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Disappearing Polymorphs Reappear in the Mill: The Case of Ritonavir [dataset] Open Access

Organic compounds can crystallise in different forms known as polymorphs. Discovery and control of polymorphism is of key importance to the pharmaceutical industry since polymorphs can have significantly different physical properties impacting, therefore, their utilisation in drug delivery. Certain polymorphs have been reported to ‘disappear’ from the physical world leading to polymorphs. These unwanted polymorph conversions (initially prevented by the slow nucleation kinetics of the stable forms) are driven by significant gains in thermodynamic stabilities. The most infamous of these cases is that of the HIV drug ritonavir: once its reluctant form was unwillingly nucleated for the first time, its desired form could not be produced again with the same manufacturing process. Here we show that Ritonavir’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 (with the aid of computer simulations) is driven by crystal size as well as crystal shape and conformational effects. We also show that those effects can be controlled through careful changes in the 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 hard to nucleate, recovery of disappearing polymorphs, and polymorph control of complex flexible drug compounds such as Ritonavir.

Descriptions

Resource type

Dataset

Contributors

Sacchi, Pietro ¹
Wright, Sarah ²
Neoptolemou, Petros ²
Lampronti, Giulio I. ³
Rajagopalan, Ashwin Kumar ²
Kras, Weronika ²
Evans, Caitlin L. ⁴
Hodgkinson, Paul ⁴
Creator: Cruz-Cabeza, Aurora J. ⁴

¹ The Cambridge Crystallographic Data Centre
² The University of Manchester
³ Cambridge University
⁴ Durham University

Funder

Eli Lilly and Company
Engineering and Physical Sciences Research Council
Cambridge Structural Data Centre
AstraZeneca
Royal Society

Research methods

Powder diffraction data for milled products and reference materials.

Other description

Keyword

Crystals
Polymorphism
Ritonavir
Mechanochemistry

Subject

Chemistry
Chemistry, Physical and theoretical

Location

Durham

Language

Cited in

doi:10.26434/chemrxiv-2023-gz7kb

Identifier

ark:/32150/r26395w717f
doi:10.15128/r26395w717f

Rights

Creative Commons Attribution 4.0 International (CC BY)

Publisher

Durham University

Date Created

File Details

Depositor

A.J. Cruz Cabeza

Date Uploaded

23 January 2024, 17:01:17

Date Modified

24 January 2024, 13:01:48

Audit Status

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Characterization

File format: zip (ZIP Format)

Mime type: application/zip

File size: 1268293

Last modified: 2024:01:23 17:07:25+00:00

Filename: ESI_material_XRD.zip

Original checksum: f72e60103ab12ccfb137333944e93d1a