amorphous pharmaceutical systems during dissolution. Pharm. Res. 2010, 27 (4), 608– 618, DOI: 10.1007/s11095-009-0021-1
  27
  Understanding the Behavior of Amorphous Pharmaceutical Systems during Dissolution
  Alonzo, David E.; Zhang, Geoff G. Z.; Zhou, Deliang; Gao, Yi; Taylor, Lynne S.
  Pharmaceutical Research (2010), 27 (4), 608-618CODEN: PHREEB; ISSN:0724-8741. (Springer)
  Purpose: To investigate the underlying phys. processes taking place during dissoln. of amorphous pharmaceuticals and correlate them to the obsd. soln. concn.-time profiles. Felodipine and indomethacin were used as model hydrophobic compds. Concn.-time profiles were monitored during dissoln. of the model amorphous compds. using in situ fiber-optic UV spectroscopy. Crystn. of the solid exposed to an aq. environment was monitored using Raman spectroscopy and/or powder x-ray diffraction. Polarized light microscopy was used to provide qual. information about crystn. processes. For felodipine, a small extent of supersatn. was generated via dissoln. at 25°C but not at 37°C. The amorphous solid was found to crystallize rapidly at both temps. upon exposure to the dissoln. medium. Addn. of low concns. of polymers to the dissoln. medium was found to delay crystn. of the amorphous solid, leading to the generation of supersatd. solns. Amorphous indomethacin did not crystallize as readily in an aq. environment; hence, dissoln. resulted in supersatd. solns. However, crystn. from these supersatd. solns. was rapid. Polymeric additives were able to retard crystn. from supersatd. solns. of both indomethacin and felodipine for up to 4 h. The dissoln. advantage of amorphous solids can be negated either by crystn. of the amorphous solid on contact with the dissoln. medium or through rapid crystn. of the supersatd. soln. Polymeric additives can potentially retard both of these crystn. routes, leading to the generation of supersatd. solns. that can persist for biol. relevant timeframes.
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28. 28
  Mah, P. T.; Peltonen, L.; Novakovic, D.; Rades, T.; Strachan, C. J.; Laaksonen, T. The effect of surfactants on the dissolution behavior of amorphous formulations. Eur. J. Pharm. Biopharm. 2016, 103, 13– 22, DOI: 10.1016/j.ejpb.2016.03.007
  28
  The effect of surfactants on the dissolution behavior of amorphous formulations
  Mah, Pei T.; Peltonen, Leena; Novakovic, Dunja; Rades, Thomas; Strachan, Clare J.; Laaksonen, Timo
  European Journal of Pharmaceutics and Biopharmaceutics (2016), 103 (), 13-22CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)
  The optimal design of oral amorphous formulations benefits from the use of excipients to maintain drug supersatn. and thus ensures adequate absorption during intestinal transit. The use of surfactants for the maintenance of supersatn. in amorphous formulations has not been investigated in detail. The main aim of this study was to investigate the effect of surfactant on the dissoln. behavior of neat amorphous drug and binary polymer based solid dispersion. Indomethacin was used as the model drug and the surfactants studied were polysorbate 80 and poloxamer 407. The presence of surfactants (alone or in combination with polymers) in the buffer was detrimental to the dissoln. of neat amorphous indomethacin, suggesting that the surfactants promoted the crystn. of neat amorphous indomethacin. In contrast, the presence of surfactants (0.01% w/v) in the buffer resulted in a significant improvement on the dissoln. behavior of binary polymer based solid dispersion. Incorporating the surfactant to the formulation to form ternary solid dispersion adversely affected the dissoln. behavior. In conclusion, the use of surfactants (as wetting or solubilization agents) in dissoln. studies of neat amorphous drugs requires prudent consideration. The design of amorphous formulations with optimal dissoln. performance requires the appropriate selection of a combination of excipients and consideration of the method of introducing the excipients.
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29. 29
  Karmwar, P.; Graeser, K.; Gordon, K. C.; Strachan, C. J.; Rades, T. Investigation of properties and recrystallisation behaviour of amorphous indomethacin samples prepared by different methods. Int. J. Pharm. 2011, 417 (1–2), 94– 100, DOI: 10.1016/j.ijpharm.2010.12.019
  29
  Investigation of properties and recrystallisation behaviour of amorphous indomethacin samples prepared by different methods
  Karmwar, Pranav; Graeser, Kirsten; Gordon, Keith C.; Strachan, Clare J.; Rades, Thomas
  International Journal of Pharmaceutics (2011), 417 (1-2), 94-100CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
  The aim of this study was to investigate if amorphous indomethacin samples, prepd. using different prepn. methods, exhibit different structural and kinetic characteristics and if these differences can be correlated to their phys. stability (time to crystn.). Samples were prepd. by melt quenching, spray drying, ball milling, and cryo-milling. The resulting amorphous materials were characterized using X-ray diffraction, Raman spectroscopy and differential scanning calorimetry. All freshly prepd. samples were completely X-ray amorphous (with a halo being the only feature in the diffractograms). The shape of the halos in the diffractograms, however, varied depending on the prepn. method, suggesting structural variations in the near order of the mols. between the differently prepd. amorphous forms. Principal component anal. of the Raman spectra of the various amorphous forms revealed that the samples clustered in the scores plot according to prepn. method, again suggesting structural differences due to prepn. method. The range of vibrations assocd. with the largest spectral differences in the loadings plot