Phase Separation Kinetics in Amorphous Solid Dispersions Upon

Article pubs.acs.org/molecularpharmaceutics

Phase Separation Kinetics in Amorphous Solid Dispersions Upon Exposure to Water Hitesh S. Purohit and Lynne S. Taylor* Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States ABSTRACT: The purpose of this study was to develop a novel fluorescence technique employing environment-sensitive fluorescent probes to study phase separation kinetics in hydrated matrices of amorphous solid dispersions (ASDs) following storage at high humidity and during dissolution. The initial miscibility of the ASDs was confirmed using infrared (IR) spectroscopy and differential scanning calorimetry (DSC). Fluorescence spectroscopy, as an independent primary technique, was used together with conventional confirmatory techniques including DSC, X-ray diffraction (XRD), fluorescence microscopy, and IR spectroscopy to study phase separation phenomena. By monitoring the emission characteristics of the environment-sensitive fluorescent probes, it was possible to successfully monitor amorphous−amorphous phase separation (AAPS) as a function of time in probucol− poly(vinylpyrrolidone) (PVP) and ritonavir−PVP ASDs after exposure to water. In contrast, a ritonavir−hydroxypropylmethylcellulose acetate succinate (HPMCAS) ASD, did not show AAPS and was used as a control to demonstrate the capability of the newly developed fluorescence method to differentiate systems that showed no phase separation following exposure to water versus those that did. The results from the fluorescence studies were in good agreement with results obtained using various other complementary techniques. Thus, fluorescence spectroscopy can be utilized as a fast and efficient tool to detect and monitor the kinetics of phase transformations in amorphous solid dispersions during hydration and will help provide mechanistic insight into the stability and dissolution behavior of amorphous solid dispersions. KEYWORDS: amorphous solid dispersions, water, phase separation, fluorescence

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leading to a decrease in the nucleation and growth rates.12−14 In addition to inhibiting crystallization, formulation with a hydrophilic polymer improves the wetting properties and dissolution rate of the drug.15 Because of its disordered nature, the ASD matrix has an inherent tendency to sorb water during storage and during dissolution.4,16 Absorbed water molecules plasticize the amorphous phase increasing molecular mobility and accelerating phase transformations such as crystallization and amorphous−amorphous phase separation (AAPS).17 In AAPS, the molecularly mixed ASD matrix phase separates and drug−polymer concentration gradients develop throughout the dispersion, with the components remaining (at least initially) in the amorphous form.18 The resultant drug-rich domains will be more susceptible to crystallization due to the lower polymer concentration, which can adversely affect the dissolution performance of the dispersion. The phenomenon of

INTRODUCTION Solubilization of orally administered drugs in an aqueous medium is a prerequisite for absorption from the gastrointestinal tract (GIT). A large percentage of marketed drugs and an even larger percentage of compounds in developmental pipelines have limited solubility, falling into classes II and IV of the biopharmaceutical classification system (BCS).1,2 Using the amorphous form of the drug is a viable strategy for solubility enhancement,3 although there is always a risk of crystallization due to the higher free energy of the amorphous solid relative to the crystalline counterpart.4,5 Crystallization negates the solubility enhancement,3 which can potentially lead to a decrease in bioavailability. To prevent crystallization, the drug is typically molecularly dispersed with an amorphous polymer, and the formulation thus obtained is commonly referred to as an amorphous solid dispersion (ASD).5 Addition of polymer to the amorphous drug imparts physical stability against crystallization by increasing the glass transition temperature (Tg) of the system,6,7 decreasing the mobility in the matrix due to coupling of drug and polymer molecular motions,8 reducing the chemical potential of the drug,9 and forming specific interactions (such as hydrogen bonds with the drug10,11) © 2015 American Chemical Society

Received: Revised: Accepted: Published: 1623

January 15, 2015 April 7, 2015 April 8, 2015 April 8, 2015 DOI: 10.1021/acs.molpharmaceut.5b00041 Mol. Pharmaceutics 2015, 12, 1623−1635

Article

Molecular Pharmaceutics

Figure 1. Structures of the model drugs and the polymer used: Probucol (a), PVP (b), ritonavir (c), and HPMCAS (d).

the method, solid dispersions of probucol with PVP (PB− PVP), a system known to undergo moisture-induced AAPS,17 were investigated. Subsequently, the phase behavior of ritonavir−PVP (RTV−PVP) dispersions upon exposure to water was investigated. Control experiments were performed using ritonavir-HPMCAS (RTV−HPMCAS) ASDs, which do not undergo AAPS. The phase behavior was verified using a variety of complementary techniques including IR spectroscopy, differential scanning calorimetry (DSC), X-ray diffraction (XRD), and fluorescence microscopy.

AAPS and its impact on the performance of an ASD is not currently fully understood, in part because of its dependence on multiple factors17 including drug−polymer interaction strength, polymer type, drug−polymer ratio, drug physicochemical properties, and storage conditions and in part due to the analytical challenges of detecting this phenomenon.19 Methods used to detect AAPS include infrared (IR) and solid state nuclear magnetic resonance spectroscopy (ss-NMR),20−23 Xray scattering,19,24 differential scanning calorimetry,20,25 and atomic force microscopy.26 There are limitations associated with each of these methods, and therefore, additional approaches are of interest. The goal of the current study was to develop a novel analytical fluorescence technique employing environmentsensitive probes to monitor phase transformations in a hydrated ASD matrix. Environment-sensitive fluorescent probes have been widely used to study phase separation in polymer blends,27,28 polymerization reactions and sol−gel transformations,29,30 pH monitoring of the biological cells,31 water uptake in polymeric films,32,33 for determining the polarity of micellar systems,34,35 and to determine the critical micelle concentration (CMC) of surfactants.36 Recently, they have also been used to determine the “amorphous solubility” of pharmaceutical compounds.37,38 These probes typically exhibit a blue shift (lower emission wavelength maximum) when the environment becomes less polar, and a red shift (increase in the emission wavelength maximum) when the environment becomes more polar. We hypothesize that when an ASD matrix containing trace amounts of these fluorescent probes undergoes AAPS, the probe molecules, being inherently lipophilic, will partition into the lipophilic drug-rich phase. As the probe concentrates in the drug-rich phase, it will then “sense” a hydrophobic environment leading to changes in the fluorescence emission spectrum, thus making it possible to monitor the transformation in situ in the ASD as hydration occurs. To test the hypothesis and develop

