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Effect of Polymer Molecular Weight on the Crystallization Behavior of Indomethacin Amorphous Solid Dispersions Sarat Mohapatra, Subarna Samanta, Khushboo Kothari, Pinal Mistry, and Raj Suryanarayanan* College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, United States S Supporting Information *

ABSTRACT: The influence of the molecular weight of polyvinylpyrrolidone (PVP) on the molecular mobility and physical stability of indomethacin (IMC)− PVP solid dispersions was investigated over a wide temperature range in the supercooled state. As the polymer molecular weight increased, there was a decrease in molecular mobility as evident from the longer α-relaxation times. Inhibition of IMC crystallization also increased as a function of polymer molecular weight. The extent of H-bonding interaction between drug and polymer, quantified by ssNMR, was independent of polymer molecular weight. Over a polymer concentration range of 5−20% w/w, the temperature dependence of mobility and viscosity was reasonably similar for different grades of PVP. It was concluded that the increase in effectiveness in crystallization inhibition as a function of polymer molecular weight is due to the increased viscosity, which slows down the mobility of these systems.

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INTRODUCTION

as crystallization inhibition. Thus, the stabilization of the system is brought about by reducing the mobility. The risk of drug crystallization can be minimized or eliminated by using a high polymer concentration in the dispersion. However, this approach will not be practically feasible if the drug dose is high. An added limitation is that, above a certain polymer concentration, the drug−polymer interaction can become “saturated”. For example, in indomethacin−PVP amorphous dispersion, at 40% w/w PVP concentration, most of the drug was hydrogen bonded to PVP.7 Above this polymer concentration, drug−polymer interaction cannot be the basis for stability enhancement. The molecular weight of the polymer provides another avenue to overcome the above-mentioned limitations. An increase in polymer molecular weight was reported to enhance the physical stability of the drug in the dispersion.8−10 However, a fundamental understanding of the mechanism governing the physical stability is required. We hypothesize that an increase in polymer molecular weight, by reducing the molecular mobility, enhances the physical stability of the ASDs. However, increasing the polymer molecular weight will also result in an increase in viscosity. For example, when the in vitro performance of PVP K17 and K90 was compared, the high viscosity of the latter was responsible for the decrease in dissolution rate of piroxicam from ASDs.11 Furthermore, increasing the polymer chain length can make it less flexible, which may affect the extent of interaction between drug and

Numerous polymers are available to formulate poorly soluble drugs as amorphous solid dispersions (ASD).1 Such an approach, by converting the crystalline drug to its amorphous state, can enhance its solubility and potentially the oral bioavailability.2 The polymer can also enhance the physical stability, i.e., prevent crystallization of the amorphous drug from the dispersion. The stabilizing effect of the polymer can be attributed to its effect on the molecular mobility of the system. For example, α-relaxation time (a measure of global molecular mobility) of amorphous itraconazole was compared with that of its dispersion with hydroxyproplymethylcellulose (HPMC). HPMC considerably increased the relaxation time (reflecting a decrease in molecular mobility) as well as the crystallization onset time revealing a correlation between mobility and stability.3 In a follow-up investigation, the effect of polymer concentration on the mobility and stability of nifedipine− polyvinypyrrolidone (PVP) dispersions was systematically investigated.4 With an increase in polymer loading, there was a progressive decrease in the molecular mobility, and the time for nifedipine crystallization was longer. Importantly, molecular mobility served as an effective predictor of nifedipine crystallization. The strength of interaction between drug and polymer provides another avenue to enhance the stability of the drug in the dispersion.5 Ionic interaction between ketoconazole and poly(acrylic acid) translated to a pronounced decrease in molecular mobility as well as crystallization inhibition.6 Hydrogen bonding of the drug with poly(2-hydroxyethyl methacrylate) (PHEMA), an interaction much weaker than ionic interaction, had a much smaller effect on mobility as well © XXXX American Chemical Society