showed that these differences were due to a range of mol. conformations and intermol. interactions. The ranking of the samples with respect to stability was: quench cooled amorphous samples > cryo-milled (α-form) > spray dried > ball milled (α-form) > ball milled (γ-form) = cryo-milled (γ-form). This ranking was not correlated with the diffractogram shapes or sample distribution in the scores plot of the Raman spectra, suggesting that phys. stability was not directly affected by structural variation in the samples. However, ranking of stability of the differently prepd. amorphous forms of the drug could be predicted by detg. the relaxation time values, for all amorphous samples. The relaxation times, calcd. by using the Adam Gibbs and Kohlrausch-Williams-Watts equations, were in accordance with the exptl. detd. stability order. This study showed that correlation of phys. stability with calcd. relaxation time is possible for the same amorphous systems prepd. by different methods. This could aid in selecting the most appropriate prepn. techniques in situations where there are a variety of suitable methods.
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30. 30
  Wu, T.; Yu, L. Surface crystallization of indomethacin below Tg. Pharm. Res. 2006, 23 (10), 2350– 2355, DOI: 10.1007/s11095-006-9023-4
  30
  Surface Crystallization of Indomethacin Below Glass Transition Temperature
  Wu, Tian; Yu, Lian
  Pharmaceutical Research (2006), 23 (10), 2350-2355CODEN: PHREEB; ISSN:0724-8741. (Springer)
  Purpose. To study the surface crystn. of indomethacin (IMC) below T g and its effects on the kinetics of overall crystn. Methods. Crystal growth rates in liq. layers formed between microscope cover glasses were measured with the top cover glass in place and removed. Polymorphs were identified by powder x-ray diffraction, Raman microscopy, and melting-point detn. by hot-stage microscopy. Surface crystals were identified by scratching the sample surface, by cutting the sample to expose its interior, and by analyzing the intensity of x-ray diffraction. Amorphous IMC particles of different sizes were stored at 40° (T g-2°) and analyzed at different times by differential scanning calorimetry to obtain the kinetics of crystn. Results. Crystal growth of IMC below T g at the free surface was approx. two orders of magnitude faster than that in the bulk, resulting in a surface layer of crystals around a slower-crystg. interior. Surface crystn. yielded mainly the γ polymorph. Amorphous IMC powders showed rapid initial crystn. at 40°, but the crystn. abruptly slowed down at "satn. levels" below 100%; the larger the particles, the lower the "satn. level." Conclusion. The faster surface crystn. of IMC than the bulk crystn. leads to unusual crystn. kinetics wherein a rapid initial increase of crystallinity is followed by an abrupt slowdown of crystn. Surface crystn. should be distinguished from bulk crystn. in modeling and controlling the crystn. of amorphous solids.
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31. 31
  Andronis, V.; Yoshioka, M.; Zografi, G. Effects of sorbed water on the crystallization of indomethacin from the amorphous state. J. Pharm. Sci. 1997, 86 (3), 346– 351, DOI: 10.1021/js9602711
  31
  Effects of Sorbed Water on the Crystallization of Indomethacin from the Amorphous State
  Andronis, Vlassios; Yoshioka, Minoru; Zografi, George
  Journal of Pharmaceutical Sciences (1997), 86 (3), 346-351CODEN: JPMSAE; ISSN:0022-3549. (American Chemical Society)
  The water sorption isotherm and the crystn. rates for amorphous indomethacin were detd. at 30° as a function of relative humidity (RH), along with the effects of water content on the glass transition temp. (Tg). Below 43% RH, only the stable γ crystal form appears, whereas at higher RH, only the metastable α crystal form appears. The tendency for the α crystals to form at higher RH is consistent with the Ostwald step rule. The crystn. rate of the α form continuously increased with increasing RH due to increasing mol. mobility. The crystn. mechanism of the γ form changed from surface-initiated to bulk-initiated crystn. at 21% RH, and although crystn. rates of the γ form increased with increasing RH in both cases, they were higher when crystn. was surface-initiated. The complex crystn. behavior of the γ form is explained by the higher water content and mol. mobility of the surface relative to the bulk and the general effect of water on α or γ crystal form selection as described by the Ostwald step rule.
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32. 32
  Priemel, P. A.; Grohganz, H.; Gordon, K. C.; Rades, T.; Strachan, C. J. The impact of surface- and nano-crystallisation on the detected amorphous content and the dissolution behaviour of amorphous indomethacin. Eur. J. Pharm. Biopharm. 2012, 82 (1), 187– 193, DOI: 10.1016/j.ejpb.2012.05.012
  32
  The impact of surface- and nano-crystallisation on the detected amorphous content and the dissolution behaviour of amorphous indomethacin
  Priemel, P. A.; Grohganz, H.; Gordon, K. C.; Rades, T.; Strachan, C. J.
  European Journal of Pharmaceutics and Biopharmaceutics (2012), 82 (1), 187-193CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)
