Experimental design approach for development of cocrystals and immediate release cocrystal tablet of atorvastatin calcium for enhancement of solubility and dissolution

Abstract

The objective of the present work was to prepare cocrystals of poorly soluble drug Atorvastatin Calcium(AVA) with the aim of increasing its solubility and dissolution properties. Screening of 8 cocrystal formers (CCFs) wasperformed by Hansen solubility parameter (HSPs) using 4 methods- neat grinding, solvent drop grinding, solventevaporation and sonocrystallization in equimolar ratio. Solubility of AVA cocrystal (1.9 fold increase) in comparison toplain AVA drug has been demonstrated with solubility experiments. FTIR spectra of AVA cocrystal showeddisappearance of O-H group indicating the formation of hydrogen bond synthon between the drug and CCFs. DSCthermogram showed drastic reduction in melting point from 164.6°C to 71.9 °C indicating the reduction in cohesiveenergy and increase in solubility. XRD pattern showed new crystalline peaks at 2θ values of 9.858°, 15.201°, 22.907°,25.407°, 29.496°. SEM analysis showed changes in the morphological characteristics as compared to drug and CCFs,indicating different crystalline nature. Experimental design was applied to optimize AVA cocrystal IR tablet forconcentration of aerosil (X1) and MMC 102 (X2) and were evaluated for drug release (Y1) and friability (Y2). It was foundthat as the concentration of aerosil and MMC 102 increased friability decreased and %drug release increased. A drugrelease of 98.54±1.163% and friability of 0.515±0.090 % was obtained for optimized batch. Ex vivo diffusion study wascarried out by isolating rat stomach tissue, exhibiting higher drug release (95.71±0.98 %) than plain AVA and marketedtablet. Thus formulating AVA cocrystal and its subsequent formulation in optimized IR tablet gives a promisingopportunity for manufacturing a drug with increased bioavailability.