Cocrystallization of an Antiretroviral Drug Nevirapine: An Eutectic, a Cocrystal Solvate, and a Cocrystal Hydrate

Abstract

Nevirapine (NEV) is an antiretroviral drug which falls under the Biopharmaceutics Classification System (BCS) class II category. In this work, we report the synthesis of new eutectic and cocrystal of NEV with enhanced dissolution. NEV resulted into an eutectic with paracetamol (PAR) at a NEV mole fraction (XNEV) of 0.25 (corresponding to a NEV-PAR stoichiometric ratio of 1:3). Evaporative crystallization using ultrasound and a slurry conversion of NEV with trimesic acid (TMA) in methanol yielded a methanol solvate of NEV-TMA (1:1) cocrystal. Also, a new NEV-trimellitic acid methyl ester (TMEA methyl ester) (1:1) cocrystal hydrate was obtained during ultrasound assisted evaporative cocrystallization of NEV-trimellitic acid anhydride (TMEA)-XNEV-0.5 owing to transformation (esterification) of the coformer, TMEA to TMEA methyl ester in methanol. The single crystals of these cocrystals were characterized by single crystal X-ray diffraction (SCXRD) analysis. The eutectic and cocrystals were also characterized by powder X-ray diffraction (PXRD) analysis, field emission-scanning electron microscopy (FE-SEM) analysis, thermal analysis, and vibrational spectroscopic analysis. Powder dissolution studies conducted in deionized water containing 0.1 wt % of sodium dodecyl sulfate (SDS) at 37 °C showed that NEV-PAR-SSG-XNEV-0.25 eutectic exhibited 3.07 times enhanced dissolution than raw NEV, whereas NEV-TMA (1:1) cocrystal methanol solvate prepared by evaporative crystallization and slurry conversion exhibited 2.51 times and 2.42 times enhanced dissolution than raw NEV.