  The crystallinity and phys. stability of amorphous drugs has previously been studied using different anal. techniques. However, the effect of the measurement method on obsd. crystallinity and its importance for crit. quality attributes, such as dissoln., has not yet been widely investigated.The aim of this study was to (i) qual. analyze and understand the recrystn. behavior of amorphous indomethacin during storage, (ii) quantify the amorphous content during storage with complementary anal. techniques and (iii) investigate the relationship between obsd. recrystn. behavior and dissoln. behavior.Quench cooled indomethacin was stored and the samples were visualized by SEM to gain spatially resolved information about the recrystn. behavior. Crystn. was quantified by Fourier transform attenuated total reflectance IR (FT-ATR-IR) spectroscopy, differential scanning calorimetry and X-ray powder diffraction.These techniques resulted in different obsd. recrystn. profiles. The physicochem. phenomena detected and sampling geometry for each technique together with the sample recrystg. from the surface and appearance of nano-crystals were used to explain the differences.The dissoln. behavior at the obsd. recrystn. endpoints for the different anal. techniques revealed that FT-ATR-IR spectroscopy predicted the changes in dissoln. behavior due to crystn. best.
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33. 33
  Tres, F.; Treacher, K.; Booth, J.; Hughes, L. P.; Wren, S. A. C.; Aylott, J. W.; Burley, J. C. Indomethacin-Kollidon VA64 extrudates: A mechanistic study of pH-dependent controlled release. Mol. Pharmaceutics 2016, 13 (3), 1166– 1175, DOI: 10.1021/acs.molpharmaceut.5b00979
  33
  Indomethacin-Kollidon VA64 Extrudates: A Mechanistic Study of pH-Dependent Controlled Release
  Tres, Francesco; Treacher, Kevin; Booth, Jonathan; Hughes, Leslie P.; Wren, Stephen A. C.; Aylott, Jonathan W.; Burley, Jonathan C.
  Molecular Pharmaceutics (2016), 13 (3), 1166-1175CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
  Because of its weakly acidic nature (pKa of 4.5), indomethacin presents an aq. soly. that significantly increases when changing from acidic to neutral/alk. pH (1.5 μg/mL at pH 1.2 and 105.2 μg/mL at pH 7.4). We have therefore investigated the impact of the dissoln. medium pH on the dissoln. performance of indomethacin:Kollidon VA64 extrudates. The impact of the drug loading on the dissoln. properties of these systems was also examd. (5%, 15%, 30%, 50%, 70%, and 90% drug loading). Time-resolved Raman spectroscopy along with in-line UV-vis spectrophotometry was employed to directly relate changes in dissoln. behavior to physicochem. changes that occur to the extrudate during the test. The dissoln. tests were performed in pH 2 HCl (to mimic the stomach conditions), and this was then switched during the expt. to pH 6.8 phosphate buffer (to simulate the poststomach conditions). The rotating disk dissoln. rate test was also used to simultaneously measure the dissoln. rate of both the drug and the polymer. We found that in pH 2 HCl buffer, for the 15% or higher drug-loaded extrudates, Kollidon VA64 preferentially dissolves from the exterior of the compact leaving an amorphous drug-rich hydrophobic shell, which, similarly to an enteric coating, inhibits the drug release. The in situ formation of an enteric coating has been previously hypothesized, and this has been the first time that is directly obsd. in a pH-variable dissoln. test. The dissoln. medium switch to pH 6.8 phosphate buffer, due to the large increase of the aq. soly. of indomethacin at this pH, leads to rapid dissoln. of the material forming the coating and therefore total drug release. In contrast, the 5% extrudate is fully hydrated and quickly dissolves at low pH pointing to a dissoln. performance dependent on highly water-sol. Kollidon VA64.
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34. 34
  Koranne, S.; Thakral, S.; Suryanarayanan, R. Effect of formulation and process parameters on the disproportionation of indomethacin sodium in buffered lyophilized formulations. Pharm. Res. 2018, 35 (11), 214, DOI: 10.1007/s11095-018-2499-x
  There is no corresponding record for this reference.
35. 35
  Peltonen, L.; Liljeroth, P.; Heikkilä, T.; Kontturi, K.; Hirvonen, J. Dissolution testing of acetylsalicylic acid by a channel flow method—correlation to USP basket and intrinsic dissolution methods. Eur. J. Pharm. Sci. 2003, 19 (5), 395– 401, DOI: 10.1016/S0928-0987(03)00140-4
  35
  Dissolution testing of acetylsalicylic acid by a channel flow method-correlation to USP basket and intrinsic dissolution methods
  Peltonen, Leena; Liljeroth, Peter; Heikkila, Tiina; Kontturi, Kyosti; Hirvonen, Jouni
  European Journal of Pharmaceutical Sciences (2003), 19 (5), 395-401CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)
  A new modification of the channel flow dissoln. method is introduced together with the theor. basis to ext. the soly. and mass transfer parameters from the dissoln. expts. Correlation of drug dissoln. profiles in the channel flow app. was evaluated with respect to USP basket and intrinsic dissoln. methods at pH 1.2 or 6.8. Acetylsalicylic acid (ASA) was studied as a pure drug substance and as three simple tablet compns. with microcryst. cellulose (MCC) and/or lactose as excipients. The channel flow measurements of 100% ASA tablets correlated well with the results of intrinsic dissoln. tests. In the channel flow method as well as in the USP basket method the release of ASA was fastest from the tablet compns. contg. lactose, while the slowest dissoln. rate was obsd. with the compn. contg. MCC as the only excipient. As presumed, the dissoln. rate of the weak acid was decreased as the pH of the medium was lowered, which was clearly confirmed also by the three dissoln. methods. MCC forms matrix tablets and in the USP basket method the dissoln. profiles followed square root of time kinetics indicating that diffusion was the rate-controlling step of ASA dissoln. Also the channel flow results indicated that the dissoln. Of ASA was controlled by mass transfer. The swelling behavior of the tablets is different in the channel flow method as compared to the basket method: only one tablet surface is exposed to the dissoln. medium in the channel flow system. The contact between the tablet surface and the dissoln. medium is more similar between the channel flow and intrinsic dissoln. methods.
