Solubility of Solid Dispersions of Pizotifen Malate and Povidone

We analyzed the physicochemical characteristics of solid dispersions of pizotifen malate and povidone (Kollidon 12) at different proportions; we used X-ray diffraction, infrared spectrometry, and differential scanning calorimetry (DSC) and tested the solubility of the solid dispersions in equilibrium. The results were compared with findings for physical mixtures with the same proportions. A solid dispersion with a drug proportion of 16%–17% formed a eutectic mixture. Solubility of pizotifen malate increased with the proportion of drug in the solid dispersion up to a drug:polymer ratio of 40:60. The hydrotropic effect of the polymer also favored solubility: In physical mixtures, this effect was greatest at a drug:polymer ratio of 10:90; solubility at this proportion was equal to that of the solid dispersion at the same proportion.     

Solubility and Dissolution of Etoposide from Solid Dispersions of PEG 8000

The Solubility and dissolution of etoposide from solid dispersion of PEG 8000, prepared by the fusion method, were investigated. Stability studies revealed that the etoposide was stable in water for three days at 37 ± 0.5°C alone and as a physical mixture with PEG 8000. However, nearly 5% decomposition was oberved in aqueous solutions made from solid dispersions. TLC, IR and HPLC studies showed both the drug and carrier were stable during the fusion process. Aqueous solubility of etoposide from solid dispersions with etoposide: PEG 8000 ratios of 1:5, 1:10, 1:20, 1:30 and 1:40, was studied at 37 ± 0.5°C, and found to be significantly higher than that of etoposide alone or from its physical mixtures with PEG 8000. These dispersions increased the solubility of etoposide by 32.3%, 96.8%, 133.5%, 280.7% and 326.6% respectively compared to that of etoposide alone, whereas only 1:40 etoposide: PEG 8000 physical mixture demonstrated a significant increase in etoposide solubility (16.1%). Dissolution studies, on the solid dispersions in water at 37 ± 0.5°C, revealed a marked increase in the dissolution rate of etoposide from 1:20, 1:30 and 1:40 solid dispersions with 100% drug dissolving within 1 minute; dissolution time for 1:5 and 1:10 dispersions, and all physical mixtures was 3 minutes while etoposide alone required 30 minutes for complete drug dissolution. The melting behavior of the etoposide-PEG 8000 mixtures and subsequent thermal analysis of the melts suggested that the increase of solubility of etoposide was mostly due to the formation of a solid solution of etoposide in PEG 8000.     

Solid dispersions of diflunisal-PVP: polymorphic and amorphous states of the drug

Coprecipitates of diflunisal and polyvinylpyrrolidone (PVP K15, K30, and K90) and physical mixtures were studied using x-ray diffraction analysis, infrared (IR) spectroscopy, differential scanning calorimetry (DSC), and hot-stage microscopy. X-ray diffraction results revealed an almost amorphous state, even in coprecipitates with a high content of drug, next to 70%, which was independent of the polymer molecular weight. The IR spectra of 70:30 drug-PVP solid dispersions suggest the formation of diflunisal-PVP hydrogen bonds. For 70:30 drug-polymer ratio, the physical mixture showed linear dissolution kinetics of free crystals, but the corresponding coprecipitates exhibit two different dissolution processes. When the 25:75 drug-polymer dispersion is analyzed by hot-stage microscopy, only solid plates of PVP are observed; the absence of drug particles may be due to a molecular dispersion of the drug into the polymer. Moreover, polymorphic changes of diflunisal were detected in the solid dispersions in comparison with the corresponding physical mixtures, which are always formed by polymorph II. At high concentrations of drug (75:25 and 80:20), x-ray diffraction patterns of solid dispersions showed the partial recrystallization of the drug, displaying the main diffraction peaks of polymorph I when ethanol was used as coprecipitation solvent, whereas diflunisal form IV was obtained in chloroform.     

