Crystal engineering of exemestane to obtain a co-crystal with enhanced urease inhibition activity

Abstract

Co-crystallization is a phenomenon widely employed to enhance the physiochemical and biological properties of active pharmaceutical ingredients (APIs). Exemestane, or 6-methylideneandrosta-1,4-diene-3,17-dione, is an anabolic steroid used as an irreversible steroidal aromatase inhibitor, which is in clinical use to treat breast cancer. The present study deals with the synthesis of cocrystals of exemestane with thiourea by liquid-assisted grinding. The purity and homogeneity of the exemestane-thiourea (1:1) co-crystal were confirmed by single-crystal X-ray diffraction followed by thermal stability analysis on the basis of differential scanning calorimetry and thermogravimetric analysis. Detailed geometric analysis of the co-crystal demonstrated that a 1:1 co-crystal stoichiometry is sustained by N-HÁ Á ÁO hydrogen bonding between the amine (NH 2 ) groups of thiourea and the carbonyl group of exemestane. The synthesized co-crystal exhibited potent urease inhibition activity in vitro (IC 50 = 3.86 AE 0.31 mg ml À1 ) compared with the API (exemestane), which was found to be inactive, and the co-former (thiourea) (IC 50 = 21.0 AE 1.25 mg ml À1 ), which is also an established tested standard for urease inhibition assays in vitro. The promising results of the present study highlight the significance of cocrystallization as a crystal engineering tool to improve the efficacy of pharmaceutical ingredients. Furthermore, the role of various hydrogen bonds in the crystal stability is successfully analysed quantitatively using Hirshfeld surface analysis.

New cocrystals of heterocyclic drugs: structural, antileishmanial, larvicidal and urease inhibition studies

“…Crystal engineering approaches for the preparation of APIs and biological compounds significantly improved the physicochemical and biological properties of bioactive compounds (Saha et al, 2014;Kiyonga et al, 2022;Duan et al, 2022). Our research group has reported previously the antileishmanial (Hussain et al, 2018), and urease inhibition (Fatima et al, 2020) properties of bioactive compounds via a cocrystallization approach.…”

Crystal engineering in IUCrJ: from `the' crystal structure to `a' crystal structure

“…In keeping with the theme of 'structure' a number of papers dealt with cocrystals both in the pharmaceutical context (Fatima et al, 2020;Ranjan et al, 2020) and in a more general sense (Rajkumar & Desiraju, 2021). Other areas addressed included charge density (Chodkiewicz et al, 2020;Sanjuan-Szklarz et al, 2020;Duverger-Né dellec et al, 2020), phase transformations (Smets et al, 2020;Rekis et al, 2021), crystals obtained under exotic conditions (Buganski & Bindi, 2021;Hu et al, 2020;Né meth, 2020), and MOFs (Yadava et al, 2020;Park et al, 2020) apart from core papers on supramolecular synthons and synthetic strategy.…”

Crystal engineering in all its hues in IUCrJ

“…For comparison, about 150 papers in the crystal engineering area have been published since the inception of the journal itself. Recent papers that have been published in IUCrJ cover a variety of frontier topics and some representative papers are listed below (Alex et al, 2019;Brink & Helliwell, 2019;Broadhurst et al, 2020;Fatima et al, 2020;Gianopoulos et al, 2019;Oburn et al, 2019;Ranjan et al, 2020). These cover areas like charge density, polymorphism and isomorphism, mechanical properties, pharmaceutical solids, and core papers on supramolecular synthons and synthetic strategy.…”