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MATERIALS AND METHODS Materials. Methanol and dichloromethane were purchased from Macron Chemicals (Phillipsburg, NJ). Probucol, pyrene, pyrenecarboxyaldehyde, dansyl glycine, and poly(acrylic acid) (PAA) were purchased from Sigma-Aldrich Co. (St. Louis, MO). Prodan was obtained from AnaSpec, Inc. (Fremont, CA). (4-(4-(Diethylamino)styryl)-N-methylpyridinium iodide) (4Di-2-ASP) was obtained from Life Technologies (Grand Island, NY). Ritonavir was obtained from Attix PharmaChem (Ontario, Canada). Procaine was procured from Spectrum Chemical Mfg Corp. (New Brunswick, NJ). Various polymer samples were generous gifts from the following manufacturers: poly(vinylpyrrolidone) (PVP) K-90 from ISP Technologies, Inc. (Wayne, NJ) and hydroxypropyl methylcellulose (HPMC) 606 grade and hydroxypropyl methylcellulose acetate succinate (HPMCAS) MF grade from Shin-Etsu Chemical Co. Ltd. (Tokyo, Japan). Poly(vinylpyrrolidone)-vinyl acetate (PVPVA) 64 grade was obtained from BASF (Ludwigshafen, Germany). Polyvinyl acetate (PVAc), polyvinyl-2-pyridine (P-2-Py), and polyvinyl-4-pyridine (P4-Py) were purchased from Scientific Polymer Products, Inc. (Ontario, NY). The novel cellulose derivatives cellulose acetate phthalate-482 (CAP-482) and cellulose acetate butyrate adipate (CAB-ADP) used in the study were synthesized in Dr. Kevin J. Edgar’s lab at Virginia 1624

DOI: 10.1021/acs.molpharmaceut.5b00041 Mol. Pharmaceutics 2015, 12, 1623−1635

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exposed to 97% RH and immersed in the buffer. Excitation wavelengths of 360 and 332 nm were used for prodan and pyrene, respectively. A Nikon Eclipse E600 Pol microscope equipped with a 10× objective was used with NIS-Elements software package (Version 2.3; Nikon Company, Tokyo, Japan) to observe films under a cross polarized microscope to detect crystallization in the ASD films. Fluorescence Imaging. The spin-coated films of PVP, HPMCAS, RTV, RTV−HPMCAS, and RTV−PVP containing the probes were imaged with an Olympus BX51 fluorescence microscope (Olympus Corporation, Melville, NY) before and after exposure to 97% RH to monitor moisture induced phase transformations in the matrix. The filter setting used provided an excitation range of 330−380 nm and emission from 420 nm onward making it possible to image the fluorescence emission of pyrene, which fluoresces close to this wavelength. Infrared Spectroscopy. Samples for infrared (IR) analysis were prepared as described above. IR spectra were obtained in transmission mode using a Bruker Optics IR spectrophotometer (Billerica, MA) equipped with a globar infrared source, a KBr beam splitter, and a DTGS detector. The scan range from 400 to 4000 cm−1 was used with coaddition of 64 scans and a resolution of 4 cm−1. The detector and the sample compartment were continuously flushed with dry air to avoid interference from moisture present in air. For thin ASD films exposed to 97% RH, IR spectra were collected after drying the samples under vacuum and flushing them in situ with dry air until the OH and NH regions of the spectrum remained unchanged thus confirming moisture removal from samples to an extent that would not interfere with the IR absorption peaks of drug and polymer in the ASD films. Reference spectra of amorphous drugs and pure polymers were also collected in a similar manner. X-ray Diffraction. XRD was used to characterize the rotary evaporated bulk solid dispersions. The dispersion powder was passed through a 425 μm sieve, and the size fraction that was retained on the 250 μm sieve was used. The dispersion was loaded onto glass XRD sample holders, and data were obtained by CuKα radiation using a Rigaku Smartlab diffractometer (The Woodlands, TX) operating at 40 kV and 20 mV. Measurements were performed in the range of 5−35° 2θ with a scan rate of 2° 2θ/min and a step size of 0.04° using Bragg−Brentano mode. The Si peak was used as an external standard. Analysis was performed before and after exposure to 97% RH to study changes in the phase behavior of the ASDs. Differential Scanning Calorimetry. Samples obtained by the bulk dispersion preparation method were used for thermal analysis. Amorphous PB and RTV were prepared in situ by heating their crystalline counterparts above their melting points and quench cooling. PB−PVP and RTV−PVP ASDs were analyzed to confirm miscibility before exposure to moisture. After exposure to 97% RH, the samples were analyzed to detect any phase transformations. Approximately 5 mg of ASD was weighed and sealed in a pinholed Tzero aluminum pan and placed in a TA Q2000 DSC equipped with a refrigerated cooling accessory (RCS) (TA Instruments, New Castle, DE). The samples were purged with nitrogen at a rate of 50 mL/min for 10 h followed by heating at a rate of 5 °C/min up to 200 °C with modulation of 2 °C every 60 s. The changes in the glass transition temperature and appearance or disappearance of the melting endotherms were used as indicators of phase changes. The enthalpic response was calibrated using indium, whereas

Tech, and the method of preparation of these polymers has been described elsewhere.39 Structures of the model compounds and select polymers are shown in Figure 1. Methods. Preparation of Thin Amorphous Films. Amorphous films for fluorescence and infrared spectroscopic measurements were prepared by spin coating. Specific ratios of drug and polymer were dissolved in methanol to give a final concentration of 50 mg/mL. For the films prepared for fluorescence measurements, a fluorescent probe (0.1% w/w) was dissolved in the methanolic solution of drug and polymer to give a final concentration of 1 μg/mg probe in the dispersion. A spin coater KW-4A (Chemat Technology Inc., Northridge, CA) was used to prepare films. One hundred microliters of the solution was placed on the appropriate substrate and rotated at 3000 rpm for 30 s. Samples were prepared on KRS-5 discs for infrared measurements and on quartz coverslips for fluorescence measurements. The obtained films were dried under vacuum for at least 24 h before conducting further studies. Pure polymer films containing the probe were prepared by spin coating 100 μL of a 20 mg/mL polymer solution onto quartz slides. Polymer solutions were prepared by dissolving the polymer in a 1:1 v/v ratio of methanol and dichloromethane. Amorphous drug films with the probe were prepared by dissolving the drug and the probe in methanol and spin coating onto quartz coverslips. Preparation of Bulk Solid Dispersions. Bulk solid dispersions were prepared by rotary evaporating a methanolic solution of the drug and the polymer using Buchi Rotavapor-R (New Castle, DE) equipped with Yamato BM-200 water bath under reduced pressure at 45 °C. The resulting dispersion was further dried for 24 h under vacuum to remove residual solvents. The prepared dispersions were stored in desiccators containing phosphorus pentoxide in order to maintain 0% relative humidity (RH). Feasibility Study with Fluorescent Probes. To determine the environment sensitivity of fluorescent probes viz. dansylglycine, pyrene, prodan, and pyrenecarboxyaldehyde, amorphous films of procaine and probucol containing the probes were prepared. The films were analyzed for the changes in the emission wavelengths/spectra of the probes. Spin coated films of PVP, HPMC, HPMCAS-MF, PVPVA, PAA, PV-2-Py, PV-4-Py, CAP-482, CAB-ADP, and PVAc containing fluorescent probes were also prepared. Fluorescence analysis of the probes in the pure amorphous drug and polymer films was then performed using a Shimadzu RF-5301PC spectrofluorophotometer (Kyoto, Japan) to understand how the probe emission spectrum varied in the different amorphous films. Film Hydration Using Fluorescence Spectroscopy. Hydration studies of PB−PVP films with 50:50 and 20:80 drug− polymer ratio containing prodan as the probe and RTV−PVP films with 20:80, 50:50, and 80:20 drug−polymer ratio containing pyrene as the probe were performed at 97% RH by storing the films in desiccators containing a saturated solution of K2SO4. To analyze the phase changes in the ASD matrix as it hydrated upon exposure to bulk water, spin coated films containing 50:50 PB−PVP and 50:50 RTV−PVP were immersed in 100 mM pH 6.8 phosphate buffer for specific time intervals, followed by removal and analysis. Fluorescence emission wavelength measurements of the vapor-exposed and water-immersed films were obtained by evaluating the films in a solid sample stage assembly (Shimadzu product no. 204-2683601) with a Shimadzu RF-5301PC spectrofluorophotometer. RTV−HPMCAS ASD films, which served as controls, were also 1625