Evaluation of solid dispersions of Clofazimine

Clofazimine (CLF) was formulated with polyethylene glycol (PEG) and polyvinyl pyrrolidone (PVP) as a solid solid dispersion (SSD) to increase the aqueous solubility and dissolution rate of the drug. Different molecular weights of PEG (1500, 4000, 6000, and 9000 Da) and PVP (14,000 and 44,000 Da) were used in different drug:carrier weight ratios (1:1, 1:5, and 1:9) and their effect on the dissolution performance of the drug was evaluated in USP Type 2 apparatus using 0.1 N HCl medium. The dissolution rate was compared with corresponding physical mixtures, a currently marketed soft gelatin capsule product, and free CLF. The effect of different methods of preparation (solvent/melt) on the dissolution rate of CLF was evaluated for PEG solid dispersions. Saturation solubility and phase solubility studies were carried out to indicate drug:carrier interactions in liquid state. Infrared (IR) spectroscopy and X-ray diffraction (XRD) were used to indicate drug:carrier interactions in solid state. Improvement in the drug dissolution rate was observed in solid dispersion formulations as compared to the physical mixtures. The dissolution rate improved with the decreasing weight fraction of the drug in the formulation. Polyvinyl pyrrolidone solid dispersion systems gave a better drug release profile as compared to the corresponding PEG solid dispersions. The effect of molecular weight of the PEG polymers did not follow a definite trend, while PVP 14,000 gave a better dissolution profile as compared to PVP 44,000. Improvement in saturation solubility of the drug in the solid dispersion systems was noted in all cases. Further, IR spectroscopy indicated drug:carrier interactions in solid state in one case and XRD indicated reduction in the crystallinity of CLF in another. It was concluded that solid-dispersion formulations of Clofazimine can be used to design a solid dosage form of the drug, which would have significant advantages over the currently marketed soft gelatin capsule dosage form.     

Compression of Indomethacin Coprecipitates with Polymer Mixtures: Effect of Preparation Methodology

The objective of this study was to prepare, characterize, formulate and compare coprecipitates, solid dispersions and physical mixtures of indomethacin with Eudragit polymer mixtures, RS100 and L100. Coprecipitates, solid dispersions (melting-solvent method) and physical mixtures were prepared with a drug : polymer ratio of 12.6: 1.0 respectively. Biconvex tablets of 7 mm diameter were compressed. Response variables studied were cumulative percent released and T₅₀. Dissolution was performed by exposing the tablets to SGF (PH 1.2) for 1 hour followed by pH 7.2 phosphate buffer for 24 hours. T₅₀ values obtained were 7.5 hours for coprecipitates, 4.5 hours for solid dispersions and 17 hours for physical mixtures. The drug loading for all the three formulations did not show significant difference. The formulations were characterized by X-ray diffraction (qualitative and quantitative) and IR. IR data did not indicate any significant difference between the pure drug and the formulations. However, significant differences were seen in X-ray diffractograms. The crystallinity did not change for physical mixtures, was reduced for coprecipitates and solid dispersions. Also the diffraction patterns for solid dispersions and coprecipitates were similar. The coprecipitates and physical mixture followed the Higuchi's square-root-of-time equation suggesting a matrix effect. These results suggest that compression of coprecipitates offer most efficient release as compared to solid dispersions and physical mixtures.     

Nimesulide-modified gum karaya solid mixtures: preparation, characterization, and formulation development

Solid mixtures of nimesulide (NS) and modified gum karaya (MGK) were prepared to improve the dissolution rate of NS. The effect of drug-carrier ratio on dissolution rate of NS was investigated by preparing the solid mixtures of different ratios by cogrinding method. Solid mixtures were also prepared by physical mixing, kneading, and solid dispersion techniques to study the influence of method of preparation. Differential Scanning Calorimetry (DSC), X-ray Diffraction (XRD), and equilibrium solubility studies were performed to explain the results of in vitro dissolution rate studies. It was clearly evident from the results that the NS dissolution rate was dependent on the concentration of MGK in the solid mixtures, and optimum weight ratio was found to be 1:4 (NS:MGK). Though the dissolution rate of NS from all solid mixtures prepared by different methods improved significantly, maximum improvement in dissolution rate was observed with solid dispersions. The order of methods basing on their effect on dissolution efficiency is solid dispersion > kneading > cogrinding > physical mixing > pure NS. Tablets of pure drug and solid mixtures (1:4 w/w, NS:MGK) were prepared. Though the best results from the dissolution test were obtained for the tablets containing solid dispersions, tablets containing cogrinding mixture were found to be suitable, from a practical point of view, for commercialization.     

