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Strength of Drug−Polymer Interactions: Implications for Crystallization in Dispersions Pinal Mistry and Raj Suryanarayanan* Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota 55455, United States S Supporting Information *

ABSTRACT: We investigated the influence of the strength of drug−polymer interactions on the crystallization behavior of a model drug in amorphous solid dispersions (ASDs). Ketoconazole ASDs were prepared with each poly(acrylic acid), poly(2-hydroxyethyl methacrylate), and polyvinylpyrrolidone. Over a wide temperature range in the supercooled region, the α-relaxation time was obtained, which provided a measure of molecular mobility. Isothermal crystallization studies were performed in the same temperature interval using either a synchrotron (for low levels of crystallinity) or a laboratory X-ray (for crystallization kinetics) source. The stronger the drug−polymer interaction, the longer was the delay in crystallization onset time, indicating an increase in physical stability. Stronger drug−polymer interactions also translated to a decrease in the magnitude of the crystallization rate constant. In amorphous ketoconazole as well as in the dispersions, the coupling coefficient, a measure of the extent of coupling between relaxation and crystallization times was ∼0.5. This value was unaffected by the strength of drug−polymer interactions. On the basis of these results, the crystallization times in ASDs were predicted at temperatures very close to Tg, using the coupling coefficient experimentally determined for amorphous ketoconazole. The predicted and experimental crystallization times were in good agreement, indicating the usefulness of the model.

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INTRODUCTION Amorphous solid dispersions (ASDs) are increasingly emerging as a viable approach for enhancement in aqueous solubility of poorly soluble drugs.1−4 In spite of the remarkable solubility advantage, this high-energy metastable form is not a preferred choice during formulation development. The reluctance stems from the risk of amorphous → crystalline transition (drug crystallization) during storage. Additionally, our limited ability to predict crystallization times in ASDs makes their development challenging. For successfully utilizing ASDs as a potential strategy for enhancement in solubility and oral bioavailability, a better understanding of factors influencing drug crystallization is warranted. In the past two decades several studies have attempted to comprehend the key factors governing physical stability. Both kinetic (molecular mobility) and thermodynamic (configurational entropy, heat of fusion and entropy, surface energy) factors affect the crystallization propensity of drugs.5−8 This discussion will focus on kinetic factors influencing crystallization. In an effort to predict crystallization onset times, the molecular mobility has been probed in numerous amorphous compounds including sucrose, trehalose, indomethacin, and flopropione.9−11 Calorimetric techniques enable measurement of enthalpic recovery and enthalpic relaxation, while dielectric spectroscopy provides a direct measurement of different mobility modes. These modes include both global (referred to as α-relaxation) and local (secondary relaxations) motions. © 2016 American Chemical Society

More than the intrinsic stability of the drug substance, the crystallization propensity of a drug formulated as a solid dispersion is of practical interest. Only limited attempts have been made to predict crystallization in ASDs, partly due to the very slow crystallization kinetics. Pikal et al. pioneered the work in this field and attempted to predict crystallization times below Tg, based on the coupling between relaxation time (a measure of molecular mobility) and crystallization times above Tg.12 Unfortunately, long crystallization times precluded any meaningful comparisons between the predicted and experimental values. Moreover, the extrapolation was carried out over a large temperature range, and, as a first approximation, the authors assumed that the coupling between mobility and crystallization time was the same in the supercooled and glassy states. More recent studies indicate that this assumption may not hold true. The predicted crystallization times in nifedipine-PVP ASDs varied considerably depending on the experimental technique used to measure the relaxation times.13 Recently, in nifedipinePVP ASDs, the relaxation and crystallization times were determined over a narrow temperature range above Tg.14 The extent of coupling between relaxation and crystallization times, quantified using the coupling coefficient value (M), was obtained at a low polymer concentration (2.5% w/w). Received: May 10, 2016 Revised: July 5, 2016 Published: July 11, 2016 5141

DOI: 10.1021/acs.cgd.6b00714 Cryst. Growth Des. 2016, 16, 5141−5149

Crystal Growth & Design

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radiation (1.54 Å, 40 kV × 40 mA), data were collected over the range of 10−30° 2θ with a step size of 0.05° 2θ and 0.5 s dwell time. The measurements were performed in triplicate using a fresh amorphous sample for each run. Quantification of Laboratory Source XRD Data. The fraction crystallized (expressed as % crystallinity) was calculated using eq 1,

