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

Abstract

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.

Supramolecular Structure, Hirshfeld Surface Analysis, Morphological Study and DFT Calculations of the Triphenyltetrazolium Cobalt Thiocyanate Complex

“…There are good relationships between an investigational pharmaceutical compound's crystal structure, crystal morphology, and physicochemical characteristics [23,24]. The theoretical crystal morphology of (1) was simulated using Materials Studio 7.0 [25] utilizing the Bravais-Friedel-Donnay-Harker (BFDH) model and growth morphology (GM) models.…”

Influence of Solvent Selection on the Crystallizability and Polymorphic Selectivity Associated with the Formation of the “Disappeared” Form I Polymorph of Ritonavir

“…Polymorphism is related to the ability of a compound to crystallize in different crystallographic structures but with the same chemical composition. − For organic materials, where the solid-state chemistry is mostly characterized by a combination of weak undirected van der Waals interactions coupled, in some cases, with stronger directed hydrogen bonds (HBs), polymorphism is not an unexpected phenomenon (e.g., ref ). Indeed, it has often been reported that the number of polymorphic forms discovered for a given material depends upon the efforts (time and resources) committed. ,, In conformational polymorphism, flexible organic molecules can adapt different molecular conformations, resulting in the different polymorphic forms. ,, As a result, a multitude of polymorphic forms may be observed e.g., in tolfenamic acid and paritaprevir, − ritonavir, − ROY, , acridine, and aripiprazole . For pharmaceutical materials, the different polymorphs of a substance may exhibit different physicochemical properties, such as solubility, stability, density, and bioavailability. ,, Therefore, gaining an understanding and then control of the crystallization of an active pharmaceutical ingredient (API) from solution can form an essential part of both its development and subsequent formulation as a drug product.…”

“…However, the mechanisms could include the effects of solute/solvent interactions in the solution state − on the nucleation process and hence on polymorphism. , Nucleation can play a significant role in controlling the final product properties ,− with its rate being very sensitive to solution chemistry. ,,,− Using classical nucleation theory (CNT), the interfacial energies between the solid and solution forms can be calculated and correlated to solvent properties such as solubility, boiling point, and dipole moment to examine nucleation behavior. − Although, nucleation from solution can be strongly influenced by solvent selection, the detailed mechanisms underpinning solvent-dependent behavior also remain quite elusive. In this respect, modeling intermolecular solute/solvent interactions provided helpful insights into both the strength of solvation interactions and the associated solvent coordination to solute molecules as a function of solvent type. ,,− Crystallizability as a function of solvent selection has also been assessed through meta-stable zone width (MSZW) measurements , and also through the determination of nucleation kinetics using CNT. ,,,, …”