Influence of different polymers on the crystallization tendency of molecularly dispersed amorphous felodipine

The ability of various polymers to inhibit the crystallization of amorphous felodipine was studied in amorphous molecular dispersions. Spin-coated films of felodipine with poly(vinylpyrrolidone) (PVP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), and hydroxypropylmethylcellulose (HPMC) were prepared and used for measurement of the nucleation rate and to probe drug-polymer intermolecular interactions. Bulk solid dispersions were prepared by a solvent evaporation method and characterized using thermal analysis. It was found that each polymer was able to significantly decrease the nucleation rate of amorphous felodipine even at low concentrations (3-25% w/w). Each polymer was found to affect the nucleation rate to a similar extent at an equivalent weight fraction. For HPMC and HPMCAS, thermal analysis indicated that the glass transition temperature (T(g)) of the solid dispersions were not significantly different from that of felodipine alone, whereas an increase in T(g) was observed for the PVP containing solid dispersions. Infrared spectroscopic studies indicated that hydrogen bonding interactions were formed between felodipine and each of the polymers. These interactions were stronger between felodipine and PVP than for the other polymers. It was speculated that, at the concentrations employed, the polymers reduce the nucleation rate through increasing the kinetic barrier to nucleation.     

Comparison of HPMC based polymers performance as carriers for manufacture of solid dispersions using the melt extruder

Preparation of amorphous solid dispersions using hot-melt extrusion process for poorly water soluble compounds which degrade on melting remains a challenge due to exposure to high temperatures. The aim of this study was to develop a physically and chemically stable amorphous solid dispersion of a poorly water-soluble compound, NVS981, which is highly thermal sensitive and degrades upon melting at 165 °C. Hydroxypropyl Methyl Cellulose (HPMC) based polymers; HPMC 3cps, HPMC phthalate (HPMCP) and HPMC acetyl succinate (HPMCAS) were selected as carriers to prepare solid dispersions using hot melt extrusion because of their relatively low glass transition temperatures. The solid dispersions were compared for their ease of manufacturing, physical stability such as recrystallization potential, phase separation, molecular mobility and enhancement of drug dissolution. Two different drug loads of 20 and 50% (w/w) were studied in each polymer system. It was interesting to note that solid dispersions with 50% (w/w) drug load were easier to process in the melt extruder compared to 20% (w/w) drug load in all three carriers, which was attributed to the plasticizing behavior of the drug substance. Upon storage at accelerated stability conditions, no phase separation was observed in HPMC 3cps and HPMCAS solid dispersions at the lower and higher drug load, whereas for HPMCP, phase separation was observed at higher drug load after 3 months. The pharmaceutical performance of these solid dispersions was evaluated by studying drug dissolution in pH 6.8 phosphate buffer. Drug release from solid dispersion prepared from polymers used for enteric coating, i.e. HPMCP and HPMCAS was faster compared with the water soluble polymer HPMC 3cps. In conclusion, of the 3 polymers studied for preparing solid dispersions of thermally sensitive compound using hot melt extrusion, HPMCAS was found to be the most promising as it was easily processible and provided stable solid dispersions with enhanced dissolution.     

Ability of Different Polymers to Inhibit the Crystallization of Amorphous Felodipine in the Presence of Moisture

Purpose To investigate the ability of various polymers to inhibit the crystallization of amorphous felodipine from amorphous molecular dispersions in the presence of absorbed moisture. Methods Spin coated films of felodipine with poly(vinylpyrrolidone) (PVP), hydroxypropylmethylcellulose acetate succinate (HPMCAS) and hydroxypropylmethylcellulose (HPMC) were exposed to different storage relative humidities and nucleation rates were measured using polarized light microscopy. Solid dispersions were further characterized using differential scanning calorimetry, infrared spectroscopy and gravimetric measurement of water vapor sorption. Results It was found that the polymer additive reduced nucleation rates whereas absorbed water enhanced the nucleation rate as anticipated. When both polymer and water were present, nucleation rates were reduced relative to those of the pure amorphous drug stored at the same relative humidity, despite the fact that the polymer containing systems absorbed more water. Differences between the stabilizing abilities of the various polymers were observed and these were explained by the variations in the moisture contents of the solid dispersions caused by the different hygroscopicities of the component polymers. No correlations could be drawn between nucleation rates and the glass transition temperature (T _g) of the system. PVP containing solid dispersions appeared to undergo molecular level changes on exposure to moisture which may be indicative of phase separation. Conclusions In conclusion, it was found that for a given storage relative humidity, although the addition of a polymer increases the moisture content of the system relative to that of the pure amorphous drug, the crystallization tendency was still reduced.     

