New multicomponent crystals of nevirapine with improvement on solubility: preparation, characterization, calculation and analysis

The poor water solubility of nevirapine (NVP) significantly restricts its bioavailability. To address this challenge, this work proposes an efficient method for screening NVP multicomponent crystals using the full interaction map (FIM) and the Conductor-like screening model for real solvents (COSMO-RS) model. Two NVP salts and two NVP cocrystals with enhanced solubility were prepared using liquid-assisted grinding method and solvent evaporation method, namely nevirapine-5-sulfosalicylate (NVP-5SA), nevirapine-2,6-dihydroxybenzoate (NVP-2,6DBA), nevirapine-2,3-dihydroxybenzoic acid cocrystal (NVP-2,3DBA) and nevirapine-2,5-dihydroxyterephthalic acid cocrystal (NVP-2,5DTA). Systematic characterization, structural analysis, solubility measurement, dissolution evaluation and theoretical calculations were conducted on these multicomponent crystals. Notably, the solubility of NVP-5SA and NVP-2,6DBA increased to 5.32 and 3.90-fold respectively compared with NVP in phosphate buffer (pH = 6.8). The structures of four multicomponent crystals were characterized using single crystal X-ray diffraction. Quantum chemical calculations, including Hirshfeld surface analysis, atoms in molecules theory, independent gradient model based on Hirshfeld partitioning, and molecular electrostatic potentials surface, were employed to study molecular interactions at the microscopic level. The lattice energy (E_L) and hydration-free energy (E_HF) of NVP and its four multicomponent crystals were calculated, and the relationships between these parameters and the changes of melting point and dissolution behavior were analyzed. So, the variations and origins of these physicochemical properties were rationalized and explained on the atomic scale. Meanwhile, the efficiency of the novel combined coformers screening method was verified.