title: Pharmaceutical Co-Crystal of Flufenamic Acid: Synthesis and Characterization of Two Novel Drug-Drug Co-Crystal.
abstract: Two novel pharmaceutical co-crystals of anti-inflammatory drug flufenamic acid (FFA) with 2-chloro-4-nitrobenzoic acid (CNB) and ethenzamide (ETZ) have been synthesized by solvent evaporation method as well as by solvent drop-assisted grinding method. The synthesized co-crystals were characterized thoroughly by various spectroscopic methods and crystal structures were determined by single-crystal x-ray diffraction technique. In FFA-CNB co-crystal, robust supramolecular acid-acid homosynthon was observed. FFA-ETZ co-crystal is formed via robust supramolecular acid-amide heterosynthon. In FTIR spectra, a significant shift in the carbonyl stretching frequency was observed for the co-crystals due to the presence of intermolecular hydrogen bond.1H nuclear magnetic resonance study suggests the presence of hydrogen bond in the solution state of FFA-ETZ co-crystal; however, it was absent for FFA-CNB co-crystal. Solubility study in Millipore water revealed that the solubility of FFA is increased by 2-fold when it is in the form of FFA-CNB co-crystal and no increment in the solubility of FFA was observed in FFA-ETZ co-crystal. About 5-fold increment in the solubility of FFA was observed in both the co-crystals in 0.1 N HCl (pH 1) solution. The synthesized co-crystals were found to be non-hygroscopic at ∼75% relative humidity and stable for a period of 6 months at ambient temperature (∼25°C).
authors.affiliation: Department of Chemistry, Supramolecular Chemistry Laboratory, National Institute of Technology, Karnataka (NITK), Srinivas Nagar, Surathkal, Mangaluru, Karnataka 575025, India.
authors.forename: Sunil Kumar
authors.initials: SK
authors.lastname: Nechipadappu
authors.affiliation: Department of Chemistry, Supramolecular Chemistry Laboratory, National Institute of Technology, Karnataka (NITK), Srinivas Nagar, Surathkal, Mangaluru, Karnataka 575025, India.
authors.forename: Venkatadri
authors.initials: V
authors.lastname: Tekuri
authors.affiliation: Department of Chemistry, Supramolecular Chemistry Laboratory, National Institute of Technology, Karnataka (NITK), Srinivas Nagar, Surathkal, Mangaluru, Karnataka 575025, India. Electronic address: darshak_rtrivedi@yahoo.co.in.
authors.forename: Darshak R
authors.initials: DR
authors.lastname: Trivedi
mesh_terms: D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis*; D003460:Crystallization; D004338:Drug Combinations; D005439:Flufenamic Acid / Q000138:chemical synthesis*; D014961:X-Ray Diffraction / Q000379:methods*
chemical_list: D000893:Anti-Inflammatory Agents; D004338:Drug Combinations; D005439:Flufenamic Acid
keywords: co-crystal; crystal engineering; hygroscopicity; pharmaceutical co-crystal; solubility; stability