Chum, Clarence KeiKwan;
Gladwell, Iain Robert;
Marziano, Ivan;
Salvalaglio, Matteo;
(2024)
Unravelling the Impact of Process Impurities on the Crystallization of Ritlecitinib Tosylate Using Molecular Dynamics.
Organic Process Research & Development
, 28
(9)
pp. 3587-3593.
10.1021/acs.oprd.4c00106.
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Abstract
We investigate the influence of oligomeric impurities on the crystallization of ritlecitinib tosylate, an active pharmaceutical compound, using a combined experimental and molecular modeling approach. Ritlecitinib oligomers, particularly hexamers, were identified as key species hindering crystal growth. Experimental outcomes highlighted the inhibitory effects of oligomers on crystallization kinetics, yield, and physical properties. Simplified free energy methods based on the linear interaction energy model revealed a nonmonotonic relationship between oligomer size and surface affinity, with hexamers having the most prominent tendency to block the surface of ritlecitinib tosylate crystals, thus impacting crystal growth. A competitive Langmuir adsorption isotherm model quantified the reduction in crystal growth rates due to oligomer adsorption, providing a systematic approach to understanding these inhibitory effects. This research enhances our understanding of the molecular mechanisms governing oligomer adsorption, and more generally, impurity adsorption, on crystal surfaces and offers insights for designing crystal growth inhibitors in pharmaceutical applications.
| Type: | Article |
|---|---|
| Title: | Unravelling the Impact of Process Impurities on the Crystallization of Ritlecitinib Tosylate Using Molecular Dynamics |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1021/acs.oprd.4c00106 |
| Publisher version: | http://dx.doi.org/10.1021/acs.oprd.4c00106 |
| Language: | English |
| Additional information: | Copyright © 2024 The Authors. Published by American Chemical Society. This publication is licensed under CC-BY 4.0, https://creativecommons.org/licenses/by/4.0/. |
| Keywords: | Crystallization; molecular dynamics; modeling; crystal growth; process impurities |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Chemical Engineering |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10198564 |
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