Evaluation of the polymorphic forms of ritonavir and lopinavir in raw materials and co-milled systems

Pinheiro, Lucas Barboza Moreira; Tao, Songsheng; Culbertson, Elizabeth; Araújo, Gabriel Lima Barros de; Billinge, Simon J. L.; Ferreira, Fábio Furlan

doi:10.1016/j.ijpharm.2022.122329

Cited by 4 publications

(1 citation statement)

References 29 publications

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“…Ritonavir (Figure ) is a highly representative example of a high molecular weight pharmaceutical API. Since Bauer’s seminal paper published over 20 years ago, there has been significant interest within the medical and pharmaceutical communities in ritonavir with a number of high-impact papers on its solid-state characterization. − ,,, The drug has also attracted interest in an antivirus medication for Covid-19 treatment . In the current work, the nucleation behavior of the (now) metastable and “disappeared” form I has been examined using isothermal induction time measurements carried out as a function of solvent selection using apolar, polar aprotic, and polar protic solvents.…”

Section: Introductionmentioning

confidence: 99%

Influence of Solvent Selection on the Crystallizability and Polymorphic Selectivity Associated with the Formation of the “Disappeared” Form I Polymorph of Ritonavir

Wang,

Ma,

Hong

et al. 2024

Mol. Pharmaceutics

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Section: Introductionmentioning

confidence: 99%

Influence of Solvent Selection on the Crystallizability and Polymorphic Selectivity Associated with the Formation of the “Disappeared” Form I Polymorph of Ritonavir

Wang,

Ma,

Hong

et al. 2024

Mol. Pharmaceutics

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

Sacchi,

Wright,

Neoptolemou

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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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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Physicochemical interaction of rifampicin and ritonavir-lopinavir solid dispersion: an in-vitro and ex-vivo investigation

Nair,

Vullendula,

Yarlagadda

et al. 2024

Drug Development and Industrial Pharmacy

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Evaluation of the polymorphic forms of ritonavir and lopinavir in raw materials and co-milled systems

Cited by 4 publications

References 29 publications

Influence of Solvent Selection on the Crystallizability and Polymorphic Selectivity Associated with the Formation of the “Disappeared” Form I Polymorph of Ritonavir

Influence of Solvent Selection on the Crystallizability and Polymorphic Selectivity Associated with the Formation of the “Disappeared” Form I Polymorph of Ritonavir

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

Physicochemical interaction of rifampicin and ritonavir-lopinavir solid dispersion: an in-vitro and ex-vivo investigation

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