The Role of Drug–Polymer Hydrogen Bonding Interactions on the

Article pubs.acs.org/molecularpharmaceutics

The Role of Drug−Polymer Hydrogen Bonding Interactions 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 55455, United States S Supporting Information *

ABSTRACT: We investigated the influence of drug−polymer hydrogen bonding interactions on molecular mobility and the physical stability in solid dispersions of nifedipine with each of the polymers polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMCAS), and poly(acrylic acid) (PAA). The drug−polymer interactions were monitored by FT-IR spectroscopy, the molecular mobility was characterized using broadband dielectric spectroscopy, and the crystallization kinetics was evaluated by powder X-ray diffractometry. The strength of drug−polymer hydrogen bonding, the structural relaxation time, and the crystallization kinetics were rank ordered as PVP > HPMCAS > PAA. At a fixed polymer concentration, the fraction of the drug bonded to the polymer was the highest with PVP. Addition of 20% w/w polymer resulted in ∼65-fold increase in the relaxation time in the PVP dispersion and only ∼5-fold increase in HPMCAS dispersion. In the PAA dispersions, there was no evidence of drug−polymer interactions and the polymer addition did not influence the relaxation time. Thus, the strongest drug−polymer hydrogen bonding interactions in PVP solid dispersions translated to the longest structural relaxation times and the highest resistance to drug crystallization. KEYWORDS: nifedipine, solid dispersion, polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMCAS), poly(acrylic acid) (PAA), dielectric spectroscopy, FT-IR spectroscopy, molecular mobility, crystallization

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INTRODUCTION A large number of new drug candidates in the pipeline suffer from the problem of aqueous insolubility.1,2 According to USP, a compound is considered insoluble if 1 part of solute dissolves in 10,000 or more parts of solvent.3 Among the numerous approaches, drug amorphization is a very promising route to improve the solubility and consequently the oral bioavailability of these new drug candidates.4−7Solid dispersions (SD), homogeneous drug−polymer mixtures, are known to physically stabilize amorphous drugs.7,8 Several mechanisms have been postulated for the physical stabilization brought about by the polymer.9−12 In order to formulate a robust SD, it is crucial to develop a thorough understanding of the mechanisms governing physical instability. Currently a large number of polymers are available for SD development, and rational polymer selection is a challenge.13−19 Several polymer screening methodologies have been developed based on potential stabilization mechanisms. We will investigate the influence of drug−polymer interactions, © XXXX American Chemical Society

specifically hydrogen bonding and molecular mobility, on the physical stability of drugs in SD. The role of specific drug−polymer interactions as a mechanism of physical stabilization of drugs has formed the basis of several successful polymer screening studies.13−15 Matsumoto and Zografi attributed the superior physical stability of indomethacin SD with both polyvinylpyrrolidone (PVP) and PVP-co-vinylacetate (PVAC) to the hydrogen bonding interactions between the drug and the polymer.20 Kestur et al. evaluated the stabilizing effect of several polymers and concluded that the polymers which formed stronger and extensive hydrogen bonds with felodipine were more effective inhibitors of drug crystallization.21 Drug−polymer ionic interactions, which are Received: July 28, 2014 Revised: October 19, 2014 Accepted: October 27, 2014

A

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Shin Etsu Chemicals, respectively. PAA (Mw ∼ 1800 g mol−1) was purchased from Sigma-Aldrich, USA. Preparation of Amorphous Materials. Amorphous NIF was prepared by melting crystalline NIF (to ∼5 °C above its melting temperature of 174 °C) in aluminum pans and then quenched on aluminum blocks precooled to −20 °C. The NIFpolymer SD were prepared by a solvent evaporation technique followed by melt quenching. Physical mixtures of NIF (90−80% w/w) and the polymer (10−20% w/w) were dissolved in the appropriate solvent (acetone, methanol, or dichloromethane). The solvent was then evaporated at 40 °C under reduced pressure (IKA-HB10, Werke GmbH and Co., Germany) and the drying was continued at room temperature for 24 h. Finally, the powder samples were melt quenched and the SD were lightly crushed using a mortar and pestle in a glovebox at room temperature (RH < 5%). The powders were stored at −20 °C in desiccators containing anhydrous calcium sulfate. Karl Fischer Titrimetry. The water content in the amorphous materials was determined coulometrically using a Karl Fischer titrimeter (model DL 36 KF coulometer, Mettler 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. The powder was accurately weighed in a glovebox 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. Dielectric Spectroscopy. 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 to 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).

