The Role of Polymer Concentration on the Molecular Mobility and

Article pubs.acs.org/molecularpharmaceutics

The Role of Polymer Concentration on the Molecular Mobility and Physical Stability of Nifedipine Solid Dispersions Khushboo Kothari,†,‡ Vishard Ragoonanan,†,‡ and Raj Suryanarayanan*,† †

Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55445, United States S Supporting Information *

ABSTRACT: We investigated the influence of polymer concentration (2.5− 20% w/w) on the molecular mobility and the physical stability in solid dispersions of nifedipine (NIF) with polyvinylpyrrolidone (PVP). With an increase in polymer concentration, the α-relaxation times measured by broadband dielectric spectroscopy were longer, which reflects a decrease in molecular mobility. In the supercooled state, at a given temperature (between 55 and 75 °C), the relaxation time increased linearly as a function of polymer concentration (2.5−20% w/w). The temperature dependence of the relaxation time indicated that the fragility of the dispersion, and by extension the mechanism by which the polymer influences the relaxation time, was independent of polymer concentration. The time for NIF crystallization also increased as a function of polymer concentration. Therefore, by using molecular mobility as a predictor, a model was built to predict NIF crystallization from the dispersions in the supercooled state. The predicted crystallization times were in excellent agreement with the experimental data. KEYWORDS: nifedipine, solid dispersion, polyvinylpyrrolidone (PVP), dielectric spectroscopy, molecular mobility, crystallization, X-ray powder diffractometry

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INTRODUCTION By formulating as amorphous solid dispersions, there is a potential to enhance the solubility and the oral bioavailability of poorly water-soluble compounds.1,2 A wide variety of polymers are available to formulate amorphous drugs into solid dispersions.3 However, when the drug loading is high, it can be a challenge to develop robust solid dispersions that can resist crystallization.4,5 In practice, only a few polymers have been used as is evident from the commercial solid dispersions on the market.6 Polymer selection can be rationalized by developing a comprehensive understanding of the mechanisms governing drug stabilization by the polymer. The ideal polymer should be effective enough at a low concentration to physically stabilize the drug during manufacture as well as the shelf life of the dispersion. Several studies have investigated the role of thermodynamic and kinetic factors to help provide a scientific rationale for the selection of an appropriate polymer.4 In particular, the role of molecular mobility as a predictor of physical stability of amorphous pharmaceuticals has received a lot of attention.7−16 The correlation between global mobility (α-relaxation) and the crystallization propensity has recently been established in nifedipine (NIF) with polyvinylpyrrolidone (PVP) solid dispersions in the supercooled as well as the glassy states.17 Apart from molecular mobility, the influence of drug− polymer interactions (hydrogen bonding and ionic) on physical stability of drugs in solid dispersions has been the topic of numerous investigations.18−23 We recently investigated the © XXXX American Chemical Society

possible role of drug−polymer interactions and molecular mobility on the physical stability of NIF dispersions with each PVP, hydroxypropylmethyl cellulose acetate succinate (HPMCAS), and poly(acrylic acid) (PAA). The strength of drug−polymer hydrogen bonding, the structural relaxation time, and the resistance to crystallization were rank ordered as PVP > HPMCAS > PAA.24 Thus, PVP was much more effective than HPMCAS and PAA in stabilizing NIF in the dispersion, and its effectiveness could be attributed to the decrease in molecular mobility brought about by the strong hydrogen bonding of the drug with the polymer. Having established the effectiveness of PVP in stabilizing NIF dispersions, as a next step, we have investigated the influence of PVP concentration on the molecular mobility and physical stability. The polymer concentration needed to stabilize the drug in a dispersion is of immense practical importance. In pharmaceutical dosage forms, the goal is to physically stabilize the drug (i.e., prevent drug crystallization) during processing and storage (shelf life) of the dosage form. It is also instructive to recognize that high-dose drugs can be formulated as solid dispersions only if the polymer is effective at a low concentration. Received: December 1, 2014 Revised: March 15, 2015 Accepted: March 19, 2015