Preparation of the Disperse Systems of Sulfathiazole-Polyvinylpyhrolidone by Mechanical Activation

The potential value of solid-state dispersions of insoluble drugs in water-soluble matrices is known to bring about enhancement of solubility, dissolution rate and bioavailability of the drugs. The conventional methods of preparation of solid dispersions such as fusion or solvent technique are somewhat limited. The method of mechanical activation analogous to that which is employed in the mechanical alloying method may be used in preparation of dispersions of organic solids. In this paper, the method of mechanical activation is applied to obtain a solid-state dispersion of sulfathiazole in polyvinylpyrrolidone. The mechanical treatment of sulfathiazole with polyvinylpyrrolidone in a planetary ball mill transfers crystalline drug into amorphous state, the process being accompanied by formation of hydrogen bonds of sulfathiazole with matrice. The apparent solubility and rate of solvation of sulfathiazole were greatly increased if it was previously mechanically treated with polyvinyl -pyrrolidone. The release of sulfathiazole from solid dispersions with polymer to drug ratio of 1:3, 1:1, 3:1 was examined, a polymer to drug ratio of 3:1 gave the highest solubility.     

Evaluation of Solid Dispersions of Clofazimine

ABSTRACT

Clofazimine (CLF) was formulated with polyethylene glycol (PEG) and polyvinyl pyrrolidone (PVP) as a solid solid dispersion (SSD) to increase the aqueous solubility and dissolution rate of the drug. Different molecular weights of PEG (1500, 4000, 6000, and 9000 Da) and PVP (14,000 and 44,000 Da) were used in different drug:carrier weight ratios (1:1, 1:5, and 1:9) and their effect on the dissolution performance of the drug was evaluated in USP Type 2 apparatus using 0.1 N HCl medium. The dissolution rate was compared with corresponding physical mixtures, a currently marketed soft gelatin capsule product, and free CLF. The effect of different methods of preparation (solvent/melt) on the dissolution rate of CLF was evaluated for PEG solid dispersions. Saturation solubility and phase solubility studies were carried out to indicate drug:carrier interactions in liquid state. Infrared (IR) spectroscopy and X-ray diffraction (XRD) were used to indicate drug:carrier interactions in solid state. Improvement in the drug dissolution rate was observed in solid dispersion formulations as compared to the physical mixtures. The dissolution rate improved with the decreasing weight fraction of the drug in the formulation. Polyvinyl pyrrolidone solid dispersion systems gave a better drug release profile as compared to the corresponding PEG solid dispersions. The effect of molecular weight of the PEG polymers did not follow a definite trend, while PVP 14,000 gave a better dissolution profile as compared to PVP 44,000. Improvement in saturation solubility of the drug in the solid dispersion systems was noted in all cases. Further, IR spectroscopy indicated drug:carrier interactions in solid state in one case and XRD indicated reduction in the crystallinity of CLF in another. It was concluded that solid-dispersion formulations of Clofazimine can be used to design a solid dosage form of the drug, which would have significant advantages over the currently marketed soft gelatin capsule dosage form.     

