Felodipine nanodispersions as active core for predictable pulsatile chronotherapeutics using PVP/HPMC blends as coating layer

In the present study predictable pulsatile chronotherapeutics of felodipine (FELO), which is a poorly-water soluble drug, were prepared in the form of two layered tablets. As active core PVP/FELO nanodispersion was used while as effective coating layer different PVP/HPMC blends were added. From dissolution studies of FELO nanodispersions it was revealed that PVP/FELO 90/10 w/w dispersion is an ideal system for pulsatile formulations since the whole amount of FELO is released within the first 30 min. This dissolution enhancement and fast release was attributed to FELO amorphisation, as was found from XRD and DMTA techniques and the effective particle size reduction. Transmission electron microscopy (TEM) studies revealed that FELO creates amorphous nanodispersions into the PVP matrix while particle sizes are directly dependable upon FELO concentration. Drug particles with sizes lower than 150 nm may be the optimal level for a substantial enhancement of FELO dissolution rate. The time of FELO release initiated by the two-layered tablets was adequately adjusted by using different PVP/HPMC blends as coating layer, which is a swellable and erodible barrier. The delaying time of FELO release is directly depended by HPMC concentration and this correlation was mathematically expressed. The significance of these blends is that they are completely miscible over the entire compositional range, thus forming a new matrix with different physicochemical properties, contrary to the initial polymers.     

Physicochemical Characterization and Dissolution Study of Solid Dispersions of Lovastatin with Polyethylene Glycol 4000 and Polyvinylpyrrolidone K30

Solid dispersions in water-soluble carriers have attracted considerable interest as a means of improving the dissolution rate, and hence possibly bioavailability, of a range of hydrophobic drugs. The aim of the present study was to improve the solubility and dissolution rate of a poorly water-soluble drug, Lovastatin, by a solid dispersion technique. Solid dispersions were prepared by using polyethylene glycol 4000 (PEG 4000) and polyvinylpyrrolidone K30 (PVP K30) in different drug-to‐carrier ratios. Dispersions with PEG 4000 were prepared by fusion-cooling and solvent evaporation, whereas dispersions containing PVP K30 were prepared by solvent evaporation technique. These new formulations were characterized in the liquid state by phase solubility studies and in the solid state by differential scanning calorimetry, X-ray powder diffraction, and FT-IR spectroscopy. The aqueous solubility of Lovastatin was favored by the presence of both polymers. The negative values of the Gibbs free energy and enthalpy of transfer explained the spontaneous transfer from pure water to the aqueous polymer environment. Solid-state characterization indicated Lovastatin was present as amorphous material and entrapped in polymer matrix. In contrast to the very slow dissolution rate of pure Lovastatin, the dispersion of the drug in the polymers considerably enhanced the dissolution rate. This can be attributed to improved wettability and dispersibility, as well as decrease of the crystalline and increase of the amorphous fraction of the drug. Solid dispersion prepared with PVP showed the highest improvement in wettability and dissolution rate of Lovastatin. Even physical mixture of Lovastatin prepared with both polymers also showed better dissolution profile than that of pure Lovastatin. Tablets containing solid dispersion prepared with PEG and PVP showed significant improvement in the release profile of Lovastatin compared with tablets containing Lovastatin without PEG or PVP.     

Preparation of dextran glassy particles through freezing-induced phase separation

The aim of the present study was to experimentally examine whether poorly water-soluble drugs dispersed in a polymeric matrix exist as amorphous nanodispersions or molecularly dispersed compounds. Felodipine (Felo) dispersed in PVP matrix (solid dispersion) was used as a model drug in this study. Drug/polymer ratios have an impact on the drug average particle size, morphology and dissolution profile while solid dispersions containing up to 50 wt% Felo are completely amorphous. SEM, TEM micrographs, and micro-Raman mapping reveal that Felo is dispersed in the form of nanoparticles into the PVP matrix. Due to the high spatial resolution of TEM, it was established that these nanoparticles are not uniform particles, but rather agglomerates of individual particles with sizes smaller than 5–10 nm. Moreover, micro-Raman mapping allowed us to observe the size and spatial distribution of domains where the drug existed as molecularly or nanodispersed. Experimental evidence presented in this work contradicts the common belief that amorphous poorly water-soluble drugs exist only in the state of molecular dispersion inside a polymer matrix by showing that both types of dispersions (molecular-level and nanodispersions) can coexist.     

