Effects of Moisture on the Growth Rate of Felodipine Crystals in the

Nov 12, 2009 - When HPMCAS was added at a 2.5% level (% dry wt), no significant difference was observed in the growth rates ..... Ford , J. L. Pharm...
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DOI: 10.1021/cg901157w

Effects of Moisture on the Growth Rate of Felodipine Crystals in the Presence and Absence of Polymers

2010, Vol. 10 747–753

Alfred C. F. Rumondor,†,‡ Matthew J. Jackson,† and Lynne S. Taylor*,† †

Department of Industrial and Physical Pharmacy, School of Pharmacy, Purdue University, West Lafayette, Indiana 47907 and ‡Pharmaceutical and Analytical Research and Development, AstraZeneca Pharmaceuticals LP, Wilmington, Delaware, 19850 Received September 21, 2009; Revised Manuscript Received October 27, 2009

ABSTRACT: The purpose of this study was to examine how moisture affects the growth rate of felodipine crystals from amorphous systems. Amorphous felodipine films with 0-10% w/w poly(vinylpyrrolidone) (PVP) or hypromellose acetate succinate (HPMCAS) were prepared by spin coating and stored at room temperature at different relative humidities (RHs). Linear growth rates were determined using optical microscopy. Crystals grown from felodipine alone had the fastest growth rate under all conditions. An approximately log-linear relationship between crystal growth rate and storage RH was observed between 13% and 80% RH. Above 80% RH, an abrupt 15-40-fold increase in growth rate occurred, producing crystals of a different morphology. Polymeric additives decreased crystal growth rates, more so with increasing polymer concentration. Growth rates from PVP-containing films increased with increasing storage RH, but thosefor HPMCAS systems did not. Below 52% RH, PVP was the better growth inhibitor; above 64% RH, HPMCAS inhibited crystal growth more effectively. At high RH, the dependence of crystal growth rate on PVP concentration was vastly reduced probably as a result of moisture-induced drug-polymer phase separation.Polymeric additives were thus found to inhibit the crystal growth rate of felodipine in the presence of moisture, with the extent of the inhibition dependent on a number of different factors.

Introduction Delivering a small-molecule active pharmaceutical ingredient (API) in the amorphous form is generally accepted as one strategy to improve its aqueous solubility, dissolution rate, and bioavailability. However, to effectively use this approach, conversion of the drug to the thermodynamically more stable crystalline form(s) over pharmaceutically relevant time scales must be prevented. One way to achieve this is through the addition of a crystallization inhibitor, typically a polymer. The resulting intimately mixed amorphous matrix is commonly referred to as an amorphous solid dispersion.1-4 Physical stabilization of the amorphous API by the polymeric component has been attributed to different factors, including decreased molecular mobility, a reduction in the thermodynamic force for crystallization, and disruption of the molecular recognition events necessary for crystallization to occur.5,6 Despite their ability to retard drug crystallization, many of the polymers used in pharmaceutical solid dispersions are hygroscopic in nature. As a result, amorphous solid dispersions containing a hydrophobic drug would absorb larger amounts of moisture compared with the pure amorphous drug.7,8 In general, absorption of water by amorphous pharmaceutical systems promotes crystallization of the drug, for example, as reported by Andronis et al. for amorphous indomethacin9,10 and by Shamblin and Zografi for sucrosepoly(vinylpyrrolidone) (PVP) and sucrose-poly(vinylpyrrolidone -co-vinyl acetate) (PVP/VA) solid dispersions.11 Since crystallization is generally considered to occur through two underlying subprocesses (i.e., crystal nucleation and growth), a complete understanding of the effects of polymers in inhibiting

the overall crystallization rate of an API in the presence of moisture cannot be achieved without separately studying these subprocesses. Although the effects of polymers and sorbed moisture on the nucleation rate of felodipine from amorphous dispersions has been investigated, corresponding studies on crystal growth rates have not been undertaken.12 The goal of this study was to address this knowledge gap. Felodipine was used as the model drug, while two polymers with differing hygroscopicity and chemistry were chosen as the model polymers, namely, poly(vinylpyrrolidone) (PVP) and hypromellose acetate succinate (HPMCAS). Experimental Section

*Corresponding author. E-mail: [email protected]. Tel: þ1-765-4966614. Fax: þ1-765-494-6545.

