In situ monitoring of competitive coformer exchange reaction by 1H MAS Solid-state NMR
Publication date
2024-03Rights
© 2024 ACS. This document is the Accepted Manuscript version of a Published Work that appeared in final form in Molecular Pharmaceutics, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.molpharmaceut.3c01118.Peer-Reviewed
YesOpen Access status
embargoedAccessAccepted for publication
2024-02-07
Metadata
Show full item recordAbstract
In a competitive coformer exchange reaction, a recent topic of interest in pharmaceutical research, the coformer in a pharmaceutical cocrystal is exchanged with another coformer which is expected to form a cocrystal that is more stable. There will be a competition between coformers to form the most stable product through formation of hydrogen bonds. Thus, to monitor each and every step of such reactions, employing a very sensitive technique is crucial. 1H nuclear magnetic resonance (NMR) is a very powerful technique that is very sensitive to the hydrogen bond interactions. In this study, an in situ monitoring of a coformer exchange reaction is carried out by 1H magic angle spinning (MAS) solid-state NMR (SSNMR) at a spinning frequency of 60 KHz. The changes in caffeine maleic acid cocrystals on addition of glutaric acid, and caffeine glutaric cocrystal on addition of maleic acid were monitored. In all the reactions, it has been observed that caffeine glutaric acid Form I is formed. When glutaric acid was added to 2:1 caffeine maleic acid, the formation of metastable 1:1 caffeine glutaric acid Form I was observed, at the start of the experiment, indicating that the centrifugal pressure is enough for the formation. The difference in the end product of the reactions with similar reaction pathway of 1:1 and 2:1 reactant stoichiometry indicate that a complete replacement of maleic acid has only occurred only in the 1:1 stoichiometry of the reactants. The polymorphic transition of caffeine glutaric acid Form II to Form I at higher temperature was crucial reason which triggers the exchange of glutaric acid with maleic acid in the reaction of caffeine glutaric acid and maleic acid. Based on these results, new reaction pathways in competitive coformer exchange reactions could be distinguished, and the remarkable role of stoichiometry, polymorphism, temperature and centrifugal pressure could be established.Version
Accepted manuscriptCitation
Hareendran C, Alsirawan B, Paradkar AR et al (2024) In situ monitoring of competitive coformer exchange reaction by 1H MAS Solid-state NMR. Molecular Pharmaceutics. 21(3): 1479-1489.Link to Version of Record
https://doi.org/10.1021/acs.molpharmaceut.3c01118Type
ArticleNotes
The full-text of this article will be released for public view at the end of the publisher embargo on 19 Feb 2025.ae974a485f413a2113503eed53cd6c53
https://doi.org/10.1021/acs.molpharmaceut.3c01118