Improvement Of Dissolution Profile Research Articles

Effect of hydrophilic polymers on the solubility and dissolution enhancement of rivaroxaban/beta-cyclodextrin inclusion complexes

BCS class II drugs exhibit low aqueous solubility and high permeability. Such drugs often have an incomplete or erratic absorption profile. This study aimed to predict the effects of β-cyclodextrin (βCD) and different hydrophilic polymers (poloxamer 188 (PXM-188), polyvinyl pyrrolidone (PVP) and soluplus (SOLO)) on the saturated solubility and dissolution profile of hydrophobic model drug rivaroxaban (RIV). Binary inclusion complex with βCD were prepared by kneading and solvent evaporation method, at drug to cyclodextrin weight molar ratios of 1:1, 1:2, and 1:4. Saturated solubility of the hydrophobic model moiety was evaluated with βCD to explore the increment in saturated solubility. Dissolution test was carried out to assess the drug release from the produced binary inclusion complex in the aqueous medium. Solid state analysis was performed using Fourier transform infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Scanning electron microscopy (SEM) techniques. When compared to pure drug, the binary complex (Drug: βCD at molar ratio of 1:2 w/w) demonstrated the best performance in terms of enhanced solubility and drug release. Furthermore, ternary inclusion complex was prepared with hydrophilic polymers SOLO, PVP K-30 and PXM-188 at 0.5%,1%,2.5%,5% and 10% w/w to optimized binary formulation RIV:βCD (1:2) prepared by kneading (KN) and solvent evaporation (S.E) method. The findings demonstrated that among ternary formulations (1:2 Drug: βCD: SOLO 10% S.E) manifested greatest improvement in saturated solubility and dissolution rate. Results of solubility enhancement and improvement in dissolution profile of model drug by ternary inclusion complexation were also supported by FTIR, DSC, XRD, and SEM analysis. So, it can be concluded that the ternary inclusion systems were more effective compared to the binary combinations in improving solubility as well as dissolution of hydrophobic model drug rivaroxaban.

FORMULATION AND EVALUATION OF COCRYSTALS OF A BCS CLASS II DRUG USING GLYCINE AS COFORMER

Objective: Development of pharmaceutical co-crystals is an interesting area of research as co-crystals are unique because they have the advantages of maintaining drug’s intrinsic properties along with improvement in its physicochemical attributes. Objective of this research was to improvise solubility of a Biopharmaceutics Classification System (BCS) class II drug (Ezetimibe) along with better dissolution profile using cocrystallization technique. Methods: In the present study, pharmaceutical cocrystals of a BCS class II drug, Ezetimibe, were prepared using glycine as coformer using neat grinding method. Prepared cocrystals were characterized using Hot Stage Microscopy (HSM), Differential Scanning Calorimetry (DSC), Fourier Transform Infrared (FTIR) and Powder X-Ray Diffract meter (PXRD). In addition, solubility and dissolution studies were also performed. Results: HSM study and DSC study represented melting at Ezetimibe (166 °C), Glycine (233 °C) and cocrystals (174 °C), respectively. Melting point of cocrystal is between API and coformer, indicating towards interaction. During XRD studies, a new peak was observed at 14.7193 and 23.3211 at position 2θ in comparison to parent peaks of Ezetimibe (18.5537, 19.2737 and 21.6487) and Glycine (19.0631, 21.8418, 25.3521, 35.4189, 39.0489 and 39.1631). PXRD pattern of cocrystals represented several newer peaks (-OH group in API shifted from 3241.42 cm-1 to 3202.61 cm-1and-NH2 in Glycine shifted from 1601.86 cm-1 to 1690.18 cm-1). This indicated towards possible interaction between these two-group leading to cocrystal formation. Improvement in dissolution profile of cocrystals (89.59%) was observed over the pure drug (32.41%) in 90 min. Conclusion: Pharmaceutical cocrystals of Ezetimibe with glycine as coformer represented a promising approach in tailoring the physicochemical properties.

