Cocrystallization of Progesterone with Benzoic Acid and Its Derivatives

Abstract

Thirty three cocrystals and cocrystal solvates of progesterone (PRO) with benzoic acid and its derivatives were prepared under solvent-free grinding conditions. Twenty five cocrystals and cocrystal solvates were reported for the first time, of which 15 cocrystals and cocrystal solvates had single crystal data (CCDC deposition numbers 2131358–2131360, 2131363, 2131364, 2131366–2131373, 2131376, and 2131377). For cocrystal formers (CCF), the carboxyl group attached directly to the aromatic ring had a role similar to that of the orientation effect. The cocrystallization between PRO and benzoic acid or substituted benzoic acids was highly likely to take place regardless of the presence of electron-withdrawing or electron-donating groups in the o-, m-, p-position of the carboxyl group. When CCFs were hydrogen-bonded to PRO, they bonded to the carbonyl group on ring “A” of PRO first and then to the carbonyl group attached to ring “D”. The calculation results of the electrostatic potential maximum value confirmed this conclusion. Quantum chemical calculations of PRO/benzoic acid/H₂O (4:2:1) showed that the most important force in this system was the C–H···π among PRO-benzoic acid-PRO. All cocrystals and cocrystal solvates were more soluble than PRO in water. The preparation of cocrystals is an effective attempt to design a new PRO administration method.