Received: January 20, 2017 Revised: April 21, 2017

A

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was accurately weighed in a glovebox (≤5% RH) 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. Data were analyzed using Universal Analysis software (TA Instruments, New Castle, DE). Dielectric Spectroscopy (DES). A broadband dielectric spectrometer (Novocontrol) was used for the measurements of complex permittivity (ε* = ε′ − iε″). The samples were analyzed as tablets, although the dielectric relaxation data were compared with sample configuration as powders and films. No significant differences were observed across all these sample configurations. Four hundred milligrams of powder was compressed into 19 mm tablets under a compression pressure of 69 MPa. The tablet was placed between two stainless steel electrodes, and the dielectric loss was measured in the frequency range of 10−2 to 107 Hz. Isothermal measurements were conducted, in 2 °C increments, from 0 to 100 °C. The Havriliak− Negami (HN) model (eq 2) was used to fit the dielectric data so as to obtain the average α-relaxation time (τ).13

polymer thereby compromising the stabilization brought about by the drug−polymer interaction. In this paper, indomethacin (IMC) and poly(vinylpyrrolidone) (PVP) were chosen as the model drug and polymer, respectively. Amorphous indomethacin has a high propensity to crystallize. PVP, a widely used pharmaceutical excipient, has a much higher Tg than IMC which will help in reducing the mobility by its antiplasticization effect. Hydrogen bonding between drug and polymer can also provide stabilization of the resultant ASD by favoring miscibility, preventing the tendency for phase separation, and reducing the thermodynamic driving force for crystal nucleation and growth. This study had the following objectives: (i) Investigate the influence of the formulation variables (polymer concentration and molecular weight) on the molecular mobility (measured as α-relaxation time) of ASDs. (ii) Since the drug and polymer interact by hydrogen bonding, spectroscopically determine the influence of polymer molecular weight on the drug−polymer interaction. Solid state NMR spectroscopy was used for this purpose. (iii) Evaluate the crystallization behavior of the ASDs and determine the coupling between physical stability and mobility in the ASDs. We hypothesize that molecular mobility is the determinant of physical stability.

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MATERIALS

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EXPERIMENTAL SECTION

ε*(ω) = ε′(ω) − iε′′(ω) εs − ε∞ = ε∞ + − i[σ0/ε0ω]N [1 + (iωτ )βHN ]γHN

In this equation, ε′ (ω) and ε″ (ω) are the real and imaginary components of the complex permittivity, ε*(ω). ε∞ and εs are the limiting dielectric permittivities at high and low frequencies respectively, ε0 is the vacuum permittivity (8.85 × 10−12 F/m), while βHN and γHN (0 < βHN, βHNγHN < 1) represent the symmetric and asymmetric shape parameters of the relaxation peak respectively, and σ0 is the conductivity. Solid State NMR (ssNMR). 13C spectra were acquired (Bruker ADVANCE III-500 spectrometer), using 4 mm double resonance probe, under magic angle spinning using cross-polarization (CP/ MAS). Typical operating conditions included a contact time during CP of 2 ms, a recycle delay of 6 s, and a spin rate of 8 kHz. 13C chemical shifts were externally referenced to tetramethylsilane (TMS). Approximately, 300 mg of the sample was used for each run. Rheology. The viscosity of the pure drug and ASDs were measured with a viscometer equipped with a forced convection oven (ARES G2, TA Instruments). The measurements were done in parallel plate configurations (Ø25 mm) in oscillatory mode with continuous nitrogen purge. Approximately 300 mg of sample was placed on the bottom plate, and then the gap was closed by bringing down the upper plate until a normal force was recorded. The samples were heated to approximately 160 °C, held for a minute and then cooled to 130 °C. At first, a dynamic strain sweep was recorded at a fixed frequency of 1 rad/s in the strain range of 0.1−100% and linear viscoelastic behavior was confirmed. Then dynamic frequency sweep test was performed at a fixed strain (usually 0.1−1%) within the frequency range of 0.1−100 rad/s, and complex viscosity values were recorded. The procedure was repeated at 10 °C intervals, usually up to 80 °C. After each cooling step, the sample was equilibrated at the desired temperature for 2 min. For plotting the viscosity as a function of temperature, the complex viscosity at a frequency of 1 rad/s was used.

IMC (γ-form) was a gift from Laborate Pharmaceuticals (Haryana, India). The three grades of PVP used had average molecular weights of ∼50 000 (PVP K30), ∼9000 (PVP K17), and ∼2500 (PVP K12) and were gifts from BASF (New Jersey, USA). Methanol (HPLC grade) was purchased from Sigma-Aldrich (Missouri, USA). All chemicals were used without further purification.