Materials. Dichloromethane (ChromAR grade) and ethanol (200 proof) were obtained from Mallinckrodt Baker, Inc., Paris, KY, and PHARMCO-AAPER, Brookfield, CT, respectively. Felodipine was a generous gift from AstraZeneca, S€ odert€ alje, Sweden. Poly(vinyl pyrrolidone) PVP K29-32 was purchased from SigmaAldrich Co., St. Louis, MO, and hypromellose acetate succinate (HPMCAS AQOAT AS-MF) was obtained from ShinEtsu Chemical Co., Niigata, Japan. Growth Rate Measurements of Felodipine Crystals Grown from Pure Amorphous Drug Films. Thin film samples of amorphous felodipine were produced by first dissolving the drug in a 1:1 (weight basis) mixture of ethanol and dichloromethane. One to two drops of the solution were placed on a microscope slide, which was rotated on a KW-4A two-stage spin coater (Chemat Technology, Northridge, CA) at 500 and 1000 rpm for 18 and 30 s, respectively. The slide was then transferred onto a hot plate set to 90 °C. This heating step was performed to remove residual solvents and to allow felodipine crystals to nucleate and grow to a detectable size. As soon as spherulitic crystals began to appear, the slides were removed from the hot plate and stored in a controlled humidity microscope stage (Surface Measurement Systems, Ltd., Alperton, Middlesex, U.K.) set to 25 °C and different relative humidities (RHs). The humidity accessory was then placed on the stage of a Nikon Eclipse E600POL microscope (Nikon Instruments Inc.,

r 2009 American Chemical Society

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Figure 1. Growth rate of felodipine crystals at 25 °C, plotted as a function of storage relative humidity (n = 3). Seven crystals were grown at 86% RH; five crystals grew as tight spherulites (see Figure 2a) at lower rates (gray diamond), while two crystals grew as needles (see Figure 2b) at higher rates (black diamond).

Figure 2. Photomicrographs of felodipine spherulitic crystals grown at (a) 75% and (b) 93% RH. Size indicators are 0.1 mm. Melville, NY). Periodically, digital images were obtained using a CoolSNAPcf digital camera (Photometrics, Tucson, AZ, USA) controlled with MetaVue software, version 6.1r6 (Universal Imaging Corp., Ardmore, PA). The diameter of the drug crystals was determined from acquired photomicrographs either through direct comparison against microruler standards or by measuring the area of the circular spherulitic crystals using ImageJ software (v 1.37, National Institute of Health, Bethesda, MD). The growth rate, reported as millimeters per minute, was calculated as the change in crystal radius as a function of time. At least four time points were collected for each crystal, and the growth rates reported are average values from three or more crystals from different samples. Growth Rate Measurements of Crystals Grown from Amorphous Solid Dispersion Films. Thin film samples of solid dispersions of felodipine and the model polymers were prepared using the spin coating technique described above, and spherulitic crystals were again nucleated by heating at 90 °C. Subsequently, the slides were removed from the hot plate and placed in airtight plastic sample holders prepared in-house. The sample holders were then filled with saturated salt solutions, sealed from external atmosphere, and stored at room temperature. Seven different salts were used to control RH: LiCl (13% RH), MgCl2 (33%RH), Mg(NO3)2 (52% RH), CoCl2 (64% RH), NaCl (75% RH), KCl (86% RH), and KNO3 (93% RH).13,14 Periodically, photomicrographs of the samples were obtained without removing the samples from the sample holders, and the growth rates of the crystals were calculated as described above. Raman Spectroscopy. Raman microscopy for select samples was performed using a Renishaw Ramascope Raman microscope system (Renishaw Plc., New Mills, Gloucestershire, U.K.) equipped

