Impact of Polymer Enrichment at the CrystalâLiquid Interface on

Subscriber access provided by MIDWESTERN UNIVERSITY

Article

Impact of Polymer Enrichment at the Crystal-Liquid Interface on Crystallization Kinetics of Amorphous Solid Dispersions Jie Zhang, Qin Shi, Jun Tao, Yayun Peng, and Ting Cai Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/ acs.molpharmaceut.8b01331 • Publication Date (Web): 04 Feb 2019 Downloaded from http://pubs.acs.org on February 5, 2019

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Molecular Pharmaceutics

Impact of Polymer Enrichment at the Crystal-Liquid Interface on Crystallization Kinetics of Amorphous Solid Dispersions Jie Zhang†, Qin Shi†, Jun Tao†, Yayun Peng†, Ting Cai*,† †State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China

ABSTRACT: Amorphous solid dispersions have been widely used as an effective formulation strategy in the oral delivery of poorly soluble drugs. However, one of the main challenges in the development of amorphous drugs is to maintain their physical stability. The underlying mechanism of amorphous drugs crystallized in polymeric matrices is still poorly understood. Herein, we report the phenomenon of polymer enrichment at the crystal-liquid interface during the crystallization of griseofulvin (GSF) containing poly (ethylene oxide) (PEO). Confocal Raman microscopy, scanning electron microscope (SEM) and energy-dispersive X-ray spectroscopy (EDS) are employed to reveal the heterogeneous distribution of GSF and PEO at the crystal growth front. The concentration of PEO in the polymer-rich phase at the crystal-liquid interface is determined by Raman spectroscopic analysis. At a given temperature, the crystal growth rates of GSF initially increase with increasing the PEO loading in the bulk and then reach a plateau at high polymer loadings. We propose that the crystal growth rates of GSF is predominantly controlled by the local concentration of PEO at the growth front rather than the overall bulk concentration. This study provides the direct evidence of physical mechanisms that contribute to the local phase separation occurred at the crystal-liquid interface, which governs the kinetics of crystal growth in amorphous solid dispersions. These results are important for understanding the crystallization behavior of amorphous solid dispersions and beneficial for the rational design of robust amorphous formulations. KEYWORDS: griseofulvin; poly (ethylene oxide); crystal growth; phase separation; interface ACS Paragon Plus Environment

Molecular Pharmaceutics 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 29

INTRODUCTION Amorphization is considered an effective formulation approach to improve the solubility and oral bioavailability of poorly water-soluble drugs.1,2 However, amorphous drugs exhibit higher free energy compared to their crystalline counterparts.1,3 They tend to revert back to the thermodynamically stable crystalline form over time, resulting in decreased dissolution rate and solubility.4-6 Polymeric additives are frequently incorporated with amorphous drugs at the molecular level to create amorphous solid dispersions with enhanced physical stability.7 However, various polymers may have very dramatic influence on physical stability of amorphous drugs.8-11 A thorough understanding of effect of polymers on crystallization of amorphous drugs is crucial for developing stable amorphous formulations. The impact of polymers on physical stability of amorphous solid dispersion has been intensively studied over the past decade.8,9,12-14 Several mechanisms have been proposed to interpret the effect of polymers on crystal growth of amorphous drugs. The polymer-drug intermolecular interactions, such as ionic interactions, hydrogen bonding, dipole-dipole interactions, and van der Waals interactions, have been demonstrated to play important roles in governing the physical stability of amorphous solid dispersions.7,15,16 A polymer with a high Tg can act as an antiplasticizer to reduce the molecular mobility of an amorphous drug in the solid dispersion, leading to slower crystallization kinetics.17 A recent research proposes that the effect of polymer on crystal growth of the amorphous drug is dependent on the segmental mobility of the polymer relative to the dynamics of host molecules.9 Recently, we report that the low-concentration poly (ethylene oxide) (PEO) can significantly increase crystal growth rates of amorphous drug griseofulvin (GSF, an antifungal drug with low water solubility). This accelerating effect can be attributed to the increase of global mobility and the high segmental mobility of PEO.10 In the following study, the addition 3% w/w PEO increases the ACS Paragon Plus Environment

Page 3 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


crystal growth rates of -form and -form of indomethacin, but has a negligible effect on the -form. We hypothesize that this selective accelerating effect on growth kinetics of indomethacin polymorphs by PEO could be caused by the different adsorptions of polymer at the crystal growth front.18 Yu et al. propose a model that polymer molecules are rejected by the growing crystal and enriched at the growth front during the crystallization.9 The hypothesized polymer-rich layer at the growth front is believed to be the kinetic barrier which drug molecules need to migrate through and eventually reach the crystals.9 To better understand the underlying mechanism of amorphous drugs crystallized in polymeric matrices, there has been a growing interest in exploring the microstructure of amorphous solid dispersions.19,20 Raman mapping has been used to characterize the phase separation of amorphous mixtures processed under different conditions, which could not be discernable by the conventional methods such as differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD).21 The crystalline/amorphous domains and chemical compositions of different pharmaceutical systems were studied using the thermal and spectroscopic probe-based approaches, including atomic force microscopy (AFM), localized nanothermal analysis (nanoTA), and photothermal microspectroscopy (PTMS).

22,23,24

In addition, transmission electron microscopy with energy dispersive X-ray

spectroscopy and confocal fluorescence microscopy in combination with fluorescent probes have been employed to provide detailed information and mechanistic understanding of the impact of water on the phase separation and microstructure of amorphous solid dispersions.19,25 In this study, we observed the phenomenon of polymer enrichment at the crystal-liquid interface during the crystallization of GSF amorphous solid dispersions containing certain amounts of PEO. Confocal Raman microscopy, scanning electron microscope (SEM) and energy-dispersive X-ray spectroscopy (EDS) were employed to reveal the heterogeneous distribution of drug and polymer at the crystal growth front. This study provides direct evidence of physical mechanisms that contribute ACS Paragon Plus Environment


Page 4 of 29

to the enriched polymer layer at the crystal-liquid interface which controls the kinetics of crystal growth in amorphous solid dispersions. The polymer loadings and the temperature were found to be the factors affecting the phase separation at the crystal-liquid interface.

MATERIALS AND METHODS Materials. Griseofulvin was obtained from J&K Scientific Co., Ltd. China (Purity >99.0%, form I). Poly (ethylene oxide) (PEO, Mv =100 000, Tg = -47 ℃) was obtained from Sigma-Aldrich (St.Louis, MO, USA).

Figure 1. Chemical structures of (a) poly (ethylene oxide) and (b) griseofulvin.