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when in a more hydrophobic environment relative to when dispersed in a more hydrophilic environment. Figure 2 shows the emission spectra of the probes prodan and pyrene in the amorphous drug films of probucol and procaine. As can be seen from Figure 2, in case of pyrene, a complex five peak emission spectrum is obtained whereby the ratio of intensity of peak I to peak III is used as indication of environment hydrophobicity (a lower I to III ratio (I/III) corresponds to a more hydrophobic environment). It is apparent that the probes dispersed in amorphous probucol register a more hydrophobic environment than the probes present in amorphous procaine films. Prodan shows a large shift in emission maximum, undergoing a blue shift of 30 nm from procaine to probucol. These shifts reflect the much more hydrophobic character of probucol, which has a log P value of 10, while procaine is relatively more hydrophilic with a log P of 1.3. Results with pyrene show a decrease in the I/III ratio from 1.4 to 1.2 on moving from procaine to probucol. Probe emission characteristics of prodan dispersed in thin films of a variety of polymers with a wide range of hydrophilicities/phobicities are reported in Table 2. These data were gathered in order to evaluate probe characteristics in polymer-rich environments. The solubility parameters of the polymers were used as indicators of polymer polarity. The solubility parameter (SP) provides an indication of the relative polarity by estimating the cohesive interactions in a material. Thus, the higher the SP, the more polar the material, and vice versa. Experimental SP values from the literature were used wherever available whereas the method described by Fedors40 was used to calculate SP for the remaining polymers. Table 2 reveals that prodan has the highest emission maximum when dispersed in PAA suggesting that this is the most polar polymer evaluated. Conversely, PVAc appears to be the least polar polymer. The emission maximum of prodan varies by approximately 33 nm between these two systems. Interestingly, the emission maxima values show the same relative order as the SP values, providing support for the supposition that

benzophenone and indium were used to calibrate the temperature scale.

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RESULTS Fluorescence Properties of Environment Sensitive Probes Dispersed in Single Component Amorphous Films. Although environment-sensitive fluorescent probes have been utilized to investigate a variety of diverse systems, there is limited knowledge on how they interact with solid drug phases. Hence feasibility studies were performed by dispersing the probes in amorphous films of pure drug and pure polymer in order to determine the probe sensitivity in different environments. Table 1 summarizes the emission wavelength maximum Table 1. Wavelength Changes for the Emission Characteristics of the Fluorescent Probes in Amorphous Films of Probucol and Procainea emission wavelength (λem, nm) probe pyrene (I/III) 4-Di-2ASP prodan dansyl glycine

excitation wavelength (λex, nm)

in probucol (log P = 10)

in procaine (log P = 1.3)

332

1.2

1.4

488

548

570

360 300

418 473

448 501

a

Based on the log P values, probucol is the more hydrophobic compound, whereas procaine is more hydrophilic.

of four different fluorescent probes in amorphous films of procaine and probucol. Probucol was chosen because of its high log P value, indicating that it is hydrophobic, whereas procaine was chosen because it has a much lower log P value, and hence, it can be categorized as being considerably more hydrophilic than probucol. It is expected that the environment-sensitive probes will have a lower wavelength for the emission peak

Figure 2. Environment-dependent changes in the emission spectra of fluorescent probes. Emission maximum for prodan in a relatively hydrophilic (amorphous procaine, PC, black curve) and relatively hydrophobic (amorphous probucol, PB, blue curve) environment. (a) Pyrene spectrum showing five emission peaks of different intensities in amorphous procaine (black curve) and amorphous probucol (blue curve). (b) The ratio of the intensities of peaks I and III is sensitive to environment change with a decrease in the ratio corresponding to more hydrophobic environment and an increase relating to a more hydrophilic environment. 1626


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RH. For the 50:50 ASD, the initial value is 437 nm, which is lower than the value for pure PVP (451 nm) and higher than the value for pure amorphous probucol (418 nm). This shift relative to the pure component values is consistent with the formation of a miscible film with properties intermediate to the pure components. Upon exposure to 97% RH, there is a gradual blue shift to a minimum wavelength of 425 nm indicating that the average probe environment is increasing in hydrophobicity. This can be explained by the absorption of water, which leads to phase separation into drug-rich and polymer-rich domains. The probe molecules, being inherently hydrophobic, partition into the hydrophobic drug-rich phase resulting in a blue shift in the emission wavelength. Phase separation of the probucol−PVP system upon exposure to moisture has been observed previously.17 After 21 h, there is a sharp increase in the prodan emission wavelength with a final value of 435 nm being obtained. Figure 4 shows a standard

Table 2. Emission Maxima of the Fluorescent Probe Prodan in Various Polymer Films polymer PAA PVP-k-90 polyvinyl-4pyridine PVPVA HPMC CAP-482 HPMCAS-MF polyvinyl-2pyridine CAB-ADP PVAc

emission wavelength (λmax, nm)

solubility parameter (δ, MPa1/2)a

460.0 450.7 444.1

25.92 25.6053 24.72

443.0 442.5 441.8 441.5 440.0

22.8454 22.68 22.48 22.44 21.2655

434.0 427.0

20.86 19.2056

a

Solubility parameters were calculated from the method shown by Fedors40 unless otherwise stated.

fluorescent probes, prodan in this case, provide a measure of the polarity of the local polymer environment. Film Hydration and Dissolution. Having established that environment sensitive fluorescence probes show different emission spectra in amorphous films of different single component systems, the next step was to evaluate the probe spectrum when dispersed in a drug−polymer blend prior to and after exposure to high RH such that AAPS is induced. As AAPS proceeds, the microenvironment is expected to change with the formation of hydrophobic drug-rich domains and hydrophilic polymer-rich domains. The probe is anticipated to distribute between the two phases, concentrating more in the hydrophobic drug-rich phase. Figure 3 summarizes the changes in the emission wavelength of prodan as a function of time when dispersed in 50:50 and 20:80 wt % PB−PVP ASD films, which were exposed to 97%

Figure 4. Brightfield microscopic image of PB−PVP system after exposure to 97% RH for 21 h (a) and an image of the same sample under cross-polarized light showing birefringence (b).

brightfield and a cross polarized microscope image of the hydrated film indicating that crystallization commenced at the 21 h time point; the red shift can be explained by the