Dissolution and precipitation behavior of amorphous solid dispersions

Amorphous solid dispersions (ASDs) are widely utilized in the pharmaceutical industry for bioavailability enhancement of low solubility drugs. The important factors governing the dissolution behavior of these systems are still far from adequately understood. As a consequence, it is of interest to investigate the behavior of these systems during the dissolution process. The purpose of this research was twofold. First, the degree of supersaturation generated upon dissolution as a function of drug-polymer composition was investigated. Second, an investigation was conducted to correlate physical behavior upon dissolution with polymer loading. Felodipine and indomethacin were selected as model drugs and hydroxypropylmethylcellulose (HPMC) and polyvinylpyrrolidone (PVP) were used to form the dispersions. Diffusion and nuclear magnetic resonance spectroscopy experiments revealed that the extent of bulk supersaturation generated on dissolution of the ASD did not depend on the drug-polymer ratio. Interestingly, the maximum supersaturation generated was similar to the predicted amorphous solubility advantage. However, dynamic light scattering measurements revealed that particles on the submicron scale were generated during dissolution of the solid dispersions containing 90% polymer, whereas solid dispersions at a 50% polymer loading did not yield these nanoparticles. The nanoparticles were found to result in anomalous concentration measurements when using in situ ultraviolet spectroscopy. The supersaturation generated upon dissolution of the solid dispersions was maintained for biologically relevant timeframes for the HPMC dispersions, whereas PVP appeared to be a less effective crystallization inhibitor.     

Enhanced kinetic solubility profiles of indomethacin amorphous solid dispersions in poly(2-hydroxyethyl methacrylate) hydrogels

The feasibility of forming solid molecular dispersions of poorly water-soluble drugs in crosslinked poly(2-hydroethyl methacrylate) (PHEMA) hydrogel has recently been reported by our group. The purpose of the present study is to investigate the extent of enhancement of kinetic solubility of amorphous solid dispersions (ASDs) of indomethacin (IND) in crosslinked PHEMA hydrogels as compared with those based on conventional water-soluble polymer carriers. Our results show that under non-sink conditions, the initial solubility enhancement is higher for ASDs based on polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose acetate succinate (HMPCAS), but the ability to maintain this solubility enhancement at longer times is better for ASDs based on PHEMA over a period of 24h with the extent of solubility enhancement of IND ASDs in PHEMA falling between those in PVP and HPMCAS at 10.0% IND loading after 6h and outperforming those in PVP and HPMCAS at 32.9% IND loading after 8h. The observed kinetic solubility profiles reflect the fact that the amorphous IND is released from PHEMA by a different mechanism than those from water-soluble polymer carriers. In this case, the dissolution of IND ASD from water-soluble PVP and HPMCAS is almost instantaneous, resulting in an initial surge of IND concentration followed by a sharp decline due to the nucleation and crystallization events triggered by the rapid build-up of drug supersaturation. On the other hand, the dissolution of IND ASD from insoluble crosslinked PHEMA hydrogel beads is less rapid as it is regulated by a feedback-controlled diffusion mechanism, thus avoiding a sudden surge of supersaturation in the dissolution medium. The absence of an apparent decline in drug concentration during dissolution from IND-PHEMA ASD further reflects the diminished nucleation and crystallization events during IND dissolution from hydrogel-based solid molecular dispersions. Based on the XRD analyses, a threshold IND loading level of about 34% in PHEMA has been identified, above which amorphous to crystalline transition tends to occur. Also, by selecting the appropriate particle sizes, immediate to controlled release of IND from IND-PHEMA ASD can be readily achieved as the release rate increases with decreasing PHEMA bead size. Furthermore, a robust physical stability has been demonstrated in IND-PHEMA ASD with no drug precipitation for up to 8 months at IND loadings below 16.7% under direct open cup exposure to accelerated stability conditions (40°C/75% RH).     