Mechanism of increased dissolution of diazepam and temazepam from polyethylene glycol 6000 solid dispersions

Solid dispersion literature, describing the mechanism of dissolution of drug-polyethylene glycol dispersions, still shows some gaps; (A). only few studies include experiments evaluating solid solution formation and the particle size of the drug in the dispersion particles, two factors that can have a profound effect on the dissolution. (B). Solid dispersion preparation involves a recrystallisation process (which is known to be highly sensitive to the recrystallisation conditions) of polyethylene glycol and possibly also of the drug. Therefore, it is of extreme importance that all experiments are performed on dispersion aliquots, which can be believed to be physico-chemical identical. This is not always the case. (C). Polyethylene glycol 6000 (PEG6000) crystallises forming lamellae with chains either fully extended or folded once or twice depending on the crystallisation conditions. Recently, a high resolution differential scanning calorimetry (DSC)-method, capable of evaluating qualitatively and quantitatively the polymorphic behaviour of PEG6000, has been reported. Unraveling the relationship between the polymorphic behavior of PEG6000 in a solid dispersion and the dissolution characteristics of that dispersion, is a real gain to our knowledge of solid dispersions, since this has never been thoroughly investigated. The aim of the present study was to fill up the three above mentioned gaps in solid dispersion literature. Therefore, physical mixtures and solid dispersions were prepared and in order to unravel the relationship between their physico-chemical properties and dissolution characteristics, pure drugs (diazepam, temazepam), polymer (PEG6000), solid dispersions and physical mixtures were characterised by DSC, X-ray powder diffraction (Guinier and Bragg-Brentano method), FT-IR spectroscopy, dissolution and solubility experiments and the particle size of the drug in the dispersion particles was estimated using a newly developed method. Addition of PEG6000 improves the dissolution rate of both drugs. Mechanisms involved are solubilisation and improved wetting of the drug in the polyethylene glycol rich micro-environment formed at the surface of drug crystals after dissolution of the polymer. Formulation of solid dispersions did not further improve the dissolution rate compared with physical mixtures. X-ray spectra show that both drugs are in a highly crystalline state in the solid dispersions, while no significant changes in the lattice spacings of PEG6000 indicate the absence of solid solution formation. IR spectra show the absence of a hydrogen bonding interaction between the benzodiazepines and PEG6000. Furthermore, it was concluded that the reduction of the mean drug particle size by preparing solid dispersions with PEG6000 is limited and that the influence of the polymorphic behavior of PEG6000 (as observed by DSC) on the dissolution was negligible.     

Nanoparticle formation and growth during in vitro dissolution of ketoconazole solid dispersion

The aim of this study is to examine the physical mechanisms during the dissolution of a solid dispersion, so as to provide further understanding behind the enhanced dissolution properties. X-ray amorphous solid dispersions of ketoconazole (KC), a poorly aqueous soluble drug, were prepared by melt extrusion with polyvinlypyrrolidone 17 (PVP 17) and PVP-vinyl acetate (PVP-VA64) copolymer. Prior to dissolution, Raman mapping showed a fully homogeneous spatial distribution of KC in polymer and possible drug dispersion at molecular level, whereas Fourier transform infrared spectroscopy revealed no drug-polymer chemical interaction. During in vitro dissolution test, a burst release followed by a gradual decline in dissolution could be explained by the release of KC in molecular form followed by formation of drug nanoparticles and their subsequent growth to micron size range as shown by dynamic light scattering analysis. Observations using transmission electron microscopy and cryogenic scanning electron microscopy provided support to the suggested mechanisms. The results suggested that the release of KC from the solid dispersions was carrier controlled initially, and PVP 17 PF is more efficient in inhibiting particle growth as compared with PVP-VA64. The particle growth inhibition during dissolution may be an important consideration to achieve the full benefits of dissolution enhancement of solid dispersions.     