generally stronger than hydrogen bonding, translated to better physical stabilization of amorphous resveratrol in SD.22 Eerdenbrugh and Taylor demonstrated the ability of seven chemically diverse polymers to inhibit the crystallization of several small molecule pharmaceuticals. Acidic polymers, while very effective in stabilizing basic drugs with amide functional groups, were ineffective with acidic drugs.14 Another approach utilized crystal engineering methodologies to identify polymers which could disrupt drug−drug interactions in favor of drug− polymer interactions. The predictions agreed well with the experimental results.15 Gunawan et al. speculated that the hydrogen bonding in glassy acetaminophen contributed to the decrease in the enthalpy and the entropy of the system. The structural relaxation in acetaminophen was believed to be influenced by the strength of hydrogen bonds, since molecular rearrangement in hydrogen bonded systems will require the breaking and re-forming of hydrogen bonds.23 In another investigation, enthalpic recovery as an indirect estimate of the molecular mobility was measured by differential scanning calorimetry in acetaminophen SD with both poly(acrylic acid) (PAA) and PVP dispersions. The stronger hydrogen bonding interactions between the drug and the polymer in the former were believed to be responsible for the reduced molecular mobility and the increased physical stability. However, the authors provided no direct experimental evidence of the drug− polymer hydrogen bonding interactions.24 Although these studies have implied a relationship between mobility and physical stability, the role of the specific molecular mobility involved in physical stabilization was not systematically investigated. Few studies in the literature have investigated the role of the specific molecular mobility on the physical stability of amorphous pharmaceuticals. 25 Recently, Bhardwaj et al. established an excellent correlation between global mobility (structural or α-relaxation time) and the physical stability of itraconazole in the supercooled state.26 A similar correlation, sometimes indirect, between global mobility and physical stability has also been established for other pharmaceuticals including trehalose, indomethacin, felodipine, flopropione, and celecoxib.27−31 Similar investigations to identify the role of specific molecular mobility involved in physical stability have been extended to SD.32 Although these studies establish a relationship between the type of molecular mobility and physical instability, the combined effect of the mobility mode involved in the instability and the influence of hydrogen bonding has not been investigated. We hypothesize that hydrogen bonding interactions between the drug and the polymer, by reducing the molecular mobility of the system, will enhance the physical stability. To test this hypothesis, we have chosen nifedipine (NIF) as our model drug and prepared SD with PVP, PAA, and hydroxypropylmethyl cellulose acetate succinate (HPMCAS). The SD, in the supercooled state, were characterized by several techniques: molecular mobility by dielectric spectroscopy, the strength and extent of drug−polymer hydrogen bonding interaction by FT-IR spectroscopy, and the physical stability by powder X-ray diffractometry.

ε*(ω) = ε∞ +

Δε σ + αHN βHN iε0ω (1 + (iωτHN) )

(1)

In eq 1, 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). ε′ is a measure of the permittivity, and ε″ is a measure of the dielectric loss of the sample. The shape parameters account for the symmetric (αHN) and asymmetric (βHN) peak broadening with 0 < α (or β) < 1. The shape parameters provide a measure of the distribution of the relaxation time in the system. At higher temperatures, the contribution of conductivity was observed on the low frequency side of the dielectric spectra. This was taken into consideration by adding the conductivity component, σ0/iε0ω, to the HN equation, where σ0 is the contribution from the dc conductivity and ε0 is the permittivity of the vacuum. 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 spacer confined the sample between the electrodes. Measurements were corrected for stray capacitance, spacer capacitance, and edge compensation. The validity of the relaxation time measurements obtained

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MATERIALS AND METHODS NIF (C17H18N2O6) was purchased from Laborate Pharmaceuticals, India (purity > 98%), and used without further purification. PVP (Mw ∼ 2000−3000 g mol−1) and HPMCAS−HF (Mw ∼ 18,000 g mol−1) polymers were supplied by BASF Corp. and B

