ArticleProceedings of the National Academy of Sciences of the United States of America2024
Crystal size, shape, and conformational changes drive both the disappearance and reappearance of ritonavir polymorphs in the mill.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- Structure-stability relationships of pure cannabinoids and their cocrystals under forced degradation conditions.Journal of cannabis research · 2026Article
- Crystal engineering for poorly water-soluble drugs: From design to applications.Acta pharmaceutica Sinica. B · 2026Review
- Control of site-specific deprotonation through mechanochemical interconversion of two ionic cocrystal forms of resveratrol.Journal of materials chemistry. B · 2026Article
- When Reality Defies Prediction: Polymorphism, Twinning, and Accordion Crystals.Journal of the American Chemical Society · 2026Article
- How Crystal Size and Number Steer Asymmetric Crystallization.The journal of physical chemistry letters · 2026Article
- Phase diagrams of pharmaceutical solvates from mechanochemistry.Nature communications · 2026Article
- A benchmark study of force fields implemented in CSD software.Structural chemistry · 2026Article
- Predicting the ritonavir crisis by revisiting the polymorph landscape with crystal structure prediction and form 4 structure solution.Communications chemistry · 2025Article
- Polymorphism in Cannabinol Piperazine Cocrystals: Structural, Morphological, and Energetic Perspectives.Crystal growth & design · 2025Article
- Mechanochemistry for Metal-Organic Frameworks and Covalent-Organic Frameworks (MOFs, COFs): Methods, Materials, and Mechanisms.Advanced materials (Deerfield Beach, Fla.) · 2025Review
- Lattice Energy Partitions in Crystals of Flexible Molecules and the 40% Limit.Journal of the American Chemical Society · 2025Article
- Structural origin of fracture-induced surface charges in piezoelectric pharmaceutical crystals for engineering bulk properties.Nature communications · 2025Article
- Comprehensive Investigation of Polymorphic Stability and Phase Transformation Kinetics in Tegoprazan.Pharmaceutics · 2025Article
- Simple Quantification of Sticking Propensities of Pharmaceuticals with Mechanochemistry.Molecular pharmaceutics · 2025Article
- Enantiopurity by Directed Evolution of Crystal Stabilities and Nonequilibrium Crystallization.Journal of the American Chemical Society · 2025Article
- Influence of Solvent Selection on the Crystallizability and Polymorphic Selectivity Associated with the Formation of the "Disappeared" Form I Polymorph of Ritonavir.Molecular pharmaceutics · 2024Article
- Chemistry and crystal engineering.IUCrJ · 2024Article
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9 authors.
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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.
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