Physical Properties of Solid Molecular Dispersions of Indomethacin with Poly(vinylpyrrolidone) and Poly(vinylpyrrolidone-co-vinyl-acetate) in Relation to Indomethacin Crystallization

Purpose. To measure solid-state features of amorphous molecular dispersions of indomethacin and various molecular weight grades of poly(vinylpyrrolidone), PVP, and poly(vinylpyrrolidone-co-vinylacetate), PVP/VA, in relation to isothermal crystallization of indomethacin at 30°C Methods. The glass transition temperatures (Tg) of molecular dispersions were measured using differential scanning calorimetry (DSC). FT-IR spectroscopy was used to investigate possible differences in interactions between indomethacin and polymer in the various dispersions. The enthalpy relaxation of 5% w/w and 30% w/w polymer dispersions was determined following various aging times. Quantitative isothermal crystallization studies were carried out with pure indomethacin and 5% w/w polymers in drug as physical mixtures and molecular dispersions. Results. All coprecipitated mixtures exhibited a single glass transition temperature. All polymers interacted with indomethacin in the solid state through hydrogen bonding and in the process eliminated the hydrogen bonding associated with the carboxylic acid dimers of indomethacin. Molecular mobility at 16.5°C below Tg was reduced relative to indomethacin alone, at the 5% w/w and 30% w/w polymer level. No crystallization of indomethacin at 30°C was observed in any of the 5% w/w polymer molecular dispersions over a period of 20 weeks. Indomethacin alone and in physical mixtures with various polymers completely crystallized to the form at this level within 2 weeks. Conclusions. The major basis for crystal inhibition of indomethacin at 30°C at the 5% w/w polymer level in molecular dispersions is not related to polymer molecular weight and to the glass transition temperature, and is more likely related to the ability to hydrogen bond with indomethacin and to inhibit the formation of carboxylic acid dimers that are required for nucleation and growth to the crystal form of indomethacin.     

The Effect of Low Concentrations of Molecularly Dispersed Poly(Vinylpyrrolidone) on Indomethacin Crystallization from the Amorphous State

Purpose. To investigate the effect of low concentrations of molecularly dispersed poly(vinylpyrrolidone) (PVP) on indomethacin (IMC) crystallization from the amorphous state using particle size effects to identify possible mechanisms of crystallization inhibition. Methods. Different particle sizes of amorphous IMC and 1, 2, and 5% PVP were stored dry at 30°C for 84 days. PXRD was used to calculate the rate and extent of crystallization and the polymorph formed. Results. Crystallization from amorphous IMC and IMC/PVP molecular dispersions yielded the polymorph of IMC. Crystallization rates were reduced at larger particle size and in the presence of 1, 2, and 5%PVP. Crystallization did not reach completion in some IMC/PVP samples, with the quantity of uncrystallized amorphous phase proportional to particle size. Conclusions. Low concentrations of molecularly dispersed PVP affected IMC crystallization from the amorphous state. Formation of -IMC at rates dependent on particle size indicated that surface nucleation predominated in both the absence and presence of PVP. Excellent correlation was seen between the extent of crystallization and simulated depths of crystal penetration, supporting the hypothesis that increasing local PVP concentration inhibits crystal growth from surface nuclei into the amorphous particle.     

Phase Behavior of Binary and Ternary Amorphous Mixtures Containing Indomethacin, Citric Acid, and PVP

Purpose. To better understand the nature of drug-excipient interactions we have studied the phase behavior of amorphous binary and ternary mixtures of citric acid, indomethacin and PVP, as model systems. Methods. We have prepared amorphous mixtures by co-melting or coprecipitation from solvents, and have measured glass transition temperatures with differential scanning calorimetry. Results. Citric acid and indomethacin in the amorphous state are miscible up to 0.25 weight fraction of citric acid, equivalent to about 2 moles of citric acid and 3 moles of indomethacin. Phase separation, as reflected by two Tg values, occurs without crystallization leading to a saturated citric acid-indomethacin amorphous phase and one essentially containing only citric acid. PVP-citric acid and PVP-indomethacin form non-ideal miscible systems at all compositions. A ternary system containing 0.3 weight fraction of PVP produces a completely miscible system at all citric acid-indomethacin compositions. The use of 0.2 weight fraction of PVP, however, only produces miscibility up to a weight fraction of 0.4 citric acid relative to indomethacin. The two phases above this point appear to contain citric acid in PVP and citric acid in indomethacin, respectively. Conclusions. Two components of an amorphous solid mixture containing citric acid and indomethacin with limited solid state miscibility can be solublized as an amorphous solid phase by the addition of moderate levels of PVP.     