Correlating the Behavior of Polymers in Solution as Precipitation Inhibitor to its Amorphous Stabilization Ability in Solid Dispersions

Our major goals were to understand the mechanism of dipyridamole (DPD) precipitation inhibition in the presence of polymers and to correlate the polymers-mediated precipitation inhibition in solution to the amorphous stabilization in the solid state. A continuous UV spectrophotometer was used to monitor the DPD concentration with time in the absence and presence of different polymers. Six polymers: PVP K90, hydroxypropylmethylcellulose (HPMC), Eudragit E100, Eudragit S100, Eudragit L100, and PEG 8000 were screened at different drug-to-monomer ratios. Solid dispersions were characterized by X-ray powder diffraction and modulated differential scanning calorimetry, whereas infrared (IR) and Raman were used to investigate the possible drug-polymer interactions. Eudragit E100 and HPMC were found to delay both DPD precipitation initiation time and precipitation rates. Eudragit S100 delayed only the precipitation initiation time and PVP K90 decreased only the precipitation rates. In solid state, Eudragit S100, PVP K90, HPMC, and Eudragit L100 were effective stabilizers of the DPD solid dispersion. Eudragit S100 was found to be most effective DPD-stabilizing polymer. The IR and Raman spectra of the solid dispersion of Eudragit S100 and HPMC showed peak shift, indicating drug-polymer molecular interactions. It is concluded that the drug-polymer interaction plays a significant role in precipitation inhibition and amorphous stabilization.     

Crystallization rate of amorphous nifedipine analogues unrelated to the glass transition temperature

To examine the relative contributions of molecular mobility and thermodynamic factor, the relationship between glass transition temperature (T(g)) and the crystallization rate was examined using amorphous dihydropyridines (nifedipine (NFD), m-nifedipine (m-NFD), nitrendipine (NTR) and nilvadipine (NLV)) with differing T(g) values. The time required for 10% crystallization, t(90), was calculated from the time course of decreases in the heat capacity change at T(g). The t(90) of NLV and NTR decreased with decreases in T(g) associated with water sorption. The t(90) versus T(g)/T plots almost overlapped for samples of differing water contents, indicating that the crystallization rate is determined by molecular mobility as indicated by T(g). In contrast, differences in the crystallization rate between these four drugs cannot be explained only by molecular mobility, since the t(90) values at a given T(g)/T were in the order: NLV>NTR>NFD approximately m-NFD. A lower rate was obtained for amorphous drugs with lower structural symmetry and more bulky functional groups, suggesting that these factors are also important. Furthermore, the crystallization rate of NTR in solid dispersions with poly(vinylpyrrolidone) (PVP) and hydroxypropyl methylcellulose (HPMC) decreased to a greater extent than expected from the increased T(g). This also suggests that factors other than molecular mobility affect the crystallization rate.     

Cefuroxime axetil solid dispersions prepared using solution enhanced dispersion by supercritical fluids

Cefuroxime axetil (CA) solid dispersions with HPMC 2910/PVP K-30 were prepared using solution enhanced dispersion by supercritical fluids (SEDS) in an effort to increase the dissolution rate of poorly water-soluble drugs. Their physicochemical properties in solid state were characterized by differential scanning calorimeter (DSC), powder X-ray diffraction (PXRD), Fourier transform infrared spectrometry (FT-IR) and scanning electron microscopy. No endothermic and characteristic diffraction peaks corresponding to CA were observed for the solid dispersions in DSC and PXRD. FTIR analysis demonstrated the presence of intermolecular hydrogen bonds between CA and HPMC 2910/PVP K-30 in solid dispersions, resulting in the formation of amorphous or non-crystalline CA. Dissolution studies indicated that the dissolution rates were remarkably increased in solid dispersions compared with those in the physical mixture and drug alone. In conclusion, an amorphous or non-crystalline CA solid dispersion prepared using SEDS could be very useful for the formulation of solid dosage forms.     

Effect of Temperature and Moisture on the Physical Stability of Binary and Ternary Amorphous Solid Dispersions of Celecoxib

The effectiveness of different polymers, alone or in combination, in inhibiting the crystallization of celecoxib (CEX) from amorphous solid dispersions (ASDs) exposed to different temperatures and relative humidities was evaluated. It was found that polyvinylpyrrolidone (PVP) and PVP-vinyl acetate formed stronger or more extensive hydrogen bonding with CEX than cellulose-based polymers. This, combined with their better effectiveness in raising the glass transition temperature (T_g) of the dispersions, provided better physical stabilization of amorphous CEX against crystallization in the absence of moisture when compared with dispersions formed with cellulose derivatives. In ternary dispersions containing 2 polymers, the physical stability was minimally impaired by the presence of a cellulose-based polymer when the major polymer present was PVP. On exposure to moisture, stability of the CEX ASDs was strongly affected by both the dispersion hygroscopicity and the strength of the intermolecular interactions. Binary and ternary ASDs containing PVP appeared to undergo partial amorphous–amorphous phase separation when exposed 94% relative humidity, followed by crystallization, whereas other binary ASDs crystallized directly without amorphous–amorphous phase separation.     