A

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were periodically exposed to Cu Kα radiation (40 kV x 40 mA) over an angular range of 6−27° 2θ with a step size of 0.04° and a dwell time of 0.5 s. Synchrotron XRD (SXRD). Isothermal crystallization studies in the glassy state were conducted in select systems. The samples were stored at the desired temperature in hermetically sealed DSC pans and then exposed to synchrotron radiation (17-BM-Sector; 0.72910 Å; Argonne National Laboratory, IL). The synchrotron experiments were conducted at room temperature. The sample to detector distance was set at 900 mm. The calibration was performed using Al2O3 (NIST; SRM-647a) standard. The two-dimensional (2D) data were integrated to yield 1D d-spacing (Å) or 2θ (deg) scans using the FIT2D software developed by A. P. Hammersley of the European Synchrotron Radiation Facility. Quantification of XRD Data. At each storage time point, the crystallinity index (intensity of crystalline peaks/total diffracted intensity) was calculated. The crystallinity index can be equivalent to the % crystallinity, if the total integrated intensity (crystalline + amorphous) remains constant throughout the isothermal crystallization experiment.17,25 A custom built software (Fortran 77; Tucson, AZ) was used to quantify crystallinity, wherein the amorphous intensity contribution was based on the experimental XRD pattern of the amorphous “reference” material (preparation method is provided above). The subtraction of the amorphous intensity from the total pattern yielded the intensity contribution from the crystalline peaks. This enabled calculation of percent crystallinity as a function of time. Since crystallization occurred slowly, the reaction kinetics were not monitored to completion. Therefore, the characteristic crystallization time (tc), defined as time for 10% crystallization, was used. Dielectric Spectroscopy (BDS). By using a broadband dielectric spectrometer (Novocontrol Alpha-AK high performance frequency analyzer, Novocontrol Technologies, Germany), isothermal dielectric measurements were conducted over the frequency range of 10−2−107 Hz and between −100 and 150 °C. The Havriliak−Negami (HN) model (eq 1) was used to fit the dielectric data so as to obtain the average relaxation time (τHN) and shape parameters (αHN and βHN):26

We hypothesize that PVP, in a concentration-dependent manner, will reduce the molecular mobility of the system and thereby enhance the physical stability of NIF in the dispersion. In a previous investigation, we had established a relationship between molecular mobility and physical stability (measured as crystallization time) in a single component system using amorphous trehalose.14 In this manuscript, we have extended the coupling model to successfully predict, for the first time, NIF crystallization in solid dispersions. More importantly, by using the crystallization data obtained at elevated temperatures in dispersions with low polymer concentrations (conditions of rapid crystallization), we have successfully predicted the crystallization behavior in systems exhibiting much slower crystallization kinetics (higher polymer concentrations and lower temperatures). If our approach is successful, it can be used to predict crystallization during the shelf life of the dosage form and significantly reduce the time for solid dispersion development.

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EXPERIMENTAL SECTION Materials and Methods. NIF (C17H18N2O6; purity >98%) was purchased from Laborate Pharmaceutical Ltd., India and was used without further purification. NIF was confirmed to be the α-polymorph by X-ray diffractometry, and its melting point, determined by differential scanning calorimetry, was 174 °C. PVP (K12 grade) was supplied by BASF Corporation. Preparation of Amorphous Systems. Amorphous NIF was prepared by melting crystalline NIF in an aluminum pan and then quenching on an aluminum block precooled to −20 °C. The NIF−PVP solid dispersion was prepared by a solvent evaporation technique followed by melt quenching. Physical mixtures of NIF and PVP (polymer concentration ranged between 2.5 and 20% w/w) were dissolved in either acetone or acetone and methanol mixtures (50:50 v/v), and the solvent evaporated at 40 °C under reduced pressure (IKA-HB10 digital system, Werke GmbH and Co. Staufen, Germany). The mixture was further dried under reduced pressure at room temperature for 24 h. It was then heated to 5 °C above the melting point of NIF and quenched to −20 °C. The meltquenched materials were lightly crushed using a mortar and pestle in a glovebox at room temperature (RH < 5%). The amorphous materials were stored at −20 °C in desiccators containing anhydrous calcium sulfate. Karl Fischer Titrimetry. The water content in the amorphous model systems was determined coulometrically using a Karl Fischer titrimeter (Model DL 36 KF Coulometer, Metler Toledo, Columbus, OH). Accurately weighed samples were directly added to the Karl Fischer cell, and the water content was determined. Thermal Analysis. A differential scanning calorimeter (DSC) (Q2000, TA Instruments, New Castle, DE) equipped with a refrigerated cooling accessory was used. The instrument was calibrated with tin and indium. In a glovebox, the powder was accurately weighed and sealed hermetically in aluminum pans. All the measurements were done under dry nitrogen purge (50 mL/min) at a heating rate of 10 °C/min. Powder X-ray Diffractometry (XRD). A powder X-ray diffractometer (D8 ADVANCE; Bruker AXS, Madison, WI) equipped with a variable temperature stage (TTK 450; Anton Paar, Graz-Straßgang, Austria) and Si strip one-dimensional (1D) detector (LynxEye; Bruker AXS) was used. The isothermal crystallization studies were conducted in the NIF systems at four temperatures above Tg (55 to 70 °C). Samples