Crystal engineering of valproic acid and carbamazepine to improve hygroscopicity and dissolution profile

Sodium valproate, the most common solid form of valproic acid, is highly hygroscopic and carbamazepine has extremely low aqueous solubility. Producing a salt form of valproic acid with tromethamine and a cocrystal form of valproic acid with carbamazepine have been studied as two approaches to improve physicochemical properties of the intended drugs. Characterization methods including differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FTIR) are applied to characterize the synthesized salt and cocrystal. The stability of sodium valproate and tromethamine valproate were examined in 33, 53, 75 and 100 percent of relative humidity. The dissolution profile studies were performed in phosphate buffer media (pH = 6.8) for carbamazepine (a low soluble drug) and carbamazepine-valprocic acid cocrystal. Tromethamine valproate was physically more stable than sodium valproate in exposure to humidity. Carbamazepine-valproic acid cocrystal did not show an extreme improvement in dissolution profile when compared with carbamazepine, however after 24 hcocrystal was more soluble.

Comparative Study of Etoricoxib Loaded Solid Dispersion and Beta-cyclodextrin Complexes for improvement of Dissolution Profile

Comparative Study of Etoricoxib Loaded Solid Dispersion and Beta-cyclodextrin Complexes for improvement of Dissolution Profile

Steep improvement in dissolution profile of ezetimibe through co-inclusion in urea

The main objective of the present study was to simultaneously improve the dissolution profile and content uniformity of ezetimibe (EZ), a low dose poorly soluble drug, through co-inclusion in urea. EZ, a new category of cholesterol absorption inhibitor used in the treatment of primary hypercholesterolemia and sitosterolemia, reveals extremely poor solubility in water and dissolution rate limited absorption resulting in its low bioavailability. In the current study, EZ—a highly substituted potent compound which is normally non-complexing guest (NNCG) was successfully incorporated in urea lattice in the presence of readily complexing guest (RCG). The modified Zimmerschied calorimetric method was used for the estimation of the minimum amount of RCG required per unit weight of drug for co-inclusion in urea. Ezetimibe urea co-inclusion complexes (EZUCIC) containing varying proportions of RCG and NNCG were prepared and subjected to thermal analysis using DSC. The formation of EZUCIC was confirmed by FTIR, DSC, XRD and 1H-NMR studies. The thermal data was subjected to the regression studies to study the effect of the relative molar fraction of RCG on the heat of decomposition of EZUCIC. Study exhibited improved content uniformity of EZ in EZUCIC. In vitro dissolution rate studies exhibited steep improvement in the dissolution profile of EZ, a BCS class II drug. The dissolution data was subjected to various release kinetic models. Steep improvement in the dissolution profile offer urea co-inclusion technique a promising alternative for formulation of poorly soluble potent drug candidates into immediate release products with improved content uniformity.

Influence of auxiliary agents on solubility and dissolution profile of repaglinide with hydroxypropyl-β-cyclodextrin: inclusion complex formation and its solid-state characterization

Inclusion complexation of repaglinide (RPG) with hydroxypropyl-β-cyclodextrin (HPβCD) in presence and absence of auxiliary substances such as polyvinyl pyrrolidone-K30 (PVP) and l-arginine (ARG) was formulated in an attempt to improve its physicochemical properties by using three different techniques viz. physical mixing—by geometric mixing of individual components, kneading method—by incorporating binder solution in physical mixture and co-evaporation method—by using rotary evaporator. Phase solubility studies showed formation of complex in 1:1 M ratio with AL type of curve in presence and absence of both auxiliary substances. The rise in stability constant was observed in presence of auxiliary substances suggests positive effect on complex formation. As compared to the complexes with PVP, tremendous improvement in aqueous solubility of RPG in supramolecular inclusion complex with ARG was observed. The solid state characterization of inclusion complexes prepared by different methods were carried out by differential scanning calorimetry (DSC), powder X-ray diffraction (PX-RD), fourier transformation-infrared spectroscopy (FT-IR), scanning electron microscopy (SEM) and in vitro dissolution studies. Among all complexes, ternary complex with ARG prepared by co-evaporation method showed improvement in dissolution profile of RPG indicating complete amorphization and entrapment of pure drug in HPβCD which is evident by DSC and PX-RD. Investigation concludes that ARG and PVP can show synergistic effect in inclusion complex formation of RPG with HPβCD.

