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Crystal size, shape, and conformational changes drive both the disappearance and reappearance of ritonavir polymorphs in the mill.

Sacchi, Pietro; Wright, Sarah E; Neoptolemou, Petros; Lampronti, Giulio I; Rajagopalan, Ashwin Kumar; Kras, Weronika; Evans, Caitlin L; Hodgkinson, Paul; Cruz-Cabeza, Aurora J

Crystal size, shape, and conformational changes drive both the disappearance and reappearance of ritonavir polymorphs in the mill. Thumbnail


Authors

Pietro Sacchi

Sarah E Wright

Petros Neoptolemou

Giulio I Lampronti

Ashwin Kumar Rajagopalan

Weronika Kras

Caitlin Evans caitlin.l.evans@durham.ac.uk
PGR Student Doctor of Philosophy



Abstract

Organic compounds can crystallize in different forms known as polymorphs. Discovery and control of polymorphism is crucial to the pharmaceutical industry since different polymorphs can have significantly different physical properties which impacts their utilization in drug delivery. Certain polymorphs have been reported to 'disappear' from the physical world, irreversibly converting to new ones. These unwanted polymorph conversions, initially prevented by slow nucleation kinetics, are eventually observed driven by significant gains in thermodynamic stabilities. The most infamous of these cases is that of the HIV drug ritonavir (RVR): Once its reluctant form was unwillingly nucleated for the first time, its desired form could no longer be produced with the same manufacturing process. Here we show that RVR's extraordinary disappearing polymorph as well as its reluctant form can be consistently produced by ball-milling under different environmental conditions. We demonstrate that the significant difference in stability between its polymorphs can be changed and reversed in the mill-a process we show is driven by crystal size as well as crystal shape and conformational effects. We also show that those effects can be controlled through careful design of milling conditions since they dictate the kinetics of crystal breakage, dissolution, and growth processes that eventually lead to steady-state crystal sizes and shapes in the mill. This work highlights the huge potential of mechanochemistry in polymorph discovery of forms initially difficult to nucleate, recovery of disappearing polymorphs, and polymorph control of complex flexible drug compounds such as RVR.

Citation

Sacchi, P., Wright, S. E., Neoptolemou, P., Lampronti, G. I., Rajagopalan, A. K., Kras, W., …Cruz-Cabeza, A. J. (2024). Crystal size, shape, and conformational changes drive both the disappearance and reappearance of ritonavir polymorphs in the mill. Proceedings of the National Academy of Sciences, 121(15), Article e2319127121. https://doi.org/10.1073/pnas.2319127121

Journal Article Type Article
Acceptance Date Feb 19, 2024
Online Publication Date Apr 1, 2024
Publication Date Apr 1, 2024
Deposit Date May 13, 2024
Publicly Available Date May 13, 2024
Journal Proceedings of the National Academy of Sciences of the United States of America
Print ISSN 0027-8424
Publisher National Academy of Sciences
Peer Reviewed Peer Reviewed
Volume 121
Issue 15
Article Number e2319127121
DOI https://doi.org/10.1073/pnas.2319127121
Keywords pharmaceuticals, crystal polymorphism, mechanochemistry, particle size and shape
Public URL https://durham-repository.worktribe.com/output/2392373

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