Assuming that the M value would remain unaffected for small changes in polymer concentration, crystallization times were predicted in ASDs at higher polymer content (5 and 10% w/ w). While restricted only to the supercooled state, there was a good agreement between the predicted and experimental crystallization times. Interestingly, there was no significant difference between the coupling coefficient of nifedipine (M = 0.62 ± 0.05) and nifedipine−2.5% PVP ASDs (M = 0.67 ± 0.07).13,14 This raises an important question: Since a polymer can inhibit crystallization even at a low concentration, can we simply use the coupling coef f icient of drug (typically a fast crystallizing system) to estimate crystallization times in ASDs (much slower crystallization)? If the extent of coupling between relaxation and crystallization times is about the same in the drug and in the drug dispersions, the information can be very useful in predicting the time scales of crystallization in ASDs. Ketoconazole (KTZ) was the model compound and ASDs were prepared with each poly(acrylic acid) (PAA), poly(2hydroxyethyl methacrylate) (PHEMA), and polyvinylpyrrolidone (PVP). These polymers differed widely in their strength of interaction with KTZ. Stronger drug−polymer interaction translated to slower molecular mobility (longer relaxation time).15 If molecular mobility is correlated with crystallization, the decrease in mobility brought about by the strong drug− polymer interaction should translate to increased physical stability. We hypothesize that stronger the drug−polymer interaction, the longer is the crystallization lag time and smaller the magnitude of the crystallization rate constant. Our first objective was to compare the extent of coupling between relaxation and crystallization times in different amorphous systemsdrug alone followed by ASDs with increasing strength of drug−polymer interactions. This not only allowed a comparison between drug and dispersion but also dispersions with different polymers. The coupling coefficient value was approximately the same for all the systems. Therefore, our second objective was to estimate the crystallization time scales in ASDs using the coupling coefficient determined for amorphous KTZ. Thus, by using the crystallization data obtained for a “fast crystallizing system” (drug alone), we have successfully predicted the crystallization behavior in relatively “stable” ASDs. These findings would provide a basis for rational polymer selection and can enable the development of a model to predict drug crystallization during drug product storage.

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% crystallinity =

intensity of crystalline peaks × 100 total diffracted intensity

(1)

If the total diffracted intensity (crystalline peak intensity + amorphous halo) remains constant throughout the isothermal crystallization process, the crystallinity index can be equivalent to the fraction crystallized.16 A custom-built program (Fortran 77; Tucson, AZ) was used for the data analysis. After a baseline correction was applied, the amorphous halo was subtracted from the total diffracted pattern to obtain the crystalline peaks. For quantification, intensities of all the crystalline peaks were considered in the 2θ range between 10 and 30°. The % crystallinity in ASDs was normalized to account for the presence of polymer (4% w/w). To obtain the crystallization rate constant, the modified Kolmogorov−Johnson−Mehl−Avrami (KJMA) model (eq 2) was used in its linear form (eq 3).17−21

Xc(t ) = 1 − exp[− (k(t − t0))n ]

(2)

ln[− ln(1 − Xc)] = n ln(t − t0) + n ln k

(3)

In the above equations, Xc is the fraction crystallized at time t, t0 is the induction time, n is the Avrami exponent that describes the nucleation and growth mechanisms, and k is the crystallization rate constant. The crystallinity, in the range between 10 and 60%, was linearly extrapolated to obtain the t0 value. The Avrami exponent (n) and the rate constant k were obtained respectively from the slope and intercept of the plot of ln[ − ln(1 − Xc)] vs ln(t − t0). Synchrotron X-ray Diffraction (XRD). Crystallization of KTZ was studied at four temperatures, in the range of 60−75 °C, by storing the samples in ovens (UFE 500 Memmert, Schwabach, Germany) for the desired time period. The powders were then hermetically sealed in DSC pans (Tzero, TA Instruments, DE) in a glovebox (RH < 5%; room temperature). The samples were exposed to synchrotron radiation (0.72808 Å; 17-BM-Sector; Argonne National Laboratory, IL) in transmission mode with a sample-to-detector distance of 900 mm. The pan was oscillated (±1 mm from the center) along the horizontal axis using a stepper motor. The results from 30 scans were averaged, with an exposure time of 1 s per scan. The calibration was performed using Al2O3 standard (SRM-647a, NIST). The twodimensional (2D) data collected using the amorphous silicon flat panel detector (XRD 1621, PerkinElmer, CA) was integrated to obtain the one-dimensional (1D) pattern using GSAS-II software.22 In order to enable comparison with the laboratory X-ray data, the 2θ values were converted for Cu Kα radiation. Quantification of Synchrotron XRD Data. Several low intensity peaks could be attributed to the DSC sample holder (i.e., aluminum DSC pans) which can be a serious source of error in the quantification of crystallinity. In order to account for the contribution of the sample pan, the XRD patterns of 15 empty pans were averaged, and their integrated crystalline intensities were subtracted from both the crystalline and the total diffracted intensities. The following modified equation was used for % crystallinity determination,