Simultaneous improvement in dissolution profile and content uniformity of lafutidine through co-inclusion in urea

In the present study, simultaneous improvement in dissolution profile and content uniformity of Lafutidine (LAF) has been achieved through co-inclusion in urea. LAF, a recently reported histamine H2 receptor antagonist used in the treatment of peptic ulcer, exhibits low aqueous solubility and dissolution rate limited absorption leading to its poor bioavailability. LAF is a potent and normally non-complexing substituted cyclic organic compound. Urea, a well known host for forming inclusion complexes with linear organic compounds was successfully employed for co-inclusion of LAF in the presence of readily complexing guest (RCG). The modified Zimmerschied calorimetric method was employed for the estimation of the minimum amount of RCG required for co-inclusion of lafutidine in urea. The formation of lafutidine urea co-inclusion complexes (LUCIC) was confirmed by DSC, FTIR, XRD and 1H-NMR studies. LUCIC complexes containing varying proportions of guests were prepared and subjected to thermal analysis using DSC. The thermal data was subjected to the regression analysis to study the influence of the relative molar proportion of RCG on the heat of decomposition of LUCIC. Study revealed good content uniformity of lafutidine in LUCIC. In vitro dissolution rate studies demonstrated steep improvement in dissolution profile of LAF—a BCS class II drug. The resulting dissolution data was subjected to various release kinetic models. Studies reveal that urea co-inclusion complex formation may be a promising technique for the formulation of potent poorly soluble drugs into immediate release products with improved content uniformity.

Studies on urea co-inclusion complexes of simvastatin for improvement of pharmaceutical characteristics

Urea is a well known molecular host for forming inclusion complexes with linear long chain organic compounds. In the present study, simvastatin (SMV), a highly substituted, potent and non-complexing cyclic organic compound, was successfully incorporated in urea lattice in the presence of a suitable readily complexing guest (RCG). The formation of simvastatin urea co-inclusion complex (SMVIC) was confirmed by DSC, FTIR, XRD and 1H-NMR studies. A modified Zimmerschied calorimetric method was utilized to estimate the minimum amount of RCG required for inclusion of simvastatin in urea. Urea-SMV-RCG co-inclusion complexes containing varying proportions of guests were prepared and their thermal behaviour was studied by DSC. Regression analysis revealed an excellent r2 value with regard to the influence of the relative proportion of RCG on the heat of decomposition of SMVIC. The inclusion complexes were found to exhibit good content uniformity. In vitro dissolution rate studies revealed significant improvement in dissolution profile of SMV which is a potent BCS class II drug with poor solubility in water and dissolution rate limited absorption. Studies reveal that urea co-inclusion complex formation can be exploited as a promising approach for the development of improved pharmaceutical formulation of SMV.

Influence of polymers/excipients on development of agglomerated crystals of secnidazole by crystallo-co-agglomeration technique to improve processability

Background: Direct tabletting is a need of Pharmaceutical industries. Poor mechanical properties of drug particles require wet granulation which is uneconomical, laborious, and tedious.Objective: Objective of this work was to study influence of various polymers/excipients on formation of directly compressible Crystallo-co-agglomerates (CCA) of water soluble drug Secnidazole (hydroxy-2-propyl)-1-methyl-2-nitro-5-imidazole), an antimicrobial agent.Method: Acetone-petroleum ether system was used to develop CCA of drug in the presence of polymers/excipients. Clarity of the supernatant was considered an endpoint for completion of agglomeration. The prepared CCA were subjected for topographic, micromeritic, mechanical, compressional, and drug release properties.Results: The process yielded ~92 to 98% wt/wt CCA containing secnidazole with the diameter between 0.2 and 0.7 mm. CCA showed excellent flow, packability, compatibility, and crushing strength. Heckel plot showed lower σ0 and higher tensile strength with lower elastic recovery (0.55–1.28%) of CCA. Dissolution profile of CCA was improved. Differential scanning calorimetry , fourier transform infra-red, and x-ray diffractometry results showed absence of drug–excipient interaction.Discussion: Matrix beads were generated with uniform dispersion of crystallized drug. Excellent flow, packability, and compactability were due to sphericity of agglomerates. Higher crushing strength of CCA was an indication of good handling qualities. Lower σ 0, higher tensile strength, and lower elastic recovery indicated excellent compressibility of agglomerates. Improvement in dissolution profile was due to porous nature of CCA.Conclusion: Excipients and polymers can play a key role to prepare CCA, an excellent alternative to wet granulation process to prepare particles for direct compression.