Figure 3. Wavelength changes in the emission maximum of prodan as the ASD hydrates. An increase in the wavelength represents a more hydrophilic environment, whereas a decrease represents a more hydrophobic environment. The emission wavelengths for the pure amorphous drug and polymer are also shown at the zero time point for reference. The schematic below the graph pictorially depicts the changes occurring in the ASD as the system absorbs water molecules. Water absorption in the ASD leads to formation of drug-rich domains as a result of AAPS followed by crystallization of PB. 1627


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drug−polymer ratios; however, the extent of the shift varies for the different systems. To confirm our supposition that the probe is concentrating in the more hydrophobic drug-rich phase that evolves as a consequence of moisture-induced AAPS, the films were viewed under a high-resolution fluorescence microscope. Figure 6

crystallization of probucol. As crystallization progresses, the probe molecules are expelled into the hydrophilic PVP-rich environment resulting in a red shift. The emission peak after crystallization does not correspond to pure PVP as there might be residual amorphous probucol in the system that did not completely crystallize. The presence of residual amorphous probucol is also evident from the DSC data where the Tg corresponded to the Tg of amorphous probucol (see DSC results section for details). A similar trend in the shifts for the probe emission spectrum with exposure to high RH was obtained for the 20:80 PB−PVP ASD film (Figure 3). The initial wavelength was higher than 50:50 ratio due to the higher polymer amount. The phase separation of the PB−PVP system has been studied previously,17 and for this reason, it was a good system to check the validity of the fluorescence technique. With this initial success, the technique was then applied to study the phase behavior of the RTV−PVP system during hydration. Hydration experiments were performed at different ratios, namely, 20:80, 50:50, and 80:20 wt % RTV−PVP films containing pyrene as the probe. The phase behavior of this system in response to the absorption of water has not been explored previously. However, based on the hydrophobicity and chemistry of the API,17 it was expected that this drug−polymer combination would undergo AAPS. Pyrene was used in this case as it was found to show a greater response than other dyes. For the 50:50 blend prior to exposure to high RH, the pyrene I/III ratio was intermediate to the value for the pure components, as shown in Figure 5. Following exposure to

Figure 6. Fluorescence microscope images (40× objective) of 80:20 RTV−PVP ASD containing pyrene before and after exposure to 97% RH.

shows the fluorescence image of the 80:20 RTV−PVP dispersion before and after exposure to 97% RH. Initially, the probe appears to be uniformly dispersed with a low and uniform signal being observed. However, following exposure to high RH, it can be clearly seen that the probe has concentrated in certain regions of the film, presumably the drug-rich amorphous domains formed following AAPS. The fluorescence imaging thus provides a complementary tool to understand the phase behavior in ASD films. Thin films containing just the fluorescent probes in pure PVP and pure amorphous RTV were also analyzed using fluorescence microscopy, and as expected, no change in probe distribution was observed in the images after exposure to humidity, i.e., they remained visually homogeneous. However, bulk fluorescence spectroscopic analysis on these films (Figure 7) showed the expected increase in the wavelength and the peak ratio due to the water sorption in the films when stored at high RH and hence an increase in the hydrophilicity of the probe environment. This observation supports the supposition that the blue shift seen in the ASD films was indeed due to moisture-induced AAPS with the probe

Figure 5. Effects of storage at 97% RH on the pyrene I/III ratio for RTV−PVP ASDs. The peak ratios in pure PVP and pure RTV films are shown for reference. For the 50:50 and 80:20 RTV−PVP ASDs, as AAPS proceeds with time, the pyrene peak ratio decreases until it reaches a value that is very close to the ratio for pyrene in pure amorphous RTV films.

high RH, an immediate decrease in the I/III ratio was observed even at very short exposure times, indicating that the probe experienced a more hydrophobic environment. Because RTV is a very slow crystallizer, crystallization was not seen for the time duration of the experiment and a plateau in the I/III ratio was observed at 1.30, which is very close to the value observed for pure ritonavir. As is evident from Figure 5, the trends in the probe shifts are the same for the ASD films with different

Figure 7. Wavelength shifts in pure PVP films containing prodan (primary Y-axis, squares) and I/III peak ratio of pyrene in amorphous RTV films (secondary Y-axis, circles) after exposure to 97% RH. 1628


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Figure 8. Change in probe emission properties in amorphous films immersed in buffer for different periods of time prior to analysis of the undissolved film material: (a) 50:50 wt % PB−PVP and (b) 50:50 wt % RTV−PVP.

interacting with the more hydrophobic drug-rich phase, rather than due to the absorption of water per se. Having established that AAPS can occur in amorphous matrices exposed to high RH, an intriguing question is, do these systems undergo AAPS during dissolution or is dissolution sufficiently fast that it occurs prior to AAPS? To address this question, ASD films of PB−PVP and RTV−PVP (50:50 ratio) containing prodan and pyrene, respectively, were immersed in pH 6.8 100 mM phosphate buffer for different time periods and then evaluated using fluorescence spectroscopy. The results obtained are shown in Figure 8. It can be seen from the fluorescence spectra that there is an immediate decrease in the emission maximum following immersion. With increased immersion time, the wavelength shifts to lower values until a point is reached where the majority of the film is dissolved, and hence, the signal from the fluorescence probe disappears. Based on the fluorescence spectra shown in Figure 8, it is apparent that AAPS is very fast following immersion, with the largest shifts in the emission peak occurring within a few seconds. The final peak position is around 425 nm for PB−PVP films, the same as that obtained after exposing the ASD film to 97% RH. For the RTV−PVP film, the final pyrene peak ratio is 1.3 suggesting that the probe is experiencing an RTV-rich environment. Dissolution of ASD pellets of 50:50 drug− polymer ratio consisting of either PB−PVP or RTV−PVP was also carried out, and the fluorescence spectra were collected after exposing the pellets to the dissolution buffer. The trends in the shifts of the wavelength and the peak ratios in both cases was the same as obtained for the ASD thin films (data not shown). Control Experiment with a Nonphase Separating System. To aid in confirming that the changes in emission characteristics of the environment sensitive probes were due to AAPS, hydration studies at 97% RH and dissolution studies in pH 6.8 phosphate buffer were also performed on 50:50 RTV− HPMCAS ASD films containing pyrene. The RTV−HPMCAS system at this ratio is resistant to moisture-induced phase separation (see infrared spectroscopy results). Figures 9 and 10 show the emission spectra obtained from pyrene dispersed in the RTV−HPMCAS ASD, following exposure to 97% RH and to the buffer for different periods of time. The pyrene peak ratio did not show a decrease with time, which indicates that the

Figure 9. I/III ratio for pyrene in amorphous RTV (circles), HPMCAS (triangles), and 50:50 RTV−HPMCAS ASD (squares) after exposure to 97% RH for various time intervals. Note that the peak ratio does not show a decrease even after 5 days of exposure to moisture, but an increase, indicating that a more hydrophilic environment results due to the absorption of moisture.