Phase Behavior of Amorphous Molecular Dispersions II: Role of Hydrogen Bonding in Solid Solubility and Phase Separation Kinetics

No HeadingPurpose. To determine the factors influencing solid solubility and phase separation kinetics of drugs from amorphous solid dispersions.Methods. Solid dispersions of griseofulvin-poly(vinyl pyrrolidone) (PVP) and indoprofen-PVP were prepared using solvent evaporation technique. Dispersions demonstrating single T_g were exposed to 40°C/69% RH for 90 days. Drug solid solubility in the polymer and phase separation rates were determined from changes in T_g of solid dispersions. FTIR spectroscopy and XRD were used to characterize drug-polymer interactions and drug crystallinity, respectively.Results. Freshly prepared solid dispersion of up to 30% w/w griseofulvin and indoprofen were molecularly miscible with PVP. Hydrogen bonding was evident in indoprofen-PVP, but not in griseofulvin-PVP dispersions. When exposed to 40°C/69% RH, griseofulvin phase separated completely, whereas the solid solubility of indoprofen was determined as 13% w/w. The first-order rate constants of phase separation for 10%. 20%, and 30% w/w griseofulvin dispersions were estimated as 4.66, 5.19, and 12.50 (×10²) [day^–1], and those of 20% and 30% w/w indoprofen were 0.62 and 1.25 (×10²) [day^–1], respectively.Conclusions. Solid solubility of griseofulvin and indoprofen in PVP is 0% w/w and 13% w/w, respectively. Drug-polymer hydrogen bonding in indoprofen-PVP dispersions favors solid solubility. Phase separation rate of drug from the solid dispersions depends on the initial drug content and the nature of drug-polymer interactions.     

Correlation of Inhibitory Effects of Polymers on Indomethacin Precipitation in Solution and Amorphous Solid Crystallization Based on Molecular Interaction

Purpose

To correlate the polymer’s degree of precipitation inhibition of indomethacin in solution to the amorphous stabilization in solid state.

Methods

Precipitation of indomethacin (IMC) in presence of polymers was continuously monitored by a UV spectrophotometer. Precipitates were characterized by PXRD, IR and SEM. Solid dispersions with different polymer to drug ratios were prepared using solvent evaporation. Crystallization of the solid dispersion was monitored using PXRD. Modulated differential scanning calorimetry (MDSC), IR, Raman and solid state NMR were used to explore the possible interactions between IMC and polymers.

Results

PVP K90, HPMC and Eudragit E100 showed precipitation inhibitory effects in solution whereas Eudragit L100, Eudragit S100 and PEG 8000 showed no effect on IMC precipitation. The rank order of precipitation inhibitory effect on IMC was found to be PVP K90?>?Eudragit E100?>?HPMC. In the solid state, polymers showing precipitation inhibitory effect also exhibited amorphous stabilization of IMC with the same rank order of effectiveness. IR, Raman and solid state NMR studies showed that rank order of crystallization inhibition correlates with strength of molecular interaction between IMC and polymers.

Conclusions

Correlation is observed in the polymers ability to inhibit precipitation in solution and amorphous stabilization in the solid state for IMC and can be explained by the strength of drug polymer interactions.     

Properties of solid dispersions of piroxicam in polyvinylpyrrolidone.