with a Leica microscope and a 783 nm diode laser source. Spectra were acquired using 60 s exposure time, with an average of three spectra over the wavenumber range of 2000-750 cm-1, using a 50 objective, and laser power of ∼21 mW. Raman spectra of pure crystalline and amorphous felodipine were collected using a Perkin-Elmer FT System 2000 spectrometer (PerkinElmer Life and Analytical Sciences, Inc., Waltham, MA) equipped with a 1064 nm Nd:YAG laser operating with a power of 1000 mW. For these measurements, glass vials containing the powder form of the samples were placed in the laser path. To produce spectra with desirable signal-to-noise ratio, 128 or more spectra were accumulated at a 1.0 cm-1 intervals with spectral resolution of 4 cm-1. In order to increase the sampling volume and reduce the risk of sample heating, the glass vials were rotated using an electric motor during the measurements.

Results Growth Rate of Felodipine Crystals from Amorphous Drug Thin Films. The growth rates of felodipine crystals at 25 °C are plotted in Figure 1 as a function of storage RH, while select photomicrographs of the crystals are shown in Figure 2. In general, it can be observed that crystal growth rates increased as the storage RH was increased. Over the RH range 13-80%, the crystal growth rate was found to increase approximately 2-fold. Interestingly, when the RH was further increased to 87%, a 40-fold increase in growth rate was observed. This sudden increase in growth rate was accompanied by a morphology change from spherulitic to

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Figure 3. Growth rate of felodipine crystals from films containing (black square) 2.5%, (gray square) 5%, and (white square) 10% (w/w) HPMCAS at room temperature, plotted as a function of storage relative humidity (RH). The growth rate of felodipine crystals from pure amorphous films (white diamond) are plotted in the same graph for comparison.

needle-like (see Figure 2a,b). To our knowledge, this is the first time such an abrupt increase in crystal growth rate as a function of storage RH is reported. Growth Rate of Felodipine Crystals from HPMCASContaining Films. The growth rates of felodipine crystals from HPMCAS-containing films at room temperature are plotted in Figure 3 as a function of storage RH. When HPMCAS was added at a 2.5% level (% dry wt), no significant difference was observed in the growth rates compared with crystals grown from pure amorphous felodipine up to a RH of 52%. Above this RH, the growth rate was lower in the presence of this polymer level compared with drug alone. Increasing the amount of polymer added resulted in a reduced crystal growth rate over the complete range of RH studied. Thus the growth rates of felodipine crystals from samples containing 10% polymer were found to be at least 1 order of magnitude lower than those from samples containing drug alone. However, no discernible trends were observed for any given polymer concentration with storage RH. In other words, the growth rates are remarkably insensitive to the storage RH. Similar results have also been observed for bulk crystallization rates of felodipine from HPMCAS-containing amorphous solid dispersions, albeit at higher polymer concentrations.8 The addition of HPMCAS at any level also suppressed the sudden increase in crystal growth rate at 86% RH and above that was observed for pure amorphous felodipine. Close examination of the photomicrographs showed that felodipine crystals grown from HPMCAS-containing films do not show smooth spherulitic-type crystals but instead show a disrupted spherulitic morphology with irregular boundaries. The disruption of crystal growth was especially obvious for samples containing higher levels of polymer (see Figure 4c,d). Growth Rate of Felodipine Crystals from PVP-Containing Films. The growth rates of felodipine crystals from PVPcontaining films at room temperature are plotted in Figure 5 as a function of storage RH. At 52% RH and below, the felodipine crystal growth rates are very dependent on the amount of polymer present: the higher the PVP content, the lower the growth rate of the felodipine crystals. For example,