Physicochemical characterization and dissolution study of solid dispersions of Lovastatin with polyethylene glycol 4000 and polyvinylpyrrolidone K30

Solid dispersions in water-soluble carriers have attracted considerable interest as a means of improving the dissolution rate, and hence possibly bioavailability, of a range of hydrophobic drugs. The aim of the present study was to improve the solubility and dissolution rate of a poorly water-soluble drug, Lovastatin, by a solid dispersion technique. Solid dispersions were prepared by using polyethylene glycol 4000 (PEG 4000) and polyvinylpyrrolidone K30 (PVP K30) in different drug-to-carrier ratios. Dispersions with PEG 4000 were prepared by fusion-cooling and solvent evaporation, whereas dispersions containing PVP K30 were prepared by solvent evaporation technique. These new formulations were characterized in the liquid state by phase solubility studies and in the solid state by differential scanning calorimetry, X-ray powder diffraction, and FT-IR spectroscopy. The aqueous solubility of Lovastatin was favored by the presence of both polymers. The negative values of the Gibbs free energy and enthalpy of transfer explained the spontaneous transfer from pure water to the aqueous polymer environment. Solid-state characterization indicated Lovastatin was present as amorphous material and entrapped in polymer matrix. In contrast to the very slow dissolution rate of pure Lovastatin, the dispersion of the drug in the polymers considerably enhanced the dissolution rate. This can be attributed to improved wettability and dispersibility, as well as decrease of the crystalline and increase of the amorphous fraction of the drug. Solid dispersion prepared with PVP showed the highest improvement in wettability and dissolution rate of Lovastatin. Even physical mixture of Lovastatin prepared with both polymers also showed better dissolution profile than that of pure Lovastatin. Tablets containing solid dispersion prepared with PEG and PVP showed significant improvement in the release profile Lovastatin compared with tablets containing Lovastatin without PEG or PVP.     

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     

Polymer swelling, drug mobilization and drug recrystallization in hydrating solid dispersion tablets studied by multinuclear NMR microimaging and spectroscopy

Despite the advantages offered by solid dispersions, the marketed products based on this technology are few. The most frequent concern is the stability of the amorphous drug. The state of the drug in solid dispersions is, in general, poorly characterized as the number of characterization techniques available to monitor nanometer-sized drug particles embedded in a matrix are limited. Here we present a combination of localized NMR spectroscopic and NMR imaging techniques which allow in situ monitoring of the state of the drug during tablet disintegration and dissolution. (19)F NMR relaxation is shown to be sensitive to both the crystalline/amorphous state and the size of the model nanoparticles made of the drug substance flutamide. The time course of drug mobilization and recrystallization is detected with spatial resolution within swelling solid dispersion tablets. Comparing results from spatially resolved (19)F, (2)H and (1)H NMR experiments, recrystallization is related to its enabling factors such as local hydration level and local mobility of the polymer matrix. The initially amorphous drug may recrystallize either by nanoparticle coalescence or by ripening of crystalline grains.     

An investigation into the dissolution properties of celecoxib melt extrudates: understanding the role of polymer type and concentration in stabilizing supersaturated drug concentrations

In this study, the dissolution properties of celecoxib (CX) solid dispersions manufactured from Eudragit 4155F and polyvinylpyrrolidone (PVP) were evaluated. Hot-melt extrusion (HME) technology was used to prepare amorphous solid dispersions of drug/polymer binary systems at different mass ratios. The drug concentrations achieved from the dissolution of PVP and Eudragit 4155F solid dispersions in phosphate buffer, pH 7.4 (PBS 7.4) were significantly greater than the equilibrium solubility of CX (1.58 μg/mL). The degree of supersaturation increased significantly as the polymer concentration within the solid dispersion increased. The maximum drug concentration achieved by PVP solid dispersions did not significantly exceed the apparent solubility of amorphous CX. The predominant mechanism for achieving supersaturated CX concentrations in PBS 7.4 was attributed to stabilization of amorphous CX during dissolution. Conversely, Eudragit 4155F solid dispersions showed significantly greater supersaturated drug solutions particularly at high polymer concentrations. For example, at a drug/polymer ratio of 1:9, a concentration of 100 μg/mL was achieved after 60 min that was stable (no evidence of drug recrystallization) for up to 72 h. This clearly identifies the potential of Eudragit 4155F to act as a solubilizing agent for CX. These findings were in good agreement with the results from solubility performed using PBS 7.4 in which Eudragit 4155F had been predissolved. In these tests, Eudragit 4155F significantly increased the equilibrium solubility of CX. Solution (1)H NMR spectra were used to identify drug/polymer interactions. Deshielding of CX aromatic protons (H-1a and H-1b) containing the sulfonamide group occurred as a result of dissolution of Eudragit 4155F solid dispersions, whereas deshielding of H-1a protons and shielding of H-1b protons occurred as a result of the dissolution of PVP solid dispersions. In principle, it is reasonable to suggest that the different drug/polymer interactions observed give rise to the variation in dissolution observed for the two polymer/drug systems.     

