ArticleMolecular pharmaceutics2024
Influence of Solvent Selection on the Crystallizability and Polymorphic Selectivity Associated with the Formation of the "Disappeared" Form I Polymorph of Ritonavir.
Article in Molecular pharmaceutics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Syn-Anti Conformational Equilibrium of Indomethacin: A Combined NOESY and Quantum Chemical Study.Pharmaceutical research · 2026Article
- Fluid shear driven secondary nucleation using α-and γ-glycine seeds confirmed with rigorous control experiments.CrystEngComm · 2026Article
- A Conceptual Framework for the Crystallizability of Organic Compounds.Journal of the American Chemical Society · 2025Article
- Predicting the ritonavir crisis by revisiting the polymorph landscape with crystal structure prediction and form 4 structure solution.Communications chemistry · 2025Article
- Molecular, Crystal, and Surface Chemistry ofCrystal growth & design · 2025Review
- Polymorphic Control in Pharmaceutical Gel-Mediated Crystallization: Exploiting Solvent-Gelator Synergy in FmocFF Organogels.Gels (Basel, Switzerland) · 2025Article
- Formulation and Bioequivalence Evaluation of a Miniaturized Fexofenadine Hydrochloride Tablet.Pharmaceutics · 2025Article
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Authors and funding
8 authors.
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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.
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