at 13% RH, the growth rates of crystals from films containing 10% polymer are approximately 2 orders of magnitude lower than those from films containing 2.5% polymer. For any given PVP concentration, felodipine crystal growth rates increased with increasing storage RH. In addition, the sensitivity of the growth rates to storage RH depended on the polymer concentration, as evidenced by the steeper slope for samples containing 10% PVP compared with the slopes for samples containing 5% and 2.5% PVP. For all RH storage conditions except 86% RH, the presence of the polymer led to a slower crystal growth rates compared with the drug alone. When the samples were stored at 64% RH or higher, felodipine crystal growth rates from samples containing various PVP concentrations started to merge and showed a lower dependence on the polymer concentration. In addition, the growth rates of samples containing 2.5% and 5% PVP become more sensitive to increased RH, as shown by the increasing slope of the growth rate vs RH data. At 64% RH and below, felodipine crystals grown from PVP-containing films also showed disrupted spherulitic morphology, which resulted in the appearance of different spherulitic segments, particularly at the higher polymer concentrations studied (see Figure 6a,c). However, for samples stored at 75% RH and above, the overall circular shape of the spherulites appeared to be better maintained. Discussion Growth Rate of Felodipine Crystals from Pure Amorphous Films. In amorphous materials, water can be absorbed into the solid matrix in addition to being adsorbed at the interface.15,16 Due to its large free volume, the absorption of water by amorphous materials has been shown to increase molecular mobility in the system, for example, as indicated by a reduction in measured glass transition temperature (Tg). The plasticizing effects of water have been reported for indomethacin9,17 and its sodium salt,18 glucose, trehalose, and dextran,19 as well as for felodipine.20 Since crystal growth rate is dependent on molecular mobility, the absorption of water by amorphous felodipine is expected to result in

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Figure 4. Photomicrographs of felodipine crystals grown from films containing 2.5% (a,b) and 10% (c,d) (w/w) HPMCAS. Crystals in images a and c were grown at 32% RH, while crystals in images b and d were grown at 93% RH. Size indicators are 0.1 mm.

Figure 5. Growth rate of felodipine crystals from films containing (black square) 2.5%, (gray square) 5%, and (white square) 10% (w/w) PVP at room temperature, plotted as a function of storage relative humidity (RH). The growth rates of felodipine crystals from pure amorphous films (white diamond) are plotted in the same graph for comparison.

an increase in crystal growth rate. This trend was indeed observed for crystals grown from pure amorphous felodipine films, whereby the growth rate showed an approximately log-linear relationship with RH up to 80% (see Figure 1). Different models exist that try to describe molecular mobility in amorphous systems. One commonly employed model is the Adam-Gibbs-Vogel (AGV) model, which describes the mean molecular relaxation time of an amorphous material (τ) at any temperature (T) as 2 3 6 7 DT0 6 7  7 τ ¼ τ0 exp6 4 T0 5 T -T Tf

ð1Þ

In this equation, Tf is the fictive temperature, τ0 is a preexponential factor (assumed to be on the order of the lifetime of atomic vibrations, 10-14 s), T is the temperature in kelvin, and D and T0 are constants. For felodipine, the values of D, T0, and Tf have been reported as 9.2, 253.4 K, and 310 K.21 Using this equation and assuming that none of the parameters apart from Tg are altered upon exposure to moisture, one can calculate the molecular relaxation time of amorphous felodipine at any temperature, and then compare it with τΤg, the molecular relaxation time at Tg (reported as 317 K21). For amorphous felodipine stored at 0, 13%, 33%, 52%, 64%, and 75% RH, the Tg values have been reported as 317, 316, 314, 310, 308, and 306 K, respectively.20,21 By plotting the values of log (τTg/τ) against T/Tg, estimated changes of molecular

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Figure 6. Photomicrographs of felodipine crystals grown from films containing 2.5 (a,b) and 10% (c,d) (w/w) PVP. Crystals in images a and c were grown at 33% RH, while crystals in images b and d were grown at 93% RH. Size indicators are 0.1 mm.

