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

Nirmatrelvir(NMT) is an orally administered severe acute respiratorysyndrome coronavirus 2 main protease inhibitor with several crystalforms, including form 1 and form 4. In this work, the crystal formtransformation process in suspension was first studied, and the stableexistence conditions of the two crystal forms were identified. Thesolubility of the crystal form 1 NMT in six mono-solvents (1-butanol,1-pentanol, isoamyl alcohol, 1-octanol, nitromethane, and isopropylacetate) 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 determinedby the dynamic method. The solubility of the form 4 NMT in the samesolvent systems was also determined from 273.15 to 288.15 K. The Apelblatequation and the Yaws equation were employed to describe the solubilitydata concerning temperature, and the CNIBS/R-K equation wasused to acquire the solubility data with different solvent compositions.The ARD maximum of these models was 4.40%, which indicated that themodels provided good fitting results.