Preparation of GSF/PEO Mixtures. The uniform GSF/PEO physical mixtures containing various drug/polymer ratios were prepared by cryogenic milling (6770 Freezer/Mill, SPEX SamplePrep, NJ, USA). For instance, a total of 1 g of pure crystalline GSF and PEO mixture was cryomilled at 10 Hz for 5 cycles, using liquid nitrogen as a coolant. Each cycle of milling was conducted for 2 min, followed by a 2 min cool-down process.

Thermal Analysis. The phase diagram was constructed by means of melting temperature depression described in the literature.26 Differential Scanning Calorimetry (DSC) measurements were conducted using a TA Instruments DSC Q2000 (New Castle, DE, USA) under 50 mL/min N2 purge. 5-10 mg materials were weighed and loaded in sealed aluminum pans. The sample was heated at a rate of 1 ℃/min to ACS Paragon Plus Environment

Page 5 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


230 ℃. The melting point (Tm) was taken as the extrapolated onset of the bulk melting endotherm. For obtaining the Tg values, the samples were melted at 230 ℃ for 3 min, equilibrated to -50 ℃, and then heated up to 230 ℃ at a rate of 10 ℃/min.

Crystal Growth Measurement. The crystal morphology and growth rates were monitored and measured by using the polarized light microscope (Olympus BX53, Olympus, Tokyo, Japan). The temperatures were controlled by using a hot stage (Linkam THMS 600, Surrey, UK). About 3 mg of GSF/PEO mixtures were melted at 230 ℃ between two 15 mm diameter round glass coverslips for 3 min, and then the sample was immediately quenched to room temperature to form a glass. The crystallizations of GSF in the presence of different amounts of PEO were initiated by seeding with GSF form I crystals at 120 ℃, and the sample was subsequently transferred and maintained at different temperatures ranging from 120°C to 50°C. The crystal growth rate at a defined temperature was measured by measuring the increase in diameter of the spherulitic crystal into the supercooled liquid. Each crystal growth rate was performed in triplicate.

Raman Microscopy. Determination of the Concentration of PEO at the Growth Front by Raman Microscopy. For determining the concentration of GSF and PEO in an unknown sample by confocal Raman microscopy, a calibration curve was constructed and validated. A series of GSF/PEO physical mixtures with known concentration (0, 20, 30, 40, 50, 60, 70, 80 and 100% w/w of PEO) were prepared. The resulting samples were melted above the melting temperature of GSF (230 ℃ ) between two 15 mm diameter round glass coverslips for 3 min, and followed by quenching to room temperature to form single-phase glasses. The samples containing 0, 30, 50, 70, and 100% w/w PEO ACS Paragon Plus Environment


Page 6 of 29

were used to create a calibration curve, while samples with 20, 40, 60, and 80% w/w PEO were tested to validate the accuracy of the calibration curve. The Raman spectra were collected by a confocal Raman Microscope (DXR, Thermo Fisher Scientiﬁc, Madison, USA) equipped with a 780 nm externally stabilized diode laser source. Fluorescence and background corrections were performed. The Raman spectra were collected by using a 50 X objective with a total exposure time of 20 s (1 s acquisition 20). The laser power was set to 15 mW. Data analysis was performed using TQ Analyst 6.1.1, and a PLS (partial least squares) model was employed. Savitzky-Golay and multiplicative scatter correction (MSC) pre-processing were performed on Raman spectra before PLS analysis to exclude inter-batch variation and variation caused by baseline-shifts, respectively.27,28 The PLS calibration model was constructed based on the 750-1050 cm-1 regions and a three factors model was selected. The concentration of PEO in a binary mixture is obtained by PLS analysis. Confocal Raman Mapping. Raman mapping were performed on the samples sandwiched between two 15 mm diameter round coverslips. Raman spectra were collected in a desired area of 50×50 μm with the aid of a computer-controlled translational stage. The smallest step size of Raman mapping was 1 μm along the x and y directions for high spatial resolution. A 15 mW 780 nm laser was used for excitation. Raman spectra were collected by using a 50 X objective in a total exposure time of 3 s (1 s acquisition3).

Scanning Electron Microscopy (SEM) and Energy-dispersive X-ray Spectroscopy (EDS). The morphology and chemical imaging of samples were characterized by field emission scanning electron microscope (SEM-S4800, Hitachi, Japan) equipped with an energy-dispersive X-ray spectroscopy. Prior to SEM analysis, one side of cover glass was detached from the sample to expose ACS Paragon Plus Environment

Page 7 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


the free surface. The sample was then coated with a gold film (about 10 nm thick) using a sputter coater. Electron beam energy of 20.0 keV was applied for SEM analysis and EDS mapping.

RESULTS State of Mixing between GSF and PEO. The GSF/PEO mixture has been previously identified as a miscible system with a negative Flory-Huggins interaction parameter χ.10 Figure 2a shows the DSC traces of GSF/PEO mixtures with various compositions. We observe that the melting point depression increases with increasing the PEO bulk content. Figure 2b shows a monotectic phase diagram of GSF with PEO, which seems similar to the reported data of GSF and PEG8000 system.29 The similar phase diagrams demonstrate that the molecular weight of PEO has negligible impact on the melting point depression curve.26,29 The fresh prepared amorphous GSF/PEO samples are optically clear with no evidence of heterogeneity, suggesting that GSF are miscible with PEO at all compositions. A further test of the miscibility is signaled by a single Tg of the amorphous GSF/PEO mixtures prepared by melt quenching.

Figure 2. (a) DSC traces of GSF-PEO physical mixtures. (b) Onset of GSF melting as a function of volume fraction of PEO.

Crystallizations of GSF in the Presence of Different Amounts of PEO ACS Paragon Plus Environment


Page 8 of 29

The influence of 1% and 3% w/w PEO on the crystal growth of amorphous GSF has been studied previously.10 The spherulitic morphology of GSF crystals grown from 60 to 120 ℃ was not affected by doping with low-concentration PEO.10 Figure 3 shows the morphologies of GSF crystals grown in the presence of 5%, 20% and 40% w/w PEO. For the amorphous GSF containing 5% w/w PEO, the crystals grow as compact spherulites with the weak birefringence at 60 ℃, but exhibiting high birefringence at 90 and 120 ℃. For the samples containing higher content of PEO (20% and 40% w/w), a transparent layer can be observed at the crystal growth front at 60 ℃. The layer expands with increasing the PEO bulk concentration, while vanishing at the elevated temperatures. The transparent layer appeared at the growth front suggests a local phase separation occurred at the crystal-liquid interface during the crystallization, which is further characterized and discussed below.