MATERIALS AND METHODS

Materials. Ketoconazole (C26H28Cl2N4O4; Laborate Pharmaceuticals, Haryana, India; purity >98%) was used without further purification. PAA (Mw (weight-average) ≈ 1800) was purchased from Sigma-Aldrich (Missouri, USA) and PVP (K12 grade, Mw ≈ 2000−3000) was supplied by BASF (New Jersey, USA). PHEMA (Mw ≈ 3700) was custom synthesized by Polymer Source (Quebec, Canada). The polymers were dried at 110 °C for 1 h and stored in desiccators containing anhydrous calcium sulfate until used. Preparation of Amorphous Systems. The preparation method was detailed earlier.15 Briefly, amorphous KTZ was prepared by melting crystalline KTZ at 160 °C and quench-cooling the melt in liquid nitrogen. ASDs were prepared by dissolving the drug (96% w/ w) and polymer (4% w/w) in methanol, followed by solvent evaporation and melt-quenching. Powder X-ray Diffractometry (XRD). Isothermal crystallization growth rate was evaluated using an X-ray diffractometer (D8 ADVANCE, Bruker AXS, WI) equipped with a variable-temperature stage (TTK 450; Anton Paar, Graz-Straßgang, Austria), and a Si strip one-dimensional detector (LynxEye; Bruker AXS, WI). Using Cu Kα

%crystallinity = [total integrated intensity of crystalline peaks − total integrated intensity of crystalline peaks of empty pans]/[total diffracted intensity − total integrated intensity of crystalline peaks of empty pans] × 100

(4)

The % crystallinity in ASDs was normalized to account for the presence of polymer (4% w/w). The % crystallinity was plotted as a 5142



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Figure 1. (a−d) Powder XRD patterns of amorphous KTZ and ASDs held at 85 °C. A baseline correction was applied to all the patterns. The appearance of characteristic KTZ peaks are marked by arrows (first evidence of crystallization). The peak intensities progressively increased as a function of time. For the sake of clarity, all the axes labels are shown only in panel (a).

Figure 2. (a) Crystallization kinetics of amorphous KTZ and ASDs following storage at 85 °C. (b) The data from (a) plotted and fitted using eq 3 (KJMA plots). The slope values were virtually identical (discussed in the text).

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function of time (average of three measurements). The spline interpolation function was used to calculate the time for 2% drug crystallization (t2%) using MATLAB R2015b (MathWorks, Natick, MA). Some representative data are presented in Supporting Information (Figure S1). Dielectric Spectroscopy. A broadband dielectric spectrometer (Novocontrol Alpha-AK high performance frequency analyzer, Novocontrol Technologies, Germany) was used. The instrument was equipped with a temperature controller (Novocool Cryosystem), and the dielectric measurements were performed between 75 and 100 °C, in the frequency range of 10−2 to 106 Hz. The details of sample preparation and relaxation time calculations were provided earlier.15 Polarized Light Microscopy (PLM). The growth morphology of KTZ crystals was studied using polarized light microscopy. The samples were melt-quenched on a glass slide with a coverslip, annealed for 10 days at 75 °C, and observed using a microscope (Nikon Eclipse E200 POL, Japan; equipped with a DS-Fi1 microscope digital camera for capturing digital images).