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36. 36
  Sarnes, A.; Østergaard, J.; Jensen, S. S.; Aaltonen, J.; Rantanen, J.; Hirvonen, J.; Peltonen, L. Dissolution study of nanocrystal powders of a poorly soluble drug by UV imaging and channel flow methods. Eur. J. Pharm. Sci. 2013, 50 (3), 511– 519, DOI: 10.1016/j.ejps.2013.08.030
  36
  Dissolution study of nanocrystal powders of a poorly soluble drug by UV imaging and channel flow methods
  Sarnes, Annika; Oestergaard, Jesper; Jensen, Sabrine Smedegaard; Aaltonen, Jaakko; Rantanen, Jukka; Hirvonen, Jouni; Peltonen, Leena
  European Journal of Pharmaceutical Sciences (2013), 50 (3-4), 511-519CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)
  Application of drug nanocrystals provides advantageous options for the pharmaceutical formulation development of poorly sol. drugs. The objective of this study was to investigate the dissoln. behavior improving effects of differently sized nanocrystals of a poorly sol. model drug, indomethacin. Nanocrystal suspensions were prepd. using a top-down wet milling technique with three stabilizers: poloxamer F68, poloxamer F127 and polysorbate 80. The dissoln. of the differently sized indomethacin nanocrystals were investigated using a channel flow dissoln. method and by UV imaging. Unmilled bulk indomethacin and phys. mixts. were used as refs. According to both the dissoln. methods, the dissoln. properties of indomethacin were improved by the particle size redn. UV imaging was used for the first time as a dissoln. testing method for fast dissolving nanoscale material. The technique provided new information about the concn. of the dissolved drug next to the sample surface; with the smallest nanocrystals (580 nm) the indomethacin concn. next to the particle surface exceeded five-fold the thermodn. satd. indomethacin soln. concn. Thus the soly. improvement itself, not only the increased surface area for dissoln., may have an important role in the higher dissoln. rates of nanocrystal formulations. Poloxamer F68 was the most optimal stabilizer in the prepn. of the indomethacin nanocrystal suspensions and in the soly. and dissoln. enhancement as well.
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37. 37
  Sunesen, V. H.; Pedersen, B. L.; Kristensen, H. G.; Müllertz, A. In vivo in vitro correlations for a poorly soluble drug, danazol, using the flow-through dissolution method with biorelevant dissolution media. Eur. J. Pharm. Sci. 2005, 24 (4), 305– 313, DOI: 10.1016/j.ejps.2004.11.007
  37
  In vivo in vitro correlations for a poorly soluble drug, danazol, using the flow-through dissolution method with biorelevant dissolution media
  Sunesen, Vibeke Hougaard; Pedersen, Betty Lomstein; Kristensen, Henning Gjelstrup; Muellertz, Anette
  European Journal of Pharmaceutical Sciences (2005), 24 (4), 305-313CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)
  The purpose of the study was to design dissoln. tests that were able to distinguish between the behavior of danazol under fasted and fed conditions, by biorelevant media. In vitro dissoln. of 100 mg danazol capsules was performed using the flow-through dissoln. method. Flow rates were 8, 16 or 32 mL/min, corresponding to total vols. dissoln. medium of 960, 1920 and 3840 mL, resp. The media used contained bile salt and phospholipid levels relevant for either fasted or fed conditions in vivo. Crude and inexpensive bile components, Porcine Bile Ext. and soybean phospholipids, were used as the bile source. The effect of adding different concns. and molar ratios of monoglycerides and fatty acids to the fed state media was investigated. In vivo release profiles under fasted and fed conditions were obtained from a previous study by deconvolution [Sunesen, V.H., Vedelsdal, R., Kristensen, H.G., Christrup, L., Muellertz, A. 2005]. Effect of liq. vol. and food intake on the abs. bioavailability of danazol, a poorly sol. drug, [Eur. J. Pharm. Sci. 24, 297-303]. In the fasted state, the physiol. most relevant correlation with in vivo results was achieved with a medium contg. 6.3 mM bile salts and 1.25 mM phospholipids (8 mL/min). A medium contg. 18.8 mM bile salts, 3.75 mM phospholipids, 4.0 mM monoglycerides and 30 mM fatty acids (8 mL/min) gave the closest correlation with fed state in vivo results. By using the flow-through dissoln. method it was possible to obtain correlations with in vivo release of danazol under fasted and fed conditions. Both hydrodynamics and medium compn. were important for the dissoln. of danazol. In the fed state an IVIVC could only be obtained by including monoglycerides and fatty acids in the medium.
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38. 38
  Greco, K.; Bogner, R. Solution-mediated phase transformation: Significance during dissolution and implications for bioavailability. J. Pharm. Sci. 2012, 101 (9), 2996– 3018, DOI: 10.1002/jps.23025
  38
  Solution-mediated phase transformation: Significance during dissolution and implications for bioavailability
  Greco, Kristyn; Bogner, Robin
  Journal of Pharmaceutical Sciences (2012), 101 (9), 2996-3018CODEN: JPMSAE; ISSN:0022-3549. (John Wiley & Sons, Inc.)
