Abstract
Pharmaceutical cocrystals are currently gaining interest among the scientific community, due to their great potential for providing novel crystalline forms with superior properties such as solubility, dissolution rate, bioavailability, and stability. Robust computational tools are valuable tools in the rationalization of cocrystal formation, by providing insight into the intermolecular interactions of multicomponent molecular solids. In this study, various computational techniques based on charge density analysis were implemented to assess structural and energetical perspectives of the interactions responsible for the formation and stability of entacapone-theophylline-water (ETP-THP-water, 1:1:1). Significant non-covalent interactions (NCIs) were identified and evaluated by Hirshfeld surface analysis and density functional theory (DFT) computations, and three-dimensional networks (energy vector diagrams, lattice energy frameworks) were constructed, outlining the crucial stabilizing role of water and the dominance of π-π stacking interactions in the cocrystal. Furthermore, thermal dehydration studies confirmed the strong binding of water molecules in the crystal lattice, as expressed by the high activation energy.
Highlights
Pharmaceutical cocrystals are crystalline multi-component phases, usually consisting of a single active pharmaceutical ingredient (API) and one or more coformers in a stoichiometric ratio [1]
Solvent evaporation (SE) of equimolar methanol solutions of ENT and THP monohydrate provided the same X-ray diffractogram (Figure 2) as the reference cocrystals prepared by Bommaka et al, via liquid-assisted grinding (LAG) [31]
Physicochemical characterization of physical mixtures was applied for a better monitoring of the cocrystal formation and purity upon production
Summary
Pharmaceutical cocrystals are crystalline multi-component phases, usually consisting of a single active pharmaceutical ingredient (API) and one or more coformers in a stoichiometric ratio [1]. Pharmaceutical cocrystallization is a very promising strategy for the successful modification of several properties of APIs, including solubility, dissolution rate, bioavailability, and mechanical and physicochemical properties [4,5]. The solid state and crystalline nature offers cocrystals advantages in terms of reproducibility in their properties and stability under storage and manufacturing, compared with the individual components or other formulations, such as amorphous dispersions or solid solutions [6]. They are easier to handle and process, resulting in great academic and industrial interest. Theoretical calculations, like pKa value difference [7] and Hansen solubility parameters [8], to more advanced
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