Solid dispersions of piroxicam were prepared with polyvinylpyrrolidone (PVP) K-17 PF and PVP K-90 by solvent method. The physical state and drug:PVP interaction of solid dispersions and physical mixtures were characterized by X-ray diffraction, Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). FTIR analysis demonstrated the presence of intermolecular hydrogen bonding between piroxicam and PVP in solid dispersions. These interactions reflected the changes in crystalline structures of piroxicam. The amorphousness within the PVP moeity might be predicted in piroxicam dispersions by the disappearance of N-H or O-H peak of piroxicam. Dissolution studies indicated a significant increase in dissolution of piroxicam when dispersed in PVP. The better results were obtained with the lower molecular weight PVP K-17 than with higher molecular weight PVP K-90. The non-amorphous solid dispersions in PVP K-17 showed almost equally fast dissolution rates to amorphous dispersions in PVP K-90. The mechanism of dissolution of solid dispersion in PVP K-90 is predominantly diffusion-controlled due to the very high viscosity of PVP K-90. Dissolution was maximum with the amorphous solid dispersions containing drug:PVP K-17 1:5 and 1:6 which showed a 40-fold increase in dissolution in 5 min as compared with pure drug. Copyright     

Molecular mobility of nifedipine-PVP and phenobarbital-PVP solid dispersions as measured by 13C-NMR spin-lattice relaxation time

Amorphous nifedipine-PVP and phenobarbital-PVP solid dispersions with various drug contents were prepared by melting and subsequent rapid cooling of mixtures of PVP and nifedipine, or phenobarbital. Chemical shifts and spin-lattice relaxation times (T(1)) of PVP, nifedipine, and phenobarbital carbons were determined by (13)C-CP/MAS NMR to elucidate drug-PVP interactions and the localized molecular mobility of drug and PVP in the solid dispersions. The chemical shift of the PVP carbonyl carbon increased as the drug content increased, appearing to reach a plateau at a molar ratio of drug to PVP monomer unit of approximately 1:1, suggesting hydrogen bond interactions between the PVP carbonyl group and the drugs. T(1) of the PVP carbonyl carbon in the solid dispersions increased as the drug content increased, indicating that the mobility of the PVP carbonyl carbon was decreased by hydrogen bond interactions. T(1) of the drug carbons increased as the PVP content increased, and this increase in T(1) became less obvious when the molar ratio of PVP monomer unit to drug exceeded approximately 1:1. These results suggest that the localized motion of the PVP pyrrolidone ring and the drug molecules is reduced by hydrogen bond interactions. Decreases in localized mobility appear to be one of the factors that stabilize the amorphous state of drugs.     

Evidence for solid- and liquid-state interactions in a furosemide-polyvinylpyrrolidone solid dispersion

The solid-state interactions between furosemide (FUR) and polyvinylpyrrolidone (PVP) in a solid dispersion system have been investigated by dispersive and Fourier Transform IR. Using spectral subtraction procedures, shifts to lower frequencies are seen in FUR-NH stretching vibrations in amorphous FUR-PVP systems in comparison with the crystalline FUR spectrum. The magnitude of shifts are similar to those seen when FUR is dissolved in the hydrogen-bonding solvent 1,4 dioxan (0.015-0.155 M, 20 degrees C). Spectral assignment indicates the FUR sulfonamide group binds to PVP in preference to the FUR secondary amine which is shown to possess an intramolecular hydrogen bond by analysis of published X-ray crystal data. With a molecular graphics computer program, the FUR crystal unit cell was compiled, and analyses of nonbonded intermolecular distances are useful in interpreting IR shift data in amorphous solid dispersions. A study of FUR-PVP interactions in solution, examined by proton NMR, reveals a downfield shift of the FUR sulfonamide proton resonance. This shift exhibits dilution and temperature (298-338 K) dependence consistent with an intermolecular hydrogen bond. The secondary amine proton resonance exhibits temperature but not dilution or solvent bonding potential dependence, characteristics of an intramolecular hydrogen bond. The proposed hydrogen bond FUR-PVP interaction may account for the formation and stabilization of the amorphous solid dispersion.     

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.     