ASD is not undergoing phase separation into drug-rich domains. A small increase was observed, which was because of the increase in the hydrophilicity of the ASD due to absorbed water. The peak ratios in pure RTV and HPMCAS films are shown for reference. It can be seen that the individual components also show an increase in the ratio when exposed to water. Monitoring AAPS and Crystallization Using IR, DSC, and XRD. Complementary analytical techniques including IR spectroscopy, DSC, and XRD were also employed in order to aid in the characterization of the phase behavior of the ASD films. Figure 1 shows the structures of RTV, PB, PVP, and HPMCAS. The behavior of the PB−PVP system exposed to high RH conditions has been investigated previously using IR spectroscopy, and so this system was not studied using this technique.17 For the RTV−PVP system, RTV has N-H and OH-type H-bond donors, while PVP has a carbonyl H-bond 1629


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corresponding to an amorphous RTV-rich phase and the peak at 1681 cm−1 corresponding to the PVP-rich phase. This is indicative of AAPS in the ASD matrix following exposure to moisture and correlates well with the fluorescence data. Figure 12 shows the IR spectra obtained from the RTV−HPMCAS

Figure 10. Pyrene I/III ratio in RTV−HPMCAS ASD (squares) after immersion in buffer for various time intervals. I/III ratio of pyrene in amorphous RTV (circle) and HPMCAS (triangle) is shown for reference.

acceptor and no H-bond donor. Hence, the ASD of RTV and PVP is expected to show changes in the O−H, N−H, and C O regions of the infrared spectrum when drug−polymer mixing occurs. Dry amorphous RTV has two peaks in the carbonyl region at 1630 and 1717 cm−1. The carbonyl peak in pure, dry PVP can be found at 1681 cm−1. If a molecular dispersion is formed between RTV and PVP, peak shifts or new peaks are expected in the carbonyl region. Figure 11 shows the IR peaks

Figure 12. IR scans of 50:50 RTV−HPMCAS ASD before (blue) and after (pink) exposure to moisture. The IR spectra of amorphous RTV (red) and HPMCAS (black) are shown for reference.

ASD, where a new peak emerges at 1733 cm−1, due to the interactions between RTV and HPMCAS. The IR spectrum of this ASD does not undergo change upon exposure to 97% RH followed by subsequent drying indicating that the ASD is resistant to moisture induced AAPS. This data also correlates well with the fluorescence studies on RTV−HPMCAS ASDs. Figures 13 and 14 show the DSC thermograms of ASDs, before and after exposure to moisture, for PB−PVP and RTV− PVP systems. Both the ASDs show a single Tg event prior to exposure to high RH, consistent with the formation of a molecularly mixed dispersion. After exposure to moisture, the reversing heat flow trace shows two Tg events, suggesting phase separation. Of note is the observation that one Tg event is close to the Tg of the pure amorphous drug in both cases. For the PB−PVP ASD, DSC was performed on samples after 6 and 30 h of exposure to moisture. PB does not start crystallizing until 21 h and hence two Tgs can be seen in the reversible trace obtained at 6 h of exposure. After 30 h, the obtained Tg at 25 °C corresponds to the Tg of amorphous PB. An endotherm, which occurs close to the melting point of crystalline PB, is also observed, indicating that the amorphous drug-rich domains have started to crystallize, either due to continued moisture exposure or during the DSC heating cycle. The RTV−PVP ASD also shows two Tgs whereby the one with the midpoint of 50 °C corresponds to the RTV-rich phase and the one with the midpoint of 140 °C corresponds to the PVP-rich phase. This is indicative of AAPS in the RTV−PVP ASD. RTV, being a slow crystallizer, did not crystallize over the time frame of the experiments. XRD was used to check the ASDs for the presence of any detectable crystallinity. RTV and PB ASDs showed a halo pattern prior to exposure to moisture confirming the initially amorphous nature of dispersions. After exposure to moisture for short periods of time, the dispersions remained amorphous (Figures 15 and 16). Exposure of PB ASDs to moisture for longer than 30 h resulted in the emergence of crystalline peaks,

Figure 11. IR spectra of 80:20 RTV−PVP ASD before (red) and after (black) exposure to moisture. The IR spectra of amorphous RTV (green) and PVP (blue) are shown for reference. The arrow shows a peak that is present in the unexposed dispersion, indicative of drug− polymer interactions that disappear following exposure to moisture and subsequent drying.

for the 80:20 RTV−PVP ratio as a representative example. It can be seen that a new peak appears at 1654 cm−1, which is assigned to H-bond formation between the PVP carbonyl and RTV H-bond donors. When exposed to 97% RH, the interactions between RTV and PVP are disrupted due to AAPS and the formation of drug-rich and polymer-rich domains. This results in reformation of cohesive interactions as evident from the peaks at 1630 and 1717 cm −1 1630


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Figure 13. DSC scans of amorphous PB (1), PB−PVPk90 ASD (2), 6 h moisture exposed PB−PVPk90 ASD (3), and 30 h moisture exposed PB− PVPk90 (4). The inset 4a shows the Tg that corresponds to the Tg of amorphous PB. All samples were dried at room temperature under a nitrogen purge before running the DSC scans.

Figure 14. DSC scans of amorphous RTV (1), RTV−PVPk90 ASD (2), and moisture exposed RTV−PVPk90 ASD (3).

polymer matrix. Miscibility of the drug and polymer, ideally at a molecular level,15 is considered essential to obtain the desired performance from an ASD. Thus, if the polymer is substantially phase separated from the drug, its protective impact as a crystallization inhibitor is largely lost. However, assessing the extent of dispersion of a drug in a polymer matrix, i.e., if the

whereas crystallization was not seen in RTV ASDs during the time frame of experiments.

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DISCUSSION An ASD typically consists of a poorly water-soluble BCS class II or a class IV drug dispersed within a relatively hydrophilic 1631


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of which can lead to an increased propensity for nucleation and crystallization of the drug.12,46 In addition, it has been previously reported that crystallization can be preceded by moisture-induced AAPS, a phenomenon whereby the drug and the polymer are still amorphous but the system has separated into drug-rich and drug-lean domains.17,47 AAPS has been reported for pharmaceutical ASDs41 and for polymer blends.48 Moisture-induced AAPS can be considered as a classic case of solvent-induced immiscibility, where one of the components of the ASD, in this case the polymer, has higher affinity for the solvent, water, whereas the other component, the drug, experiences unfavorable interactions with water molecules. Thus, as water molecules are sorbed, the polymer chains interact with the water molecules at the expense of drug− polymer interactions, and given sufficient mobility, a drug-rich phase forms. While moisture-induced AAPS has been studied previously in thin drug−polymer ASD films exposed to high relative humidity conditions, it has not been possible to date to investigate if this process occurs following ASD hydration during the dissolution process, due to analytical challenges with evaluating samples containing water. Given the complexity of dissolution from ASD systems, it is clearly important to better understand how changes in the matrix structure during hydration impact the resultant dissolution profile. Results obtained in this study (Figure 8) using environment sensitive fluorescence probes strongly suggest that both probucol and ritonavir ASDs formulated with PVP undergo AAPS in the ASD film as it hydrates as part of the dissolution process. It is reasonable to expect that this occurs since it is clear that both systems are susceptible to AAPS upon exposure to high RH, based not only on the fluorescence data shown in Figures 3 and 5 but also using independent methods including IR spectroscopy (Figure 11 and ref 17) and DSC data (Figures 13 and 14). Therefore, exposure to bulk water would be expected to induce the same changes as high RH, albeit with faster kinetics, as observed in this study. Tables 3 and 4 show

Figure 15. XRD overlay diffractograms of PB−PVP ASD exposed to 97% RH for different time intervals.

