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In situ monitoring of competitive coformer exchange reaction by 1H MAS Solid-state NMR
Hareendran, C. Alsirawan, B. Ajithku, T.G.am
Hareendran, C.
Alsirawan, B.
Ajithku, T.G.am
Publication Date
2024-03
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© 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.
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openAccess
Accepted for publication
2024-02-07
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Abstract
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.
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Accepted manuscript
Citation
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.
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Article