Formulation optimization of solid dispersion of mosapride hydrochloride

Mosapride citrate (MSP) is a gastroprokinetic agent that acts as a selective 5-HT₄ agonist and accelerates the gastric emptying, and is used for the treatment of acid reflux, irritable bowel syndrome, and functional dyspepsia. The purpose of this study is to investigate the solid dispersion formulations of MSP with controlled release characteristic using various polymers, elucidate the release mechanism, and characterize the interaction patterns between MSP and polymers. Solid dispersions of MSP with different drug-to-polymer ratios were prepared by a solvent evaporation method and characterized in comparison with the simple physical mixtures. Eudragit RSPO, Eudragit RLPO, hydroxypropylmethylcellulose (HPMC) or Kollidon SR® was used as a controlled-release polymer along with polyvinylpyrrolidone (PVP) as a carrier. Characterization of MSP solid dispersion was performed using thermal analysis (DSC), powder X-ray diffraction (XRD), Fourier transform-infrared (FT-IR) spectroscopy, where the drug was converted from the crystalline state to amorphous state in all polymeric carriers used. In vitro dissolution studies showed that the drug release has been extended up to 24 h by using Eudragit RSPO or HPMC. Moreover, the formulations containing higher polymer content ratio showed better slow-release profile. These results indicate that the solid dispersion formulation containing PVP/Eudragit RSPO or HPMC mixture could serve as a good controlled-release system for MSP.     

Crystallization of Amorphous Solid Dispersions of Resveratrol during Preparation and Storage—Impact of Different Polymers

The objective of this study was to investigate intermolecular interactions between resveratrol and polymers in amorphous blends and to study the potential correlations between compound–polymer interactions, manufacturability, and stability of the amorphous system to crystallization during storage. Polymers included two grades of poly (vinylpyrrolidone) (PVP), Eudragit E100 (E100), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), carboxymethyl cellulose acetate butyrate, and poly (acrylic acid) (PAA). Amorphous blends (“solid dispersions”) were prepared by dissolving both resveratrol and polymer in a solvent followed by rotary evaporation. Crystallinity was evaluated using X‐ray powder diffraction and was studied as a function of time. Mid‐infrared (IR) spectroscopy was used to investigate resveratrol–polymer interactions. Polymer influence on the crystallization behavior of resveratrol varied and could be correlated to the polymer structure, whereby polymers with good hydrogen bond acceptor groups performed better as crystallization inhibitors. Resveratrol–polymer hydrogen bonding interactions could be inferred from the IR spectra. Somewhat surprisingly, E100 and resveratrol showed evidence of an acid–base reaction, in addition to intermolecular hydrogen bonding interactions. PVP K29/32 appeared to form stronger hydrogen bond interactions with resveratrol relative to HPMC, HPMCAS, and PAA, consistent with acceptor group chemistry. Long‐term stability of the systems against crystallization suggested that stability is linked to the type and strength of intermolecular interactions present. whereby resveratrol blended with E100 and PVP K29/32 showed the greatest stability to crystallization. In conclusion, amorphous resveratrol is unstable and difficult to form, requiring the assistance of a polymeric crystallization inhibitor to facilitate the formation of an amorphous solid dispersion. Polymers effective at inhibiting crystallization were identified, and it is rationalized that their effectiveness is based on the type and strength of their intermolecular interactions with resveratrol.     

