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

Abstract

Purpose: Application of multi-scale modelling workflows to characterise polymorphism in ritonavir with regard to its stability, bioavailability and processing.

Methods: Molecular 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.

Results: The 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.

Conclusion: Inter-relationship between molecular, solid-state and surface structures of the polymorphic forms of ritonavir are quantified in relation to their physical-chemical properties.

Keywords: Ritonavir; conformation / packing energy balance; crystal morphology; inter-molecular packing; lattice energy; molecular conformational deformation energy; particle surface energy; solvent selection; surface chemistry.

Fig. 1

High level predictive workflow creating a digital fingerprint of the solid-state features of a new chemical entity development highlighting the 3 stage pathway from the molecular state through solid-state and surface properties to the particle properties important in formulation, overviewing the methodology for understanding the differences in structural informatics.

Fig. 2

The molecular structure of ritonavir displaying the major functional groups in the molecule with the carbamate conformation highlighted in dashed green to show the trans and cis conformations of this functionality in form I and II respectively. The hydrogen bond acceptors which are active in the molecule are also highlighted with the label HA and the subscript I and II indicating the polymorphic form in which the group is active. The atoms and specific functional groups (in dashed red boxes) were found to show relatively large calculated Mopac charge differences between the form I and form II conformers. The isopropyl group at thiazole 1 (yellow dashed boxes) is disordered in the form I crystal structure.

Fig. 3

The distributions of selected molecular descriptors, relevant to drug-likeness, of single-component approved drugs in the CSD Drug Subset (59). Values of these descriptors for ritonavir are given alongside solid vertical lines. These distributions highlight ritonavir’s high molecular weight, high lipophilicity, large numbers of hydrogen bond donors and acceptors and very high number of rotatable bonds, and hence flexibility, relative to most approved drugs.

Fig. 4

Space filling models of the molecular conformations for a) form I and b) form II where the atoms have been colored to represent their calculated charge with partial negative charge is colored blue and a partial positive charge is red. The important functional groups involved in the conformational changes between the two forms, Thiazole 2 and phenyl 2 are highlighted to show their steric position in relation to the hydroxyl group.

Fig. 5

(a) Molecular structure of ritonavir; a) identification of key torsion angles; b) differences in the molecular conformation between (b) form I; (c) form II; in this, the molecular structure is segmented into four sections for ease of comparison. An enlargement of the key conformation of the γ fragment is shown in (d) for form I and (e) for form II.

Fig. 6

Convergence of the intermolecular summation associated with the determination of (a) the lattice energy showing the contribution of electrostatic interactions to the overall lattice energy (b, c) radial discretized distribution plots showing the % contribution to the lattice energy as a function of intermolecular summation distance for (b) form I and (c) form II.

Fig. 7

Molecular structure highlighting: (a) the absolute energetic and relative contributions of the four constitutive molecular fragments α, β, γ and δ to the overall lattice energy of ritonavir forms I and II; (b) a more detailed breakdown of the γ fragment highlighting the increased importance of the H-bonding group in form II.

Fig. 8

(a) Predicted crystal morphologies for form I and (b) form II (bottom) highlighting the expected surface chemistry of the morphologically important habit faces.

Fig. 9

SEM and optical micrographs (respectively) of the observed morphologies as a function of crystallization solvent used together with associated morphological sketches (inset) of (a) form I and (b) form II. It is noteworthy that some crystals prepared from the polar solvents (labelled A) show evidence of some tapering consistent with a polar morphology.

Fig. 10

Details of the surface chemistry of the {0 1 1 and {1 0 1} capping face for forms I (a) and II (b) respectively which highlight the inter-atomic hydrogen bonds and their directionality associated with the A_I, A_II and B_I synthons. It is noteworthy that B_I does not significantly contribute to the growth of the capping faces of form I.