Mechanochemistry is an effective method for the preparation of multicomponent crystal systems. In the present work, we propose an alternative to the established liquid-assisted grinding (LAG) approach. Polymer-assisted grinding (POLAG) is demonstrated to provide a new class of catalysts for improving reaction rate and increasing product diversity during mechanochemical cocrystallization reactions. We demonstrate that POLAG provides advantages comparable to the conventional liquid-assisted process, whilst eliminating the risk of unwanted solvate formation as well as enabling control of resulting particle size. It represents a new approach for the development of functional materials through mechanochemistry, and possibly opens new routes toward the understanding of the mechanisms and pathways of mechanochemical cocrystal formation.

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.

Mechanochemistry is an effective method for the preparation of multicomponent crystal systems.I nt he present work, we propose an alternative to the established liquidassisted grinding (LAG) approach.P olymer-assisted grinding (POLAG) is demonstrated to provide an ew class of catalysts for improving reaction rate and increasing product diversity during mechanochemical cocrystallization reactions.W edemonstrate that POLAGp rovides advantages comparable to the conventional liquid-assisted process,whilst eliminating the risk of unwanted solvate formation as well as enabling control of resulting particle size. It represents an ew approachf or the development of functional materials through mechanochemistry,and possibly opens new routes towardthe understanding of the mechanisms and pathwayso fm echanochemical cocrystal formation.