Characterization and stability of solid dispersions based on PEG/polymer blends

Solid dispersions were prepared by a melting method from the water-insoluble model drugs carbamazepine and nifedipine and polyethylene glycol 1500 (PEG 1500) or 1:1 mixtures of PEG 1500 and the polymers polyvinylpyrrolidone (PVP 30, PVP 12), polyvinylpyrrolidone-co-vinylacetate (PVPVA) and Eudragit EPO (Eudragit) in order to combine advantages of the different carrier polymers (recrystallization inhibition, processability and stability). The solid dispersions were characterized by dissolution, powder X-ray diffractometry and microscopy directly after preparation and after storage for 3 and 6 months at 25 °C/0% relative humidity (RH) or 3 months at 40 °C/75% RH. More than 80% drugs were released from all solid dispersions within 20 min. The dissolution rate of carbamazepine decreased in the order of PEG 1500 > PEG 1500/Eudragit > PEG 1500/PVP 30 > PEG 1500/PVPVA > PEG 1500/PVP 12. The dissolution rank order was not directly correlated to the amorphous/crystalline state of the drugs, but rather to the properties of the PEG 1500/polymer compositions. Nifedipine was released in the order of PEG 1500 > PEG 1500/PVPVA > PEG 1500/PVP 30 > PEG 1500/PVP 12 > PEG 1500/Eudragit. Amorphous nifedipine was present in all PEG 1500/polymer dispersions except in pure PEG 1500 solid dispersion. The significant increase in dissolution rate of PEG 1500 solid dispersions was due to the reduced crystallinity of the drug and the excellent solubilisation properties of PEG 1500. After 6 months storage at 25 °C/0% RH, the solid dispersions released both drugs in the order PEG 1500/PVPVA > PEG 1500/PVP 30 > PEG 1500/PVP 12 > PEG 1500/Eudragit > PEG 1500. The stabilized amorphous state of the drug resulted in stable dissolution profiles of PEG 1500/PVPVA, PEG 1500/PVP 30 and PEG 1500/PVP 12 when compared to the PEG 1500 solid dispersions, which contained a higher amount of crystalline drug. The solid dispersions with PEG 1500/PVPVA or PEG 1500/PVP stored for 3 months at 40 °C/75% RH showed phase separation due to the hygroscopic properties of the polymers. The influence of 10% (w/w) of the solubilisers polyoxyl 40 hydrogenated castor oil (Cremophor), macrogol-15-hydroxystearate (Solutol) and fatty alcohol alkoxylate (Pluronic) on the dissolution rate and the physical state of the drug was significant.     

Application of PVP/HPMC miscible blends with enhanced mucoadhesive properties for adjusting drug release in predictable pulsatile chronotherapeutics.

The aim of the present study was to prepare pulsatile release formulations consisting of two-layered tablets appropriate for preventing ischemic heart diseases. For this reason the active core was constituted by a FELO/PVP 10/90 w/w solid dispersion while for the adjustment of the drug release time the coating layer was composed of PVP/HPMC blends at different compositions, acting as a stimulus responsible layer. These blends as was found by DSC studies are miscible in the entire composition range, ensured by the interactions taking place between hydroxyl groups of HPMC and carbonyl groups of PVP. The miscibility of the system enhances the mucoadhesive properties of the blends, compared with those of pure HPMC, which is desired for such applications. The enhancement was attributed to the higher rate of wetting and flexibility of the new matrices due to the faster dissolution of the PVP macromolecules. Upon exposure of the prepared tablets to the release medium it was found that the coating layer disintegrates first, followed by the immediate release of FELO from the active core. The delaying time is based on a complicated mechanism, which is a combination of swelling and erosion of the PVP/HPMC polymer blends. Varying the PVP/HPMC blend ratios, the exact time that FELO is released during a daytime can be effectively adjusted and this ability is expressed mathematically by the equation t = 0.028 C1.5, where C is the concentration of HPMC in the blend.     