Figure 3. Crystal morphologies of GSF grown in the presence of 5, 20, 40% w/w PEO at 60 ℃, 90 ℃, and 120 ℃.

Figure 4a shows the crystal growth kinetics of amorphous GSF containing different amounts of PEO as a function of temperature. Generally, the crystal growth rates of GSF increase with increasing the temperature. For neat amorphous GSF and GSF doped with 1% and 3% w/w PEO, the ACS Paragon Plus Environment

Page 9 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


discontinuity of growth kinetics at 88 C is due to the activation of GC growth, a fast crystal growth mode which has been extensively investigated in the literature.10,30 However, the GC growth is no longer observed in the dispersions containing higher amounts of PEO (10-40% w/w). Interestingly, if the PEO loading in the binary mixture is more than 10% w/w, the crystallization kinetics of GSF overlaps as a function of temperature. Figure 4b shows the crystal growth kinetics of amorphous GSF as a function of PEO loading at 60 and 120 C, and the Tg values of the corresponding drug-polymer compositions are plotted for comparison. It is found that the Tg value of dispersions decreases continuously with increasing the polymer content, whereas the crystal growth rates reach a plateau when the PEO loading is above 10% w/w.10,31

Figure 4. (a) Crystal growth kinetics of amorphous GSF as a function of temperature and PEO bulk concentration. (b) Comparison between Tg (blue empty circles) and crystal growth rates of amorphous GSF containing 0-40% w/w PEO at 60 ℃ (red empty squares) and 120 ℃ (red empty triangles).

Qualitative Analysis of the Phase Separation at the Crystal Growth Front by Raman Microscopy. Figure 5a shows the crystal growth front of amorphous GSF containing 20% w/w PEO at 60 ℃ under the polarized microspore. A transparent layer can be clearly observed at the growth front of the GSF crystalline phase at 60 ℃. The sample is then transferred from 60 ℃ to 25 ℃ prior to Raman ACS Paragon Plus Environment


Page 10 of 29

analysis (Figure 5b), and the transparent layer become opaque immediately due to the crystallization at low temperature (Figure 5b). As shown in Figure 5b, there are three distinct regions: the bulk crystals (region I), the amorphous region (region II) and the phase-separated domain at crystal-amorphous interfacial region (region III). The Raman spectra of these different regions measured at 25 ℃ are shown in Figure 5c. The bulk crystal (region I) is confirmed as GSF form I by Raman spectroscopy.10,32 The Raman spectrum of region II exhibits a pattern similar to those of GSF form I, which agrees with the fact that GSF is dominant in the amorphous bulk sample (80% w/w GSF). In contrast, the spectrum of region III is similar to the pattern of pure PEO, indicating the presence of a polymer-rich phase. The actual concentration of PEO in the phase-separated layer at the growth front (region III) will be determined in the following sections.

Figure 5. Photomicrographs of GSF crystals grown in the presence 20% w/w PEO at (a) 60 ℃ and then (b) ACS Paragon Plus Environment

Page 11 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


immediately transferred to 25 ℃ for Raman analysis; (c) Raman spectra of pure GSF, pure PEO, and crystalline region (I), amorphous region (II) and crystal-amorphous interfacial region (III).

Confocal Raman spectroscopy can be used to evaluate local phase separation or the distribution of drug/polymer in solid dispersions with high spatial resolution.21,33 Figure 6a shows an optical image of crystal growth of amorphous GSF containing 20% w/w PEO at 60 ℃ (the image is taken at 25 ℃ prior to Raman mapping). The 972 cm-1 peak in the GSF Raman spectrum is used to map the spatial distribution of the GSF at the crystal growth front (Figure 6b) and the bulk crystalline domain as well (Figure 6d), while the 844 cm-1 peak in the PEO Raman spectrum is used to map the spatial distribution of the PEO at the same regions (Figure 6c and 6e). As shown in Figure 6b, the intensity of GSF at the crystal-amorphous interfacial region is significantly lower than those of the crystalline and amorphous regions. On the other hand, Figure 6c shows that the intensity of PEO at the crystal-amorphous interfacial region is significantly higher than those of the crystalline and amorphous regions, which strongly support the view that the polymer is indeed enriched at the crystal growth front. It is worth noting that the distribution of GSF is not uniform throughout the bulk crystalline domains. The dark regions (low birefringence) in the optical image of bulk crystals (Figure 6a) are actually the PEO enriched regions, as evidenced by the Raman maps (Figure 6d and 6e). This result suggests that during the crystallization, some of PEO are pushed out to form a PEO-rich phase at the growth front; while some of PEO are trapped in the GSF crystalline domains as crystals keep advancing into the liquid.

ACS Paragon Plus Environment


Page 12 of 29

Figure 6. Photomicrograph and Raman mapping of crystal growth front of GSF containing 20% w/w PEO (the sample was initially grown at 60 ℃ and then immediately transferred to 25 ℃ for imaging and Raman mapping) (a) morphology of GSF crystal growth front. (b) and (d) a red color corresponds to a high intensity of the characteristic peak of GSF at 972 cm-1, indicating the presence of GSF in the regions, a blue color corresponds to a low peak intensity, indicating the absence of GSF in those regions. (c) and (e) a red color corresponds to a high intensity of the characteristic peak of PEO at 844 cm-1, indicating the presence of PEO in the regions, a blue color corresponds to a low peak intensity, indicating the absence of PEO in those regions.

Characterization of the Phase Separation at the Crystal Growth Front by SEM-EDS. SEM-EDS can be applied to perform chemical imaging of amorphous solid dispersion based on the distribution of atomic components.34 Figure 7a shows the SEM image of the growth front of GSF containing 20% w/w PEO at 60 ℃. The EDS elemental mapping of carbon, oxygen and chlorine atoms of the corresponding SEM image are presented in Figure 7b-d. Figure 7b and 7c show that the carbon and oxygen are both homogenously distributed in the field due to the fact that the percentages ACS Paragon Plus Environment

Page 13 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


of carbon and oxygen in the PEO are comparable to those in the GSF molecule. However, chloride is the unique chemical element only present in the structure of GSF rather than PEO. Figure 7d shows that the signals of chlorine are significantly weaker at the crystal-amorphous interfacial region and the gaps within the GSF bulk crystals. The SEM-EDS results are consistent with the conclusion obtained from the Raman mapping, which strongly support the view of enrichment of PEO at the crystal-amorphous interface as well as the separate domains of GSF bulk crystals during the melt crystallization.