Preparation of Amorphous Materials. Amorphous IMC was prepared by melting crystalline IMC (at ∼175 °C) in aluminum cups and quench cooling in liquid nitrogen. The polymers were dried at 100 °C for 2 h before they were used for the preparation of ASDs. The ASDs were prepared by a solvent evaporation technique followed by melt quenching. Briefly, physical mixtures of IMC (95−70% w/w) and the polymer (5−30% w/w) were dissolved in methanol. The solvent was then evaporated at 50 °C under reduced pressure (IKA-HB10, Werke GmbH and Co., Germany). ASDs in the flask were dried for 12 h in a vacuum desiccator and were subsequently melt quenched as described earlier.4 X-ray Diffractometry. A powder X-ray diffractometer (D8 ADVANCE; Bruker AXS, Madison, WI) equipped with a variable temperature stage (TTK 450; Anton Paar, Graz-Straβgang) and a onedimensional silicon detector (LynxEye, Bruker AXS) was used. An Xray source emitting Cu Kα radiation (40 kV × 40 mA) was used, over the angular range of 5−40° 2θ, with a step size of 0.05° and a dwell time of 1 s. Baseline characterization was done at room temperature. For isothermal crystallization studies, powder samples were held at the desired temperature (between 80 and 100 °C), and the XRD patterns were collected. Nitrogen was continuously purged in the sample chamber. The percent crystallinity (sometimes expressed as fraction crystallized) was calculated based on the following equation:12

% crystallinity =

intensity of the crystalline peaks × 100% total diffracted intensity

(2)

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RESULTS AND DISCUSSION Baseline Characterization. The melt-quenched IMC as well as the IMC ASDs were observed to be X-ray amorphous (data not shown). The DSC of IMC revealed a Tg at 46 °C followed by a crystallization exotherm at 105 °C (Figure S1A; Supporting Information). IMC crystallized predominantly as the γ-polymorph which melted at 160 °C. The melting endotherm observed at 150 °C can be attributed to the αpolymorph. Literature reports indicate that on cooling amorphous indomethacin a mixture of IMC polymorphs were obtained, with the composition dependent on the cooling rate.14

(1)

The percent crystallinity was plotted as a function of time, and a characteristic crystallization time (tc) was defined as the time taken for 5% of the drug to crystallize. Differential Scanning Calorimetry (DSC). A differential scanning calorimeter (DSC) (Q2000, TA Instruments, New Castle, DE) equipped with a refrigerated cooling accessory was used. The instrument was calibrated with indium and sapphire discs. The powder B

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therefore of interest to study the molecular mobility of the dispersions. Temperature dependence of the dielectric loss curves in IMC−PVP ASDs was monitored using dielectric spectroscopy in the supercooled state (α-relaxation range). With an increase in temperature, the dielectric loss peak for α-relaxation shifted to higher frequencies, indicating an increase in the global mobility of the system, i.e., shorter relaxation times (Figure S3A; Supporting Information). This is expected because of the reduction in viscosity of the solid dispersion with an increase in temperature. A similar trend in temperature dependence of dielectric loss vs frequency was observed in dispersions prepared with PVP K12 and K17 (not shown). The dielectric loss curves showed a dc conductivity (σ0) contribution, which was pronounced at lower frequencies (eq 2). This contribution was subtracted from the total loss (an example is shown in Figure S3B; Supporting Information). All our data have been plotted with subtracting the conductivity contribution. The effect of polymer concentration on molecular mobility is evident from Figure 2. An increase in polymer concentration

The glass transition temperatures of the different grades of PVP could be readily discerned from their DSC curves (Figure S1B; Supporting Information). The water content in all the ASDs was 15% w/w. The DSC results of the ASDs prepared with the different grades of PVP (5−30% w/w) are summarized (Table S1; Supporting Information). Irrespective of the polymer molecular weight, no crystallization exotherm was observed when the polymer concentration was >15%. PVP showed a similar inhibitory effect on celecoxib crystallization in ASDs at concentrations ≥20%.16 Next, the influence of polymer molecular weight was investigated. At 5% w/w polymer concentration, the molecular weight of polymer did not influence the Tg of the ASD (Table S1; Supporting Information). These results are in excellent agreement with previously reported Tg values for IMC−PVP ASDs.15 As the polymer molecular weight increased, the IMC crystallization exotherm was shifted to higher temperatures (Figure 1). The peak crystallization temperature was observed

