Molecular, Solid-State and Surface Structures of the Conformational Polymorphic Forms of Ritonavir in Relation to their Physicochemical Properties

Chang Wang,Thomas D. Turner,Ian Rosbottom,Sydney Laing,Robert Docherty,Kevin J. Roberts,Qiuxiang Yin,Andrew G. P. Maloney,Ahmad Y. Sheikh

doi:10.1007/s11095-021-03048-2

Abstract

PurposeApplication of multi-scale modelling workflows to characterise polymorphism in ritonavir with regard to its stability, bioavailability and processing.MethodsMolecular conformation, polarizability and stability are examined using quantum mechanics (QM). Intermolecular synthons, hydrogen bonding, crystal morphology and surface chemistry are modelled using empirical force fields.ResultsThe form I conformation is more stable and polarized with more efficient intermolecular packing, lower void space and higher density, however its shielded hydroxyl is only a hydrogen bond donor. In contrast, the hydroxyl in the more open but less stable and polarized form II conformation is both a donor and acceptor resulting in stronger hydrogen bonding and a more stable crystal structure but one that is less dense. Both forms have strong 1D networks of hydrogen bonds and the differences in packing energies are partially offset in form II by its conformational deformation energy difference with respect to form I. The lattice energies converge at shorter distances for form I, consistent with its preferential crystallization at high supersaturation. Both forms exhibit a needle/lath-like crystal habit with slower growing hydrophobic side and faster growing hydrophilic capping habit faces with aspect ratios increasing from polar-protic, polar-aprotic and non-polar solvents, respectively. Surface energies are higher for form II than form I and increase with solvent polarity. The higher deformation, lattice and surface energies of form II are consistent with its lower solubility and hence bioavailability.ConclusionInter-relationship between molecular, solid-state and surface structures of the polymorphic forms of ritonavir are quantified in relation to their physical-chemical properties.

Highlights

As the 20th anniversary of the seminal paper by Bauer et al [1] which described the extraordinary case of the polymorphic behavior of the active pharmaceutical ingredient (API) ritonavir has been reached, we have revisited the form I and II polymorphic structures by performing molecular, crystallographic and surface modelling calculations
This paper describes the integration of a digital fingerprint of the solid state structure and particle properties into the solid form selection process using the Ritonavir case study as an example
A 2D view of the molecular structure of ritonavir is given in Fig. 2 with the molecule being separated into eight important fragments or functionalities, these include two thiazole and phenyl rings, a N-methyl urea functionality, an amide linkage, hydroxyl group and a carbamate group

Summary

Introduction

As the 20th anniversary of the seminal paper by Bauer et al [1] which described the extraordinary case of the polymorphic behavior of the active pharmaceutical ingredient (API) ritonavir has been reached, we have revisited the form I and II polymorphic structures by performing molecular, crystallographic and surface modelling calculations. These results are related to the unusual differences in physical properties between these forms, assessing how the digital workflows that are being embedded into the pharmaceutical drug R&D can unpick the complex structural chemistry that underpins polymorphic behavior of this representative API. The problem was further compounded in that the facilities which were previously making form I could only crystallize form II, leading the compound to be labelled a ‘disappearing’ polymorph [5]

Methods

Results

Conclusion