ε*(ω) = ε∞ +

Δε (1 + (iωτHN)αHN )βHN

(1)

where ω is the angular frequency, ε*(ω) is the complex dielectric permittivity consisting of real (ε′) and imaginary (ε″) components, and dielectric strength, Δε = εs − ε∞, where εs gives the low frequency limit (ω → 0) of ε′(ω) and ε∞, is the high frequency limit (ω → ∞) of ε′(ω). The shape parameters account for the symmetric (αHN) and asymmetric (βHN) peak broadening with 0 < αHN (or βHN) < 1. At higher temperatures, the contribution of conductivity was taken into consideration by adding the conductivity component, σ0/iε0ω to the HN equation, where σ0 is the dc conductivity, and ε0 is the vacuum permittivity. The powder was filled between two gold plated copper electrodes (20 mm diameter) using a PTFE ring (thickness, 1 mm; area, 59.69 mm2; capacitance, 1.036 pF) as a spacer. The validity of the relaxation time measurements using powder samples has been the subject of a previous manuscript.27 The spacer confined the sample between the electrodes. Measurements were corrected for stray capacitance, spacer capacitance, and the edge compensation. B

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RESULTS AND DISCUSSION Baseline Characterization. The model amorphous systems were observed to be X-ray amorphous. The glass transition temperatures were determined by DSC, and the heating curves for select systems and the Tg values of the dispersions are included in the Supporting Information (S1 and S2). Karl Fischer titrimetry revealed a water content 10% w/w, the pronounced contribution of dc conductivity increased the values of ε″ (Figure 1; indicated by arrow). Shinyashaki et al. also reported significant dc conductivity contribution to the dielectric loss spectra of PVP−chloroform mixtures.28 To account for the conductivity contribution, the relaxation times were calculated using an additional conductivity term in the HN model (details in Materials and Methods section). The temperature dependence of the relaxation time (for select systems) is shown in Figure 2. As indicated earlier, with an increase in polymer concentration, there was a progressive increase in the α-relaxation time, and this effect became more pronounced at higher polymer concentrations. At 70 °C, a change in polymer concentration from 5 to 10% w/w resulted in an about three-fold increase in the relaxation time (5% polymer concentration, data not shown). When the polymer concentration was raised to 20% w/w, the relaxation time increased dramatically (∼15-fold). An increase in polymer concentration, by making the matrix more viscous, will

Figure 3. Cole−Cole plots obtained from dielectric data of NIF (green squares) and NIF solid dispersions with 10 (red triangles) and 20% (black circles) w/w PVP at 70 °C. Both symmetric and asymmetric broadening were observed. Each data set was normalized with respect to its maximum loss value. C

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Figure 4. Isothermal (70 °C) X-ray powder diffraction patterns, as a function of time, of (a) NIF and NIF solid dispersions with (b) 2.5, (c) 10, and (d) 20% w/w PVP.