Figure 2. Frequency dependence of ε″ in IMC−PVP K30 ASDs (at 80 °C). The polymer concentration ranged from 5 to 30% w/w. For simplicity, the DC conductivity contribution was subtracted, and the curves were normalized with respect to the maximum loss value.

shifted the α-relaxation peak to a lower frequency, indicating a decrease in molecular mobility. Dielectric loss data were used to calculate the relaxation times as a function of temperature using the Havriliak−Negami model (eq 2). A similar effect of polymer concentration on molecular mobility was observed in both nifedipine and ketoconazole ASDs.4,6 The effect of polymer concentration on the relaxation time was comprehensively evaluated by plotting the temperature dependence of α-relaxation time for IMC−PVP K30 ASDs, over a polymer concentration range of 5−30% w/w (Figure 3). The temperature dependence of the relaxation time was described by the VTF model18,19 given by

Figure 1. DSC heating curves of IMC ASDs prepared with each PVP K12, 17, and 30. The polymer concentration was 5% w/w. The melting endotherms of the α- and γ-forms are pointed out.

at 110, 118, and 124 °C in ASDs with PVP K12, K17, and K30 respectively (5% w/w polymer). A similar trend was observed in a previous study of lactose−PVP dispersions.8 The polymer molecular weight also influenced the polymorphic composition of the crystallizing IMC (α- and γ-forms). With an increase in molecular weight, there seems to be preferential crystallization of the γ-form (Figure S2; Supporting Information). Our results indicate that the polymer molecular weight can provide an avenue for selecting the polymorphic form of indomethacin crystallizing from the amorphous state. However, more detailed studies are needed before any firm conclusions can be drawn. Influence of Polymer Molecular Weight on Molecular Mobility. The results presented in Figure 1 clearly indicate that the polymer molecular weight had a pronounced influence on the crystallization behavior of IMC. We had earlier documented a coupling, in some instances very strong, between molecular mobility and crystallization from dispersions.17,4 It was

⎡ DT0 ⎤ τ = τ0 exp⎢ ⎥ ⎣ (T − T0) ⎦

(3)

where τ is the relaxation time at temperature T, τ0 is the relaxation time at very high temperature (taken as 10−14 s),20 D is the strength parameter, and T0 is the zero mobility temperature often associated with the Kauzmann temperature.21,22 The VTF fit to the relaxation data are shown as solid lines in Figure 3. The m values (a measure of fragility) of IMC and the ASDs varied between 79 and 94, indicating that both the drug and the dispersions were quite fragile (Table S2; C

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increase in molecular weight or polymer concentration has the same effect on mobility. Considering the correlation between molecular mobility and crystallization time, this would suggest an increase in physical stability with increasing molecular weight of the polymer (PVP K30 > PVP K17 > PVP K12). However, in our model system, there is a confounding factor. IMC hydrogen bonds with PVP, and the influence of molecular weight on the drug polymer interaction is not known. This was evaluated using spectroscopic techniques. IMC Crystallization. Our DSC experiments had indicated that PVP at a polymer concentration >15% w/w completely inhibited IMC crystallization (Figure S1A; Supporting Information). There was no evidence of crystallization in ASDs (20% PVP; K12, K17, or K30) held at 80 °C in the X-ray stage for 10 h (data not shown). We had also observed that IMC− PVP K90ASDs (20% w/w polymer) was physically stable (again no evidence of crystallization) when stored at 70 °C for more than 20 days. The ASD retained its noncrystalline character for more than 18 months at 25 °C. In light of the concentration-dependent crystallization inhibitory effect of PVP, our crystallization studies were restricted to ASDs with a polymer concentration of 10% w/w. The crystallization kinetics appeared to be virtually identical for the dispersions prepared with PVP K12 and K17 (Figure 5).

