Origins and Implications of Extraordinarily Soft Crystals in a Fixed-Dose Combination Hepatitis C Regimen

Paritaprevir and ombitasvir are part of a triple combination, first-generation, direct-acting antiviral regimen as a fixed-dose tablet. The commercially manufactured Form II of paritaprevir and Form I of ombitasvir are high stoichiometry crystalline hydrates with 2.5 and 4.5 molar equivalent of water, respectively. The dominant (001) surface for paritaprevir interacts with adjacent non-interlocking layers via weak dispersion forces due to large interlayer d-spacing. On the other hand, the dominant (001) surface of ombitasvir is characterized by interdigitated layers and a three-dimensional H-bonding network, albeit in a relatively low-density crystalline structure. A comparative analysis of hardness and Young’s modulus with a larger data set of molecular crystals corroborates the structural features and helps quantify the extraordinarily soft viscoelastic nature of the dominant surface of paritaprevir Form II (H and E of 0.014 and 0.029 GPa, respectively) and the slightly softer and more elastic dominant surface of ombitasvir Form I (H and E of 0.29 and 6.6 GPa, respectively). The surface of paritaprevir can therefore undergo irreversible compression-induced deformation; however, its viscoelastic nature makes the extent of such deformation inconsequential for product quality during process relevant perturbations. The elastic features of the dominant surface of ombitasvir in combination with well-designed process controls allow crystals to heal from or avoid the loss of mechanical integrity when undergoing two solid–solid phase conversions that are an essential feature of the commercial isolation process.