Figure 7. (a) SEM micrograph of interface of the GSF crystals containing 20% w/w PEO grown at 60 ℃ and the corresponding EDS elemental mapping of (b) carbon, (c) oxygen and (d) chlorine.

Measurement of PEO Concentration by Raman Spectroscopy. Raman spectroscopy has been used to quantitatively determine the material content in an intact tablet.27 In the present study, Raman spectra along with the PLS model are utilized to determine the concentrations of PEO in the specific regions. Amorphous solid dispersions (30%, 50% and 70% w/w PEO), along with pure PEO and GSF are tested to validate the accuracy of the analytical method based on Raman spectra (Figure 8a). The PLS calibration model is constructed using the spectra over the wavenumber range of 750-1050 cm-1. Figure 8b shows the correlation between the actual and predicted PEO concentration, the correlation coefficient is 0.992. Thus, the PLS model based Raman spectroscopy is suitable for measuring the PEO content in an unknown region, which can be further used to investigate the factors influencing the phase separation and crystal growth kinetics. ACS Paragon Plus Environment


Page 14 of 29

Figure 8. (a) Raman spectra of GSF/PEO amorphous solid dispersions with the known concentrations for calibration. (b) Correlation between the actual and the predicted concentration of PEO in the standard samples. Linear line: regression curve from the calibration set; Black Squares: calibration set; red circles: validation set. Bars represent standard deviations (n = 3).

The Study of the Phase Separation at the Crystal-liquid Interface. Time-dependence. Figure 9a displays the consecutive optical images of GSF crystals grown in the presence of 20% w/w PEO at 60 ℃ during 45 mins. As shown in Figure 9b, the advance distance of the crystal growth front vs. time is linear (black squares), and the crystal growth rate of GSF in the presence of PEO is independent of time. Based on Raman spectroscopic analysis, the concentration of PEO in the phase-separated layer at the growth front is determined to be 70-80% w/w, which remains constant over time as the crystal grows (Figure 9c).


Page 15 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 9. (a) Photomicrographs of crystal growth of GSF in the presence of 20% w/w PEO at 60 ℃. (b) growth distance vs time at 60 ℃. (c) the concentration of PEO in the phase-separated layer at the growth front vs time at 60 ℃.

Temperature-dependence. Figure 10a shows the crystallization of GSF containing 20 % w/w PEO at the temperature over the range from 50 to 80 ℃. At 50 ℃, the transparent phase-separated layer at the growth front (the PEO-rich phase) can be clearly observed by the optical microscope, with the width of 15-20 m. The width of the phase-separated layer at the crystal-liquid interface decreases with increasing the temperature (Figure 10b). At 80 ℃, the phase-separated layer at the growth front become quite thin and the width of the layer is estimated to be 7 m. The phase-separated layer at the crystal-liquid interface can no longer be observed at 90 ℃ or above (Figure 3). Although the dimension of the phase-separated layer at the growth front depends on temperature, the concentration of PEO in the enriched layer exhibits no significant difference over the temperature range of 50 to 80 ℃. The concentrations of PEO in the phase-separated layers at the growth front are found to be maintained at 70-80% w/w by Raman spectroscopy (Figure 10c). ACS Paragon Plus Environment


Page 16 of 29

Figure 10. Crystallization of GSF in the presence of 20% w/w PEO at 50, 60, 70 and 80 ℃ (a) crystal morphologies at the growth front, (b) the width of phase-separated layer and (c) the concentration of PEO in the phase-separated layer at the growth front as a function of temperature

Effect of PEO Bulk Concentration. Figure 11a shows the morphologies of GSF crystals grown in the presence of different amounts of PEO (10-40% w/w PEO) at 60 ℃. For the GSF containing 10% w/w PEO, the transparent PEO-rich layer at the growth front is quite thin, and the width of the layer is estimated to be 3-5 m. The phase separation at the growth front become easier to observe if the PEO loading is higher than 20% w/w. The images in Figure 11a show that the width of the PEO-rich layer at the growth front expands significantly with increasing the PEO loading in the bulk. In the presence of 40% w/w PEO, the width of PEO-rich layer at the growth front is estimated to be 30-50 m (Figure 11b). Meanwhile, with increasing the PEO loading in the solid dispersions, the morphology of crystals at the growth front becomes more dendritic than spherulitic with many unfilled spaces at the frontier (Figure 11a). It can be observed that some PEO enriched amorphous phases at the growth front are compassed by ACS Paragon Plus Environment

Page 17 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


the fast-growing crystals and subsequently trapped into the GSF polycrystalline domains. Surprisingly, the concentrations of PEO in the phase-separated layers exhibit no significant difference between the amorphous solid dispersions containing PEO over a range of 20-40% w/w (Figure 11c). Note that the concentration of PEO in the phase-separated layer of the sample with 10% w/w PEO loading is difficult to determine due to the limitation of spatial resolution of confocal Raman spectroscopy.

Figure 11. Crystallization of GSF in the samples with different bulk concentrations of PEO at 60 ℃ (a) crystal morphologies at the growth front, (b) the width of phase-separated layer and (c) the concentration of PEO in the phase-separated layer at the growth front as a function of PEO bulk concentration.

DISCUSSION PEO, one of the semi crystalline carriers, has been widely applied in pharmaceutical formulations for its good water solubility, plasticizing effect, and mucoadhesive properties etc.18,35-39 For example, PEO is often used as the hydrophilic carrier to enhance the solubility and dissolution rate of poorly water-soluble drugs.38,40 PEO has been reported to decrease the physical stability of amorphous solid ACS Paragon Plus Environment


Page 18 of 29

dispersions by accelerating crystal growth of drugs.9-11,18 In our previous study, the addition of 3% w/w PEO could significantly increase the crystal growth rates of GSF in either a supercooled liquid or glassy state. From a liquid dynamic perspective, the overlapping of the -relaxation times for systems with and without 3 % w/w PEO as a function of Tg/T indicates the “plasticization” effect of PEO in the amorphous solid dispersions.10 However, the crystallization rates of GSF in the presence or absence of PEO could not be overlapped as a function of Tg/T, suggesting that the global mobility is not sufficient to explain the impact of PEO on crystallization kinetics.10 In this work, we further study the crystallization behavior of amorphous GSF containing higher concentration PEO. At a given temperature, the crystal growth rate of GSF increased initially with increasing the PEO content until reaching a plateau above 10% w/w PEO in the bulk. However, the Tg of GSF/PEO dispersion was reduced continuously with increasing PEO loading up to 40% w/w. Therefore, the change of Tg and global mobility of the amorphous solid dispersion are insufficient to explain the effects of polymers on crystallization kinetics of drugs. The microstructure at the crystal-liquid interface is relevant to interpret the crystallization kinetics of GSF in the presence of PEO and will be discussed in further detail below.