Figure 3. Temperature dependence of α-relaxation time (τα) in IMC− PVP K30 ASDs. The PVP concentration ranged from 0 to 30% w/w, and the VTF fits to the data are shown as red lines. The vertical error bars indicate standard deviation with 3−5 replicates.

Supporting Information). At a low concentration of 5% (w/w), the polymer did not have a significant influence on the relaxation time. But at a polymer concentration of 30% w/w, at any given temperature, there is a more than 5 orders of magnitude increase in the relaxation time with respect to amorphous IMC. This can be partially explained by the increase in viscosity due to the presence of the polymer at a concentration of 30% w/w. In addition, the hydrogen bonding between the drug and polymer is also expected to have a pronounced effect on mobility. These effects are discussed in detail later. A similar, but relatively less pronounced, influence of the polymer concentration on the relaxation time was observed for PVP K12 and PVP K17 ASDs (Figures S4 and S5; Supporting Information). In order to determine the effect of molecular weight on mobility, the dielectric loss curves of the dispersions, at a fixed polymer concentration of 20% w/w, have been compared (Figure 4). It is evident from the figure that, qualitatively, an

Figure 5. Fraction of IMC crystallized from ASDs prepared with each PVP K12, K17, and K30. The dispersions were stored at 80 °C. The lines are drawn to assist in visualizing the trends.

About 30% of the IMC crystallized in 10 h. The two dispersions had very similar α-relaxation times at 80 °C: 1.59 × 10−4 and 1.96 × 10−4 s (for the K12 and K17 dispersions, respectively). IMC crystallized as a mixture of the α- (predominant) and γpolymorphs. However, in the case of the K30 ASD, with a much longer relaxation time of 3.42 × 10−4 s, only 25% of the IMC crystallized over a 24 h period. Because the effect of PVP K12 and K17 were virtually identical with respect to both crystallization onset and kinetics, further studies were conducted only with one lower (PVP K12) and one higher molecular weight (PVP K30) polymers. The effect of these two grades of polymers on IMC crystallization was compared at two more temperatures (Figure 6). The αrelaxation time at 85 °C, for K12 and K30 dispersions were 4.85 × 10−5 and 9.45 × 10−5 s respectively, while at 90 °C, the relaxation times were 1.66 × 10−5 and 2.97 × 10−5 s, respectively. Thus, an increase in molecular weight of PVP from 2500 to 50 000 caused the relaxation time to be approximately doubled. Thus, at a fixed polymer concentration, ASD prepared with the higher molecular weight polymer exhibited reduced molecular mobility, which further translated

Figure 4. Frequency dependence of ε″ for PVP−IMC ASDs prepared with each PVP K12, K17, and K30. The spectra were recorded at 80 °C, and the polymer concentration was 20% w/w. The solid lines in the plots are the HN fit to the dielectric loss data. For simplicity, the DC conductivity was subtracted, and the curves were normalized with respect to the maximum loss value. D

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and 1.14Tg, we expect a decoupling between translational and rotational motions.25 In our earlier investigation of the influence of PVP concentration on nifedipine crystallization, a coupling value of ∼0.67 was observed.4 Our results therefore suggest a significant coupling between mobility and crystallization. The polymer molecular weight influences crystallization by its effect on molecular mobility. ssNMR Study. A confounding factor in our investigation is the hydrogen bonding between IMC and PVP.26 We had observed that the strength as well as extent of interaction between drug and polymer can influence the mobility and the physical stability of the dispersion.27,5 In this system, since we have only varied the polymer molecular weight (the interacting functional groups are the same), the strength of interaction between IMC and PVP is expected to be unaffected. It was therefore important to determine the effect of polymer molecular weight on the extent of drug−polymer interaction. In an earlier investigation, based on IR spectroscopy, the authors reported that the molecular weight of PVP did not influence the strength of hydrogen-bonding interactions with felodipine molecules.9 The conclusion was based on the magnitude of the peak shift (of the drug) and peak broadening, both of which were reported to be unaffected by the polymer molecular weight. Our goal was to quantify the fraction of drug hydrogen bonded to the polymer, as a function of polymer molecular weight. This could not be accomplished with IR spectroscopy. Yuan et al. used ssNMR to quantify the hydrogen bonding interactions in both amorphous IMC and in ASDs of IMC with different concentrations of PVP.7 This was accomplished by deconvolution of the carboxylic acid carbon peaks in the spectra. We followed this approach to quantify the hydrogen bonding interactions in ASDs prepared with PVP of different molecular weights. As a first step, we measured the 13C shift for amorphous indomethacin (Figure 8). Following the procedure described by Yuan et al, the spectrum was deconvoluted to identify the different “chemical species” related to the carboxylic acid group in indomethacin (Table 1).7 Compared to amorphous IMC, in the ASDs, there is a pronounced decrease in the concentration of the carboxylic

