With the fact that molecular conformation is different in the two polymorphs, as concentration increases, solute molecules rearrange their conformations to form stronger hydrogen-bonded dimers in solution, resulting in nucleation of the most stable form.

Direct-acting antiviral regimens have transformed therapeutic management of hepatitis C across all prevalent genotypes. Most of the chemical matter in these regimens comprises molecules well outside the traditional drug development chemical space and presents significant challenges. Herein, the implications of high conformational flexibility and the presence of a 15-membered macrocyclic ring in paritaprevir are studied through a combination of advanced computational and experimental methods with focus on molecular chameleonicity and crystal form complexity. The ability of the molecule to toggle between high and low 3D polar surface area (PSA) conformations is underpinned by intramolecular hydrogen bonding (IMHB) interactions and intramolecular steric effects. Computational studies consequently show a very significant difference of over 75 Å 2 in 3D PSA between polar and apolar environments and provide the structural basis for the perplexingly favorable passive permeability of the molecule. Crystal packing and protein binding resulting in strong intermolecular interactions disrupt these intramolecular interactions. Crystalline Form I benefits from strong intermolecular interactions, whereas the weaker intermolecular interactions in Form II are partially compensated by the energetic advantage of an IMHB. Like Form I, no IMHB is observed within the receptor-bound conformation; instead, an intermolecular H-bond contributes to the potency of the molecule. The choice of metastable Form II is derisked through strategies accounting for crystal surface and packing features to manage higher form specific solid-state chemical reactivity and specific processing requirements. Overall, the results show an unambiguous link between structural features and derived properties from crystallization to dissolution, permeation, and docking into the protein pocket.

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To understand how solution chemistry governs polymorphic formation of organic crystals, solution NMR measurements of tolfenamic acid were conducted in ethanol. It was unveiled by chemical shift and diffusivity results that the solute molecules self-associated as dimers in solution. Further nOe (nuclear Overhauser effect) analyses indicate that a more twisted conformation became dominant over a planar conformation under the solution conditions that favored the dimer formation. This discovery is rationalized in terms of the energy balance between the conformation and intermolecular hydrogen bonding of the solute molecule, suggesting a significant role of the cooperability between a molecule’s conformation and its intermolecular interaction in determining the nucleation outcome of distinct crystal structures.

Hydrates represent a very significant fraction of pharmaceutical molecular crystals and can be leveraged to simplify downstream processing for formulations such as wet granulation and hot-melt extrusion. In silico methods to predict hydrate formation can guide experimental screening and evaluate residual risk of selected forms. Both solution mixing thermodynamics and relative propensities of hydrogen bond formation can be used for virtual screening. Our study assessed these techniques for a previously studied set of relatively simple drug compounds (average molecular weight 300) and a new set of more complex AbbVie-pipeline compounds (average molecular weight 550). Although solution thermodynamics have been shown to successfully discriminate hydrate formation for the set of smaller drug molecules, this technique did not provide successful screening for the more complex set of AbbVie compounds tested. A single-differential hydrogen bond propensity (SD-HBP) score, which accounts for only the strongest donoracceptor pairing in both anhydrate and hydrate forms, also provides little utility. We therefore developed a multidifferential hydrogen bond propensity (MD-HBP) score that considers the competitive effect of multiple donoracceptor interactions in each form. Additionally, the MD-HBP score utilizes solid-state conformations (estimated here via COSMO-RS theory) to strengthen the data-driven analysis of the solid-state and ensure more accurate description of possible hydrogen bond networks in anhydrate and hydrate solid forms. This quantitative MD-HBP score performed well at differentiating between hydrate-forming and non-hydrate-forming compounds for both sets of compounds; thus, it can be applied more broadly in solid form development.