Enrichment of PEO at the Crystal Growth Front. Yu and coworkers proposed that polymers could be enriched at the crystal growth front during the melt crystallization of amorphous solid dispersions, given that polymers are expected to be rejected by the growing crystal.9 The segmental mobility of polymer plays an important role in crystal growth since the drug molecules need migrate through the polymer-enriched region to reach the crystal surface.9 Zhang et al. suspected that the adsorbed polymer onto the crystal surface lead to an apparent change in the crystal-liquid interfacial free energy and influence the free energy barrier of crystallization.41 ACS Paragon Plus Environment

Page 19 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


In the present work, a transparent phase-separated layer can be directly observed at the crystal growth front of GSF containing high-concentration PEO. Confocal Raman microscopy and SEM-EDS study reveal that PEO is phase-separated and enriched in that layer at the crystal-liquid interface. These results provide the strong evidence that polymers are kept being rejected from the crystalline phase and built up near the crystal-liquid interface during the process of melt crystallization. A similar observation was reported for freezing the poly (vinyl alcohol) (PVA)-water system.42 Under freezing, the PVA-rich solution phases were segregated around the growing ice crystals to form the continuous porous gel skeleton.42 At a given temperature, the crystal growth rate of a drug in the presence of a polymer usually keeps constant over time.8,15,41 Since the polymers are continually pushed out of the crystalline region, there is strong consensus that the polymer concentration near the growing crystal front must be maintained throughout the growth process in order to ensure a constant growth rate. In the study of crystallization kinetics of felodipine in the presence of poly (vinylpyrrolidone) (PVP), Taylor and coworkers conducted a diffusion model and XRD experiments to support the view that polymers remained in the separated crystalline domain without affecting the crystalline lattice of felodipine.15 In this case, the growth distance of GSF crystals is linear as a function of time in the presence of 20% w/w PEO at 60 ℃. The concentration of PEO in the phase-separated layer is found to be maintained at 70-80% w/w over the measurement time scale. More importantly, with the aid of hot stage-polarized light microscope and confocal Raman microscopy, we demonstrate the entrapment of PEO inside the GSF crystalline phase during the process of melt crystallization (Figure 6). As GSF crystals keep advancing into liquid, it can be observed that some voids are created at the growth front. Due to the fast crystallization rate, some of the rejected PEO are trapped by the growing GSF crystals into those voids so that the bulk concentration of PEO and crystallization rate can be maintained throughout the progress of crystallization. These results further support the viewpoint that ACS Paragon Plus Environment


Page 20 of 29

some excess polymers are encaged into the crystalline phase rather than being incorporated into the crystalline lattice of drug molecules during the crystallization.

The Dependence of PEO Enrichment on Temperature and Composition of Solid Dispersion. It is noteworthy that the local phase separation at the crystal growth front can be observed at the temperature range from 50 to 80 ℃ for samples containing a higher amount of PEO. The PEO-rich layer at the growth front becomes invisible at 90 ℃ under an optical microscope. We hypothesize that at low temperatures (50-80 ℃), the rejected PEO molecules diffuse slowly and accumulate at the crystal growth front, leading to the local development of phase separation. While at a higher temperature, the fast-diffusing PEO molecules in the polymer-rich layer are assumed to be in rapid equilibrium with the bulk so that the phase separation at the crystal-liquid interface would become difficult to observe. The hypothesis is further supported by the observation that the dimension of the PEO-rich layer at the crystal growth front decreases with increasing the temperature. The concentration of PEO in the polymer-rich phase at the crystal-liquid interface decreases slightly from 50 to 80 ℃, which could be interpreted by the enhanced solubility of GSF in PEO at elevated temperatures. The polymer loading in a solid dispersion is often the one of the most important factors influencing the crystallization of an amorphous drug.8-11,15,16 In this study, if the bulk concentration of PEO is at or above 10% w/w, the phase separation at the crystal-liquid interface is easy to be observed at 60 ℃ (Figure 11a). Meanwhile, the width of the phase separated layer at the growth front expands with increasing the bulk concentration of PEO. It is easy to imagine that with increasing concentration of PEO in the bulk, more PEO will be rejected by the growing crystals, resulting in more PEO accumulated at the crystal growth front. On the other hand, if the concentration of PEO in the bulk is decreased, less PEO will be rejected during the crystallization and hence the PEO-rich ACS Paragon Plus Environment

Page 21 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


layer at the growth front would become narrower. However, if the bulk concentration of PEO is below 10% w/w, the PEO-rich layer at the growth front is too thin to be observed under the optical microscope. In addition, if the bulk concentration of PEO is at or above 50% w/w, the differences between the concentration of PEO in the polymer-rich layer and the bulk are expected to be very small, and therefore the phase separation at the crystal-liquid interface may not be obvious to detect (data not shown). According to the quantitative analysis by Raman spectroscopy, the concentrations of PEO in the phase-separated layers at the growth front were determined to be 70 to 80% w/w at 60 ℃, exhibiting no significant difference for the solid dispersions containing 20 to 40% w/w PEO (Figure 11c). We believe the concentration of PEO in the enriched phase at the growth front is governed by the phase diagram and solubility curve of the drug-polymer system.43-45 At 60 ℃, the solid dispersions containing 20 to 40% w/w PEO should be well above the solubility of GSF in PEO. Therefore, the excess of GSF will tend to crystallize and the liquid phase will approach to the solubility equilibrium at this temperature. Theoretically, for a supersaturated drug–polymer system, at the equilibrium state, the composition of drug and polymer in the liquid phase is determined by the solubility at a certain temperature.46,47 It is noteworthy that the concentration of PEO in the phase separated layer at the growth front at 60 ℃ is lower than the value estimated by the solubility measurements (Figure 2). We suspect that the PEO enriched liquid phase occurring at the crystal-liquid interface is still a non-equilibrium phase, which are likely results of the interplay between thermodynamic and kinetic factors including crystallization rate, viscosity as well as diffusivities of drug and polymer.44,46,47

Effect of PEO Enrichment at the Crystal-liquid Interface on Crystallization Kinetics of GSF. The enrichment of an impurity at the crystal-liquid interface has been reported to significantly alter the rates of crystal growth. In the crystallization of a polymer blend composed of poly ACS Paragon Plus Environment