RESULTS AND DISCUSSION Effect of Strength of Interactions on Crystallization. Powder XRD revealed that the melt-quenched KTZ and the KTZ ASDs were X-ray amorphous (Figure 1; initial time point). The crystallization tendency of the amorphous drug was evaluated isothermally at 75, 80, 85, and 90 °C (Figure 1a; only the results obtained at 85 °C are shown). In amorphous drug, characteristic peaks of KTZ were first evident at 20 min indicating crystallization. In ASDs, the crystallization lag time was polymer-dependent. While the presence of PVP had no effect, in PHEMA dispersions, drug crystallization was first observed at 50 min. PAA was the most effective polymer in inhibiting crystallization as indicated by the longest lag time (∼100 min). We had reported that KTZ interacts very strongly with PAA, moderately with PHEMA, and weakly with PVP.15 Specifically, both ionic and strong H-bonding interactions were observed between PAA and KTZ. In PHEMA and PVP ASDs, the polymer interacted with weak H-bonding and dipole− dipole interactions, respectively. Thus, the strength of drug5143



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polymer interactions and crystallization lag time followed the same order: PAA > PHEMA > PVP. In all cases, once the crystallization had started, there was a progressive increase in KTZ peak intensity as a function of time (Figure 1; data shown up to 300 min), indicating an increase in extent of crystallization. The degree of effectiveness of each polymer in inhibiting drug crystallization was evident by plotting KTZ crystallinity (%) as a function of time. Figure 2a is a representative example of the data obtained at 85 °C. The crystallization kinetics of PVP ASDs was essentially identical to that of KTZ (drug alone), indicating the negligible inhibitory effect of PVP. While PHEMA was effective in retarding crystallization, the effect was most pronounced with PAA. Using the KJMA model (eq 3), the crystallization rate constants were obtained, and Figure 2b is a representative KJMA plot. The slope values, from which the exponent is obtained (i.e., n in eq 3), are virtually identical, suggesting that the crystallization mechanisms are the same for the drug and the dispersion (at low polymer concentrations). The exponent also seemed to be unaffected by temperature and ranged between 1.1 and 1.4 suggesting one-dimensional growth. This was confirmed by polarized light microscopy which revealed growth of needle-shaped crystals of KTZ (Figure 3 and Supporting Figure S2).

PHEMA, and PVP ASDs have crystallization rate constants that are respectively ∼6.4, 2.4, and 1.1 times lower than KTZ. The magnitude of inhibition of crystallization rate and the strength of interactions follow the same order: PAA > PHEMA > PVP. The activation energy, calculated from the Arrhenius plot, was 144 ± 24, 122 ± 9, 172 ± 27, 147 ± 2 kJ/mol for KTZ and ASDs of PAA, PHEMA, and PVP, respectively. The activation energy indicates the temperature dependence of the crystallization rate. No obvious trend was apparent in the values of activation energy for amorphous systems. Coupling of Molecular Mobility and Crystallization. It was earlier observed that an increase in the strength of drug− polymer interactions, by reducing molecular mobility, enhanced the physical stability of ASDs.15 While the molecular mobility of these ASDs was comprehensively evaluated, detailed crystallization studies were not conducted. We therefore expanded the temperature range over which the mobility was measured and also conducted isothermal crystallization studies at several temperatures across this range. The α-relaxation times, over the temperature range of 60−100 °C, is plotted in Figure 5. While PAA caused a substantial decrease in mobility

Figure 3. Photomicrographs of (a) amorphous KTZ and (b) PVP ASDs after annealing at 75 °C for 10 days. In both cases, needleshaped crystals were observed. The scale bar represents 50 μm. Figure 5. Temperature dependence of α-relaxation times in KTZ and in ASDs prepared with PVP, PHEMA, and PAA. Some of the results were reported earlier and have been reused with the permission of the copyright owner. 15 Every data point is the mean of three determinations. In some cases, the error bars were smaller than the symbol size.

In Figure 4, the crystallization rate constants for the different systems have been plotted as a function of inverse temperature (Arrhenius plot). The polymers differed widely in their effect on KTZ crystallization kinetics. For example, at 85 °C, PAA,

(reflected by a marked increase in relaxation time), the effect of PHEMA was much less pronounced. For example, compared with the α-relaxation times of KTZ at 85 °C, PAA and PHEMA caused ∼4.2- and ∼2.1-fold increase in relaxation times. In contrast, there was negligible difference between the αrelaxation times of KTZ and PVP ASDs. Therefore, the increase in physical stability of PAA ASDs, as evident by longer crystallization time, can be explained by the reduction in molecular mobility. Accordingly, the crystallization times appears to be coupled with molecular mobility in ASDs. We further investigated the quantitative relationship between the molecular mobility and crystallization in ASDs. The extent of coupling can be determined using eq 5 given as,13,23 log(tc) = M log(τα) + log A

Figure 4. Temperature dependence of crystallization rate constant in KTZ and in ASDs prepared with PVP, PHEMA, and PAA. The R2 values for the linear regression lines of KTZ and ASDs of PAA, PHEMA, and PVP were 0.95, 0.99, 0.95, and 1.0 respectively. Every data point is the mean of three determinations. Occasionally, the error bars were smaller than the symbol size.