Effect of temperature and moisture on the miscibility of amorphous dispersions of felodipine and poly(vinyl pyrrolidone)

The physical stability of amorphous molecular level solid dispersions will be influenced by the miscibility of the components. The goal of this work was to understand the effects of temperature and relative humidity on the miscibility of a model amorphous solid dispersion. Infrared spectroscopy was used to evaluate drug–polymer hydrogen bonding interactions in amorphous solid dispersions of felodipine and poly(vinyl pyrrolidone) (PVP). Samples were analyzed under stressed conditions: high temperature and high relative humidity. The glass transition temperature (T_g) of select systems was studied using differential scanning calorimetry (DSC). Atomic force microscopy (AFM) and transmission electron microscopy (TEM) were used to further investigate moisture-induced changes in solid dispersions. Felodipine-PVP solid dispersions showed evidence of adhesive hydrogen bonding interactions at all compositions studied. The drug–polymer intermolecular interactions were weakened and/or less numerous on increasing the temperature, but persisted up to the melting temperature of the drug. Changes in the hydrogen bonding interactions were found to be reversible with changes in temperature. In contrast, the introduction of water into amorphous molecular level solid dispersions at room temperature irreversibly disrupted interactions between the drug and the polymer resulting in amorphous-amorphous phase separation followed by crystallization. DSC, AFM, and TEM results provided further evidence for the occurrence of moisture induced immiscibility. In conclusion, it appears that felodipine-PVP solid dispersions are susceptible to moisture-induced immiscibility when stored at a relative humidity ≥75%. In contrast, the solid dispersions remained miscible on heating. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:169–185, 2010     

Molecular Motions in Sucrose-PVP and Sucrose-Sorbitol Dispersions—II. Implications of Annealing on Secondary Relaxations

Purpose

To determine the effect of annealing on the two secondary relaxations in amorphous sucrose and in sucrose solid dispersions.

Methods

Sucrose was co-lyophilized with either PVP or sorbitol, annealed for different time periods and analyzed by dielectric spectroscopy.

Results

In an earlier investigation, we had documented the effect of PVP and sorbitol on the primary and the two secondary relaxations in amorphous sucrose solid dispersions (1). Here we investigated the effect of annealing on local motions, both in amorphous sucrose and in the dispersions. The average relaxation time of the local motion (irrespective of origin) in sucrose, decreased upon annealing. However, the heterogeneity in relaxation time distribution as well as the dielectric strength decreased only for β₁- (the slower relaxation) but not for β₂-relaxations. The effect of annealing on β₂-relaxation times was neutralized by sorbitol while PVP negated the effect of annealing on both β₁- and β₂-relaxations.

Conclusions

An increase in local mobility of sucrose brought about by annealing could be negated with an additive.     

Application of quartz crystal microbalance to study the impact of pH and ionic strength on protein-silicone oil interactions

The effect of adding a third polymer to immiscible binary solid dispersions was investigated. The model actives griseofulvin (GF), progesterone (PG) and phenindione (PD) were selected because they exemplify a key property of many poorly soluble molecules of having at least one hydrogen bonding acceptor moiety while not having any hydrogen bond donating moieties. Ternary solid dispersions of the drug, PVP (polyvinylpyrrolidone) (proton acceptor) and PHPMA (poly[2-hydroxypropyl methacrylate]) (proton acceptor and donor) were prepared by spray drying. Stability results showed that binary solid dispersions (API and PVP) of GF and PVP crystallized quickly while the amorphous form was not possible to prepare for PG and PD. The amorphous form was prolonged upon the incorporation of PHPMA in the solid dispersion (API, PHPMA and PVP). Based on measuring the melting points, the energy of mixing the drug with the polymer was calculated using the Flory-Huggins theory. The results showed that GF had the lowest free energy followed by PG and finally PD which agreed well with the stability results. These results suggest that the addition of a third polymer to immiscible binary solid dispersions can significantly improve the stability of the amorphous form.     

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.     