Page 22 of 29

(ϵ-caprolactone) (PCL) and polystyrene (PS), the noncrystalline PS was segregated to the outside of PCL spherulites, forming the droplets of the PS-rich phase at the growth front.48 The crystallization kinetics of PCL was affected by the increased concentration of PS and reduced degree of undercooling at the crystal-liquid interface.48 It has been also proposed that polymers adsorbed on the solid-liquid interface can reduce crystal growth rates of drugs and prolong supersaturation.49-52 For instance, the AFM characterization revealed that the adsorption of hydroxypropyl methylcellulose acetate succinate (HPMCAS) on the surfaces of polycrystalline felodipine could poison the surface and cause step pinning, thus inhibiting the crystal growth in supersaturated solutions.53 Previous studies have shown that the addition of 1% or 3% w/w PEO could significantly speed up the crystallization rates of amorphous pharmaceuticals due to the high segmental mobility of PEO relative to the host-molecule dynamics.9-11,18 In this case, for a given temperature, the crystal growth rates of GSF increase with increasing the PEO content up to 10% w/w. However, the accelerating effect of PEO on crystal growth of GSF saturates above 10% w/w PEO in the bulk (Figure 4). We propose that the crystal growth kinetics of GSF doped with different amounts of PEO is predominantly controlled by the local concentration of PEO at the growth front. As illustrated in Figure 12, for a system containing low-concentration PEO (e.g., 1-10% w/w), the local concentration of PEO at the crystal growth front is expected to increase if the PEO content in the bulk is increased, because more PEO are supposed to be rejected and enriched at the growth front. Consequently, the increased concentration of PEO at the crystal-liquid interface will lead to the enhanced local molecular mobility and faster crystallization rates of GSF. However, when the bulk concentration of PEO is increased from 10 to 40% w/w, the area of PEO-rich phase at the growth front keeps expanding while the local concentration of PEO at the interfacial region remains unchanged, as evidenced by Raman spectroscopic analysis (Figure 11). It is conceivable that the local molecular mobility of GSF and hence the crystallization rate would correlate with the amount ACS Paragon Plus Environment

Page 23 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


of PEO present at the crystal growth front. Since the concentration of PEO at the crystal growth front remains almost unchanged for the samples with high PEO loadings, it provides an explanation why the crystal growth rates of GSF reach a plateau when the bulk concentration of PEO is increased from 10% to 40% w/w.

Figure 12 ． Schematic illustration of impact of PEO enrichment at the crystal growth front on crystallization kinetics of GSF.

CONCLUSION In summary, this study investigated the crystallization kinetics of amorphous solid dispersion of GSF containing different amounts of PEO. The crystal growth rates of GSF were significantly accelerated in the presence of PEO. However, at a given temperature, the crystal growth rates of GSF increase initially with increasing the PEO loading but the accelerating effect by PEO saturates when the PEO bulk content is above 10% w/w. Remarkably, we observed the enrichment of PEO at the crystal-liquid interface during the crystallization, which was further carefully characterized by confocal Raman microscopy and SEM-EDS. The local concentration of PEO at the growth front remains unchanged, as evidenced by Raman spectroscopic analysis. These findings strongly support ACS Paragon Plus Environment


Page 24 of 29

the proposed mechanism that the crystal growth kinetics of GSF in the presence of PEO is predominantly controlled by the local concentration of polymer at the crystal-liquid interface instead of the over bulk concentration. This study provides the direct evidence of phase separation occurred at the crystal-liquid interfacial region during the crystallization process of amorphous solid dispersions, which would be also beneficial for predicting their physical stability.

AUTHOR INFORMATION Corresponding Author *Department of Pharmaceutics, College of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Tel: 86-025-83271123. E-mail: [email protected]. ORCID Ting Cai: 0000-0001-7510-9295 Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS The authors are grateful for financial support of this work by the National Science Foundation of China (Nos.81872813, 81803452), the State Project for Essential Drug Research and Development (No.2017ZX09301075), the Program of State Key Laboratory of Natural Medicines-China Pharmaceutical University (No. SKLNMZZCX201826), the Graduate Innovative Research Project of Jiangsu Province (KYCX18_0757), and the 111 project (B16046). We also thank Prof. Lian Yu (School of Pharmacy, University of Wisconsin- Madison) for helpful discussions.

REFERENCES (1) Yu, L. Amorphous Pharmaceutical Solids: Preparation, Characterization and Stabilization. A Adv. Drug Deliv. Rev .2001, 48, 27-42. (2) Jermain, S. V.; Brough, C.; Williams, R. O. Amorphous Solid Dispersions and Nanocrystal Technologies for ACS Paragon Plus Environment

Page 25 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Poorly Water-soluble Drug Delivery - An Update. Int.J. Pharm. 2018, 535, 379-392. (3) Bhugra, C.; Pikal, M. J. Role of Thermodynamic, Molecular, and Kinetic Factors in Crystallization from the Amorphous State. J. Pharm. Sci. 2008, 97, 1329-4139. (4) Priemel, P. A.; Grohganz, H.; Rades, T. Unintended and in Situ Amorphisation of Pharmaceuticals. Adv. Drug Deliv. Rev .2016, 100, 126-132. (5) Descamps, M.; Willart, J. F. Perspectives on the Amorphisation/Milling Relationship in Pharmaceutical Materials. Adv. Drug Deliv. Rev. 2016, 100, 51-66. (6) Qi, S.; Craig, D. Recent Developments in Micro- and Nanofabrication Techniques for the Preparation of Amorphous Pharmaceutical Dosage Forms. Adv. Drug Deliv. Rev .2016, 100, 67-84. (7) Newman, A. Pharmaceutical Amorphous Solid Dispersions; Narayan, P.; Porter, W.W.; Brackhagen, M.; Tucker, C.; John Wiley & Sons, Inc.: New Jersey , 2015; pp 42-85. (8) Cai, T.; Zhu, L.; Yu, L. Crystallization of Organic Glasses: Effects of Polymer Additives on Bulk and Surface Crystal Growth in Amorphous Nifedipine. Pharm. Res. 2011, 28, 2458-2466. (9) Huang, C.; Powell, C. T.; Sun, Y.; Cai, T.; Yu, L. Effect of Low-Concentration Polymers on Crystal Growth in Molecular Glasses: A Controlling Role for Polymer Segmental Mobility Relative to Host Dynamics. J. Phys. Chem. B 2017, 121, 1963-1971. (10) Shi, Q.; Zhang, C.; Su, Y.; Zhang, J.; Zhou, D.; Cai, T. Acceleration of Crystal Growth of Amorphous Griseofulvin by Low-Concentration Poly (ethylene oxide): Aspects of Crystallization Kinetics and Molecular Mobility. Mol. Pharmaceutics 2017, 14, 2262-2272. (11) Powell, C. T.; Cai, T.; Hasebe, M.; Gunn, E. M.; Gao, P.; Zhang, G.; Gong, Y.; Yu, L. Low-Concentration Polymers Inhibit and Accelerate Crystal Growth in Organic Glasses in Correlation with Segmental Mobility. J. Phys. Chem. B 2013, 117, 10334-10341. (12) Van den Mooter, G.; Wuyts, M.; Blaton, N.; Busson, R.; Grobet, P.; Augustijns, P.; Kinget, R. Physical Stabilisation of Amorphous Ketoconazole in Solid Dispersions with Polyvinylpyrrolidone K25. Eur. J.Pharm. Sci .2001, 12, 261-269. (13) Crowley, K.J.; Zografi, G. The Effect of Low Concentrations of Molecularly Dispersed Poly(vinylpyrrolidone) on Indomethacin Crystallization from the Amorphous State. Pharm. Res. 2003, 20, 1417-1422. (14) Christian, P.; Ehmann, H. M.; Coclite, A. M.; Werzer, O. Polymer Encapsulation of an Amorphous Pharmaceutical by initiated Chemical Vapor Deposition for Enhanced Stability. ACS Appl. Mater. Interfaces 2016, 8, 21177-21184. (15) Kestur, U. S.; Lee, H.; Santiago, D.; Rinaldi, C.; Won, Y.-Y.; Taylor, L. S. Effects of the Molecular Weight and Concentration of Polymer Additives, and Temperature on the Melt Crystallization Kinetics of a Small Drug Molecule. Cryst. Growth Des. 2010, 10, 3585-3595. ACS Paragon Plus Environment