Table 3. Wavelength and Peak Ratio Values for ASD Films after Exposure to 97% RH

Figure 16. XRD spectra of RTV−PVP ASD before and after exposure to 97% RH.

PB−PVP (λ, nm)

system is miscible or exhibits drug-rich and polymer-rich domains, may be problematic. Several methods are commonly used to evaluate miscibility in dry drug−polymer blends including DSC,25 nuclear magnetic resonance spectroscopy,22,23 IR spectroscopy,17,18,20,21,41 XRD,19,24 and more recently, highresolution microscopy methods such as atomic force microscopy.26,42,43 Many of these approaches have limitations19,43,44 such as low sensitivity, long analysis times, and sample preparation constraints, all of which can hamper characterization of the system of interest. It is also of interest to evaluate the impact of water on miscibility during storage and dissolution, which is even more challenging from an analytical perspective. Because of the hygroscopic nature of the amorphous components, especially the hydrophilic polymer, ASDs have an inherent tendency to hydrate by absorbing water during storage and when they come into contact with aqueous solutions during dissolution. The sorption of water molecules in an ASD gives rise to a ternary system with altered kinetic and thermodynamic properties as compared to the dry, binary ASD.18 The kinetic effects of water molecules include a decrease in Tg,45 increased mobility of the components, and decreased viscosity within the ASD matrix, all

RTV−PVP (I/III)

RTV−HPMCAS (I/III)

λ or I/III

20:80

50:50

20:80

50:50

80:20

50:50

initial lowest end point

443 437 445

437 425 435

1.72 1.48 1.51

1.60 1.30 1.30

1.44 1.29 1.29

1.42 1.42 1.47

the compilation of the fluorescence wavelength and peak ratios for the ASD systems studied at different drug−polymer ratios. For the PB−PVP ASDs during hydration, the initial wavelength of the probe is higher in the 20:80 drug−polymer ratio than 50:50 ratio indicating the higher relative hydrophilicity due to the high polymer loading. However, the decrease in the wavelength following hydration is higher for the 50:50 ratio than for the 20:80 ratio suggesting that the extent of AAPS is higher in the 50:50 ratio; a similar dependence on the extent of phase separation for different drug−polymer ratios has been observed for this system previously, when exposed to high RH.17 Although not reported to date, the moisture-induced AAPS phenomenon was expected in RTV−PVP dispersions based on the chemistry of the two components.17 RTV has three H-bond donating −NH groups, which can hydrogen bond with the carbonyl group of PVP as demonstrated by the 1632


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Molecular Pharmaceutics Table 4. Wavelength and Peak Ratio Values for ASD Films after Immersion in Buffer λ or I/III

PB−PVP−prodan (50:50)

RTV−PVP−pyrene (50:50)

RTV−HPMCAS−pyrene (50:50)

initial lowest

437 425

1.57 1.29

1.42 1.42

within the ASD matrix resulting in lower levels of supersaturation. Thus, studying and detecting AAPS is likely to be extremely important to gain a better perspective on the complex dissolution process of ASDs, which is, at present, not well understood. Given the limitations of existing analytical techniques, we believe the fast and efficient in situ monitoring capability of this novel fluorescence technique will help in detecting and better understanding phase transformations in ASDs and provide researchers with a tool to evaluate a variety of different drug−polymer combinations during formulation development.

IR data in Figure 11. However, as for other systems containing NH groups,17 sorption of water leads to disruption of the drug−polymer H-bonds, leading to the formation of a drug-rich phase and changes in the IR spectrum (Figure 11) consistent with the loss of drug−polymer H-bonding. From the fluorescence studies on RTV−PVP ASDs following exposure to moisture, the 50:50 and 80:20 drug−polymer ratio appear to undergo the largest extent of AAPS based on the observation that they show the lowest pyrene peak ratios, which is very similar to the peak ratio of the probe in amorphous RTV alone. This indicates extensive AAPS with the probe partitioning into very concentrated drug-rich domains. However, for the 20:80 RTV−PVP ratio, the ASD does not undergo as extensive AAPS, as is evident from the peak ratio, which is higher than that in the RTV films alone. PVP dispersions in general seem to be particularly susceptible to moisture-induced AAPS, whereby dispersions containing several compounds, including probucol, have been found previously to undergo this phenomenon; only compounds that form very strong hydrogen bonds with PVP appear to be resistant to AAPS.18 Other factors that have been suggested to impact the tendency and extent of AAPS include the drug to polymer ratio, the relative humidity, and of course the type of polymer used for the dispersion. In this study, we found that, while RTV and PB−PVP dispersions readily underwent AAPS, the corresponding HPMCAS dispersions showed no evidence of water-induced immiscibility during hydration of the film. Similar observations have been made for other drug−HPMCAS dispersions following exposure to high RH.41,49 Implications of AAPS on ASD Performance. The primary goal of using polymers to produce an ASD is to prevent crystallization of the amorphous drug. Using a hydrophilic polymer provides additional advantages such as increasing the dissolution rate of the drug and the wetting characteristics of the ASD. The phenomenon of AAPS in the ASD matrix is likely to be important since it would be expected to (1) decrease the shelf life of the formulation because crystallization is more likely and (2) affect the dissolution performance whereby both of these occurrences (AAPS and crystallization) would be expected to decrease the bioavailability of the drug. AAPS results in the formation of drug-rich domains with decreased polymer concentration, dispersed in a polymer-rich matrix.42,47 Because the crystallization inhibition effect of the polymer is concentration dependent,10,12,50 AAPS has been found to lead to enhanced crystallization rates. This was observed in the case of felodipine−PVP dispersions exposed to high RH where the crystal growth rates from a phase separated ASD and from pure amorphous felodipine films were similar, while in a miscible dispersion, they remained lower.49 While water can be avoided during product storage through the use of appropriate packaging, this is obviously not the case during dissolution. Understanding the tendency of a system to undergo AAPS following hydration may thus help to explain why ASD dissolution profiles depend on both polymer type and amount.51,52 Hence, it might be anticipated that an ASD that undergoes AAPS while dissolving in the gastrointestinal tract (GIT) will have a higher tendency to crystallize

■

CONCLUSIONS

■

AUTHOR INFORMATION

Environment-sensitive fluorescence probes provide a new approach to monitor phase transformations in an ASD matrix during hydration following exposure to either atmospheric or to bulk water. The probes, which show different fluorescence emission spectra depending on the hydrophobicity of the environment, were found to be sensitive to changes in the ASD matrix due to hydration, moisture-induced AAPS, and drug crystallization. Thus, by combining environment-sensitive fluorescence probes with standard characterization techniques, a more complete picture of ASD properties and dynamic behavior can be gained. It is anticipated that the new insights into the phase behavior of ASD components during dissolution will lead to the improved design of optimally performing systems.