Preparation of the Disperse Systems of Sulfathiazole-Polyvinylpyhrolidone by Mechanical Activation

Abstract

The potential value of solid-state dispersions of insoluble drugs in water-soluble matrices is known to bring about enhancement of solubility, dissolution rate and bioavailability of the drugs. The conventional methods of preparation of solid dispersions such as fusion or solvent technique are somewhat limited. The method of mechanical activation analogous to that which is employed in the mechanical alloying method may be used in preparation of dispersions of organic solids. In this paper, the method of mechanical activation is applied to obtain a solid-state dispersion of sulfathiazole in polyvinylpyrrolidone. The mechanical treatment of sulfathiazole with polyvinylpyrrolidone in a planetary ball mill transfers crystalline drug into amorphous state, the process being accompanied by formation of hydrogen bonds of sulfathiazole with matrice. The apparent solubility and rate of solvation of sulfathiazole were greatly increased if it was previously mechanically treated with polyvinyl -pyrrolidone. The release of sulfathiazole from solid dispersions with polymer to drug ratio of 1:3, 1:1, 3:1 was examined, a polymer to drug ratio of 3:1 gave the highest solubility.     

Classification of solid dispersions: correlation to (i) stability and solubility (ii) preparation and characterization techniques

Solid dispersion has been a topic of interest in recent years for its potential in improving oral bioavailability, especially for poorly water soluble drugs where dissolution could be the rate-limiting step of oral absorption. Understanding the physical state of the drug and polymers in solid dispersions is essential as it influences both the stability and solubility of these systems. This review emphasizes on the classification of solid dispersions based on the physical states of drug and polymer. Based on this classification, stability aspects such as crystallization tendency, glass transition temperature (T_g), drug polymer miscibility, molecular mobility, etc. and solubility aspects have been discussed. In addition, preparation and characterization methods for binary solid dispersions based on the classification have also been discussed.     

Biopharmaceutical Study of Glybornuride-Polyethylene Glycol Systems

Glybornuride is an oral hypoglucaemiant drug which exhibits a very low water solubility. Consequently,the solid dispersions of this drug with PEG 6,000; 10,000 and 20,000 have studied. According to the phase diagrams obtained, the following solid dispersions of glybornuride were prepared: at 30% with PEG 6,000 and 10,000 and 40% with PEG 20,000.Dissolution curves show that glybornuride dissolves faster as solid dispersion, particularly with PEG 6,000. The administration of glybornuride as a solid dispersion into rabbits induced a faster decrease of glucaemia levels than a physical mixture with polyethylene-glycols.     

Studies on solid dispersions of nifedipine

Nifedipine-Polyethylene glycol solid dispersions were prepared by melting or fusion method in order to improve nifedipine solubility in the aqueous body fluids. The dissolution rate of the drug was markedly increased in these solid dispersion systems. The increase in dissolution was a function of the ratio of drug to polyethylene glycol used and the molecular weight of polyethylene glycol. The dissolution rate was compared with a 10% w/w physical mixture of drug with polyethylene glycol.

The physical state of nifedipine after fusion was determined by X-ray crystallography on the pure drug and on the solidified melts. The X-ray diffraction studies indicated that nifedipine in the solid dispersion which was obtained by sudden cooling of the melt, was in the thermodynamically unstable metastable form. It was established that the slow cooling of the melt as well as powdering of solid dispersion resulted in the emergence of crystallinity.

The effect of aging on nifedipine-polyethylene glycol 6000 solid dispersions has been investigated. After storage at room temperature for six months, solid dispersions showed no change in the dissolution rate and the X-ray diffraction pattern showed slight enhancement in crystallinity.     

Part II: bioavailability in beagle dogs of nimodipine solid dispersions prepared by hot-melt extrusion

The aim of the present work was to investigate the in vitro dissolution properties and oral bioavailability of three solid dispersions of nimodipine. The solid dispersions were compared with pure nimodipine, their physical mixtures, and the marketed drug product Nimotop. Nimodipine solid dispersions were prepared by a hot-melt extrusion process with hydroxypropyl methylcellulose (HPMC, Methocel E5), polyvinylpyrrolidone/vinyl acetate copolymer (PVP/VA, Plasdone S630), and ethyl acrylate, methyl methacrylate polymer (Eudragit EPO). Previous studies of XRPD and DSC data showed that the crystallinity was not observed in hot-melt extrudates, two T(g)s were observed in the 30% and 50% NMD-HPMC samples, indicating phase separation. The weakening and shift of the N-H stretching vibration of the secondary amine groups of nimodipine as determined by FT-IR proved hydrogen bonding between the drug and polymers in the solid dispersion. The dissolution profiles of the three dispersion systems showed that the release was improved compared with the unmanipulated drug. Drug plasma concentrations were determined by HPLC, and pharmacokinetic parameters were calculated after orally administering each preparation containing 60 mg of nimodipine. The mean bioavailability of nimodipine was comparable after administration of the Eudragit EPO solid dispersion and Nimotop, but the HPMC and PVP/VA dispersions exhibited much lower bioavailability. However, the AUC(0-12 hr) values of all three solid dispersions were significantly higher than physical mixtures with the same carriers and nimodipine powder.     