Page 26 of 29

(16) Trasi, N. S.; Taylor, L. S. Effect of Polymers on Nucleation and Crystal Growth of Amorphous Acetaminophen. CrystEngComm 2012, 14, 5188-5197. (17) Van den Mooter, G.; Wuyts, M.; Blaton, N.; Busson, R.; Grobet, P.; Augustijns, P.; Kinget, R. Physical Stabilisation of Amorphous Ketoconazole in Solid Dispersions with Polyvinylpyrrolidone K25. Eur. J.Pharm. Sci .2001, 12, 261-269. (18) Shi, Q.; Zhang, J.; Zhang, C.; Jiang, J.; Tao, J.; Zhou, D.; Cai, T. Selective Acceleration of Crystal Growth of Indomethacin Polymorphs by Low-Concentration Poly (ethylene oxide). Mol.Pharmaceutics 2017, 14, 4694-4704. (19) Saboo, S.; Taylor, L. S. Water-induced Phase Separation of Miconazole-poly (vinylpyrrolidone-co-vinyl acetate) Amorphous Solid Dispersions: Insights with Confocal Fluorescence Microscopy. Int. J.Pharm. 2017, 529, 654-666. (20) Yang, Z.; Nollenberger, K.; Albers, J.; Craig, D.; Qi, S. Microstructure of an Immiscible Polymer Blend and Its Stabilization Effect on Amorphous Solid Dispersions. Mol. Pharmaceutics 2013, 10, 2767-80. (21) Qian, F.; Huang, J.; Zhu, Q.; Haddadin, R.; Gawel, J.; Garmise, R.; Hussain, M. Is a Distinctive Single Tg a Reliable Indicator for the Homogeneity of Amorphous Solid Dispersion? Int. J. Pharm. 2010, 395, 232-235. (22) Turner, Y. T. A.; Roberts, C. J.; Davies, M. C. Scanning probe microscopy in the field of drug delivery. Adv. Drug Delivery Rev. 2007, 59, 1453−1473. (23) Dai, X.; Moffat, J. G.; Wood, J.; Reading, M. Thermal scanning probe microscopy in the development of pharmaceuticals. Adv. Drug Delivery Rev. 2012, 64 (5), 449−460. (24) Qi, S.; Moffat, J. G.; Yang, Z. Early Stage Phase Separation in Pharmaceutical Solid Dispersion Thin Films under High Humidity: Improved Spatial Understanding Using Probe-based Thermal and Spectroscopic Nanocharacterization Methods. Mol. Pharmaceutics 2013, 10, 918-930. (25) Li, N.; Gilpin, C. J.; Taylor, L. S. Understanding the Impact of Water on the Miscibility and Microstructure of Amorphous Solid Dispersions: An AFM-LCR and TEM-EDX Study. Mol. Pharmaceutics 2017, 14, 1691-1705. (26) Baird, J. A.; Taylor, L. S. Evaluation and Modeling of the Eutectic Composition of Various Drug-polyethylene Glycol Solid Dispersions. Pharm. Dev.Technol. 2011, 16, 201-211. (27) Okumura, T.; Otsuka, M. Evaluation of the Microcrystallinity of a Drug Substance, Indomethacin, in a Pharmaceutical Model Tablet by Chemometric FT-Raman Spectroscopy. Pharm. Res.2005, 22, 1350-1357. (28) Saerens, L.; Dierickx, L.; Lenain, B.; Vervaet, C.; Remon, J. P.; De Beer, T. Raman Spectroscopy for the in-line Polymer-drug Quantification and Solid State Characterization during a Pharmaceutical Hot-melt Extrusion Process. Eur. J. Pharm.Biopharm. 2011, 77, 158-163. (29) Law, D.; Wang, W.; Schmitt, E.A.; Long, M. A. Prediction of Poly (Ethylene) Glycol-Drug Eutectic Compositions Using an Index Based on the Van’t Hoff Equation. Pharm. Res.2002, 19, 315-321. (30) Shi, Q.; Cai, T. Fast Crystal Growth of Amorphous Griseofulvin: Relations between Bulk and Surface Growth ACS Paragon Plus Environment

