Simvastatin-Nicotinamide Co-Crystals: Formation, Pharmaceutical Characterization and in vivo Profile.

PURPOSE: To enhance the solubility and dissolution profile of simvastatin (SIM) through co-crystallization with varying ratios of nicotinamide (NIC) using various co-methods. MATERIALS AND METHODS: Twelve SIM:NIC co-crystal formulations (F01-F12) were prepared using dry grinding, slurry, liquid-assisted grinding, and solvent-evaporation methods, and their properties compared. Optimized formulations were selected on the basis of dissolution profiles and solubility for in vivo studies. The angle of repose, Carr Index and Hausner ratio were calculated to evaluate flow properties. Differential light scattering (DLS) was used to estimate particle-size distribution. Scanning electron microscopy (SEM) was employed to evaluate surface morphology. Thermal analyses and Fourier-transform infrared (FTIR) spectroscopy were used to determine the ranges of thermal stability and physical interaction of formulated co-crystals. X-ray powder diffraction (XPD) spectroscopy was used to determine the crystalline nature. Solubility and dissolution studies were undertaken to determine in vitro drug-release behaviors. RESULTS: Micromeritic analyses revealed the good flow properties of formulated co-crystals. DLS showed the particle size of co-crystals to be in the nanometer range. SEM revealed that the co-crystals were regular cubes. Thermal studies showed the stability of co-crystals at >300°C. FTIR spectroscopy revealed minor shifts of various peaks. XPD spectroscopy demonstrated co-crystal formation. The formulations exhibited an improved dissolution profile with marked improvements in solubility. In vivo studies showed a 2.4-fold increase in Cmax whereas total AUC(0-∞) was increased 4.75-fold as compared with that of SIM tablets. CONCLUSION: Co-crystallization with NIC improved the solubility and dissolution profile and, hence, the bioavailability of the poorly water-soluble drug SIM.

Effect of two hydrophobic polymers on the release of gliclazide from their matrix tablets.

Gliclazide is an oral hypoglycemic agent, indicated in non insulin dependent diabetes mellitus and in patients with diabetic retinopathy. It has good tolerability and is a short acting sulfonyl urea that requires large dose to maintain the blood glucose level. So development of a sustained release formulation of gliclazide (GLZ) is required for better patient compliance. This study was conducted to assess the effects of different drug polymer ratios on the release profile of gliclazide from the matrix. Oral matrix tablets of gliclazide were prepared by hot melt method, using pure and blended mixture of glyceryl monostearate (GMS) and stearic acid (SA) in different ratios. In vitro release pattern was studied for 8 h in phosphate buffer media (pH 7.4). Different kinetic models including zero order, first order, Higuchi and Peppas were applied to evaluate drug release behavior. Drug excipient compatibility was evaluated by scanning with DSC and FTIR. Higuchi model was found the most appropriate model for describing the release profile of GLZ and non-Fickian release was found predominant mechanism of drug release. The release of drug from the matrix was greatly controlled by GMS while SA appeared to facilitate the release of drug from matrix tablets. FTIR results showed no chemical interaction between drug and the polymers, and DSC results indicated amorphous state of GLZ and polymers without significant complex formation. The results indicate that matrix tablets of gliclazide using glyceryl monostearate and stearic acid showed marked sustained release properties.