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using powder samples has been the subject of a previous manuscript.33 FT-IR Spectroscopy. Following the solvent evaporation step (details given in Preparation of Amorphous Materials), the powder was melt-quenched between two CaF2 windows (16 mm diameter; 0.5 mm thickness). The FT-IR spectra were collected, as a function of temperature, using an IR microscope (ThermoNicolet continuum FT-IR spectrometer with a mercury cadmium telluride detector; Thermo Electron, Waltham, MA) equipped with an FDCS 196 freeze-drying cryostage (Linkam Scientific Instruments, U.K.). The FT-IR scan resolution was 4 cm−1, and 128 IR scans were averaged to obtain each spectrum in the 4000−900 cm−1 wavenumber range. The stage was initially set at −20 °C and then heated to 110 °C at 2 °C/min. The IR spectra were analyzed using OMNIC (Thermo-Nicolet, Madison, WI) and Peakfit4 software (Systat Software, San Jose, CA). 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 detector (LynxEye; Bruker AXS, Madison, WI) was used. Isothermal crystallization studies were conducted at 70 °C. Samples were periodically exposed to Cu Kα radiation (40 kV × 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. At each time point, the crystallinity index was calculated using eq 2. The crystallinity index can be equivalent to the % crystallinity in the sample, if the total integrated intensity (crystalline + amorphous) remains constant throughout the isothermal crystallization experiment (Supporting Information, S1).34 crystallinity index =

intensity of crystalline peaks total diffracted intensity

Figure 1. Representative DSC heating curves of NIF and NIF solid dispersions with PVP, HPMCAS, and PAA. The polymer concentration was 10% w/w. The endotherms observed at temperatures >150 °C are attributed to the melting of different physical forms of NIF.36 These events were outside the scope of our interest in this manuscript.

Influence of Polymer Type on Molecular Mobility. Dielectric spectroscopy was used to characterize the molecular mobility in NIF and NIF solid dispersions in the supercooled as well as the glassy states. Isothermal frequency experiments were conducted at several temperatures ranging from (Tg − 50 °C) up to (Tg + 75 °C). In the supercooled state, all the systems revealed well resolved α-relaxation peaks (Figure 2). In PAA SD, αrelaxation was observed in the temperature range of 45 to 75 °C. At higher temperatures (>75 °C), rapid drug crystallization precluded data collection. The SD with PVP and HPMCAS, on the other hand, were much more resistant to crystallization and α-relaxation could be monitored at temperatures >75 °C. With an increase in temperature, the α-relaxation peak shifted to higher frequencies, indicating an increase in the global mobility of the system, i.e., shorter relaxation times. However, there was a decrease in the magnitude of the dielectric loss peak, attributable to progressive sample crystallization. At any given temperature and polymer concentration, the unique effect exerted by each polymer on the molecular mobility was evident from the peak frequency of the dielectric loss (Figure 3). The dielectric loss peak in the PVP dispersions appeared at a much lower frequency, indicating a more pronounced lowering in molecular mobility than in the corresponding HPMCAS and PAA dispersions. The loss curves of the PAA dispersion could be virtually superimposed on that of NIF revealing the “ineffectiveness” of this polymer. The average α-relaxation time, determined using eq 1 (Figure 4), over the entire temperature range could be rank ordered as PVP > HPMCAS > PAA. The presence of PAA, irrespective of its concentration, did not reveal any significant influence on relaxation time. Addition of 10% w/w polymer resulted in an 8- and 3-fold increase in relaxation time with PVP and HPMCAS respectively. An increase in polymer concentration to 20% caused a disproportionate 65-fold increase in the relaxation time of the PVP system, whereas the HPMCAS system showed only a 5-fold increase. The temperature dependence of the relaxation time could be described by the VTFH model (eq 3; model fitting using Sigmaplot; Systat Software; San Jose, CA).37−40

(2)

A custom built program (using Fortran 77; Tucson, AZ) was used to quantify crystallinity. The amorphous intensity contribution was based on the experimental XRD pattern of the amorphous “reference” material (preparation method is provided above). The amorphous intensity was subtracted from the total pattern to yield the intensity contribution from the crystalline peaks.