  A review. Soly. improvement of poorly sol. drug compds. is a key approach to ensuring the successful development of many new drugs. Methods used to improve the soly. of drug compds. include forming a salt, cocrystal, or amorphous solid. These methods of improving soly. can often lead to a phenomenon called soln.-mediated phase transformation, a phase change that is facilitated through exposure to soln. Soln.-mediated phase transformation occurs in three steps: dissoln. to create a supersatd. soln. followed by nucleation of less sol. phase and the growth of that phase. When the growth of the less sol. phase occurs on the surface of the metastable solid, this phenomenon can cause a marked decrease in dissoln. rate during in vitro dissoln. evaluation, and ultimately in vivo. Therefore, transformation to a less sol. solid during dissoln. is an important aspect to consider when evaluating approaches to increase the soly. of a poorly sol. drug. Identification of soln.-mediated phase transformation during dissoln. is reviewed for powder dissoln., rotating disk method, and channel flow-through app. Types of soln.-mediated phase transformation are described in this report, including those involving salts, polymorphs, amorphous solids, and cocrystals. Many exptl. examples are provided. Evidence of potential soln.-mediated phase transformation in vivo is discussed to better understand the relationship between in vitro dissoln. evaluation and in vivo performance. © 2011 Wiley Periodicals, Inc. and the American Pharmacists Assocn. J Pharm Sci.
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39. 39
  Slavin, P. A.; Sheen, D. B.; Shepherd, E. E. A.; Sherwood, J. N.; Feeder, N.; Docherty, R.; Milojevic, S. Morphological evaluation of the γ-polymorph of indomethacin. J. Cryst. Growth 2002, 237–239, 300– 305, DOI: 10.1016/S0022-0248(01)01924-8
  39
  Morphological evaluation of the γ-polymorph of indomethacin
  Slavin, Paul A.; Sheen, David B.; Shepherd, Evelyn E. A.; Sherwood, John N.; Feeder, Neil; Docherty, Robert; Milojevic, Snezena
  Journal of Crystal Growth (2002), 237-239 (Pt. 1), 300-305CODEN: JCRGAE; ISSN:0022-0248. (Elsevier Science B.V.)
  A study was made of the polymorphic nature of crystals of the pharmaceutical indomethacin grown from a wide range of solvents and from the melt. In most solvents, growth at high supersaturations yielded either a 1:0.5 solvated form (approx.) or the α-polymorph. At low supersaturations the γ-polymorph was commonly produced. Solns. in MeOH and tBuOH yielded a 1:1 solvate. The morphol. of the γ-form showed no variation with solvent type but changed with supersatn. in a manner consistent with a differential variation in growth rates of the faces. This lack of solvent influence was confirmed by the fact that a similar morphol. resulted on growth from the melt. Morphol. predictions were carried out for the γ-polymorph and these show good agreement with exptl. observations.
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40. 40
  Hartshorn, C. M.; Lee, Y. J.; Camp, C. H.; Liu, Z.; Heddleston, J.; Canfield, N.; Rhodes, T. A.; Hight Walker, A. R.; Marsac, P. J.; Cicerone, M. T. Multicomponent chemical imaging of pharmaceutical solid dosage forms with broadband CARS microscopy. Anal. Chem. 2013, 85 (17), 8102– 8111, DOI: 10.1021/ac400671p
  There is no corresponding record for this reference.
41. 41
  Taylor, L. S.; Zografi, G. Spectroscopic characterization of interactions between PVP and indomethacin in amorphous molecular dispersions. Pharm. Res. 1997, 14 (12), 1691– 1698, DOI: 10.1023/A:1012167410376
  41
  Spectroscopic characterization of interactions between PVP and indomethacin in amorphous molecular dispersions
  Taylor, Lynne S.; Zografi, George
  Pharmaceutical Research (1997), 14 (12), 1691-1698CODEN: PHREEB; ISSN:0724-8741. (Plenum Publishing Corp.)
  The mol. structure of indomethacin-PVP amorphous solid dispersions was studied and specific interactions between the components was identified using vibrational spectroscopy. Solid dispersions of PVP and indomethacin were prepd. using a solvent evapn. technique and IR and FT-Raman spectra were obtained. A comparison of the carbonyl stretching region of γ indomethacin, known to form carboxylic acid dimers, with that of amorphous indomethacin indicated that the amorphous phase exists predominantly as dimers. The hydrogen bonding of α indomethacin is not as dimers. Addn. of PVP to amorphous indomethacin increased the intensity of the IR band assigned to non-hydrogen bonded carbonyl. Concomitantly, the PVP carbonyl stretch appeared at a lower wavenumber indicating hydrogen bonding. Model solvent systems aided spectral interpretation. The magnitude of the spectral changes were comparable for an indomethacin-PVP solid dispersion and a soln. of indomethacin in methylpyrrolidone at the same wt. percent. Indomethacin interacts with PVP in solid dispersions through hydrogen bonds formed between the drug hydroxyl and polymer carbonyl resulting in disruption of indomethacin dimers. PVP may influence the crystn. kinetics by preventing the self assocn. of indomethacin mols. The similarity of results for solid dispersions and solns. emphasizes the "soln." nature of this binary amorphous state.
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42. 42
  Trasi, N. S.; Purohit, H. S.; Taylor, L. S. Evaluation of the crystallization tendency of commercially available amorphous tacrolimus formulations exposed to different stress conditions. Pharm. Res. 2017, 34 (10), 2142– 2155, DOI: 10.1007/s11095-017-2221-4
  42
  Evaluation of the Crystallization Tendency of Commercially Available Amorphous Tacrolimus Formulations Exposed to Different Stress Conditions
  Trasi, Niraj S.; Purohit, Hitesh S.; Taylor, Lynne S.
  Pharmaceutical Research (2017), 34 (10), 2142-2155CODEN: PHREEB; ISSN:0724-8741. (Springer)
