Abstract

Co-crystallization is a phenomenon widely employed to enhance the physio-chemical 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 co-crystals 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—H⋯O hydrogen bonding between the amine (NH2) groups of thio­urea and the carbonyl group of exemestane. The synthesized co-crystal exhibited potent urease inhibition activity in vitro (IC50 = 3.86 ± 0.31 µg ml−1) compared with the API (exemestane), which was found to be inactive, and the co-former (thio­urea) (IC50 = 21.0 ± 1.25 µg ml−1), which is also an established tested standard for urease inhibition assays in vitro. The promising results of the present study highlight the significance of co-crystallization 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.

Details

Title
Crystal engineering of exemestane to obtain a co-crystal with enhanced urease inhibition activity
Author
Syeda, Saima Fatima; Kumar, Rajesh; M Iqbal Choudhary; Sammer Yousuf
Pages
105-112
Section
Research Papers
Publication year
2020
Publication date
Jan 2020
Publisher
International Union of Crystallography
e-ISSN
20522525
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2604473001
Copyright
© 2020. This article is published under https://creativecommons.org/licenses/by/4.0/ (“the License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.