Corresponding Author

*Address: Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, Unites States. Tel: (765) 496-6614. Fax: (765) 494-6545. E-mail: [email protected]. Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS The authors would like to thank the National Science Foundation Engineering Research Center for Structured Organic Particulate Systems (NSF ERC-SOPS) (EEC0540855) for financial support.

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REFERENCES

(1) Di, L.; Fish, P. V.; Mano, T. Bridging solubility between drug discovery and development. Drug Discovery Today 2012, 17 (9), 486− 495. (2) Lipinski, C. A. Poor aqueous solubility-an industry wide problem in ADME screening. Am. Pharm. Rev. 2002, 5, 82−85. (3) Yu, L. Amorphous pharmaceutical solids: preparation, characterization and stabilization. Adv. Drug Delivery Rev. 2001, 48 (1), 27−42. 1633


Article


(24) Newman, A.; Engers, D.; Bates, S.; Ivanisevic, I.; Kelly, R. C.; Zografi, G. Characterization of amorphous API: Polymer mixtures using X-ray powder diffraction. J. Pharm. Sci. 2008, 97 (11), 4840− 4856. (25) Six, K.; Berghmans, H.; Leuner, C.; Dressman, J.; Van Werde, K.; Mullens, J.; Benoist, L.; Thimon, M.; Meublat, L.; Verreck, G. Characterization of solid dispersions of itraconazole and hydroxypropylmethylcellulose prepared by melt extrusion, part II. Pharm. Res. 2003, 20 (7), 1047−1054. (26) Lauer, M. E.; Siam, M.; Tardio, J.; Page, S.; Kindt, J. H.; Grassmann, O. Rapid assessment of homogeneity and stability of amorphous solid dispersions by atomic force microscopyfrom bench to batch. Pharm. Res. 2013, 30 (8), 2010−2022. (27) Cabanelas, J.; Serrano, B.; González-Benito, J.; Bravo, J.; Baselga, J. Morphology of epoxy/polyorganosiloxane reactive blends. Macromol. Rapid Commun. 2001, 22 (9), 694−699. (28) Serrano, B.; Baselga, J.; Bravo, J.; Mikes, F.; Sese, L.; Esteban, I.; Pierola, I. Chemical imaging of phase-separated polymer blends by fluorescence microscopy. J. Fluoresc. 2000, 10 (2), 135−135. (29) Okay, O.; Kaya, D.; Pekcan, O. Free-radical crosslinking copolymerization of styrene and divinylbenzene: real time monitoring of the gel effect using fluorescence probe. Polymer 1999, 40 (22), 6179−6187. (30) Strehmel, B.; Strehmel, V.; Younes, M. Fluorescence probes for investigation of epoxy systems and monitoring of crosslinking processes. J. Polym. Sci., Part B: Polym. Phys. 1999, 37 (13), 1367− 1386. (31) Wang, R.; Yu, C.; Yu, F.; Chen, L.; Yu, C. Molecular fluorescent probes for monitoring pH changes in living cells. TrAC, Trends Anal. Chem. 2010, 29 (9), 1004−1013. (32) Miller, K. E.; Krueger, R. H.; Torkelson, J. M. Mobility-sensitive fluorescence probes for quantitative monitoring of water sorption and diffusion in polymer coatings. J. Polym. Sci., Part B: Polym. Phys. 1995, 33 (17), 2343−2349. (33) Otsuki, S.; Adachi, K. Effect of humidity on the fluorescence properties of a medium-sensitive fluorophore in a hydrophilic polymer film. J. Photochem. Photobiol., A 1993, 71 (2), 169−173. (34) Kalyanasundaram, K.; Thomas, J. Environmental effects on vibronic band intensities in pyrene monomer fluorescence and their application in studies of micellar systems. J. Am. Chem. Soc. 1977, 99 (7), 2039−2044. (35) Kalyanasundaram, K.; Thomas, J. K. Solvent-dependent fluorescence of pyrene-3-carboxaldehyde and its applications in the estimation of polarity at micelle-water interfaces. J. Phys. Chem. 1977, 81 (23), 2176−2180. (36) Ananthapadmanabhan, K.; Goddard, E.; Turro, N.; Kuo, P. Fluorescence probes for critical micelle concentration. Langmuir 1985, 1 (3), 352−355. (37) Ilevbare, G. A.; Taylor, L. S. Liquid−liquid phase separation in highly supersaturated aqueous solutions of poorly water-soluble drugs: Implications for solubility enhancing formulations. Cryst. Growth Des. 2013, 13 (4), 1497−1509. (38) Jackson, M. J.; Toth, S. J.; Kestur, U. S.; Huang, J.; Qian, F.; Hussain, M. A.; Simpson, G. J.; Taylor, L. S. Impact of polymers on the precipitation behavior of highly supersaturated aqueous danazol solutions. Mol. Pharmaceutics 2014, 11 (9), 3027−3038. (39) Kar, N.; Liu, H.; Edgar, K. J. Synthesis of cellulose adipate derivatives. Biomacromolecules 2011, 12 (4), 1106−1115. (40) Fedors, R. F. A method for estimating both the solubility parameters and molar volumes of liquids. Polym. Eng. Sci. 1974, 14 (2), 147−154. (41) Rumondor, A. C.; Taylor, L. S. Effect of polymer hygroscopicity on the phase behavior of amorphous solid dispersions in the presence of moisture. Mol. Pharmaceutics 2010, 7 (2), 477−490. (42) Van Eerdenbrugh, B.; Lo, M.; Kjoller, K.; Marcott, C.; Taylor, L. S. Nanoscale mid-infrared imaging of phase separation in a drug− polymer blend. J. Pharm. Sci. 2012, 101 (6), 2066−2073. (43) Van Eerdenbrugh, B.; Lo, M.; Kjoller, K.; Marcott, C.; Taylor, L. S. Nanoscale mid-infrared evaluation of the miscibility behavior of