Figure 6. Fraction of IMC crystallized from ASDs prepared with each PVP K12 and K30. The storage temperatures were 85 and 90 °C. The lines are drawn to assist in visualizing the trends.

to increased resistance to crystallization (increased physical stability). Molecular mobility had been used to estimate the crystallization rate and predicting the physical stability of the amorphous solid dispersions.23,24 In several of our previous investigations, we had used the coupling model to investigate the relationship between molecular mobility and crystallization propensity. The coupling between molecular mobility (τα) and crystallization time scale (tc) can be described by eq 4. ln(tc) = M ln τα + ln A

(4)

The coupling coefficient M provides a measure of the extent of coupling between τα and tc and A is a constant. An M value of 1 would reflect that the two processes are “perfectly” coupled. A plot of the crystallization time versus structural relaxation time was linear (Figure 7), and the M values (slope of the fit lines; Figure 7) give the coupling coefficient values (0.73 and 0.74 for PVP K12 and K30 respectively). The time for 5% of the drug to crystallize was arbitrarily chosen. In an earlier investigation, we had documented that the extent of crystallization (2.5−10%) did not affect the coupling coefficient.12 Since τα is a measure of the rotational relaxation time and our experimental temperature range is between 1.03Tg

Figure 7. Log−log plot of crystallization time (tc) versus α-relaxation time (τα) for IMC ASDs (10% w/w polymer) prepared with (a) PVP K12 and (b) PVP K30. Regression equation is given in the graph. Each data point in the figure represents a unique temperature. E

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acid dimers and an increase in the carboxylic acid complex7,26 This effect is attributed to the progressive increase in the extent of hydrogen bonding interactions between drug and polymer as a function of PVP concentration. This was confirmed in our systems (Figure 9). With increasing polymer concentration, the intensity ratio of the carboxylic acid dimer to the complex decreased [panel a]. The intensities of these species provide a measure of the extent of drug−polymer interaction. At a fixed polymer loading, the molecular weight had no effect on this ratio [panel b]. The free carboxylic acid and the carboxylic acid chain are no longer discussed since they are not relevant for the discussion. In order to quantify the drug−polymer interaction, the integrated intensities of the peaks attributed to the dimer and the carboxylic acid complex species were obtained for all the ASDs. This was accomplished by first deconvoluting all the ssNMR spectra (as in Figure 8; deconvoluted spectra of all the ASDs are provided as Supporting Information, Figure S6). We calculated the intensities of the peaks attributed to the cyclic dimer and the carboxylic acid complex and also the overall fitted curve. The areas, expressed as percent, are plotted in Figure 10. The addition of PVP to amorphous IMC caused a pronounced decrease in dimer peak intensity and increase in carboxylic acid complex species. However, the polymer molecular weight appeared to have little effect, if any, on the % peak area of both the species. This strongly suggests that the drug−polymer interaction is unaffected by the polymer molecular weight. When the experiments were repeated with a lower polymer concentration of 10% w/w, the results were substantially similar (Figure 10). Viscosity. The drug−polymer interaction appeared to be independent of the polymer molecular weight. Therefore, for our dispersions, the influence of drug polymer interactions on the crystallization inhibition of indomethacin can be ruled out. The increased crystallization inhibition as a function of molecular weight can be attributed to reduction in molecular mobility. The inverse relationship between mobility and viscosity is well-known in single component systems (pure liquids). We are dealing with molecular dispersions composed of compounds with widely differing molecular weights.

