title: Tuning mechanical properties of pharmaceutical crystals with multicomponent crystals: voriconazole as a case study.
abstract: Crystals of voriconazole, an antifungal drug, are soft in nature, and this is disadvantageous during compaction studies where pressure is applied on the solid. Crystal engineering is used to make cocrystals and salts with modified mechanical properties (e.g., hardness). Cocrystals with biologically safe coformers such as fumaric acid, 4-hydroxybenzoic acid, and 4-aminobenzoic acid and salts with hydrochloric acid and oxalic acid are prepared through solvent assisted grinding. The presence (salt) or absence (cocrystal) of proton transfer in these multicomponent crystals is unambiguously confirmed with single crystal X-ray diffraction. All the cocrystals have 1:1 stoichiometry, whereas salts exhibit variable stoichiometries such as HCl salt (1:2) and oxalate salts (1:1.5 and 1:1). The nanoindentation technique was applied on single crystals of the salts and cocrystals. The salts exhibit better hardness than the drug and cocrystals in the order salts ≫ drug > cocrystals. The molecular origin of this mechanical modulation is explained on the basis of slip planes in the crystal structure and relative orientations of the molecules with respect to the nanoindentation direction. The hydrochloride salt is the hardest solid in this family. This may be useful for tableting of the drug during formulation and in drug development.
authors.affiliation: Solid State and Structural Chemistry Unit, Indian Institute of Science , Bangalore 560 012, India.
authors.forename: Palash
authors.initials: P
authors.lastname: Sanphui
authors.forename: Manish Kumar
authors.initials: MK
authors.lastname: Mishra
authors.forename: Upadrasta
authors.initials: U
authors.lastname: Ramamurty
authors.forename: Gautam R
authors.initials: GR
authors.lastname: Desiraju
mesh_terms: D000935:Antifungal Agents / Q000008:administration & dosage / Q000737:chemistry; D001696:Biomechanical Phenomena; D001702:Biopharmaceutics; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D055119:Elastic Modulus; D006244:Hardness; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D012492:Salts / Q000737:chemistry; D013607:Tablets; D065819:Voriconazole / Q000008:administration & dosage / Q000737:chemistry*
chemical_list: D000935:Antifungal Agents; D012492:Salts; D013607:Tablets; D065819:Voriconazole
keywords: cocrystals; crystal engineering; elastic modulus; hardness; nanoindentation; salts