(5)

where tc is the crystallization time defined as the inverse of the rate constant (k in eq 3) and A is a constant that represents the thermodynamic “barrier” to crystallization. The value of coupling coefficient (M) can vary between 0 and 1, where M 5144



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Figure 6. Log−log plot of crystallization time (inverse of crystallization rate constant) versus α-relaxation times. The line represents the linear fit to the data. In some cases, the error bars were smaller than the symbol size.

Figure 7. (a) Fraction crystallized (expressed as % crystallinity) as a function of time in KTZ and in ASDs at 75 °C. (b) The inset in (a) is magnified to show differences in crystallization behavior at early time points.

obtained by dielectric measurements only account for rotational motions. While rotational motions are completely coupled with viscosity, diffusional motions decouple between Tg and 1.2Tg.24−27 For KTZ, our model compound, this temperature range is 319−383 K (46−110 °C). The crystallization and mobility data in Figure 6 have been reported over this range. Interestingly, the coupling coefficient for ASDs were close to that of the drug. The values were 0.46 (±0.06), 0.60 (±0.07), and 0.52 (±0.03) for ASDs with PAA, PHEMA, and PVP respectively. These results suggest that the presence of polymer as well as the strength of drug−polymer interactions do not influence the extent of coupling between molecular mobility

= 1 would indicate that these two processes are completely coupled. The coupling coefficient value for amorphous KTZ was 0.49 ± 0.06 (Figure 6a; the temperature range 75−90 °C), in reasonable agreement with the reported value of ∼0.35 over the temperature range of 50−60 °C.11 These results indicate modest but not substantial coupling between molecular mobility and crystallization time in KTZ system. The reported coupling coefficient values (M) in felodipine, spray dried sucrose, freeze-dried sucrose, nifedipine, and griseofulvin, were ∼0.43, 0.49, 0.54, 0.62, and 0.65 respectively.9,11,13 The weak coupling may be attributed, at least partially, to the decoupling of translational diffusion with viscosity. The molecular mobility 5145



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and crystallization time. In an earlier investigation, similar studies were conducted in ASDs of itraconazole, a structural analogue of KTZ. The M values for itraconazole (drug alone), and ASDs of itraconazole with each PVP and HPMCAS were 0.68, 0.78, and 0.85 respectively. In a more recent investigation, the coupling between molecular mobility and time for 10% of the drug to crystallize was investigated. In nifedipine-PVP ASDs (2.5% w/w polymer concentration, strong H-bonding) the coupling coefficient was 0.67 ± 0.07, while it was 0.62 ± 0.05 for nifedipine.13 Estimating Crystallization Times Using Molecular Mobility. The effect of each polymer on the molecular mobility of the ASDs was evident from Figure 5. Since the coupling between mobility and crystallization time seemed to be unaffected by the presence of the polymer (4% w/w), we attempted to predict the crystallization times in ASDs using the coupling coefficient determined for amorphous KTZ. If this approach is successful, then molecular mobility can serve as a tool to identify polymers which can stabilize (longest delay in crystallization) the drug in the ASDs. The prediction of the crystallization time was accomplished in three steps. First, the extent of coupling between mobility and crystallization time was determined in KTZ between 60 and 75 °C, a temperature range close to Tg (∼46 °C). Second, the crystallization and relaxation times in ASDs were experimentally determined at 75 °C, which facilitated the calculation of the value of the constant A in eq 5. Finally, the crystallization times of ASDs were predicted, using the calculated value of A. As mentioned earlier, it is assumed that the coupling coefficient value (slope of the line in eq 5) was the same for the drug and the ASDs. At the highest experimental temperature (75 °C), irrespective of the polymer, crystallization was quite rapid (Figure 7a). The early time points have been magnified in Figure 7b. As observed earlier, PAA had a pronounced crystallization inhibitory effect, evident from the long lag time and slow crystallization. At lower temperatures, crystallization was very slow, and it was not possible to monitor the entire crystallization kinetics. Therefore, the time for 2% of the drug to crystallize was determined (details discussed in Methods). The coupling coefficient of amorphous KTZ, based on measurements over the temperature range of 60−75 °C, was 0.50 ± 0.05 (Figure 8). This value is in good agreement with the determination over the temperature range of 75−90 °C (Figure 6). By substituting the values of M (i.e., 0.5) and the experimentally determined values of t2% and τα at 75 °C in eq 5, the value of A was calculated for each ASD. This enabled us to predict the crystallization times based on the experimentally determined τα values at 60, 65, and 70 °C (Table 1). As expected, the predicted crystallization time was longest for PAA ASDs. The crystallization times of the ASDs were also experimentally determined at 60, 65, and 70 °C using synchrotron radiation (Table 1). The predicted values were in very good agreement with the experimental values for PAA ASDs. At 60 °C, the predicted value was shorter than the experimental crystallization time, while it was the reverse at 70 °C. In the other two dispersions (PHEMA and PVP), there was a more pronounced deviation between the predicted and experimental crystallization times. Moreover, the actual crystallization times were consistently shorter than the predicted values. The deviation of the predicted crystallization times from the experimental values can be attributed to the difference between the assumed and experimentally determined values of the

