Ranolazine Co-Crystal: Molecular Docking, Coformer Selection, In vitro,In vivo Pharmacokinetic Assesment in Rat Plasma

Introduction: This study aims to enhance the solubility and bioavailability of Ranolazine, a poorly water-soluble anti-anginal agent, through the development of pharmaceutical co-crystals with selected co-formers. Ranolazine is effective in treating chronic angina, but its clinical utility is hindered by limited aqueous solubility and low oral bioavailability, leading to suboptimal therapeutic outcomes. The objective was to improve the physicochemical and pharmacokinetic properties of Ranolazine by co-crystallizing it with pharmaceutically acceptable co-formers. Method: The study employed a structured design integrating computational screening, experimental synthesis, and in vivo evaluation. An in silico molecular screening approach was first applied to predict potential co-formers for Ranolazine based on molecular interactions and compatibility, leading to the selection of 2-amino caffeine, nicotinamide, and benzamide. Co-crystals were then prepared using three complementary techniques: solvent-drop grinding, antisolvent addition, and slow evaporation to ensure robust formation. The resulting solids were characterized by UV spectroscopy, Fourier-transform infrared (FTIR) spectroscopy, and differential scanning calorimetry (DSC) to confirm co-crystal formation and assess physicochemical properties. Comparative in vitro dissolution testing evaluated the drug-release profiles of the co-crystals versus pure Ranolazine. For pharmacokinetic assessment, a validated reverse-phase high-performance liquid chromatography (RPHPLC) method employing hydrochlorothiazide as the internal standard was used to analyze plasma samples from rats following oral administration, enabling the determination of key pharmacokinetic parameters. Results: The study demonstrated that ranolazine co-crystals significantly enhanced dissolution rates and oral bioavailability compared to the pure drug. Pure ranolazine showed a Cmax of 17.6 µg/mL and an AUCt of 240.94 µg·h/mL, whereas co-crystals achieved substantially higher peak plasma levels, with C1 and N1 exhibiting the greatest improvement (56.62 µg/mL and 40.91 µg/mL, respectively) and B2, N3, B1, and N2 ranging from 20.81 µg/mL to 32.5 µg/mL after 4 hours. Among all formulations, C1 and N1 were the most effective in enhancing systemic exposure. The validated RP-HPLC method demonstrated high precision and sensitivity, meeting ICH requirements with low standard deviation and percentage RSD values, confirming the reliability of the pharmacokinetic analysis. Discussion: This investigation demonstrates that computationally guided co-former selection, combined with strategic co-crystallization, can substantially enhance the solubility and oral bioavailability of ranolazine. The synthesized co-crystals, particularly C1 and N1, showed markedly higher dissolution rates and significantly elevated plasma concentrations compared to the pure drug, indicating improved systemic exposure and potential for enhanced therapeutic efficacy. Conclusion: These results not only validate in silico molecular screening as an efficient tool for rational co-crystal design but also underscore co-crystallization as a viable approach to overcome biopharmaceutical limitations of poorly soluble drugs. Collectively, the findings provide a strong preclinical foundation for advancing ranolazine co-crystals toward clinical evaluation as superior anti-anginal formulations.