Studies on Flash Evaporation for Preparation of Porous Solid Dispersions Using Piroxicam as a Model Drug

An amalgamation of solid dispersion and capillarity has been attempted in present study for enhancement of dissolution rate of poorly soluble drugs. Flash evaporation technique was utilized for enhancement of the dissolution rate of piroxicam. One of the major problems with this drug is its very low solubility in biological fluids, which results in poor bioavailability after oral administration. An attempt was made to enhance the dissolution rate of piroxicam by converting it into porous solid dispersion by flash evaporation method using polyvinylpyrrolidone (PVP) 40,000 as a water-soluble carrier. The resulting solid dispersions were characterized by DSC, FTIR, and X-ray diffraction. In vitro dissolution study revealed significant improvement of dissolution profile of piroxicam. The release of drug from porous solid dispersions containing PVP was superior to those of marketed product, conventional nonporous solid dispersion prepared by solvent evaporation method and drug alone. The steep increase in dissolution rate of porous form is attributable to combined effect of solid dispersion and capillarity.

Solid dispersion of prednisolone: solid state characterization and improvement of dissolution profile

Background: Dissolution testing is an important test for judging the effectiveness of a pharmaceutical dosage form. Many drugs create adverse effect because of insufficient solubility at the physiological pH. This study is aimed to improve the dissolution properties of prednisolone (PRD) that falls under the category of class II biopharmaceutics system. Methods: In this study, preparation of solid dispersions with various water-soluble carriers was studied to improve the dissolution of PRD. To obtain the optimized formulation, solid dispersions were prepared employing different methods using different carriers with various drug:carrier ratios. Their dissolution behaviors were also compared. Fourier transform infrared (FTIR) spectroscopy, powder X-ray diffraction, and thermal analysis were studied to characterize the prepared solid dispersion. Results: PRD formed stable complexes with carriers as indicated by the stability constants (Ka) of 9.5–597.2 M−1. The results indicated that in vitro dissolution rate of PRD was remarkably improved in the solid dispersion of the drug compared with physical mixture and drug alone. This can be attributed to improved wettability, dispersibility, decrease in crystallinity, and increase in amorphous fraction of the drug. The results obtained from Fourier transform infrared spectroscopy and powrer X-ray diffraction showed good evidence of drug–carrier interaction while using carriers such as hydroxypropyl-β-cyclodextrin (HP-βCD) and polyethylene glycol (PEG). Crystallinity of the drug was reduced in the solid dispersions prepared with hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidone-co-vinyl acetate 64, and PEG as revealed from the differential scanning calorimetry thermograms. Conclusion: The results suggested that the solid dispersion with selected excipients is a powerful tool to accelerate the dissolution of poorly water-soluble drugs.

Urea co-inclusion compounds of glipizide for the improvement of dissolution profile

In the present study, urea, a well-known adductor for linear compounds was successfully utilized for inclusion of glipizide—a highly substituted cyclic organic compound through a modified technique. Formation of glipizide co-inclusion compounds in urea was confirmed by FTIR, DSC and XRD. The minimum proportion of rapidly adductible endocyte (RAE) required for adduction of glipizide in urea was estimated by a modified Zimmerschied calorimetric method. Urea–GLP–RAE inclusion compounds containing varying proportions of guests were prepared and their thermal behaviour studied by DSC. The co-inclusion compounds were found to exhibit good content uniformity. Through the formation of co-inclusion compounds of urea, it was possible to achieve steep improvement in the dissolution efficiency of glipizide, which is a BCS class II drug.