Solid carriers for improved solubility of glipizide in osmotically controlled oral drug delivery system

The purpose of this study was to increase the solubility of glipizide (gli) by solid dispersions SDs technique with polyvinylpyrrolidone (PVP) in aqueous media. The gli-PVP solid dispersion systems was prepared by physical mixing or spray drying method, and characterized by differential scanning calorimetry (DSC), X-ray powder diffraction (XRD) analysis, Fourier transformation-infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM). The elementary osmotic pumps (EOPs) were prepared with gli-PVP complex and the effect of the PVP percentages on the enhancing of gli dissolution rate was studied. The influences of various parameters e.g., drug- PVP ratio, level of solubility modifier, coating weight gain and diameter of drug releasing orifice on drug release profiles were also investigated. The solubility and dissolution rates of gli were significantly increased by solid dispersion using spray dried method as well as their physical mixture. The obtained results indicated that gli-PVP solid dispersion system has suitable solubility behavior in EOP tablets.     

Controlled-Release Matrix of Acetaminophen-Ethylcellulose Solid Dispersion

Abstract

In this study ethylcellulose was evaluated as a carrier for preparation of prolonged release acetaminophen tablets. Solid dispersions containing three levels of ethylcellulose and acetaminophen (1:3; 1:1; 3:1) were prepared by the solvent method. Also physical mixtures at the same level of ethylcellulose and acetaminophen were prepared. Systems composed of solid dispersion or physical mixture containing the equivalent weight of 50 mg acetaminophen, Lactose fast-flo as diluent and 1% magnesium stearate as lubricant were compressed into tablets and tested for dissolution. The dissolution data showed that the drug release decreased as the level of ethylcellulose increased in the solid dispersion formulations. The drug release from tablets prepared with solid dispersion followed the diffusion controlled model for inert porous matrix, while the drug release from tablets prepared with physical mixture followed the first-order kinetic model.     

Controlled-Release Matrix of Acetaminophen-Ethylcellulose Solid Dispersion

In this study ethylcellulose was evaluated as a carrier for preparation of prolonged release acetaminophen tablets. Solid dispersions containing three levels of ethylcellulose and acetaminophen (1:3; 1:1; 3:1) were prepared by the solvent method. Also physical mixtures at the same level of ethylcellulose and acetaminophen were prepared. Systems composed of solid dispersion or physical mixture containing the equivalent weight of 50 mg acetaminophen, Lactose fast-flo as diluent and 1% magnesium stearate as lubricant were compressed into tablets and tested for dissolution. The dissolution data showed that the drug release decreased as the level of ethylcellulose increased in the solid dispersion formulations. The drug release from tablets prepared with solid dispersion followed the diffusion controlled model for inert porous matrix, while the drug release from tablets prepared with physical mixture followed the first-order kinetic model.     

Dissolution Properties of Naproxen in Combinations with Polyvinylpyrrolidone

Abstract

The effect of the molecular weight of polyvinylpyrrolidone on the solubility and dissolution properties of naproxen using solid dispersions (coevaporates and colyophilized products) and physical mixtures was investigated. Factors such as method of drug incorporation with the polymer and polymer mass fraction influence the dissolution rate of naproxen from both powders and constant surface area discs. The best results were obtained with the colyophilized products at the drug-to-polymer 7:3 weight ratio, in the rank order (most effective to least) K15>K30>lK90 (dispersed amount) and K30>K90>K15 (rotating disc). The physical state of naproxen, i.e. amorphous or crystalline, in solid combinations with polyvinylpyrrolidone was checked by means of X-ray powder diffraction. Drug-polymer interactions in the liquid state were revealed with solubility experiments. Drug-polymer interactions in solid state were demonstrated by combining the X-ray diffraction data with the results of thermal analysis (DSC, TGA) and microscopic observation.     