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RESULTS Baseline Characterization. The samples prepared, both the drug substance and the dispersions, were observed to be X-ray amorphous. Figure 1 contains representative DSC heating curves of NIF-SD with PVP, HPMCAS, and PAA, and the relevant results are summarized in Table 1. The calorimetric Tg values of the three dispersions (at 10% w/w polymer) were virtually identical despite significant differences in their relaxation time (discussed in next section). This observation implies that calorimetric Tg may not be a good indicator of molecular mobility. At higher concentration, the strong specific interactions between the drug and the polymer (discussed later) can explain the much higher Tg of the PVP dispersions as was observed in thiazide diuretics.35 The authors attributed the strong hydrogen bonding interactions between the sulfonamide group of the thiazide diuretics and the PVP molecule to cause the observed positive deviation from the predicted Tg values from the Gordon−Taylor equation. Karl Fischer titrimetry revealed a water content Tg, the relaxation times appear to be independent of the polymer (Figure 4). Thus, “accelerated” studies, at temperatures ≫Tg, can be misleading. On the other hand, near Tg (∼Tg + 5 °C), the differences in the polymer effectiveness were amplified. The D value for NIF and all the dispersions was ∼7.8, reflecting the fragile nature of these systems. The T0 value was ∼262 K and independent of polymer type and concentration. We also attempted to characterize the molecular mobility of these systems in the glassy state. In NIF and NIF-SD, an excess wing was observed, attributable to βrelaxation. Due to the weak nature of the signal, its temperature dependence could not be ascertained. Influence of Polymer Type on Drug−Polymer Interactions. FT-IR spectroscopy was used to characterize the drug− polymer hydrogen bonding interactions in the SD, in both the supercooled and glassy states. The dihydropyridine NH group of

Figure 4. Relaxation time of NIF solid dispersions (10% w/w polymer concentration) as a function of temperature.

In eq 3, τ is the average α-relaxation time, D is the strength parameter, a measure of the system fragility, τ0 is the relaxation D

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amorphous NIF, at 3342 cm−1, acts as a hydrogen bond donor and interacts with the acceptor groups in the polymers (Figure 5). Both PVP and PAA have a carbonyl functional group which

Figure 7. A plot of wavenumber (NH peak of NIF; FT-IR spectra) as a function of temperature for the three solid dispersions (10% w/w polymer). For the sake of clarity, only select data points are shown.

Figure 5. Structures of (a) nifedipine, (b) PVP, (c) PAA, and (d) HPMCAS. The hydrogen bond donor group in nifedipine and the hydrogen bond acceptor group in PVP and PAA are pointed out with an asterisk (*). In HPMCAS, there are multiple hydrogen bonding sites.43

wavenumber indicates that the hydrogen bonding between the drug and the polymer is stronger than the intermolecular hydrogen bonding between the drug molecules (NIF-PVP dispersions) whereas a higher wavenumber indicates weaker interactions between the drug and the polymer (NIF-HPMCAS dispersions). Similar observations have been made in SD of felodipine, a structural analogue of NIF.43 The subtracted spectrum of PAA SD strongly suggests no hydrogen bonding interaction between the drug and polymer. The rank ordering of the strength of hydrogen bonding is the same as that of the relaxation time: PVP > HPMCAS > PAA. The extent of drug− polymer hydrogen bonding was estimated from the ratio of the height of the peak attributed to drug−polymer interaction to the height of the peak attributed to the amount of drug in the dispersion (1530 cm−1; N−O symmetric stretch peak). Only NIF absorbs at 1530 cm−1 with no interference from the three polymers. The peak intensity ratio was then adjusted for the variation in the absorption coefficient of the NH peak with wavenumber (Supporting Information, S2).44 Assuming hydrogen bonding interaction between one drug molecule and one monomer unit, the drug to monomer ratio will be highest in HPMCAS followed by PVP (see Supporting Information, S3). Theoretical calculations, without taking into consideration the strength of drug-polymer interactions, would suggest that HPMCAS would have a higher propensity of interaction with

