Solid-state compatibility studies of Ketoconazole-Fumaric acid co-crystal with tablet excipients

This work presents a detailed excipient compatibility study of the Ketoconazole-Fumaric acid (KET-FUM) co-crystal, which might be a good alternative to Ketoconazole in the oral treatment of antifungal infections, due to its substantially higher aqueous solubility. Physical mixtures of the co-crystal with hydroxypropyl-methyl cellulose K4M (HPMC), corn starch (CSt), silicon dioxide (SiO2), lactose monohydrate (Lact), talc, polyvinyl-pyrrolidone K90 (PVP) and magnesium stearate (MgSt) were prepared in a 1:1 (w:w) ratio and analyzed by thermal analysis (DSC/TG), powder X-ray diffraction, Fourier transform infrared spectroscopy (FT-IR) and Karl Fischer titration. Compatibility assessment was systematically evaluated using the above complementary techniques on the mixtures after preparation as well as after two storage conditions (12 months at ambient conditions and 3 months at elevated temperature and relative humidity (40 °C/75% RH). The solid-state compatibility of the co-crystal was confirmed with HPMC, Lact, CSt, SiO2, while in the case of MgSt and PVP possible interactions were identified. The co-crystal interaction with MgSt is heating induced, as evidenced by DSC alone. In the case of PVP, both DSC and FT-IR indicated possible hydrogen-bonding in the amorphous phase. The solid-state compatibility results evidence the potential of the KET-FUM co-crystal to be developed as an oral drug. Moreover, our study reinforces the applicability of the binary mixture approach designed for APIs and salt-based formulations to be used in the case of co-crystals, in order to assess their pharmaceutical developability.