Co-crystals and co-crystal hydrates of the antibiotic nitrofurantoin: Structural studies and physicochemical properties

Abstract

The current contribution aims to prepare a family of nitrofurantoin (NF) co-crystals and to investigate the ability of these co-crystals in enhancing the photostability and clinically relevant physicochemical properties of NF. Accordingly, supramolecular synthesis of the antibiotic drug NF with the co-formers 3-aminobenzoic acid (3ABA), 4-aminobenzoic acid (4ABA), urea, 4-hydroxybenzamide (4HBAM), phenazine (PHEN), melamine (MELA), 4,4′-bipyridine (BIPY) and 1,2-bis(4-pyridyl ethane) (BIPE) have produced five co-crystals and three co-crystal hydrates. Solid-state physical characterizations have been conducted by powder X-ray diffraction (PXRD), single crystal X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot-stage microscopy (HSM) and spectroscopy (Raman and 1H NMR). Crystal structures have been analyzed based on homo- and heterosynthons. Six out of eight multicomponent crystals are primarily stabilized by heterosynthons, whereas the remaining two co-crystals (NF-4ABA and NF-UREA) contain homosynthons. Notably, thermal analysis of co-crystal hydrates showed high thermal stability (166 °C, NF-MELA-H2O) or upon dehydration provided new anhydrous co-crystals, NF-BIPY and NF-BIPE in a 2:1 molar ratio. Physicochemical properties such as aqueous solubility, intrinsic dissolution rate and photostability have been investigated for NF-3ABA, NF-4ABA, NF-UREA and NF-4HBAM. Co-crystals display enhanced physicochemical properties as compared to that of NF: NF-4HBAM > NF-3ABA > NF-4ABA > NF-UREA > NF (β-form). The results suggest that co-crystals can be a viable alternative for improving the biopharmaceutical properties of API. © 2012 American Chemical Society.