acts as a hydrogen bond acceptor whereas in HPMCAS there are potentially multiple hydrogen bond acceptor sites (Figure 5).43 The interactions were investigated as a function of temperature from −20 to 120 °C. With an increase in temperature, the NH peak shifts to higher wavenumbers, indicating a decrease in the hydrogen bond strength (Figure 6a). As we transition from the glassy to the supercooled state, the change in the strength of intermolecular interactions is reflected by an abrupt increase in the thermal expansion coefficient. This can be observed from the change in the temperature dependence of the NH stretching vibration frequency around Tg (Figure 6b). The SD exhibited a similar behavior (Figure 7). At any given temperature and polymer concentration, the difference in the hydrogen bonding interactions between the drug and the polymer is evident from the shape and the position of the NH peak. In the PVP dispersion, a shoulder developed on the lower wavenumber side of the NH peak (Figure 8a), whereas, in the HMPCAS dispersion, this occurred at higher wavenumbers. These “shoulder peaks” could be readily discerned by subtracting the NIF spectrum from that of the dispersions (Figure 8b). The subtraction clearly shows new populations in both PVP (3290 cm−1) and HPMCAS dispersions (3363 cm−1). A lower

Figure 6. (a) FT-IR spectra of NIF as a function of temperature (−20 to 95 °C temperature range). The wavenumber range is restricted to the NH peak involved in the intermolecular hydrogen bonding. The spectra in the supercooled liquid temperature range (light blue) are clearly separated from each other, while those in the glassy region (dark blue spectra) are clustered (more details in the text). (b) The wavenumber of the NH peak as a function of temperature. The change in the temperature dependence around Tg is evident. For the sake of clarity, only select data points are shown. E

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Figure 8. (a) Overlaid FT-IR spectra of NIF and NIF-PVP dispersion. The shoulder attributed to the drug−polymer hydrogen bonding interaction is pointed out. (b) Use of a pattern subtraction technique to identify the drug−polymer hydrogen bonding interactions in solid dispersions. The peaks observed in the subtracted spectra are attributed to hydrogen bonding interactions between NIF and each polymer. The NH peak in pure NIF was observed at 3342 cm−1 (indicated by the vertical line). The peak position, relative to the NH peak in pure NIF, reveals the strength of hydrogen bonding interactions in the dispersions.

Figure 9. (a) X-ray powder diffraction patterns of the SD (10% w/w polymer) held at 70 °C for 400 min. (b) Crystallization (expressed as % crystallinity) kinetics of the SD (70 °C).

influence of polymer type on NIF stabilization in the SD, drug crystallization was monitored at 70 °C by XRD. PVP SD showed the strongest resistance to drug crystallization followed by HPMCAS and PAA, in excellent agreement with the observations under non-isothermal conditions. The XRD experiments provided a measure of both the rate and extent of crystallization (Figure 9).

NIF than PVP or PAA. However, at any given polymer concentration, the PVP dispersion always had a higher fraction of the drug molecules bonded to the polymer. Influence of Polymer Type on Physical Stability. The polymer type had a dramatic influence on the physical stability of NIF in the SD. This was first evident in the non-isothermal DSC experiments which showed a progressive delay in NIF crystallization in the order PVP > HPMCAS > PAA > NIF (Figure 1). This superior inhibitory effect of PVP was observed at both 10 and 20% polymer concentration (Table 1). This trend was also apparent from the BDS and FT-IR results. A reduction in the magnitude of the dielectric loss peak is indicative of sample crystallization. For example, at 80 °C, the decrease in the magnitude of the dielectric loss peak was more pronounced for HPMCAS than the PVP dispersion (Figures 2a and 2b). In the PAA SD, at 80 °C, due to extensive sample crystallization, it was not possible to measure the magnitude of the dielectric loss peak (Figure 2c). Finally, in the FT-IR spectra, NIF crystallization is evident from the shift in the stretching frequency of the NH group involved in hydrogen bonding to a lower wavenumber (from 3351 to 3322 cm−1; Supporting Information, S4). For the PVP and HPMCAS SD, no amorphous to crystalline transition was observed, whereas in PAA dispersions it occurred at temperatures of 100 °C. In an attempt to understand the

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DISCUSSION In the solid dispersions prepared with the three polymers (10% w/w polymer), the most pronounced drug crystallization inhibition (physical stabilization) was observed with PVP. These dispersions also exhibited the longest relaxation time (slowest molecular mobility). This enhanced physical stability can be attributed to the higher strength and consequently greater extent of drug−polymer interactions in the PVP dispersions leading to the observed reduction in mobility. There are literature reports of depression in molecular motions in associated liquids brought about by the formation of hydrogen bond chains or networks.45,46 While n-hexane and n-heptanol are structurally similar, the significantly longer relaxation times in the latter are attributed to the hydrogen bonding network.47 Moving to two component systems, in mixtures of ethanol and n-hexanol, the intermolecular hydrogen bonding interactions between the F