Effect of polymer type on the dissolution profile of amorphous solid dispersions containing felodipine

Amorphous solid dispersions are used as a strategy to improve the bioavailability of poorly water-soluble compounds. When formulating with a polymer, it is important not only for the polymer to stabilize against crystallization in the solid state, but also to improve the dissolution profile through inhibiting crystallization from the supersaturated solution generated by dissolution of the amorphous material. In this study, the dissolution profiles of solid dispersions of felodipine formulated with poly(vinylpyrrolidone) (PVP), hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose acetate succinate (HPMCAS) were compared. In addition, concentration versus time profiles were evaluated for the supersaturated solutions of felodipine in the presence and absence of the polymers. HPMCAS was found to maintain the highest level of supersaturation for the greatest length of time for both the dissolution and solution crystallization experiments, whereas PVP was found to be the least effective crystallization inhibitor. All polymers appeared to reduce the crystal growth rates of felodipine at an equivalent supersaturation and this mechanism most likely contributes to the enhanced solution concentration values observed during dissolution of the amorphous solid dispersions.     

Crystallization inhibition in solid dispersions of MK-0591 and poly(vinylpyrrolidone) polymers

The effects of poly(vinylpyrrolidone) (PVP) molecular weight, composition, and content on the crystallization of a model drug, MK-0591 (Form I), were investigated. Solid dispersions of crystalline MK-0591 with PVP homopolymers of different molecular weights (2500-1 x 10(6) g/mol) and with a copolymer containing poly(vinyl acetate) (PVA), (PVP/VA, 60:40, 5.8 x 10(4) g/mol) were prepared by the solvent method. MK-0591 in the solid dispersions was found to be X-ray amorphous. One glass transition temperature (T(g)) was observed suggesting drug-polymer miscibility. The T(g) values were higher than predicted by the Gordon-Taylor equation, indicating drug-polymer interactions. The extent of crystallization inhibition increased with PVP molecular weight and, for a comparable PVP molecular weight, the homopolymer was more effective in the crystallization inhibition of the drug than the copolymer. The first onset temperature of crystallization (T(c)(obs)) increased with polymer content. The T(c)(obs) values (normalized to polymer content) were a function of the difference between the T(g) of the polymer and drug. For PVP K-90, K-30, and K-17 dispersions, the T(c)(obs) values increased proportionally to the T(g) of the dispersions. However, for PVP K-12 and PVP/VA, the increase in T(c)(obs) values corresponded to a small decrease in the T(g) values of the dispersions. This result suggests that additional factors other than the reduction in mobility affect the crystallization behavior of MK-0591 in the solid dispersions, such as specific interactions. By Fourier transform-infrared spectroscopy, changes in the carbonyl-stretching band of PVP in the solid dispersions were observed. The existence of an ion-dipole interaction between COO(-)Na(+) of the drug and the cyclic amide group of PVP was postulated.     

Preparation of a solid dispersion of felodipine using a solvent wetting method.

A straightforward solvent wetting method was used to prepare felodipine solid dispersions in the presence of various carriers. Dichloromethane is not needed when HPMC solid dispersions were produced using the solvent wetting method. The amount of ethanol used to prepare solid dispersions did not have a significant effect on the dissolution rate of felodipine. The results of X-ray diffraction and thermal analysis indicated that the drug was in the amorphous state when PVP, HPMC, and poloxamer were used as carriers. The dissolution rates of felodipine in PVP, HPMC, or poloxamer solid dispersions were much faster than those for the corresponding physical mixtures. However, dissolution profiles were found to depend on the carrier used; the dissolution rate of felodipine increased slowly for solid dispersions prepared using HPMC, whereas rapid initial dissolution rates were observed for solid dispersions prepared using PVP or poloxamer. Increases in dissolution rates were partly dependent on the ratios of felodipine to carrier. No significant changes in crystal form were observed by X-ray diffraction or thermal analysis, and no significant changes in dissolution rate were observed when sorbitol and mannitol were used as carriers.     

Investigation of preparation methods on surface/bulk structural relaxation and glass fragility of amorphous solid dispersions

The objective of this study was to investigate the effect of preparation methods on the surface/bulk molecular mobility and glass fragility of solid dispersions. Solid dispersions containing indomethacin and PVP K30 were chosen as the model system. An inverse gas chromatography method was used to determine the surface structural relaxation of the solid dispersions and these data were compared to those for bulk relaxation obtained by DSC. The values of τ(β) for the surface relaxation were 4.6, 7.1 and 1.8h for melt quenched, ball milled and spray dried solid dispersions respectively, compared to 15.6, 7.9 and 9.8h of the bulk. In all systems, the surface had higher molecular mobility than the bulk. The glass fragility of the solid dispersions was also influenced by the preparation methods with the most fragile system showing the best stability. The zero mobility temperature (T(0)) was used to correlate with the physical stability of the solid dispersions. Despite having similar T(g) (65°C), the T(0) of the melt quenched, ball milled and spray dried samples were 21.6, -4.2 and 16.7°C respectively which correlated well with their physical stability results. Therefore, T(0) appears to be a better indicator than T(g) for predicting stability of amorphous materials.     

