Distinct Hybrid Hydrates of Paritaprevir: Combined Experimental and Computational Assessment of their Hydration–Dehydration Behavior and Implications for Regulatory Controls

Paritaprevir is a first-generation direct-acting antiviral and, as a conformationally flexible molecule containing a 15-membered macrocyclic ring, has unique chameleonic and solid-state features. The two commercially relevant forms (Forms I and II) are clearly differentiated wherein Form I benefits from strong intermolecular interactions, whereas weaker intermolecular interactions in Form II are partially compensated by the energetic advantage of an intramolecular hydrogen bond, which significantly lowers the conformational energy. Both forms are hydrated and exhibit hybrid features of stoichiometric and nonstoichiometric hydrates, albeit differently. Form I exhibits strong host–host and weak host–water interactions and contains stable channels that do not substantially change upon hydration/dehydration. Form II contains weak host–host and strong host–water interactions and a host–water hydrogen bonding planar network that evolves with the hydration state. Furthermore, periodic density functional theory calculations for potential energy differences show that a transition from enthalpic stabilization of the structure to entropic stabilization occurs at 2.5 mol equiv of water in Form II. Since the paritaprevir drug substance is manufactured as Form II, implications of its features for nomenclature and testing within the regulatory context are also discussed.