mobility as a function of the “under-cooling” below the Tg of the material can be visualized. To investigate the correlations between molecular mobility (as indicated by molecular relaxation time) and crystal growth rate, these results are plotted in Figure 7, along with the growth rate of felodipine crystals from amorphous felodipine (shifted in y-axis so the values can be plotted on the same chart). It can be seen from Figure 7, that the change in the rate of crystal growth as a function of T/Tg follows a different trend from the changes observed for molecular mobility. The results show that crystal growth rate occurred faster below Tg than values predicted by molecular mobility as calculated from the AGV model. Similar results have been reported by others. For example, Aso et al. reported decoupling between molecular relaxation and crystallization rate of amorphous nifedipine22 (an exponential coupling constant, ξ, of 0.75 was thus needed to correlate molecular relaxation rate and crystallization rate), while Zhou et al. observed the same trend with griseofulvin.23 Performing the same type of analysis using data collected in this study found that good correlation between molecular relaxation rate and crystal growth rate was obtained using a coupling constant of 0.5. Possible explanations for the faster crystal growth rate with a change in T/Tg compared with the molecular mobility could include a decoupling between drug diffusion and viscosity, as reported for a number of compounds,24,25 or the fact that the growth rate studies were performed on thin uncovered films and likely reflect the growth rate of crystals at the surface. Several studies have shown that crystal growth rates at the surface are much faster than those in the bulk,26-28 and thus it may not be reasonable to attempt to correlate estimates of bulk mobility, that is, those derived from Tg measurements, with surface growth. However, since crystallization likely occurs first at the surface, the sample preparation employed in this study is highly relevant. When the thin amorphous felodipine samples were stored above 80% RH, an abrupt increase in the crystal growth rate

Figure 7. Rate of crystal growth as a function of T/Tg is plotted together with molecular mobility of the systems as predicted by the AGV model.

was observed. However, no discontinuity in either the amount of water sorbed or Tg as a function of RH has been observed around this RH (Figure 8).12,29 In addition, following equilibration at 93% RH, the calorimetric Tg of amorphous felodipine was measured as 30 °C, which is still above the temperature range of the experiment (22-25 °C). Both the abrupt nature of the transition in the growth rate trends for samples stored between 80% and 93% RH and the observed change in the morphology of the crystals suggest a fundamental change in the mechanism of crystal growth at high RH. The reason for the abrupt increase in crystal growth rates at high RH is currently unknown. Evaluation of crystals of differing morphology grown at 75% RH and 90% RH using Raman microscopy revealed no spectroscopic differences (Figure 9), suggesting that the same crystal phase is being grown at both RHs.

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Figure 8. (a) Amount of moisture sorbed and (b) Tg of amorphous felodipine plotted as a function of storage RH. Data reproduced from refs 12 and 29.

Figure 9. Raman spectra of (top to bottom) amorphous felodipine, crystalline felodipine, spherulitic crystal nucleated from amorphous felodipine on a microscope slide, and needle-like crystal grown following storage at 93% RH. Height differences due to preferred orientation was observed; however no shifts in peak locations were detected.

Growth Rate of Felodipine Crystals from HPMCASContaining Solid Dispersion Films. The reduction in felodipine crystal growth rate in the presence of moisture when HPMCAS was added to form an intimate mixture cannot be explained by simple molecular mobility arguments, such as consideration of the calorimetric Tg of the various systems. It is known that the addition of HPMCAS to amorphous felodipine at low levels does not result in an increase in the calorimetric Tg of the system.30 In addition, when exposed to different RH environments, the amount of water sorbed by the solid dispersion films is expected to be greater than the amount of water sorbed by pure amorphous drug,12 and therefore the solid dispersion films would not be expected to have any Tg advantage relative to corresponding pure drug films. A similar lack of correlation of the nucleation rate for felodipine from HPMCAS-containing films with the calorimetric Tg has been noted previously.12 It is also noteworthy that the growth rate shows little dependence on the storage