Figure 8. Log−log plot of crystallization time versus α-relaxation time. For amorphous KTZ, the experiments were carried out at 60, 65, 70, and 75 °C (green circles). The solid green line represents the linear fit to the experimental data. For ASDs, initially the measurements were made only at 75 °C (black, blue, and red circles). These experimental data points formed the basis for the generation of the dashed lines, describing the predicted relationship between crystallization time and relaxation time for the PAA (black), PHEMA (blue), and PVP (red) ASDs. The equations of the predicted lines for PAA, PHEMA, and PVP dispersions are y = 0.50x + 6.03, y = 0.50x + 5.90, and y = 0.50x + 5.87 respectively. The agreement between the predicted and the experimental crystallization times is provided in Figure 9.

coupling coefficient. We have assumed that the coupling coefficient value (slope of the line in eq 5) was the same for the drug and the ASDs. This is the subject of detailed discussion later. Moreover, since molecular mobility is not completely coupled to crystallization times, we expect factors other than mobility to influence crystallization. The coupling coefficient values obtained from experimentally determined mobility and crystallization data were 0.55 (±0.03), 0.36 (±0.02), and 0.39 (±0.03) for ASDs with PAA, PHEMA, and PVP respectively (Figure 9). The time for crystallization (t c ) was also determined following 1 and 5% KTZ crystallization. These data were used to determine the coupling coefficient. The coupling coefficient values were essentially identical (Supporting Information, Table S3). Interestingly, Caron et al. observed a pronounced difference in the coupling coefficient values between the drug (phenobarbital) and its dispersion (with 5% w/w PVP).12 Nevertheless, on the basis of the predicted crystallization times, the crystallization inhibition by polymers can be rank ordered as PAA > PHEMA > PVP, which is in agreement with the experimental observation. A high polymer concentration in ASDs, as is typically observed in commercial products, can significantly reduce mobility and consequently delay crystallization. This can be an especially challenging problem if the temperature is lowered. Considering the long lag times and slow crystallization kinetics in ASDs, our approach can provide a screening tool for polymer selection and a rough estimation of crystallization times during formulation development. For example, at 60 °C, when compared with KTZ, the presence of 4% w/w PAA caused a ∼8-fold increase in relaxation time (Figure 6). The reduction in mobility translated to a pronounced increase in crystallization lag time, evident from the synchrotron studies (Figure 10). The amorphous nature of the dispersions was evident from the absence of any Bragg reflections, i.e., Debye rings in the freshly prepared dispersions (Figure 10a; upper panel). After storage at 60 °C for 48 h, 5146



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Table 1. Comparison of the Predicted and Experimental Crystallization Times in KTZ ASDsa time for 2% crystallization (min) 4% PAA ASDs

4% PHEMA ASDs

4% PVP ASDs

temperature (°C)

predicted

experimental

predicted

experimental

predicted

experimental

60 65 70

4445 1577 669

5820 1584 606

1446 603 283

731 373 202

1013 422 199

589 339 154

a The relaxation times experimentally determined at each temperature enabled the prediction of the crystallization time using eq 5. The equations used to predict crystallization from PAA, PHEMA, and PVP dispersions are provided in the legend of Figure 8. These “predicted” crystallization times are then compared with the experimentally determined crystallization time.