(4) Hancock, B. C.; Zografi, G. Characteristics and significance of the amorphous state in pharmaceutical systems. J. Pharm. Sci. 1997, 86 (1), 1−12. (5) Newman, A.; Knipp, G.; Zografi, G. Assessing the performance of amorphous solid dispersions. J. Pharm. Sci. 2012, 101 (4), 1355−1377. (6) Van den Mooter, G.; Wuyts, M.; Blaton, N.; Busson, R.; Grobet, P.; Augustijns, P.; Kinget, R. Physical stabilisation of amorphous ketoconazole in solid dispersions with polyvinylpyrrolidone K25. Eur. J. Pharm. Sci. 2001, 12 (3), 261−269. (7) Hancock, B. C.; Zografi, G. The relationship between the glass transition temperature and the water content of amorphous pharmaceutical solids. Pharm. Res. 1994, 11 (4), 471−477. (8) Aso, Y.; Yoshioka, S. Molecular mobility of nifedipine−PVP and phenobarbital−PVP solid dispersions as measured by 13C-NMR spinlattice relaxation time. J. Pharm. Sci. 2006, 95 (2), 318−325. (9) Marsac, P. J.; Shamblin, S. L.; Taylor, L. S. Theoretical and practical approaches for prediction of drug−polymer miscibility and solubility. Pharm. Res. 2006, 23 (10), 2417−2426. (10) Khougaz, K.; Clas, S. D. Crystallization inhibition in solid dispersions of MK-0591 and poly (vinylpyrrolidone) polymers. J. Pharm. Sci. 2000, 89 (10), 1325−1334. (11) Taylor, L. S.; Zografi, G. Spectroscopic characterization of interactions between PVP and indomethacin in amorphous molecular dispersions. Pharm. Res. 1997, 14 (12), 1691−1698. (12) Konno, H.; Taylor, L. S. Ability of different polymers to inhibit the crystallization of amorphous felodipine in the presence of moisture. Pharm. Res. 2008, 25 (4), 969−978. (13) Kestur, U. S.; Taylor, L. S. Role of polymer chemistry in influencing crystal growth rates from amorphous felodipine. CrystEngComm 2010, 12 (8), 2390−2397. (14) Kestur, U. S.; Van Eerdenbrugh, B.; Taylor, L. S. Influence of polymer chemistry on crystal growth inhibition of two chemically diverse organic molecules. CrystEngComm 2011, 13 (22), 6712−6718. (15) Williams, H. D.; Trevaskis, N. L.; Charman, S. A.; Shanker, R. M.; Charman, W. N.; Pouton, C. W.; Porter, C. J. Strategies to address low drug solubility in discovery and development. Pharmacol. Rev. 2013, 65 (1), 315−499. (16) Crowley, K. J.; Zografi, G. Water vapor absorption into amorphous hydrophobic drug/poly (vinylpyrrolidone) dispersions. J. Pharm. Sci. 2002, 91 (10), 2150−2165. (17) Rumondor, A. C.; Wikström, H.; Van Eerdenbrugh, B.; Taylor, L. S. Understanding the tendency of amorphous solid dispersions to undergo amorphous−amorphous phase separation in the presence of absorbed moisture. AAPS PharmSciTech 2011, 12 (4), 1209−1219. (18) Rumondor, A. C.; Marsac, P. J.; Stanford, L. A.; Taylor, L. S. Phase behavior of poly (vinylpyrrolidone) containing amorphous solid dispersions in the presence of moisture. Mol. Pharmaceutics 2009, 6 (5), 1492−1505. (19) Rumondor, A. C.; Ivanisevic, I.; Bates, S.; Alonzo, D. E.; Taylor, L. S. Evaluation of drug-polymer miscibility in amorphous solid dispersion systems. Pharm. Res. 2009, 26 (11), 2523−2534. (20) Vasanthavada, M.; Tong, W.-Q. T.; Joshi, Y.; Kislalioglu, M. S. Phase behavior of amorphous molecular dispersions II: Role of hydrogen bonding in solid solubility and phase separation kinetics. Pharm. Res. 2005, 22 (3), 440−448. (21) Janssens, S.; De Zeure, A.; Paudel, A.; Van Humbeeck, J.; Rombaut, P.; Van den Mooter, G. Influence of preparation methods on solid state supersaturation of amorphous solid dispersions: a case study with itraconazole and eudragit e100. Pharm. Res. 2010, 27 (5), 775−785. (22) Paudel, A.; Geppi, M.; Den Mooter, G. V. Structural and dynamic properties of amorphous solid dispersions: the role of solidstate nuclear magnetic resonance spectroscopy and relaxometry. J. Pharm. Sci. 2014, 103 (9), 2635−2662. (23) Brettmann, B. K.; Myerson, A. S.; Trout, B. L. Solid-state nuclear magnetic resonance study of the physical stability of electrospun drug and polymer solid solutions. J. Pharm. Sci. 2012, 101 (6), 2185−2193. 1634


Article

Molecular Pharmaceutics blends of dextran or maltodextrin with poly (vinylpyrrolidone). Mol. Pharmaceutics 2012, 9 (5), 1459−1469. (44) Baird, J. A.; Taylor, L. S. Evaluation of amorphous solid dispersion properties using thermal analysis techniques. Adv. Drug Delivery Rev. 2012, 64 (5), 396−421. (45) Andronis, V.; Yoshioka, M.; Zografi, G. Effects of sorbed water on the crystallization of indomethacin from the amorphous state. J. Pharm. Sci. 1997, 86 (3), 346−351. (46) Shamblin, S. L.; Zografi, G. The effects of absorbed water on the properties of amorphous mixtures containing sucrose. Pharm. Res. 1999, 16 (7), 1119−1124. (47) Marsac, P. J.; Rumondor, A. C.; Nivens, D. E.; Kestur, U. S.; Stanciu, L.; Taylor, L. S. Effect of temperature and moisture on the miscibility of amorphous dispersions of felodipine and poly (vinyl pyrrolidone). J. Pharm. Sci. 2010, 99 (1), 169−185. (48) Robard, A.; Patterson, D.; Delmas, G. The “Δχ effect” and polystyrene-poly (vinyl methyl ether) compatibility in solution. Macromolecules 1977, 10 (3), 706−708. (49) Rumondor, A. C.; Stanford, L. A.; Taylor, L. S. Effects of polymer type and storage relative humidity on the kinetics of felodipine crystallization from amorphous solid dispersions. Pharm. Res. 2009, 26 (12), 2599−2606. (50) Kestur, U. S.; Lee, H.; Santiago, D.; Rinaldi, C.; Won, Y.-Y.; Taylor, L. S. Effects of the molecular weight and concentration of polymer additives, and temperature on the melt crystallization kinetics of a small drug molecule. Cryst. Growth Des. 2010, 10 (8), 3585−3595. (51) Konno, H.; Handa, T.; Alonzo, D. E.; Taylor, L. S. Effect of polymer type on the dissolution profile of amorphous solid dispersions containing felodipine. Eur. J. Pharm. Biopharm. 2008, 70 (2), 493−499. (52) Alonzo, D. E.; Gao, Y.; Zhou, D.; Mo, H.; Zhang, G. G.; Taylor, L. S. Dissolution and precipitation behavior of amorphous solid dispersions. J. Pharm. Sci. 2011, 100 (8), 3316−3331. (53) Li, L.; Jiang, Z.; Xu, J.; Fang, T. Predicting poly(vinyl pyrrolidone)’s solubility parameter and systematic investigation of the parameters of electrospinning with response surface methodology. J. Appl. Polym. Sci. 2014, 131 (11), 40304. (54) Chokshi, R. J.; Sandhu, H. K.; Iyer, R. M.; Shah, N. H.; Malick, A. W.; Zia, H. Characterization of physico-mechanical properties of indomethacin and polymers to assess their suitability for hot-melt extrusion processs as a means to manufacture solid dispersion/ solution. J. Pharm. Sci. 2005, 94 (11), 2463−2474. (55) Arichi, S.; Matsuura, H.; Tanimoto, Y.; Murata, H. Studies of Poly-2-vinylpyridine. II. Solubilities in Various Solvents. Bull. Chem. Soc. Jpn. 1966, 39 (3), 434−439. (56) Small, P. Some factors affecting the solubility of polymers. J. Appl. Chem. 1953, 3 (2), 71−80.

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