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Figure 10. Effect of polymer concentration on the hydrogen bonding behavior and molecular mobility in (a) PVP solid dispersions and (b) HPMCAS solid dispersions. Left y-axis (blue): Normalized peak intensity ratio (3290 cm−1 (PVP) and 3363 cm−1 (HPMCAS) peak to that of 1530 cm−1) as an estimate of the hydrogen bonded population of the drug in the SD. [Normalized: The intensity ratio for the NIF-PVP dispersion (20% w/w polymer) was arbitrarily set at 1.0.] Right y-axis (red): τ/τNIF, a measure of the friction coefficient (ζ) of the solid dispersions.

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CONCLUSION With the availability of a wide variety of polymers, a major challenge in solid dispersion design is polymer selection. This will be greatly facilitated by understanding the mechanisms governing the physical stability of a drug in a SD. An ideal polymer should, at a low concentration, effectively prevent drug crystallization throughout the shelf life of the dispersion. This will enable high drug loading and will also afford flexibility to the formulator in terms of dosage form design, processing, and manufacturing. We have observed that specific drug−polymer hydrogen bonding interactions provide physical stabilization by reducing the molecular mobility of the system.

aliphatic groups were believed to play a significant role in the dynamics of molecular reorientation.47 Silica when blended with poly(methyl methacrylate) reduced the molecular mobility of the system. This concentration dependent effect was attributed to the formation of strong intermolecular hydrogen bonds between the two components.48 Similarly, in our model systems, an increase in polymer concentration caused an increase in relaxation time. However, the magnitude of this effect was polymer specific. As the polymer concentration was doubled (10 to 20% w/w), due to the strong nature of NIF-PVP interactions, a higher fraction of the drug molecules were involved in the hydrogen bonding interactions with the polymer. The strong hydrogen bonding interactions between NIF and PVP caused a disproportionate lowering in mobility (∼11-fold increase in the relaxation time) than in the HPMCAS (∼1.6-fold increase in the relaxation time) dispersions. The strength and extent of interaction between drug and polymer will be one of the determinants of the molecular mobility of the system. The addition of the polymer is believed to increase the “friction” experienced by the drug molecules, resulting in reduced molecular mobility, as was observed in polychlorinated biphenyl (Aroclor 1248) solutions containing either polystyrene or polybutadiene.49 Polystyrene, in a concentration dependent manner, disrupted the solvent clusters, through hydrogen bonding interactions with the solvent, and reduced the mobility by increasing the effective friction coefficient (ζ). A measure of ζ is τ/τNIF, where τ is the relaxation time of the dispersion and τNIF is the relaxation time of the pure solvent (NIF in our case). Similarly for the PVP and HPMCAS dispersions, with an increase in polymer concentration, we observe an increase in both the value of ζ and the extent of drug−polymer interactions (Figure 10). While the extent of drug−polymer interactions is polymer specific (PVP > HPMCAS), the differences are not very pronounced. On the other hand, there is a disproportionate influence of the strength of drug−polymer interactions in reducing the overall mobility of the system. The stronger interaction of PVP with NIF translated to a much higher friction coefficient, and this effect was amplified when the polymer concentration was increased (Figure 10). These observations establish the causal link between hydrogen bonding, specifically the strength of hydrogen bonding, and molecular mobility. The results from these studies highlight for the first time that drug− polymer interactions, by modulating the molecular mobility, influenced the drug crystallization kinetics.

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ASSOCIATED CONTENT

* Supporting Information S

Plot of the total (crystalline + amorphous), amorphous, and crystalline integrated intensity during the isothermal crystallization studies of amorphous NIF-PVP, plot of absorption coefficient versus frequency of NH stretching vibration, calculation of number of drug molecules available per monomer unit of the polymer, and FTIR spectra. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

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

K.K.: Millennium: The Takeda Oncology Company, Cambridge, MA 02184. ‡ V.R.: Allergan, Inc., 2525 Dupont Dr., RD1-2A, Irvine, CA 92612 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). Mehak Mehta and Pinal Mistry are thanked for their comments. G

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