Development, characterization and stability evaluation of solid dispersed nisoldipine for improvement of solubility

Abstract

Many challenges arise with poor water soluble drugs because of their poor dissolution and poor bioavailability. Despite being an effective method of solubility improvement, solid dispersion faces the challenges on selection of polymers, stability issues, and selection of suitable scalable method. Nisoldipine is an antihypertensive drug with poor bioavailability due to its low aqueous solubility although it has high hepatic metabolism. In order to enhance the solubility of nisoldipine, solid dispersion using hot melt mixing, solvent evaporation and freeze drying methods were carried out with formulation optimization, complete characterization as well as stability study on solid dispersed nisoldipine powders and tablets. From the results, it was found out that solid dispersion with optimized formulation; poloxamer 188 (6.55 g) and polyvinylpyrrolidone K30 (3.75 g) binary carrier system with respect to 1 g of the drug, was the most effective for solubility improvement at 115.27 ± 0.32 ?g/ml nisoldipine solubility and 1.197 ± 0.03 N/mm2 tensile strength. Attenuated total reflectance spectroscopy results revealed no physical incompatibility between drug and polymers used. Differential scanning colorimetery, optical microscopy and scanning electron microscopy results described the absence or reduction in the number of nisoldipine crystals after solid dispersion. X-ray diffractometry results confirmed that crystallinity of nisoldipine had been significantly reduced in solid dispersed formulations. Nisoldipine solubility of hot melt, solvent evaporated and freeze dried solid dispersed powders in pH 6.8 phosphate buffer saline + 0.4 % sodium lauryl sulfate were all significantly higher than that of pure drug and physical mixture (drug + polymers) with p-values less than 0.05 at 95 % confidence interval. Although hot melt and solvent evaporated samples gave slightly lesser saturation solubility result, they were much more stable than the freeze dried sample. The tableting characteristics of solid dispersed nisoldipine were found to be consistent. The dissolution study of tablets revealed that there was significant difference in terms of % drug release between hot melt, solvent evaporated and physical mixture tablets. However there was no significant difference found between freeze dried and physical mixture tablets. The stability of solid dispersed nisoldipine tablets followed the same trend as powder stability. These results demonstrated the possible applicability of optimized solid dispersed formulation of nisoldipine with binary polymeric carrier system for solubility enhancement of poorly water-soluble drugs and production of tablets. It was evidenced that selection of polymeric composition as carrier and method of preparation significantly affects the solid dispersion properties with respect to drug solubility enhancement, stability and applicability to tablet compression.