the blend. The observed α-relaxation is the sum of the individual subvolume α-relaxations within the blend. In glassy NIF and in the solid dispersions, an “excess wing” was observed, attributable to β-relaxation. Since the signal was weak, its temperature dependence could not be ascertained. Goresy and Bö hmer also observed an excess wing in amorphous NIF and acetaminophen alloys, attributable to the Johari−Goldstein relaxation.35 Influence of Polymer Concentration on Physical Stability. Our next objective was to use XRD to study the influence of polymer concentration on the physical stability of NIF in dispersions. With an increase in polymer concentration, there was a dramatic decrease in the rate and the extent of drug crystallization (Figure 4). The time taken for 10% w/w of the drug to crystallize, tc, was calculated (Figure 5). For the drug alone, at 70 °C, tc was ∼5 min. Addition of PVP (2.5% w/w) caused an ∼1.8-fold increase in tc (∼9 min). At very low

polymer concentrations, a similar dramatic increase in physical stability has been reported, both in NIF and other drugs in solid dispersions.11,36,37 With further increase in polymer concentration, crystallization took progressively longer (Figure 5). Thus, the influence of polymer concentration had similar effects on the α-relaxation (Figure 2) and crystallization times (Figure 5). To study the influence of polymer concentration on physical stability in the glassy state, the dispersions were held isothermally at 25 °C, and crystallization was monitored using synchrotron radiation. The high sensitivity afforded by this source enabled us to detect crystallization even at a polymer concentration of 10% w/w (Figure 6). When the polymer concentration was increased to 20%, drug crystallization was not observed even after 60 days of storage (Supporting Information, S4).

Figure 6. Synchrotron XRD patterns of (a) NIF and NIF solid dispersions with (b) 2.5, (c) 5, and (d) 10% w/w PVP at 25 °C.

Molecular Mobility as a Predictor of Physical Stability. The crystallization rate, G(T), at the melt-crystal interface is given by eq 3:38

G(T ) = D(T ) × f (T )

(3)

where D(T) is the temperature dependence of molecular diffusion, and f(T) is the free energy term (nucleation/crystal growth). In light of the challenges with the measurement of

Figure 5. Effect of polymer concentration on time taken for 10% of the incorporated NIF to crystallize from the solid dispersions at 70 °C. D

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Molecular Pharmaceutics translational diffusion, the above equation is often approximated by G (T ) =

f (T ) η(T )

At this low polymer concentration of 2.5% w/w, crystallization was fairly rapid, and tc was experimentally determined over a temperature range of 55−70 °C. As the polymer concentration is increased, in light of the slower crystallization, studying crystallization kinetics in practical time scales can be challenging. We therefore attempted to use eq 9 to predict crystallization in dispersions with 5 and 10% w/w PVP concentration. We believe that the value of the coupling coefficient (M = 0.67) obtained at a polymer concentration of 2.5% w/w is valid at the higher polymer concentrations. This assumption is based on three observations (Figure 7). (i)

(4)

where η(T) is the temperature dependence of viscosity. Our interest is in the supercooled state close to Tg. In the range between Tg and 1.2Tg, the temperature dependence of molecular and viscous transport exhibits a pronounced difference. This has been attributed to the breakdown of the Stokes−Einstein relationship (eq 5):41 Dtrans =

kBT 6Πηr

(5)

Here, kB is the Boltzmann constant, and r is the radius of the diffusing species. In this temperature range, the translational diffusion coefficient, Dtrans, has significantly weaker temperature dependence than does η. A pronounced enhancement of Dtrans over η is observed at temperatures close to Tg (about two orders of magnitude).38−43 The decoupling factor, ξ, between Dtrans and η is expressed as

Dtrans α T/ηξ

(6)

In light of the similar temperature dependence exhibited by viscosity and rotational motions, eq 6 can be expresses as

Dtrans α T/τα

ξ

Figure 7. A plot of relaxation time as a function of polymer concentration at a series of temperatures between 55 and 75 °C.

(7)

Linear relationship between relaxation time and polymer concentration (2.5−20% w/w; five polymer concentrations) under isothermal conditions. These experiments were conducted at five temperatures between 55 and 75 °C. (ii) Similar polymer concentration dependence of the relaxation times over this temperature range. (ii) Similar temperature dependence of the relaxation times over the studied concentration range. While these investigations were also carried out in solid dispersions with different polymer concentrations, for the sake of clarity, only a few are shown in Figure 2. These results suggest that in the polymer concentration range of 2.5−20% w/ w, the mechanism by which the polymer influences the relaxation time is unaltered. However, this assumption may not hold true at higher polymer concentrations (i.e., > 20% w/w), possibly due to the saturation of the hydrogen bonding sites available for the drug. Thus, our assumption is likely to be valid only over a defined range of polymer concentrations and temperatures. At higher polymer concentrations of 5 and 10% w/w, tc was experimentally determined at 70 °C. This enabled us to calculate the value of the constant A in eq 8. With an increase in polymer concentration, there was increased resistance to crystallization. The change in the chemical potential of the drug brought about by polymer addition was calculated using the data from Marsac et al. (Supporting Information, S6).46 The addition of polymer, in a concentration dependent manner, causes a decrease in chemical potential of the drug that will result in an increase in the free-energy barrier for drug crystallization. This is reflected in the increased values of the constant A in eqs 9−11. Thus, the relationship between tc and τ αHN for dispersions with 5 and 10% w/w polymer concentration can be expressed by eqs 10 and 11, respectively:

On the basis of experimental determinations of Dtrans and the rotational diffusion coefficient (Drot), ξ was found to be 0.75 for OTP.44,45 Similarly, in NIF, we had reported ξ to be 0.77, which reflects decoupling between rotational and translational motions (see Supporting Information, S5). Eq 3 provided the relationship between diffusion and crystallization rate, while eq 7 related the Dtrans to the rotational relaxation times. The coupling model is based on these two equations and then takes into account the relationship between crystallization time and relaxation time and any decoupling between the two. Our objective was to determine the role of molecular mobility on physical stability over a narrow (20 °C) temperature range. This was enabled by eq 8: log(tc) = M log(τα HN) + log A

(8)

From a comparison of eqs 3 and 8, we can deduce that the constant in eq 8 is related to the free-energy term in eq 3. In the above equation, tc is the time for 10% crystallization, tαHN is the α-relaxation time, M is the coupling coefficient, and A is a constant. This constant is a measure of the thermodynamic “barrier” to crystallization. An M value of 1 will indicate “perfect” coupling between the two processes. Since we are using ταHN, a measure of the rotational relaxation time, we expect a coupling coefficient of ∼0.75, given the decoupling between translational and rotational motions within the temperature range of Tg and 1.2Tg. In NIF−PVP (2.5% w/ w) solid dispersion in the supercooled state, the coupling coefficient was 0.67, reasonably close to the decoupling factor of 0.77 obtained for NIF alone.17 Therefore, the relationship between α-relaxation and crystallization time for NIF−PVP (2.5% w/w) solid dispersion could be expressed as log(tc) = 0.67 log(τα HN) + 4.8

log(tc) = 0.67 log(τα HN) + 5.4

(9) E

(10) DOI: 10.1021/mp500800c Mol. Pharmaceutics XXXX, XXX, XXX−XXX

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(2.5% w/w), crystallization occurred rapidly in both the supercooled and glassy states.17 However, commercial solid dispersions are unlikely to exhibit rapid drug crystallization. This is practically accomplished by raising the polymer concentration and storage under appropriate conditions typically in the glassy state. In such systems, the challenge will be to predict drug crystallization during the shelf life (typically two years) of the dosage form. As a first step, we monitored physical instability under conditions of rapid crystallization (low polymer concentration of 2.5% PVP; elevated temperatures) and used this information to successfully predict crystallization in dispersions with higher polymer concentrations. Since most pharmaceuticals are stored at temperatures much lower than Tg, the feasibility of using this model in the glassy state is of great practical interest. However, at temperatures substantially lower than Tg, the VTF model cannot reliably describe the temperature dependence of relaxation time. To successfully use this model, it will be necessary to independently measure the α-relaxation time below Tg. This can be accomplished by using time domain dielectric spectroscopy. Another option will be to use the Adam Gibbs Vogel model to predict the α-relaxation time below Tg. In the glassy state, contribution from the β-relaxation will also need to be considered. The concept applied for the current model dispersions can next be extended to systems of practical interest (higher polymer concentrations) stored under pharmaceutically relevant conditions (ambient or subambient temperatures).

(11)

These equations enable the prediction of the crystallization time as long as the α-relaxation time can be experimentally obtained. We predicted tc at 55, 60, and 65 °C. In an effort to check the reliability of the prediction, tc was also experimentally determined by XRD. Figure 8 shows an excellent agreement between the predicted and the experimental crystallization times.