Moisture Sorption by Polymeric Excipients Commonly Used in Amorphous Solid Dispersions and its Effect on Glass Transition Temperature: II. Cellulosic Polymers

Moisture sorption by polymeric carriers used for the development of amorphous solid dispersions (ASDs) plays a critical role in the physical stability of dispersed drugs since moisture may decrease glass transition temperature (T_g) and thereby increase molecular mobility of drugs leading to their crystallization. To assist the selection of appropriate polymers for ASDs, we conducted moisture sorption by five types of cellulosic polymers, namely, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose phthalate (HPMCP), and ethyl cellulose (EC), as functions of relative humidity (10 to 90% RH) and temperature (25 and 40 °C). The moisture sorption was in the order of HPC>HPMC>HPMCP>HPMCAS>EC, and there was no significant effect of the molecular weights of polymers on moisture uptake. There was also less moisture sorption at 40 °C than that at 25 °C. Glass transition temperatures (T_g) of the polymers decreased with the increase in moisture content. However, the plasticizing effect by moisture on HPC could not be determined fully since, despite being amorphous, there were very little baseline shifts in DSC scans. There was also very shallow baseline shift for HPMC at >1% moisture content. In contrast, T_g of HPMCAS and HPMCP decreased in general agreement with the Gordon-Taylor/Kelley-Bueche equation, and EC was semicrystalline having both T_g and melting endotherm, with only minor effect of moisture on T_g. The results of the present investigation would lead to a systematic selection of polymeric carriers for ASDs.     

Molecular mobility-based estimation of the crystallization rates of amorphous nifedipine and phenobarbital in poly(vinylpyrrolidone) solid dispersions

The overall crystallization rates and mean relaxation times of amorphous nifedipine and phenobarbital in the presence of poly(vinylpyrrolidone) (PVP) were determined at various temperatures to gain further insight into the effect of molecular mobility on the crystallization rates of amorphous drugs and the possibility of predicting stability from their molecular mobility. Nifedipine-PVP (9:1 w/w) and phenobarbital-PVP (95:5 w/w) solid dispersions were prepared by melting and rapidly cooling mixtures of each drug and PVP. The amount of amorphous nifedipine remaining in the solid dispersion was calculated from the heat of crystallization,which was obtained by differential scanning calorimetry. The amount of amorphous phenobarbital remaining in the solid dispersion was estimated from the change in the heat capacity at its glass transition temperature (T(g)). The time required for the amount of amorphous drug remaining to fall to 90% (t(90)) was calculated from the profile of time versus the amount of amorphous drug remaining. The t(90) values for the solid dispersions studied were 100-1000 times longer than those of pure amorphous drugs when compared at the same temperature. Enthalpy relaxation of the amorphous drugs in the solid dispersions was reduced compared with that in the pure amorphous drugs, indicating that the molecular mobility of the amorphous drugs is reduced in the presence of PVP. The temperature dependence of mean relaxation time (tau) for the nifedipine-PVP solid dispersion was calculated using the Adam-Gibbs-Vogel equation. Parameters D and T(0) in this equation were estimated from the heating rate dependence of T(g). Similar temperature dependence was observed for t(90) and tau values of the solid dispersion, indicating that the information on the temperature dependence of the molecular mobility, along with the crystallization data obtained at around the T(g), are useful for estimating the t(90) of overall crystallization at temperatures below T(g) in the presence of excipients.     

