No regioselectivity for the steroid α-face in cocrystallization of exemestane with aromatic cocrystal formers based on phenanthrene and pyrene

Abstract

The anti-cancer steroidal drug exemestane presents significantly different behavior in cocrystallization with arenes compared with the previously explored steroid progesterone. Mechanochemical and solution-based cocrystallization of exemestane with hydroxy derivatives of phenanthrene and pyrene leads to the formation of cocrystals exhibiting clear O–H···O type arene-steroid hydrogen bonds. So far, exemestane and 1-hydroxypyrene have been observed to form only one type of cocrystal, with the 1:1 stoichiometric ratio of the two components. However, there are two stoichiometric variations of the cocrystal of 9-hydroxyphenanthrene and exemestane, with the arene:steroid stoichiometric ratio of either 1:1 or 1:2. Importantly, although cocrystallization of progesterone with the same arene cocrystal formers was previously reported to take place regioselectively through α···π contacts between the α-face of the steroid and the π-electron surface of the arene, the herein explored cocrystals of exemestane reveal α···π and β···π contacts, as well as sidewise interactions involving the arene π-system and different edges of the steroid molecule. The loss of regioselectivity for the steroid α-face in cocrystallization with the two monohydroxylated arenes is tentatively explained by the highly positive electrostatic surface potential of the steroid β-face and a diminished number of C–H groups on the α-face of exemestane compared with progesterone.