Figure 8. 13C ssNMR spectrum of the carboxylic acid region of amorphous IMC is shown. The experimental spectrum is plotted in black and the overall fitted curve is in orange. The individual Gaussian curves were obtained by deconvolution of the 13C ssNMR spectrum.7 The peak (∼168 ppm) is not attributed to the carboxylic acid group and will not be considered further. The chemical species responsible for the rest of the peaks are provided in Table 1. The peak due to PVP in Table 1 only appears in the IMC−PVP ASDs (Supporting Information; Figure S6).

Table 1. Peak Positions of the Different “Chemical Species” in IMC and IMC−PVP ASDs Obtained by Deconvolution of Its 13C Spectrum (Supplementary Information, Figure S6) species cyclic dimer PVP carboxylic acid chain (disordered) carboxylic acid complex free carboxylic acid

peak position (in ppm)

Gaussian curve color

179.28 ± 0.21 177.67 ± 0.09 175.57 ± 0.09

green dark cyan (dotted) blue

172.26 ± 0.06 169.8 ± 0.37

red pink

Figure 9. Overlaid 13C ssNMR spectra of the carboxylic acid region of indomethacin and its solid dispersions with PVP. (a) ASDs prepared with PVP K30 (10 and 20%). (b) ASDs prepared with different PVP grades at a fixed polymer concentration of 20% w/w. F

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Further increase in polymer concentration continued to have a pronounced effect. At 20% (PVPK12/PVPK17) there was almost 2 orders of magnitude increase in viscosity when compared to IMC. Increase in polymer molecular weight (K30), while keeping the polymer concentration at 20%, resulted in up to 3 orders of magnitude increase in viscosity. We compared the effect of polymer molecular weight on the changes in mobility and viscosity over a wide temperature range. The addition of 10% PVPK12/PVPK17 to amorphous IMC caused approximately an order of magnitude increase in relaxation timevery similar to the effect observed on viscosity. Interestingly, with 10% PVP K30, only a small increase in relaxation time was observed while the viscosity increase was pronounced. The influence of polymer concentration on the changes in mobility as well as viscosity over a wide temperature range were very similar for both K12 and K17. While the results are not unambiguous, for the most part, the temperature dependence of mobility and viscosity are similar for different grades of PVP and over the investigated polymer concentration range. At a higher polymer concentration of 20%, the changes in mobility and viscosity over a wide temperature range were very similar for all the polymer grades. It is instructive to recognize that in the investigated concentration range (up to 30% w/w PVP), there was no evidence of phase separation and the system is assumed to be a single phase. The literature reports indicate the miscibility of IMC and PVP in this concentration range.30,31 Significance. In order to minimize or eliminate the risk of drug crystallization, both in the amorphous solid dispersion and when administered to patients, the current practice in the pharmaceutical community is to use a high polymer concentration in the ASD.32−34 However, for high dose drugs this can result in an unreasonable “pill burden”. Our results indicate that the polymer molecular weight provides a possible avenue to stabilize ASDs without the need for high polymer concentration. The mechanism of stabilization is related to reduction in molecular mobility brought about by the increased viscosity of the system. . Interestingly, the degree of interaction between drug and polymer was independent of the polymer molecular weight. As is evident from Figure 10, the percent peak area attributable to the carboxylic acid complex appeared to be independent of the polymer molecular weight. This was surprising in light of the pronounced increase in polymer viscosity as a function of molecular weight. We believe that the preparation method of the dispersion, wherein the drug and the polymer were dissolved in methanol, essentially attenuated any potential inhibitory effect of polymer viscosity on drug−polymer interaction. The drug crystallization in the ASD is expected to be dependent on both the concentration of “free drug” as well as its mobility. Since the polymer molecular weight did not influence the drug−polymer interaction, the crystallization inhibitory effect is attributed to molecular mobility. With an increase in PVP molecular weight there was a pronounced decrease in molecular mobility. This was evident, both from DES (Figure 4) and viscosity measurements (Figure 11). Our studies were restricted to the supercooled state so that the effect of molecular weight could be assessed rapidly. We recognize that pharmaceuticals are likely to be stored below their Tg. Therefore, predicting the behavior these systems in the glassy state will be of much practical utility. We have the ability

Figure 10. (a, b) Percent peak area of the carboxylic acid dimer and the complex species in IMC (aIMC) and the ASDs (10 or 20% w/w PVP) with different grades of PVP (K12, K17, and K30).

