Engineering Codrug Solid Forms: Mechanochemical Synthesis of an Indomethacin–Caffeine System

Bordignon, Simone; Cerreia Vioglio, Paolo; Priola, Emanuele; Voinovich, Dario; Gobetto, Roberto; Nishiyama, Yusuke; R. Chierotti, Michele

Abstract

This article reports on the preparation and solid-state characterization of an indomethacin–caffeine drug–drug cocrystal (or codrug) in a 1:1 stoichiometry. These two active ingredients are frequently coadministered as part of a therapy against strong migraines, in a commercially available fixed dose combination formulation. The X-ray crystal structure of the codrug is characterized by a hydrogen bond interaction between the carboxylic moiety of indomethacin and the purinic nitrogen atom of caffeine. The combination of multinuclear and multidimensional solid-state NMR measurements (1H MAS, 13C and 15N CPMAS, 1H DQ MAS, 13C–1H HETCOR, 14N–1H J- and D-HMQC), as well as IR data, provided spectroscopic evidence about the hydrogen atom position along the hydrogen bond axis, thereby confirming the neutral nature of the cocrystal. Furthermore, dissolution kinetic tests revealed superior bioavailability of indomethacin in the codrug compared to indomethacin alone and to an indomethacin–caffeine physical mixture. On the other hand, the melting point of indomethacin was slightly lower in the cocrystal rather than in the pure drug.

Citation

Bordignon, S., Cerreia Vioglio, P., Priola, E., Voinovich, D., Gobetto, R., Nishiyama, Y., & R. Chierotti, M. (2017). Engineering Codrug Solid Forms: Mechanochemical Synthesis of an Indomethacin–Caffeine System. Crystal Growth and Design, 17(11), 5744–5752. https://doi.org/10.1021/acs.cgd.7b00748

• Journal Article Type: Article
• Acceptance Date: Sep 25, 2017
• Online Publication Date: Oct 20, 2017
• Publication Date: Nov 1, 2017
• Deposit Date: Nov 18, 2024
• Journal: Crystal Growth & Design
• Print ISSN: 1528-7483
• Electronic ISSN: 1528-7505
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 17
• Issue: 11
• Pages: 5744–5752
• DOI: https://doi.org/10.1021/acs.cgd.7b00748
• Keywords: Crystal structure, Crystals, Nuclear magnetic resonance spectroscopy, Peptides and proteins, Pharmaceuticals
• Public URL: https://nottingham-repository.worktribe.com/output/42198753
• Publisher URL: https://pubs.acs.org/doi/10.1021/acs.cgd.7b00748