Figure 8. A plot of crystallization time versus relaxation time for NIF solid dispersions. The data for the dispersions with 2.5% polymer concentration (yellow circles) were reported earlier.17 The solid black line represents linear regression line (eq 9). At polymer concentrations of 5 (dotted black line) and 10% (dotted red line), the lines are the predicted crystallization times as a function of the experimentally determined relaxation times (eqs 10 and 11). The data points (5%, blue circles; 10%, red circles) are the experimentally obtained crystallization times.

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CONCLUSION An increase in polymer concentration led to an increase in the relaxation time as well as the crystallization time in NIF solid dispersions. The previously established relationship between crystallization and α-relaxation time in NIF−PVP (2.5% w/w) solid dispersions was used to predict crystallization in dispersions at higher polymer concentrations of 5 and 10% PVP. The predictions matched very well with the experimental data, which confirmed the usefulness of the model.

As mentioned earlier, the values of constant A in eqs 10 and 11 were based on the experimentally observed crystallization and relaxation times at 70 °C and assuming a value of 0.67 for M. The experimental data (crystallization and relaxation times between 55 and 70 °C) provided the values of M and A for the two systems. As is evident from Table 1, there is a good agreement between the two confirming the usefulness of the model. Significance. Amorphous solid dispersions will find widespread use if the potential for drug crystallization can be reliably predicted. Such a prediction will be possible by understanding the mechanisms governing instability. Crystallization is recognized as a complex process involving nucleation and crystal growth. Assuming that molecular mobility can be an effective predictor of drug crystallization, we identified the specific mobility responsible for instability in a drug (itraconazole) and an excipient (trehalose).13,14 We extended this approach and developed a model relating NIF crystallization from solid dispersions with molecular mobility. In this system, since the polymer (PVP) concentration was very low

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ASSOCIATED CONTENT

S Supporting Information *

Representative DSC heating curves of NIF and NIF solid dispersions with PVP. Summary of the DSC results of the model systems. Dielectric loss behavior of NIF solid dispersions. XRD patterns of NIF solid dispersion. Change in chemical potential of the drug due to polymer addition. This material is available free of charge via the Internet at http:// pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].

Table 1. Comparison of the Values of M and A in Eq 8 Obtained Using Our Experimental Data and the “Assumed” Values M NIF−PVP (5% w/w) NIF−PVP (10% w/w)

log A

assumeda

experimental

assumedb

experimental

0.67 0.67

0.73 0.72

5.4 6.6

5.6 6.7

a

The assumed value of M was obtained from eq 9. bThe assumed value of A was based on crystallization studies conducted in solid dispersions with 2.5% PVP at 70 °C. F