  Tacrolimus, an immunosuppressant, is a poorly water sol. compd. whereby the com. available capsule formulations contain the drug in amorphous form. The goal of this study was to evaluate the robustness of the innovator product and five generic formulations to crystn. following storage at stress conditions. Methods: Products were purchased from a pharmacy and stored at 40/75% relative humidity (RH), open dish conditions. Crystallinity was detd. using x-ray diffraction. The quantity of the ingredients in the formulations were detd. using different approaches and the various factors that might cause instability in the formulations were studied. Results: After 4 wk of open dish storage at 40/75% RH, one of the generic formulations showed evidence of tacrolimus crystn. Further investigations revealed batch-to-batch variations in crystn. tendency with the extent of crystallinity varying between 50 and 100% for different batches. Crystn. was also obsd. at lower storage temps. (30) when the RH was maintained at 75%. It was found that crystn. could be induced in a model formulation by wet granulating an ethanolic soln. of the drug with lactose and drying at 60-70 followed by exposure to stress conditions. Conclusions: It seems probable that the generic that was susceptible to crystn. contains amorphous drug phys. mixed with polymeric excipients, rather than as an amorphous solid dispersion. This study highlights the importance of considering the manufg. process on the stability of the resultant amorphous product.
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43. 43
  Sun, D. D.; Lee, P. I. Evolution of supersaturation of amorphous pharmaceuticals: The effect of rate of supersaturation generation. Mol. Pharmaceutics 2013, 10 (11), 4330– 4346, DOI: 10.1021/mp400439q
  43
  Evolution of Supersaturation of Amorphous Pharmaceuticals: The Effect of Rate of Supersaturation Generation
  Sun, Dajun D.; Lee, Ping I.
  Molecular Pharmaceutics (2013), 10 (11), 4330-4346CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
  The combination of a rapidly dissolving and supersaturating spring with a pptn. retarding parachute has often been pursued as an effective formulation strategy for amorphous solid dispersions (ASDs) to enhance the rate and extent of oral absorption. However, the interplay between these two rate processes in achieving and maintaining supersatn. remains inadequately understood, and the effect of rate of supersatn. buildup on the overall time evolution of supersatn. during the dissoln. of amorphous solids has not been explored. The objective of this study is to investigate the effect of supersatn. generation rate on the resulting kinetic soly. profiles of amorphous pharmaceuticals and to delineate the evolution of supersatn. from a mechanistic viewpoint. Exptl. concn.-time curves under varying rates of supersatn. generation and recrystn. for model drugs, indomethacin (IND), naproxen (NAP) and piroxicam (PIR), were generated from infusing dissolved drug (e.g., in ethanol) into the dissoln. medium and compared with that predicted from a comprehensive mechanistic model based on the classical nucleation theory taking into account both the particle growth and ripening processes. In the absence of any dissolved polymer to inhibit drug pptn., both our exptl. and predicted results show that the max. achievable supersatn. (i.e., kinetic soly.) of the amorphous solids increases, the time to reach max. decreases, and the rate of concn. decline in the de-supersatn. phase increases, with increasing rate of supersatn. generation (i.e., dissoln. rate). Our mechanistic model also predicts the existence of an optimal supersatn. rate which maximizes the area under the curve (AUC) of the kinetic soly. concn.-time profile, which agrees well with exptl. data. In the presence of a dissolved polymer from ASD dissoln., these obsd. trends also hold true except the de-supersatn. phase is more extended due to the crystn. inhibition effect. Since the obsd. kinetic soly. of nonequil. amorphous solids depends on the rate of supersatn. generation, our results also highlight the underlying difficulty in detg. a reproducible soly. advantage for amorphous solids.
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44. 44
  Zhu, L.; Wong, L.; Yu, L. Surface-enhanced crystallization of amorphous nifedipine. Mol. Pharmaceutics 2008, 5 (6), 921– 926, DOI: 10.1021/mp8000638
  44
  Surface-Enhanced Crystallization of Amorphous Nifedipine
  Zhu, Lei; Wong, Letitia; Yu, Lian
  Molecular Pharmaceutics (2008), 5 (6), 921-926CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
  Amorphous solids are generally more sol. and faster dissolving than their cryst. counterparts, a property useful for delivering poorly sol. drugs. Amorphous drugs must be stable against crystn., for crystn. negates their advantages. Recent studies found that crystal growth in amorphous indomethacin is orders of magnitude faster at the free surface than through the bulk and this surface-enhanced crystn. can be inhibited by an ultrathin coating. Herein, we report a second system that exhibits the same phenomena. Crystal growth at the free surface of amorphous nifedipine (NIF) was at least 1 order of magnitude faster than that through the bulk below the glass transition temp. Tg (42 °C). A thin coating of gold (10 nm) reduced the surface crystal growth rate to the bulk crystal growth rate. Surface-enhanced crystal growth was more pronounced near and below Tg than substantially above Tg, which suggests that this growth mode is more important for the glassy state. Our results support the view that a thin layer of mols. near the surface have higher mobility than the bulk mols. and can enable faster crystal growth. The higher mobility of surface mols. and the resulting fast crystal growth can be suppressed by an ultrathin coating.
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45. 45
  Hasebe, M.; Musumeci, D.; Yu, L. Fast surface crystallization of molecular glasses: creation of depletion zones by surface diffusion and crystallization flux. J. Phys. Chem. B 2015, 119 (7), 3304– 3311, DOI: 10.1021/jp512400c
  45
  Fast Surface Crystallization of Molecular Glasses: Creation of Depletion Zones by Surface Diffusion and Crystallization Flux
  Hasebe, Mariko; Musumeci, Daniele; Yu, Lian
