Wang, C., Ma, C.Y. orcid.org/0000-0002-4576-7411, Hong, R.S. orcid.org/0000-0002-4214-6847 et al. (5 more authors) (2024) Influence of Solvent Selection on the Crystallizability and Polymorphic Selectivity Associated with the Formation of the "Disappeared" Form I Polymorph of Ritonavir. Molecular Pharmaceutics, 21 (7). pp. 3525-3539. ISSN 1543-8384
Abstract
The comparative crystallizability and polymorphic selectivity of ritonavir, a novel protease inhibitor for the treatment of acquired immune-deficiency syndrome, as a function of solvent selection are examined through an integrated and self-consistent experimental and computational molecular modeling study. Recrystallization at high supersaturation by rapid cooling at 283.15 K is found to produce the metastable “disappeared” polymorphic form I from acetone, ethyl acetate, acetonitrile, and toluene solutions in contrast to ethanol which produces the stable form II. Concomitant crystallization of the other known solid forms is not found under these conditions. Isothermal crystallization studies using turbidometric detection based upon classical nucleation theory reveal that, for an equal induction time, the required driving force needed to initiate solution nucleation decreases with solubility in the order of ethanol, acetone, acetonitrile, ethyl acetate, and toluene consistent with the expected desolvation behavior predicted from the calculated solute solvation free energies. Molecular dynamics simulations of the molecular and intermolecular chemistry reveal the presence of conformational interplay between intramolecular and intermolecular interactions within the solution phase. These encompass the solvent-dependent formation of intramolecular O–H...O hydrogen bonding between the hydroxyl and carbamate groups coupled with differing conformations of the hydroxyl’s shielding phenyl groups. These conformational preferences and their relative interaction propensities, as a function of solvent selection, may play a rate-limiting role in the crystallization behavior by not only inhibiting to different degrees the nucleation process but also restricting the assembly of the optimal intermolecular hydrogen bonding network needed for the formation of the stable form II polymorph.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2024 The Authors. Published by American Chemical Society. This publication is licensed under CC-BY 4.0. |
Keywords: | conformational polymorphism; crystallizability; disappeared polymorphic form; hydrogen bonding; intra- and intermolecular interactions; molecular dynamics; nucleation kinetics; ritonavir; solvent selection |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemical & Process Engineering (Leeds) The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Inorganic Chemistry (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 05 Jul 2024 14:39 |
Last Modified: | 05 Jul 2024 14:39 |
Status: | Published |
Publisher: | American Chemical Society (ACS) |
Identification Number: | 10.1021/acs.molpharmaceut.4c00234 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:213816 |