RH; a similar trend was observed for the both the nucleation rate12 and the bulk crystallization rates of felodipine-HPMCAS dispersions.8 Several factors may explain this phenomenon. First, specific drug-polymer interactions between felodipine and HPMCAS12,30 may result in coupling of the molecular motions of the small molecule and the side chains of a polymer.31 Increasing water content may have little influence on this coupling since HPMCAS contains multiple hydrogen bond donors and acceptors per polymer repeating unit, which can interact with the absorbed moisture and prevent disruption of the drug-polymer interaction.12 Alternatively, the polymer may interact with the crystal surface, blocking some of the growth sites and reducing the growth rate via this mechanism. HPMCAS has been found to inhibit crystallization in highly dilute but supersaturated aqueous solutions of felodipine.32 Finally, the irregular boundaries of felodipine crystals grown in the presence of HPMCAS resulted in relatively larger error bars during growth rate measurements, which in turn may hide subtle differences in crystal growth rates. Growth Rate of Felodipine Crystals from PVP-Containing Solid Dispersion Films. The growth rates of surface-grown felodipine crystals from PVP-containing samples were also reduced compared with those growing from pure amorphous felodipine films. However, unlike HPMCAS-containing samples, significant reduction in drug crystal growth rate was observed for samples containing as little as 2.5% PVP when stored at low (13% and 32%) RH. Growth rates from samples containing 5% and 10% PVP were also lower than those from comparable HPMCAS films when stored at 13% RH. PVP thus appears to be a better crystal growth inhibitor for felodipine than HPMCAS under low RH conditions. This difference may arise because PVP can form stronger specific interactions with felodipine compared with HPMCAS.30 In contrast, under low RH conditions, no significant difference in the nucleation rate of felodipine was observed for a given concentration of either polymer, although the nucleation rate was reduced compared with that of pure drug.30 The growth rate of felodipine crystals from PVP-containing films was very sensitive to storage RH, in particular as the polymer content was increased (see Figure 5 and the steeper slope for the sample containing 10% PVP). PVP is known to have very strong affinity for water,33 so if felodipinePVP interactions are indeed responsible for inhibition of

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felodipine crystal growth at low RH, absorption of water at increased storage RH may result in disruption of drug-polymer specific interactions12,34 with a subsequent decrease in the ability of the polymer to inhibit the growth. Interestingly, when the storage RH was 64% or higher, little difference was observed between the growth rates of felodipine crystals from films containing 2.5%, 5%, or 10% PVP. At sufficiently high RHs, sorbed water actually induces amorphous-amorphous phase separation,6,8,34 and this phenomenon would explain why the growth rates for the films containing different concentrations of PVP merge at high RHs. Amorphous-amorphous phase separation will result in the formation of drug-rich and polymer-rich domains, the composition of which will be independent of the original composition, although the relative amounts of each phase will be dependent on the initial composition. The growth rate of felodipine crystals in this instance would be expected to be relatively independent of the amount of polymer added to the system, as observed. A recent studied of the bulk crystallization of felodipine dispersions with PVP also reported that, at high RHs, the crystallization kinetics were relatively insensitive to the polymer concentration, albeit over a different range of polymer concentrations.8 PVP has also been reported as a poor crystallization inhibitor in dilute aqueous solutions.32 Conclusions As storage relative humidity was increased, the growth rates of drug crystals from thin films of amorphous felodipine slowly increased up until 80% RH. A 15-40-fold increase in growth rates was observed when the storage RH was further increased to 87% RH. The cause for this sudden increase is currently unknown. When PVP and HPMCAS were intimately mixed with amorphous felodipine, the growth rate of the crystals decreased as the amount of polymer was increased. The growth rate of crystals grown from PVP-containing solid dispersion increased as the storage RH was increased, whereas the growth rate of crystals from HPMCAS-containing solid dispersion was relatively insensitive to moisture. At storage RHs below 52%, PVP was a better crystal-growth inhibitor for felodipine than HPMCAS. It is speculated that the strength of the drug-polymer interactions may play a role in determining the effectiveness of a given polymeric additive as a growth rate inhibitor. Thus at low RH, PVP forms stronger interactions with felodipine than does HPMCAS and is therefore a better inhibitor. Increasing levels of absorbed moisture disrupt the drug-polymer interactions in PVP-containing systems to a greater extent than those in HPMCAS systems, rendering this polymer a less effective growth inhibitor at high RHs. The lack of dependence of the growth rate on PVP content at high RH may result from moisture-induced amorphous-amorphous

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drug-polymer phase separation, which is known to occur for felodipine-PVP dispersions exposed to high RH. Acknowledgment. This work was supported by Dane O. Kildsig Center for Pharmaceutical Processing Research (CPPR), Purdue Research Foundation, Merck Research Laboratories, and a grant from the Lilly Endowment, Inc., to the School of Pharmacy and Pharmaceutical Sciences. Patrick Marsac and Hajime Konno are thanked for the use of supplemental data.