Enthalpy Relaxation in Binary Amorphous Mixtures Containing Sucrose

Purpose. To compare the enthalpy relaxation of amorphous sucrose and co-lyophilized sucrose-additive mixtures near the calorimetric glass transition temperature, so as to measure the effects of additives on the molecular mobility of sucrose. Methods. Amorphous sucrose and sucrose-additive mixtures, containing poly(vinylpyrrolidone) (PVP), poly(vinylpyrrolidone-co-vinyl-acetate) (PVP/VA) dextran or trehalose, were prepared by lyophilization. Differential scanning calorimetry (DSC) was used to determine the area of the enthalpy recovery endotherm following aging times of up to 750 hours for the various systems. This technique was also used to compare the enthalpy relaxation of a physical mixture of amorphous sucrose and PVP. Results. Relative to sucrose alone, the enthalpy relaxation of co-lyophilized sucrose-additive mixtures was reduced when aged for the same length of time at a comparable degree of undercooling in the order: dextran PVP > PVP/VA > trehalose. Calculated estimates of the total enthalpy change required for sucrose and the mixtures to relax to an equilibrium supercooled liquid state (H) were essentially the same and were in agreement with enthalpy changes measured at longer aging times (750 hours). Conclusions. The observed decrease in the enthalpy relaxation of the mixtures relative to sucrose alone indicates that the mobility of sucrose is reduced by the presence of additives having a T_g that is greater than that of sucrose. Comparison with a physically mixed amorphous system revealed no such effects on sucrose. The formation of a molecular dispersion of sucrose with a second component, present at a level as low as 10%, thus reduces the mobility of sucrose below T_g, most likely due to the coupling of the molecular motions of sucrose to those of the additive through molecular interactions.     

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     

Freeze-Concentration Separates Proteins and Polymer Excipients Into Different Amorphous Phases

Purpose. To study the miscibility of proteins and polymer excipients in frozen solutions and freeze-dried solids as protein formulation models. Methods. Thermal profiles of frozen solutions and freeze-dried solids containing various proteins (lysozyme, ovalbumin, BSA), nonionic polymers (Ficoll, polyvinylpyrrolidone [PVP]), and salts were analyzed by differential scanning calorimetry (DSC). The polymer miscibility was determined from the glass transition temperature of maximally freeze-concentrated solute (T_g) and the glass transition temperature of freeze-dried solid (T_g). Results. Frozen Ficoll or PVP 40k solutions showed T_g at –22°C, while protein solutions did not show an apparent T_g. All the protein and nonionic polymer combinations (5% w/w, each) were miscible in frozen solutions and presented single T_gs that rose with increases in the protein ratio. Various salts concentration-dependently lowered the single T_gs of the proteins and Ficoll combinations maintaining the mixed amorphous phase. In contrast, some salts induced the separation of the proteins and PVP combinations into protein-rich and PVP-rich phases among ice crystals. The T_gs of these polymer combinations were jump-shifted to PVP's intrinsic T_g at certain salt concentrations. Freeze-dried solids showed varied polymer miscibilities identical to those in frozen solutions. Conclusions. Freeze-concentration separates some combinations of proteins and nonionic polymers into different amorphous phases in a frozen solution. Controlling the polymer miscibility is important in designing protein formulations.     

Effect of storage conditions on the recrystallization of drugs in solid dispersions with crospovidone

Abstract

The physical stability of amorphous solid dispersions (SDs) is influenced by their storage conditions. The goal of this work was to investigate the factors affecting the recrystallization of drugs in SDs after storage under conditions of high temperature and high humidity. SDs of three drugs (dipyridamole, nifedipine and indomethacin) with different functional groups (amino, carbonyl and hydroxyl) and onset times for crystallization of the amorphous state were prepared using crospovidone (CrosPVP). All of the drugs in the SDs remained in an amorphous state at 25?°C/50% relative humidity (RH) in closed glass bottles for at least six months. Under conditions of high temperature (40?°C/75%RH/closed and 60?°C/open), differences in interactions between the hydrogen bond donors of the drugs and the amide carbonyl group of CrosPVP are essential factors for recrystallization of the drugs in the SDs. On the other hand, under condition of high humidity (40?°C/75%RH/open), in addition to the difference in the interaction between the drug and CrosPVP, the rate of increase in moisture content affects their recrystallization in SDs.     