Characterization of ternary solid dispersions of itraconazole, PEG 6000, and HPMC 2910 E5

In order to reduce the crystallinity of PEG 6000, blends were prepared by spray drying and extrusion with the following polymers; PVP K25, PVPVA 64, and HPMC 2910 E5. The maximal reduction of crystallinity in PEG 6000 was obtained by co-spray drying with HPMC 2910 E5. In the next step the model drug Itraconazole was added to the blend and the resulting ternary solid dispersions were characterized. The results of this study show that the addition of PEG 6000 to the Itraconazole/HPMC 2910 E5 system leads to phase separation that in most cases gives rise to recrystallization of either PEG 6000 or Itraconazole. For all ternary dispersions containing 20% of Itraconazole the drug was highly amorphous and the dissolution was improved compared to the binary 20/80 w/w Itraconazole/HPMC 2910 E5 solid dispersion. For all ternary dispersions containing 40% of Itraconazole, the drug was partially crystalline and the dissolution was lower than the dissolution of the binary 40/60 w/w Itraconazole/HPMC 2910 E5 dispersion. These results show that provided Itraconazole is highly amorphous the addition of PEG 6000 to HPMC 2910 E5 leads to an increase in drug release.     

Raman and thermal analysis of indomethacin/PVP solid dispersion enteric microparticles

Indomethacin (IMC) and three types of poly-(vinylpyrrolidone) (PVP 12PF, PVP K30 and PVP K90) were studied in the form of solid dispersion, prepared with the solvent evaporation method, by spectroscopic (Raman, FT-IR, X-ray diffraction), thermal (differential scanning calorimetry, thermogravimetry, hot-stage microscopy), fractal and image analysis. Raman and FT-IR micro-spectroscopy indicated the occurrence of drug/polymer interaction and the presence of an amorphous form of IMC, as also resulting from X-ray diffractometry. Hot-stage microscopy suggested that the interaction between IMC and the polymer occurring on heating of a physical mixture, is common to other acidic compounds and causes a depression of the temperature of the appearance of a molten phase. Co-evaporated particles were coated by spray-congealing process with molten stearic acid for gastroprotection, but also for stabilization of the amorphous structure of the drug: the final particles were spherically shaped. Dissolution tests carried out on the final microparticles showed that the coating with stearic acid prevents IMC release at acidic pH and also protects against recovery of the IMC crystallinity, at least after 9 months of aging: the extent and mode of the release, before and after aging, overlap perfectly. The test revealed a notable improvement of the drug release rate from the solid dispersion at suitable pH, with respect to pure IMC. The comparison of the present solid dispersion with IMC/PVP (surface) solid dispersion obtained by freeze-drying of an aqueous suspension, where IMC maintained its crystalline state, revealed that there was no difference concerning the release rate, but suggested a superior quality of this last process as a mean of improving IMC availability for the easiness of preparation and stability, due to the absence of the amorphous state of the drug, as a possible instability source of the system. Finally, the coating with stearic acid is discussed as a determining process for the practical application of solid dispersions.     

Intraorally fast-dissolving particles of a poorly soluble drug: Preparation and in vitro characterization

In this study, the dissolution rate of a poorly soluble drug, perphenazine (PPZ) was improved by a solid dispersion technique to permit its usage in intraoral formulations. Dissolution of PPZ (4 mg) in a small liquid volume (3 ml, pH 6.8) within one minute was set as the objective. PVP K30 and PEG 8000 were selected for carriers according to the solubility parameter approach and their 5/1, 1/5 and 1/20 mixtures with PPZ (PPZ/polymer w/w) were prepared by freeze-drying from 0.1 N HCl solutions. The dissolution rate of PPZ was improved with all drug/polymer mixture ratios compared to crystalline or micronized PPZ. A major dissolution rate improvement was seen with 1/5 PPZ/PEG formulation, i.e. PPZ was dissolved completely within one minute. SAXS, DSC and XRPD measurements indicated that solid solutions of amorphous PPZ in amorphous PVP or in partly amorphous PEG were formed. DSC and FTIR studies suggested that PPZ dihydrochloride salt was formed and hydrogen bonding was occurred between PPZ and the polymers. It was concluded that molecular mixing together with salt formation promoted the dissolution of PPZ, especially in the case of the 1/5 PPZ/PEG dispersion, making it a promising candidate for use in intraoral formulations.     