Studies on solid dispersions of nifedipine

Abstract

Nifedipine-Polyethylene glycol solid dispersions were prepared by melting or fusion method in order to improve nifedipine solubility in the aqueous body fluids. The dissolution rate of the drug was markedly increased in these solid dispersion systems. The increase in dissolution was a function of the ratio of drug to polyethylene glycol used and the molecular weight of polyethylene glycol. The dissolution rate was compared with a 10% w/w physical mixture of drug with polyethylene glycol.

The physical state of nifedipine after fusion was determined by X-ray crystallography on the pure drug and on the solidified melts. The X-ray diffraction studies indicated that nifedipine in the solid dispersion which was obtained by sudden cooling of the melt, was in the thermodynamically unstable metastable form. It was established that the slow cooling of the melt as well as powdering of solid dispersion resulted in the emergence of crystallinity.

The effect of aging on nifedipine-polyethylene glycol 6000 solid dispersions has been investigated. After storage at room temperature for six months, solid dispersions showed no change in the dissolution rate and the X-ray diffraction pattern showed slight enhancement in crystallinity.     

Release of Ibuprofen from Polyethylene glycol solid dispersions:-Equilibrium solubility approach

This work is an attempt to enhance the release of Ibuprofen by improving its aqueous solubility. This was done by dispersing the drug in a water soluble carrier such as polyethylene glycol (PEG). The solubility was found to depend on various factors such as method of preparation, carrier weight fraction and molecular weight and the pH of the medium. It was found that dispersions prepared by the fusion method gave higher solubilities than those prepared by the solvent technique. The solubility was found to vary with carrier molecular weight and its weight fraction. Decreasing the PEG molecular weight resulted in increased solubility. A polymer to drug ratio of 1:1 was found to give the highest solubility. The solubility decreased as the polymer weight fraciton was increased beyond this value. The solubility of the solid dispersion was found to be pH dependent. A greater solubility was obtained at higher pHs than at lower ones. This was attributed to the weakly acidic nature of Ibuprofen. Calculation of the heat of solution of the various systems studied showed that the non dispersed drug had a higher heat of solution than the dispersed systems. This was thought to be the cause of the higher solubility of the dispersions as compared to the original drug.     

Enhanced solubility of piperine using hydrophilic carrier-based potent solid dispersion systems

Context: Piperine alkaloid, an important constituent of black pepper, exhibits numerous therapeutic properties, whereas its usage as a drug is limited due to its poor solubility in aqueous medium, which leads to poor bioavailability.

Objective: Herein, a new method has been developed to improve the solubility of this drug based on the development of solid dispersions with improved dissolution rate using hydrophilic carriers such as sorbitol (Sor), polyethylene glycol (PEG) and polyvinyl pyrrolidone K30 (PVP) by solvent method. Physical mixtures of piperine and carriers were also prepared for comparison.

Methods: The physicochemical properties of the prepared solid dispersions were examined using SEM, TEM, DSC, XRD and FT-IR. In vitro dissolution profile of the solid dispersions was recorded and compared with that of the pure piperine and physical mixtures. The effect of these carriers on the aqueous solubility of piperine has been investigated.

Results: The solid dispersions of piperine with Sor, PEG and PVP exhibited superior performance for the dissolution of piperine with a drug release of 70%, 76% and 89%, respectively after 2?h compared to physical mixtures and pure piperine, which could be due to its transformation from crystalline to amorphous form as well as the attachment of hydrophilic carriers to the surface of poorly water-soluble piperine.

Conclusion: Results suggest that the piperine solid dispersions prepared with improved in vitro release exhibit potential advantage in delivering poorly water-soluble piperine as an oral supplement.