Physical Stability of an Amorphous Sugar Matrix Dried From Methanol as an Amorphous Solid Dispersion Carrier and the Influence of Heat Treatment

An amorphous sugar matrix, after drying from an organic solvent, was investigated for use as a method for dispersing hydrophobic drugs (solid dispersion). However, the amorphous sugar, originally contained in the organic solvent, had a significantly low glass transition temperature (T_g), thus rendering it physically unstable. In this study, we examined the physicochemical properties of a sugar in a dried matrix and in an organic solvent, using α-maltose and methanol as a representative sugar and organic solvent. The apparent molar volume of α-maltose was ∼30% smaller in methanol than in water. The methanol-originated amorphous α-maltose exhibited a much greater degree of hydrogen bonding than the water-originated one. Considering these findings, we conclude that the α-maltose maintained its compact conformation in the dried state and consequently caused the markedly low T_g. Second, it was found that heating under appropriate conditions resulted in an increase in the T_g of the methanol-originated amorphous α-maltose as well as a decrease in the level of hydrogen bonding. The aqueous dissolution of 2 model hydrophobic drugs (indomethacin and ibuprofen) from the solid dispersion was also improved as the result of the heat treatment, whereas, to the contrary, the dissolution of another model drug (curcumin) was lowered.     

Inhibition of albendazole crystallization in poly(vinylpyrrolidone) solid molecular dispersions

The main aim of the study was to investigate the mechanisms of the stabilizing effect of poly(vinylpyrrolidone) (PVP) on amorphous albendazole (ABZ). Solid dispersions of ABZ with PVP polymers and with a copolymer containing poly(vinylacetate) (PVP/VA) were prepared using the solvent casting method. The effects of PVP molecular weight, composition and content on the crystallization of ABZ from the amorphous state were investigated using differential scanning calorimetry. Stability of the amorphous drug with respect to isothermal crystallization was studied at different polymer concentrations and storage temperatures. Solid dispersions were found to be X-ray amorphous and exhibited a single glass transition temperature (Tg). Onset of crystallization and extent of inhibition increased with concentration and molecular weight of the homopolymer. In spite of its having a higher molecular weight, replacement of about 40% of vinylpyrrolidone monomers with vinylacetate groups (as in the copolymer) resulted in reduced inhibition of crystallization. ABZ crystallized from the amorphous state in the absence of polymer even when stored below the Tg. The solvent casting method greatly reduced the requirement for polymer to achieve X-ray amorphous solid dispersions. Such dispersions exhibited a significant increase in induction time and reduction in the rate of crystallization at polymer concentrations as low as 5% and at temperatures as high as 70 degrees C. Factors other than mobility, such as drug-polymer hydrogen bonding' were also found to be involved in crystallization inhibition.     

Recrystallization of Nifedipine and Felodipine from Amorphous Molecular Level Solid Dispersions Containing Poly(vinylpyrrolidone) and Sorbed Water

Purpose To compare the physical stability of amorphous molecular level solid dispersions of nifedipine and felodipine, in the presence of poly(vinylpyrrolidone) (PVP) and small amounts of moisture. Methods Thin amorphous films of nifedipine and felodipine and amorphous molecular level solid dispersions with PVP were stored at various relative humidities (RH) and the nucleation rate was measured. The amount of water sorbed at each RH was measured using isothermal vapor sorption and glass transition temperatures (T _g) were determined using differential scanning calorimetry. The solubility of each compound in methyl pyrrolidone was measured as a function of water content. Results Nifedipine crystallizes more easily than felodipine at any given polymer concentration and in the presence of moisture. The glass transition temperatures of each compound, alone and in the presence of PVP, are statistically equivalent at any given water content. The nifedipine systems are significantly more hygroscopic than the corresponding felodipine systems. Conclusions Variations in the physical stability of the two compounds could not be explained by differences in T _g. However, the relative physical stability is consistent with differences in the degree of supersaturation of each drug in the solid dispersion, treating the polymer and water as a co-solvent system for each drug compound.