Page 27 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Modes. Cryst. Growth Des. 2016, 16, 3279-3286. (31) Powell, C. T.; Xi, H.; Sun, Y.; Gunn, E.; Chen, Y.; Ediger, M. D.; Yu, L. Fast Crystal Growth in o-Terphenyl Glasses: A Possible Role for Fracture and Surface Mobility. J. Phys. Chem. B 2015, 119, 10124-1130. (32) Zhong, Z.; Guo, C.; Chen, L.; Xu, J.; Huang, Y. Co-crystal Formation between Poly (ethylene glycol) and a Small Molecular Drug Griseofulvin. Chem. Commun. 2014, 50, 6375-6378. (33) Li, S.; Yu, T.; Tian, Y.; McCoy, C. P.; Jones, D. S.; Andrews, G. P. Mechanochemical Synthesis of Pharmaceutical Cocrystal Suspensions via Hot Melt Extrusion: Feasibility Studies and Physicochemical Characterization. Mol. Pharmaceutics 2016, 13, 3054-3068. (34) Tran, H. T. T.; Park, J. B.; Hong, K.-H.; Choi, H.-G.; Han, H.-K.; Lee, J.; Oh, K. T.; Lee, B.-J. Preparation and Characterization of pH-independent Sustained Release Tablet Containing Solid Dispersion Granules of a Poorly Water-soluble Drug. Int. J. Pharm. 2011, 415, 83-88. (35) Duong, T. V.; Van den Mooter, G. The Role of the Carrier in the Formulation of Pharmaceutical Solid Dispersions. Part I: Crystalline and Semi-crystalline Carriers. Expert. Opin. Drug. Deliv.2016, 13, 1583-1594. (36) Urbanova, M.; Gajdosova, M.; Steinhart, M.; Vetchy, D.; Brus, J. Molecular-Level Control of Ciclopirox Olamine Release from Poly (ethylene oxide)-Based Mucoadhesive Buccal Films: Exploration of Structure– Property Relationships with Solid-State NMR. Mol. Pharmaceutics 2016, 13, 1551-1563. (37) Alhijjaj, M.; Bouman, J.; Wellner, N.; Belton, P.; Qi, S. Creating Drug Solubilization Compartments via Phase Separation in Multicomponent Buccal Patches Prepared by Direct Hot Melt Extrusion–Injection Molding. Mol. Pharmaceutics 2015, 12, 4349-4362. (38) Law, D.; Wang, W, Schmitt E. A.; Qiu, Y.; Krill, S. L.; Fort, J.J.

Properties of Rapidly Dissolving Eutectic

Mixtures of Poly (ethylene glycol) and Fenofibrate: The Eutectic Microstructure. J.Pharm. Sci. 2003, 92, 505-515. (39) Duong, T. V.; 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, 1037-1051. (40) Broman, E.; Khoo, C.; Taylor, L.S. A Comparison of Alternative Polymer Excipients and Processing Methods for Making Solid Dispersions of a Poorly Water Soluble Drug. Int. J. Pharm. 2001, 222, 139-151. (41) Zhang, S.; Britten, J. F.; Chow, A.; Lee, T. W. Y. Impact of Crystal Structure and Polymer Excipients on the Melt Crystallization Kinetics of Itraconazole Polymorphs. Cryst. Growth Des. 2017, 17, 3433-3442. (42) Yokoyama, F.; Shimamura, I.; Ikawa, T.; Monobe, K. Morphology and Structure of Highly Elastic Poly (vinyl alcohol) Hydrogel Prepared by Repeated Freezing-and-melting. Colloid Polym. Sci. 1986, 264, 595-601. (43) Zhao, Y.; Inbar, P.; Chokshi, H. P.; Malick, A. W.; Choi, D. S. Prediction of the Thermal Phase Diagram of Amorphous Solid Dispersions by Flory-Huggins Theory. J.Pharm. Sci.2011, 100, 3196-3207. (44) Sun, Y.; Tao, J.; Zhang, G. G.; Yu, L. Solubilities of Crystalline Drugs in Polymers: An Improved Analytical ACS Paragon Plus Environment


Page 28 of 29

Method and Comparison of Solubilities of Indomethacin and Nifedipine in PVP, PVP/VA, and PVAc. J.Pharm. Sci.2010, 99, 4023-4031. (45) Duong, T. V.; Van Humbeeck, J.; Van den Mooter, G. Crystallization Kinetics of Indomethacin/Polyethylene Glycol Dispersions Containing High Drug Loadings.Mol. Pharmaceutics 2015, 12, 2493-2504. (46) Mahieu, A.; Willart, J.-F.; Dudognon, E.; Danède, F.; Descamps, Marc. A New Protocol to Determine the Solubility of Drugs into Polymer Matrixes. Mol. Pharmaceutics 2012, 10, 560-566. (47) Knopp, M. M.; Tajber, L.; Tian, Y.; Olesen, N. E.; Jones, D. S.; Kozyra, A.; Lobmann, K.; Paluch, K.; Brennan, C. M.; Holm, R.; Healy, A. M.; Andrews, G. P.; Rades, T. Comparative Study of Different Methods for the Prediction of Drug-Polymer Solubility. Mol. Pharmaceutics 2015, 12, 3408-3419. (48) Tanaka, H.; Nishi, T. New Types of Phase Separation Behavior During the Crystallization Process in Polymer Blends with Phase Diagram. Phys. Rev. Lett. 1985, 55, 1102-1105. (49) Schram, C. J.; Smyth, R. J.; Taylor, L. S.; Beaudoin, S. P. Understanding Crystal Growth Kinetics in the Absence and Presence of a Polymer Using a Rotating Disk Apparatus. Cryst. Growth Des.2016, 16, 2640-2645. (49) Ilevbare, G. A.; Liu, H.; Edgar, K. J.; Taylor, L. S. Maintaining Supersaturation in Aqueous Drug Solutions: Impact of Different Polymers on Induction Times. Cryst. Growth Des.2013, 13, 740-751. (51) Ilevbare, G. A.; Liu, H.; Edgar, K. J.; Taylor, L. S. Understanding Polymer Properties Important for Crystal Growth Inhibition- Impact of Chemically Diverse Polymers on Solution Crystal Growth of Ritonavir.Cryst. Growth Des. 2012, 12, 3133-3143. (52) Ilevbare, G. A.; Liu, H.; Edgar, K. J.; Taylor, L. S. Inhibition of Solution Crystal Growth of Ritonavir by Cellulose Polymers - factors Influencing Polymer Effectiveness. CrystEngComm 2012, 14, 6503-6514. (53) Schram, C. J.; Beaudoin, S. P.; Taylor, L. S. Polymer Inhibition of Crystal Growth by Surface Poisoning. Cryst. Growth Des. 2016, 16,2094-2103.


Page 29 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table of Content

Impact of Polymer Enrichment at the Crystal-Liquid Interface on Crystallization Kinetics of Amorphous Solid Dispersions Jie Zhang†, Qin Shi†, Jun Tao†, Yayun Peng†, Ting Cai*,†, †State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China


Impact of Polymer Enrichment at the CrystalâLiquid Interface on

Recommend Documents

Impact of Polymer Enrichment at the CrystalâLiquid Interface on