Improved physicochemical characteristics of felodipine solid dispersion particles by supercritical anti-solvent precipitation process

Solid dispersions of felodipine were formulated with HPMC and surfactants by the conventional solvent evaporation (CSE) and supercritical anti-solvent precipitation (SAS) methods. The solid dispersion particles were characterized by particle size, zeta potential, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), solubility and dissolution studies. The effects of the drug/polymer ratio and surfactants on the solubility of felodipine were also studied. The mean particle size of the solid dispersions was 200-250 nm; these had a relatively regular spherical shape with a narrow size distribution. The particle size of the solid dispersions from the CSE method increased at 1 h after dispersed in distilled water. However, the particle sizes of solid dispersions from the SAS process were maintained for 6 h due to the increased solubility of felodipine. The physical state of felodipine changed from crystalline to amorphous during the CSE and SAS processes, confirmed by DSC/XRD data. The equilibrium solubility of the felodipine solid dispersion prepared by the SAS process was 1.5-20 microg/ml, while the maximum solubility was 35-110 microg/ml. Moreover, the solubility of felodipine increased with decreasing drug/polymer ratio or increasing HCO-60 content. The solid dispersions from the SAS process showed a high dissolution rate of over 90% within 2 h. The SAS process system may be used to enhance solubility or to produce oral dosage forms with high dissolution rate.     

The use of microviscometry to study polymer dissolution from solid dispersion drug delivery systems

Solid dispersions can be used to improve dissolution of poorly soluble drugs and PVP is a common polymeric carrier in such systems. The mechanisms controlling release of drug from solid dispersions are not fully understood and proposed theories are dependent on an understanding of the dissolution behaviour of both components of the dispersion. This study uses microviscometry to measure small changes in the viscosity of the dissolution medium as the polymer dissolves from ibuprofen-PVP solid dispersions. The microviscometer determines the dynamic and kinematic viscosity of liquids based on the rolling/falling ball principle. Using a standard USP dissolution apparatus, the dissolution of the polymer from the solid dispersion was easily measured alongside drug release. Drug release was found to closely follow polymer dissolution at the molecular weights and ratios used. The combination of sensitivity and ease of use make microviscometry a valuable technique for the elucidation of mechanisms governing drug release from polymeric delivery systems.     

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     

The Effect of Carrier-Drug Ratios on Dissolution Performances of Poorly Soluble Drug in Crystalline Solid Dispersion System

The choice of carrier and drug ratio are critical factors as far as the type of solid dispersion is concerned. Amorphous solid dispersion has been cited as the most desirable type among the different types of solid dispersion due to the benefit of amorphicity in increasing the drug solubility of a poorly soluble drug. Recent reports delineated that a partially crystalline solid dispersion system may perform better due to the inherent issue of solution mediated recrystallisation of a completely amorphous system. In oppose to the conventional choice of using amorphous polymer, this study aimed to investigate the use of a crystalline carrier, polyethylene glycol (PEG) for dissolution enhancement of a model poorly soluble drug, Flurbiprofen (FBP), a BCS Class II candidate. Solid dispersions of different FBP to PEG 6000 molar ratios via solvent evaporation were prepared. Physical characterisation of preparations was performed using differential scanning calorimetry (DSC), attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) and optical microscope. DSC and ATR-FTIR analyses suggest the obtained solid dispersion exhibits crystalline FBP. This is then supported by the optical microscope analysis as the birefringence of crystals was noted. Further increasing the drug-carrier molar ratio to one-to-three and one-to-six showed that there was an amorphous FBP constituent in the system. DSC analysis revealed the melting point depression of FBP by the carrier which signifies interaction between the drug and polymer. Dissolution study showed the solid dispersion of FBP improves the drug solubility and drug release compared to the pure drug. A higher carrier ratio in the formulation results in a higher drug release.     

Improving the solubility of ampelopsin by solid dispersions and inclusion complexes

The aim of this study was to increase the solubility of ampelopsin (AMP) in water by two systems: solid dispersions with polyethylene glycol 6000 (PEG 6000) or polyvinylpyrrolidone K-30 (PVP K30) and inclusion complexes with beta-cyclodextrin (BCD) and hydroxypropyl-beta-cyclodextrin (HPBCD). The interaction of AMP with the hydrophilic polymers was evaluated by differential scanning calorimetry (DSC), Fourier transformation-infrared spectroscopy (FTIR), scanning electron microscopy (SEM). The results from DSC, FTIR and SEC analyses of solid dispersions and inclusion complexes showed that AMP might exist as an amorphous state or as a solid solution. On the other hand, the SEM images of the physical mixtures revealed that to some extent the drug was present in a crystalline form. The influence of various factors (pH, temperature, type of polymer, ration of the drug to polymer) on the solubility and dissolution rate of the drug were also evaluated. The solubility and dissolution rates of AMP were significantly increased by solid dispersions and cyclodextrin complexes as well as their physical mixtures. The improvement of solubility using polymers was in the following order: HPBCD approximately BCD>PVP K30>PEG 6000.     

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.