Solubility Measurement of the Crystal Form 1 and Form 4 Nirmatrelvir in Six Mono-Solvents and Two Binary Solvent Mixtures

Abstract

Nirmatrelvir (NMT) is an orally administered severe acute respiratory syndrome coronavirus 2 main protease inhibitor with several crystal forms, including form 1 and form 4. In this work, the crystal form transformation process in suspension was first studied, and the stable existence conditions of the two crystal forms were identified. The solubility of the crystal form 1 NMT in six mono-solvents (1-butanol, 1-pentanol, isoamyl alcohol, 1-octanol, nitromethane, and isopropyl acetate) and two binary solvent mixtures (isopropyl acetate + n-heptane and isopropyl acetate + n-hexane) from 293.15 to 333.15 K under atmospheric pressure was determined by the dynamic method. The solubility of the form 4 NMT in the same solvent systems was also determined from 273.15 to 288.15 K. The Apelblat equation and the Yaws equation were employed to describe the solubility data concerning temperature, and the CNIBS/R–K equation was used to acquire the solubility data with different solvent compositions. The ARD maximum of these models was 4.40%, which indicated that the models provided good fitting results.