  Journal of Physical Chemistry B (2015), 119 (7), 3304-3311CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
  Mol. glasses can grow crystals much faster at the free surface than in the interior. A property of this process is the creation of depressed grooves or depletion zones around the crystals on the initially flat amorphous surface. With SEM and at. force microscopy, the authors studied this phenomenon in indomethacin (IMC), which crystallizes in two polymorphs (α and γ) of different morphologies. The obsd. depletion zones are well reproduced by the known coeffs. of surface diffusion and the velocities of crystal growth. At the slow-growing flanks of needle-like α-IMC crystals, depletion zones widen and deepen over time according to the expected kinetics for surface diffusion responding to a crystn. flux. Before fast-advancing growth fronts, depletion zones have less time to develop; their steady-state dimensions agree with the same model revised for a moving phase boundary. These results support the view that surface diffusion enables fast surface crystal growth on mol. glasses. The authors' finding helps understand crystal growth in thin films in which the formation of deep depletion zones can cause dewetting and alter growth kinetics.
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46. 46
  Zhu, L.; Jona, J.; Nagapudi, K.; Wu, T. Fast surface crystallization of amorphous griseofulvin below Tg. Pharm. Res. 2010, 27 (8), 1558– 1567, DOI: 10.1007/s11095-010-0140-8
  46
  Fast Surface Crystallization of Amorphous Griseofulvin Below Tg
  Zhu, Lei; Jona, Janan; Nagapudi, Karthik; Wu, Tian
  Pharmaceutical Research (2010), 27 (8), 1558-1567CODEN: PHREEB; ISSN:0724-8741. (Springer)
  To study crystal growth rates of amorphous griseofulvin (GSF) below its glass transition temp. (Tg) and the effect of surface crystn. on the overall crystn. kinetics of amorphous GSF. Amorphous GSF was generated by melt quenching. Surface and bulk crystal growth rates were detd. using polarized light microscope. X-ray powder diffraction (XRPD) and Raman microscopy were used to identify the polymorph of the crystals. Crystn. kinetics of amorphous GSF powder stored at 40° (Tg-48°) and room temp. (Tg-66°) was monitored using XRPD. Results: Crystal growth at the surface of amorphous GSF is 10- to 100-fold faster than that in the bulk. The surface crystal growth can be suppressed by an ultrathin gold coating. Below Tg, the crystn. of amorphous GSF powder was biphasic with a rapid initial crystn. stage dominated by the surface crystn. and a slow or suspended late stage controlled by the bulk crystn. GSF exhibits the fastest surface crystn. kinetics among the known amorphous pharmaceutical solids. Well below Tg, surface crystn. dominated the overall crystn. kinetics of amorphous GSF powder. Thus, surface crystn. should be distinguished from bulk crystn. in studying, modeling and controlling the crystn. of amorphous solids.
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47. 47
  Elkhabaz, A.; Sarkar, S.; Dinh, J. K.; Simpson, G. J.; Taylor, L. S. Variation in supersaturation and phase behavior of ezetimibe amorphous solid dispersions upon dissolution in different biorelevant media. Mol. Pharmaceutics 2018, 15 (1), 193– 206, DOI: 10.1021/acs.molpharmaceut.7b00814
  47
  Variation in Supersaturation and Phase Behavior of Ezetimibe Amorphous Solid Dispersions upon Dissolution in Different Biorelevant Media
  Elkhabaz, Ahmed; Sarkar, Sreya; Dinh, Janny K.; Simpson, Garth J.; Taylor, Lynne S.
  Molecular Pharmaceutics (2018), 15 (1), 193-206CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
  The delivery of poorly water-sol. drugs using amorphous solid dispersions (ASDs) has been widely acknowledged as a promising strategy for enhancing oral bioavailability. Upon dissoln., ASDs have accelerated dissoln. rates and yield supersatd. solns. leading to higher apparent solubilities. Understanding the complex phase behavior of ASDs during dissoln. is crucial for developing an effective formulation. Since the absorption of a lipophilic, high permeability drug is detd. primarily by the intraluminal dissoln. process and the final concn. achieved, there is a need for evaluation in biorelevant dissoln. media that simulate both fasting and fed gastrointestinal states. In this study, using ezetimibe as a model drug, three different ASDs were prepd. using poly(acrylic acid) (PAA), polyvinylpyrrolidone (PVP), and hydroxypropyl methylcellulose acetyl succinate (HPMC-AS). Dissoln. of ASDs was carried out in sodium phosphate buffer, fed-state simulated intestinal fluid (FeSSIF), and Ensure Plus to evaluate the impact of different dissoln. media on release profile, supersatn., and phase behavior. The supersatn. level and crystn. kinetics varied among the dispersions and were found to be highly dependent on the medium employed. The presence of solubilizing additives in biorelevant media greatly affected the generation and stabilization of supersatd. solns. Second harmonic generation microscopy was found to enable the detection of crystals in all media including the highly turbid Ensure Plus system. In conclusion, it is important to evaluate the impact of complex biorelevant media on the dissoln. performance of ASDs to better design supersaturating formulations for oral delivery.
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Supporting Information
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.molpharmaceut.8b00840.
- ATR-FTIR spectra of tablet surfaces after dissolution and additional CARS and SFG overlay images of tablets stored for 1 and 7 days at 30 °C/75% RH (PDF)
- mp8b00840_si_001.pdf (696.06 kb)
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Understanding Dissolution and Crystallization with Imaging: A Surface Point of ViewClick to copy article linkArticle link copied!