Moreover, the drug and polymer exhibit hydrogen bonding interactions. It was therefore necessary to confirm that the observed effect can indeed be attributed to viscosity. Baird et al. evaluated the glass forming ability of organic compounds and concluded that crystallization tendency increased as the melt viscosity decreased.28,29 Therefore, the viscosities of the dispersions, in a supercooled state, were measured over a wide temperature range (Figure 11). As expected, the

Figure 11. Viscosity of IMC and IMC−PVP ASDs in the temperature range of 80−130 °C.

temperature dependence of viscosity was non-Arrhenius. Interestingly, both the dispersions and IMC exhibited similar temperature dependence, although the absolute viscosity values were different and the magnitude of this difference depended on the concentration and molecular weight of PVP. The addition of 10% PVPK12/PVPK17 to amorphous IMC, over the entire temperature range, resulted in approximately an order of magnitude increase in viscosity. At this polymer concentration, changing the polymer grade from K12 to K30, brought about another order of magnitude increase in viscosity. G

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measurements and Robert Wenslow for helping in the interpretation of the NMR data and Seema Thakral for helpful discussions. 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. DEAC02-06CH11357. We are thankful to Dr. Gregory Halder and Dr. Wenqian Xu at Argonne National Laboratory for their help during the synchrotron data collection. The project was partially supported by the William and Mildred Peters endowment fund.

to measure the mobility in the glassy state, and this was accomplished in nifedipine−PVP and nifedipine−HPMC systems.35 It will be interesting to investigate the coupling between mobility and stability below Tg and the possible approaches to accomplish this were discussed earlier.36

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CONCLUSIONS With an increase in PVP molecular weight, there was a progressive reduction in molecular mobility of IMC−PVP dispersions revealed by longer α-relaxation times. There was an attendant increase in physical stability as evident from the inhibition of IMC crystallization. An increase, either in polymer concentration (at fixed molecular weight) or molecular weight (at a fixed polymer concentration), had a qualitatively similar effect on mobility. The temperature dependence of mobility and viscosity as well as the extent of drug−polymer interactions were independent of the polymer molecular weight. The reduced molecular mobility due to the increased viscosity is likely to be the key factor governing crystallization in these ASDs.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.7b00096. Figure containing the (i) DSC heating curves of IMC and IMC−PVPK30 ASDs, (ii) DSC heating curves of different grades of PVP, (iii) 1D XRD patterns of IMC− PVP ASDS heated to different temperatures, (iv) temperature dependence of the dielectric loss as a function of frequency in IMC−PVP K30 ASDs, (v) ε″ (total) and ε″ (with dc conductivity contribution subtracted) for IMC−PVP solid dispersions with 10 and 20% PVP (at 80 °C), (vi) temperature dependence of α-relaxation time (τα) in IMC−PVP K12 ASDs, (vii) temperature dependence of α-relaxation time (τα) in IMC−PVP K17 ASDs and (viii) The 13C ssNMR spectra of the carboxylic acid region of amorphous IMC and IMC−PVP ASDs. Tabulated summary of the (i) DSC characterization of IMC−ASDs, and (ii) zero mobility temperature (T0) and fragility (m) of indomethacin and the ASDs prepared with PVP K12, K17, and K30 (PDF)

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*Address: Department of Pharmaceutics, College of Pharmacy University of Minnesota, 308 Harvard Street S.E., Minneapolis, MN 55455, USA. Phone: 612-624-9626. E-mail: surya001@ umn.edu. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The XRD studies were carried out at the College of Science and Engineering Characterization Facility, University of Minnesota. Viscosity measurements were performed at Polymer Characterization Facility, Chemical Engineering and Materials Science Division, University of Minnesota. We acknowledge the help provided by David Giles for the viscosity measurements of the solid dispersions and Sampada Koranne for measuring the glass transition temperatures of the polymers. We thank Lingtao Ji from Crystal Pharmatech Co., Ltd. for carrying out the ssNMR H

DOI: 10.1021/acs.cgd.7b00096 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

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DOI: 10.1021/acs.cgd.7b00096 Cryst. Growth Des. XXXX, XXX, XXX−XXX