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(13) Bhardwaj, S. P.; Arora, K. K.; Kwong, E.; Templeton, A.; Clas, S.-D.; Suryanarayanan, R. Correlation between Molecular Mobility and Physical Stability of Amorphous Itraconazole. Mol. Pharmaceutics 2013, 10 (2), 694−700. (14) Bhardwaj, S. P.; Suryanarayanan, R. Molecular Mobility as an Effective Predictor of the Physical Stability of Amorphous Trehalose. Mol. Pharmaceutics 2012, 9 (11), 3209−3217. (15) Adrjanowicz, K.; Kaminski, K.; Wojnarowska, Z.; Dulski, M.; Hawelek, L.; Pawlus, S.; Sawicki, W. Dielectric Relaxation and Crystallization Kinetics of Ibuprofen at Ambient and Elevated Pressure. J. Phys. Chem. B 2010, 114 (19), 6579−6593. (16) Adrjanowicz, K.; Wojnarowska, Z.; Wlodarczyk, P.; Kaminski, K.; Paluch, M.; Mazgalski, J. Molecular Mobility in Liquid and Glassy States of Telmisartan (TEL) Studied by Broadband Dielectric Spectroscopy. Eur. J. Pharm. Sci. 2009, 38 (4), 395−404. (17) Kothari, K.; Ragoonanan, V.; Suryanarayanan, R. Influence of Molecular Mobility on the Physical Stability of Amorphous Pharmaceuticals in the Supercooled and Glassy States. Mol. Pharmaceutics 2014, 11 (9), 3048−3055. (18) Wegiel, L. A.; Mauer, L. J.; Edgar, K. J.; Taylor, L. S. MidInfrared Spectroscopy as a Polymer Selection Tool for Formulating Amorphous Solid Dispersions. J. Pharm. Pharmacol. 2014, 66 (2), 244−255. (19) Van Eerdenbrugh, B.; Taylor, L. S. An Ab Initiopolymer Selection Methodology to Prevent Crystallization in Amorphous Solid Dispersions by Application of Crystal Engineering Principles. CrystEngComm 2011, 13 (20), 6171−6178. (20) Van Eerdenbrugh, B.; Taylor, L. S. Small-Scale Screening To Determine the Ability of Different Polymers to Inhibit Drug Crystallization Upon Rapid Solvent Evaporation. Mol. Pharmaceutics 2010, 7 (4), 1328−1337. (21) Miyazaki, T.; Yoshioka, S.; Aso, Y.; Kojima, S. Ability of Polyvinylpyrrolidone and Polyacrylic Acid To Inhibit the Crystallization of Amorphous Acetaminophen. J. Pharm. Sci. 2004, 93 (11), 2710−2717. (22) Matsumoto, T.; Zografi, G. Physical Properties of Solid Molecular Dispersions of Indomethacin with Poly(vinylpyrrolidone) and Poly(vinylpyrrolidone-co-vinyl-acetate) in Relation to Indomethacin Crystallization. Pharm. Res. 1999, 16 (11), 1722−1728. (23) Konno, H.; Taylor, L. S. Influence of Different Polymers on the Crystallization Tendency of Molecularly Dispersed Amorphous Felodipine. J. Pharm. Sci. 2006, 95 (12), 2692−2705. (24) Kothari, K.; Ragoonanan, V.; Suryanarayanan, R. The Role of Drug−Polymer Hydrogen Bonding Interactions on the Molecular Mobility and Physical Stability of Nifedipine Solid Dispersions. Mol. Pharmaceutics 2015, 12 (1), 162−170. (25) Nunes, C.; Mahendrasingam, A.; Suryanarayanan, R. Quantification of Crystallinity in Substantially Amorphous Materials by Synchrotron X-Ray Powder Diffractometry. Pharm. Res. 2005, 22 (11), 1942−1953. (26) Havriliak, S.; Negami, S. A Complex Plane Analysis of αDispersions in Some Polymer Systems. J. Polym. Sci., Part C: Polym. Symp. 1966, 14 (1), 99−117. (27) Kothari, K.; Ragoonanan, V.; Suryanarayanan, R. Dielectric Spectroscopy of Small Molecule PharmaceuticalsEffect of Sample Configuration. J. Pharm. Sci. 2014, 103 (10), 3190−3196. (28) Shinyashiki, N.; Spanoudaki, A.; Yamamoto, W.; Nambu, E.; Yoneda, K.; Kyritsis, A.; Yagihara, S. Segmental Relaxation of Hydrophilic Poly(vinylpyrrolidone) in Chloroform Studied by Broadband Dielectric Spectroscopy. Macromolecules 2011, 44 (7), 2140− 2148. (29) Scherer, G. W. Theories of Relaxation. J. Non-Cryst. Solids 1990, 123 (1−3), 75−89. (30) Davidson, D.; Cole, R. Dielectric Relaxation in Glycerine. J. Chem. Phys. 1950, 18 (10), 1417−1417. (31) Davidson, D. W.; Cole, R. H. Dielectric Relaxation in Glycerol, Propylene Glycol, and n-Propanol. J. Chem. Phys. 1951, 19 (12), 1484−1490.

‡

K.K., Takeda Oncology, Cambridge, MA 02139, United States; V.R., Allergan, Irvine, CA 92612, United States. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS K.K. was partially supported by the Center for Pharmaceutical Processing and Research and Doctoral Dissertation Fellowship, University of Minnesota. The project was partially funded by the William and Mildred Peters endowment fund. Parts of this work were carried out in the Characterization Facility, University of Minnesota, a member of the NSF-funded Materials Research Facilities Network (www.mrfn.org). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. We thank Dr. Gregory Halder, Argonne National Laboratory, USA for the help during the synchrotron data collection. Dr. Sarat Mohapatra is thanked for helpful discussions.

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DOI: 10.1021/mp500800c Mol. Pharmaceutics XXXX, XXX, XXX−XXX