References (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)

Leuner, C.; Dressman, J. Eur. J. Pharm. Biopharm. 2000, 50, 47–60. Serajuddin, A. T. M. J. Pharm. Sci. 1999, 88, 1058–1066. Chiou, W. L.; Riegelman, S. J. Pharm. Sci. 1971, 60, 1281–1302. Ford, J. L. Pharm. Acta Helv. 1986, 61, 69–88. Bhugra, C.; Pikal, M. J. J. Pharm. Sci. 2008, 97, 1329–1349. Marsac, P. J. PhD Thesis, Purdue University, West Lafayette, IN, 2007. Crowley, K. J.; Zografi, G. J. Pharm. Sci. 2002, 91, 2150–2165. Rumondor, A. C. F.; Stanford, L. A.; Taylor, L. S. Pharm. Res. 2009, 26, 2599–2606. Andronis, V.; Yoshioka, M.; Zografi, G. J. Pharm. Sci. 1997, 86, 346–351. Andronis, V.; Zografi, G. J. Non-Cryst. Solids 2000, 271, 236–248. Shamblin, S. L.; Zografi, G. Pharm. Res. 1999, 16, 1119–1124. Konno, H.; Taylor, L. S. Pharm. Res. 2008, 25, 969–978. CRC Handbook of Chemistry and Physics, 68th ed.; CRC Press, Inc.: Boca Raton, FL, 1987. O’Brien, F. E. M. J. Sci. Instrum. Phys. Ind. 1948, 25, 73–76. Hancock, B. C.; Zografi, G. Pharm. Res. 1994, 11, 471–477. Hancock, B. C.; Zografi, G. J. Pharm. Sci. 1997, 86, 1–12. Andronis, V.; Zografi, G. Pharm. Res. 1998, 15, 835–842. Tong, P.; Zografi, G. AAPS Pharm. Sci. Technol. 2004, 5. Zhang, J.; Zografi, G. J. Pharm. Sci. 2000, 89, 1063–1072. Marsac, P. J.; Konno, H.; Rumondor, A. C. F.; Taylor, L. S. Pharm. Res. 2008, 25, 647–656. Mao, C.; Chamarthy, S. P.; Pinal, R. Pharm. Res. 2006, 23, 1906– 1917. Aso, Y.; Yoshioka, S.; Kojima, S. J. Pharm. Sci. 2001, 90, 798–806. Zhou, D.; Zhang, G. G. Z.; Law, D.; Grant, D. J. W.; Schmitt, E. A. Mol. Pharmaceutics 2008, 5, 927–936. Ediger, M. D.; Harrowell, P.; Yu, L. J. Chem. Phys. 2008, 128, No. 034709. Mapes, M. K.; Swallen, S. F.; Ediger, M. D. J. Phys. Chem. B 2006, 110, 507–511. Zhu, L.; Wong, L.; Yu, L. Mol. Pharmaceutics 2008, 5, 921–926. Wu, T.; Yu, L. Pharm. Res. 2006, 23, 2350–2355. Wu, T.; Sun, Y.; Li, N.; de Villiers, M. M.; Yu, L. Langmuir 2007, 23, 5148–5153. Rumondor, A. C. F.; Konno, H.; Marsac, P.; Taylor, L. J. Appl. Polym. Sci. 2010, in press. Konno, H.; Taylor, L. S. J. Pharm. Sci. 2006, 95, 2692–2705. Aso, Y.; Yoshioka, S.; Zhang, J.; Zografi, G. Chem. Pharm. Bull. 2002, 50, 822–826. Konno, H.; Handa, T.; Alonzo, D. E.; Taylor, L. S. Eur. J. Pharm. Biopharm. 2008, 70, 493–499. Taylor, L. S.; Langkilde, F. W.; Zografi, G. J. Pharm. Sci. 2001, 90, 888–901. Marsac, P. J.; Rumondor, A. C. F.; Nivens, D. E.; Kestur, U. S.; Stanciu, L.; Taylor, L. S. J. Pharm. Sci. 2010, in press http://dx.doi. org/10.1002/jps.21809.