Molecular Pharmaceutics

Abstract

1. Introduction

2. Materials and Methods

2.1. Sample Preparation

2.2. Intrinsic Dissolution Testing

2.3. Scanning Electron Microscopy (SEM)

2.4. X-ray Diffractometry (XRD)

2.5. Fourier Transform Infrared Spectroscopy (FTIR)

2.6. Multimodal Nonlinear Optical Imaging

3. Results

3.1. Dissolution Behavior

3.1.1. Pure Amorphous and Reference Crystalline Forms

Figure 1

3.1.2. Stored Samples

3.2. Visual Appearance

3.3. Surface Morphology

Figure 2

Figure 3

3.4. Solid-State Analysis

3.4.1. Freshly Prepared Amorphous Indomethacin (Day 0)

Figure 4

Figure 5

Figure 6

Figure 7

3.4.2. Tablets after Storage at Lower Humidity (30 °C/23% RH)

3.4.3. Tablets after Storage at Higher Humidity (30 °C/75% RH)

3.4.4. Reference Raman and CARS Spectra

Figure 8

4. Discussion

5. Conclusions

Supporting Information

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Author Information

Acknowledgments

Abbreviations

References

Cited By

Molecular Pharmaceutics

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Understanding Dissolution and Crystallization with Imaging: A Surface Point of View
Click to copy article linkArticle link copied!