Amorphous Stabilization and Dissolution Enhancement of Amorphous Ternary Solid Dispersions: Combination of Polymers Showing Drug–Polymer Interaction for Synergistic Effects

The purpose of this study was to understand the combined effect of two polymers showing drug–polymer interactions on amorphous stabilization and dissolution enhancement of indomethacin (IND) in amorphous ternary solid dispersions. The mechanism responsible for the enhanced stability and dissolution of IND in amorphous ternary systems was studied by exploring the miscibility and intermolecular interactions between IND and polymers through thermal and spectroscopic analysis. Eudragit E100 and PVP K90 at low concentrations (2.5%–40%, w/w) were used to prepare amorphous binary and ternary solid dispersions by solvent evaporation. Stability results showed that amorphous ternary solid dispersions have better stability compared with amorphous binary solid dispersions. The dissolution of IND from the ternary dispersion was substantially higher than the binary dispersions as well as amorphous drug. Melting point depression of physical mixtures reveals that the drug was miscible in both the polymers; however, greater miscibility was observed in ternary physical mixtures. The IR analysis confirmed intermolecular interactions between IND and individual polymers. These interactions were found to be intact in ternary systems. These results suggest that the combination of two polymers showing drug–polymer interaction offers synergistic enhancement in amorphous stability and dissolution in ternary solid dispersions. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3511–3523, 2014     

Physicochemical Characterization of Hot Melt Extruded Bicalutamide–Polyvinylpyrrolidone Solid Dispersions

Solid molecular dispersions of bicalutamide (BL) and polyvinylpyrrolidone (PVP) were prepared by hot melt extrusion technology at drug‐to‐polymer ratios of 1:10, 2:10, and 3:10 (w/w). The solid‐state properties of BL, physical mixtures of BL/PVP, and hot melt extrudates were characterized using differential scanning calorimetry (DSC), powder X‐ray diffractometry (PXRD), Raman, and Fourier transform infrared (FTIR) spectroscopy. Drug dissolution studies were subsequently conducted on hot melt extruded solid dispersions and physical mixtures. All hot melt extrudates had a single T_g between the T_g of amorphous BL and PVP indicating miscibility of BL with PVP and the formation of solid molecular dispersions. PXRD confirmed the presence of the amorphous form of BL within the extrudates. Conversely, PXRD patterns recorded for physical mixtures showed sharp bands characteristic of crystalline BL, whereas DSC traces had a distinct endotherm at 196°C corresponding to melting of crystalline BL. Further investigations using DSC confirmed solid‐state plasticization of PVP by amorphous BL and hence antiplasticization of amorphous BL by PVP. Experimentally observed T_g values of physical mixtures were shown to be significantly higher than those calculated using the Gordon–Taylor equation suggesting the formation of strong intermolecular interactions between BL and PVP. FTIR and Raman spectroscopy were used to investigate these interactions and strongly suggested the presence of secondary interaction between PVP and BL within the hot melt extrudates. The drug dissolution properties of hot melt extrudates were enhanced significantly in comparison to crystalline BL and physical mixtures. Moreover, the rate and extent of BL release were highly dependent on the amount of PVP present within the extrudate. Storage of the extrudates confirmed the stability of amorphous BL for up to 12 months at 20°C, 40% RH whereas stability was reduced under highly humid conditions (20°C, 65% RH). Interestingly, BL recrystallization after storage under these conditions had no effect on the dissolution properties of the extrudates. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1322–1335, 2010     

Solid dispersion of carbamazepine in PVP K30 by conventional solvent evaporation and supercritical methods

This study compares the physicochemical properties of carbamazepine (CBZ) solid dispersions prepared by either a conventional solvent evaporation versus a supercritical fluid process. Solid dispersions of carbamazepine in polyvinylpyrrolidone (PVP) K30 with either Gelucire 44/14 or Vitamin E TPGS, NF (d-alpha-tocopheryl polyethylene glycol 1000 succinate) were prepared and characterized by intrinsic dissolution, differential scanning calorimetry, powder X-ray diffraction and Fourier transform infrared spectroscopy. CBZ/PVP K30 and CBZ/PVP K30/TPGS solid dispersions showed increased dissolution rate. The best intrinsic dissolution rate (IDR) was obtained for supercritically processed CBZ/PVP K30 that was four-fold higher than pure CBZ. Thermograms of various solid dispersions did not show the melting peak of CBZ, indicating that CBZ was in amorphous form inside the carrier system. This was further confirmed by X-ray diffraction studies. Infrared spectroscopic studies showed interaction between CBZ and PVP K30 in solid dispersions. The amorphous state of CBZ coupled with presence of interaction between drug and PVP K30 suggests fewer, if any, stability problems. Because the supercritical-based process produced solid dispersions with IDR better than conventional solid dispersions augmented with amphiphilic carriers, stability issues associated with lipid carriers do not apply, which, in turn, implies easier scale up under current Good Manufacturing Practice for this technique.