Figure 9. Log−log plot of crystallization time versus α-relaxation times for KTZ ASDs. The plot of amorphous KTZ (presented in Figure 8) is again provided for reference. The solid black line represents the linear fit to the data (the equation is given in each panel), and the dotted red lines are the predicted crystallization times as a function of experimentally determined relaxation times (the equations of the lines given in the legends of Figure 8) for ASDs. The error bars are sometimes smaller than the size of the symbol.

valuable to predict the effect of processing at a high temperature for a short time period. The other potential applications include the effect of a transient excursion to an elevated temperature either during transport or inadvertently by the patient. For example, using the crystallization time determined at 60 °C, the behavior was predicted at 65, 70, and 75 °C. In this case as well, there was a good agreement between the predicted and experimental values (Supplementary Figure S4 and Table S5). Our results show that the strength of drug−polymer interaction strongly influences the drug crystallization in dispersions. Polymers that interact strongly with the drug provide an avenue for physical stabilization of ASDs. This approach is restricted to ionizable drugs. Since a large fraction of drugs are weakly acidic or basic, this strategy may be widely applicable. Hydrogen bonding between drug and polymer

diffraction rings reflecting drug crystallization were observed in all the systems except in the PAA dispersion. The effectiveness of PAA in inhibiting crystallization is evident from Figure 10b. A substantial fraction (>75%) of amorphous KTZ had crystallized following storage at 60 °C for 48 h. On the other hand, in the PAA dispersion, there was no evidence of drug crystallization after 48 h. The first evidence of crystallization was observed after ∼96 h (Figure 10b). So far, we have attempted to predict crystallization at lower temperatures (60, 65, and 70 °C), based on the experimentally studied crystallization at a higher temperature (75 °C). Such “accelerated stability” studies can be useful to predict the crystallization behavior at ambient or subambient (for example, refrigeration storage) conditions based on studies at elevated temperatures. The reverse approach, studying the crystallization behavior at low temperatures and predicting physical stability at higher temperatures, is also possible. Such an approach can be 5147



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predicted and experimental values of crystallization times in KTZ ASDs (PDF)

AUTHOR INFORMATION

Corresponding Author

*Address: Department of Pharmaceutics, College of Pharmacy, University of Minnesota, 9-177 WDH, 308 Harvard Street S.E., Minneapolis, MN 55455. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The project was partially funded by the William and Mildred Peters Endowment Fund and Centre for Pharmaceutical Processing and Research. 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 are thankful to Dr. Gregory Halder and Dr. Wenqian Xu at Argonne National Laboratory for their help during the synchrotron data collection.

Figure 10. (a) Two-dimensional XRD patterns of amorphous KTZ and ASDs with each PVP, PHEMA, and PAA. (a) Upper panel: Freshly prepared dispersion. (b) Lower panel: Stored at 60 °C for 48 h. (b) One- dimensional XRD patterns of KTZ and PAA ASDs stored at 60 °C for different time periods. The XRD pattern of crystalline KTZ (“as is”) is provided for reference. Some characteristic peaks of KTZ (*) and the sample holder ($) are pointed out.

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provides another avenue for drug stabilization. This approach can be particularly relevant for nonionizable drugs.

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CONCLUSIONS The influence of specific drug−polymer interactions on KTZ crystallization from amorphous dispersions was studied. PAA, a polymer that strongly interacts with KTZ, was most effective at inhibiting drug crystallization in ASDs. In comparison to PAA, PHEMA (moderately interacting polymer) was less effective, and negligible crystallization inhibition was observed with PVP. An increase in the strength of drug−polymer interactions reduced the molecular mobility and resulted in longer crystallization onset times and slower crystallization kinetics. The α-relaxation time of amorphous KTZ was moderately coupled with the crystallization kinetics. The extent of coupling between relaxation and crystallization times was unaffected by both the presence of polymer (4% w/w) and the strength of drug−polymer interactions. This formed the basis to predict the time for drug crystallization from dispersions. The predicted and the experimental crystallization times were in reasonably good agreement, establishing the utility of the prediction model. This approach demonstrates the potential of molecular mobility to predict the crystallization time scales in ASDs and provide a basis for rational polymer selection.

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REFERENCES

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.6b00714. Figure showing spline interpolation to determine 2% crystallinity, figure showing needle-shaped crystals observed on crystallization from PAA ASDs, tabulated comparison of coupling equations obtained using time for 1, 2, or 5% crystallization, plot of relaxation time versus crystallization time showing predicted and experimental values, and tabulated comparison of 5148



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