Enhancement of Physicochemical and Pharmacokinetic Characteristics of Ranolazine drug substance using Cocrystalization Technique

Abstract

Biopharmaceutical Classification System II drug, Ranolazine exhibits pH-dependent solubility and thus shows variable absorption along the gastrointestinal tract. Due to poor aqueous solubility particularly in basic pH, an attempt has been made to improve solubility through the cocrystallization technique. Cocrystals of Ranolazine with Nicotinamide have been synthesized at different molar ratios (1:1, 1:2, 1:3 2:1, and 3:1) through solvent-assisted grinding, slurry preparation, and solvent evaporation method and subsequently characterized by different analytical methodologies. Conformational characterization studies have been performed using techniques like melting point analysis, powder X-ray diffraction, and differential scanning calorimetry. Saturation solubility of Ranolazine alone along with cocrystals prepared in different molar ratios was conducted in water and buffers of different pH (1.2, 4.5, and 6.8) to establish enhancement in solubility. Ranolazine: Nicotinamide 1:2 cocrystals were found to be stable in accelerated and long-term stability conditions. In-vivo study performed in rats to demonstrate enhanced bioavailability. Ranolazine cocrystals with Nicotinamide were shown to have enhanced solubility in basic pH and improved peak plasma concentration, the area under the curve, and relative bioavailability by 2-folds.