2 : 1 5-Fluorocytosine–acesulfame CAB cocrystal and 1 : 1 5-fluorocytosine–acesulfame salt hydrate with enhanced stability against hydration

Abstract

5-Fluorocytosine (FC), a widely used antifungal drug, has poor physical stability under different relative humidity (RH) conditions, which may trigger serious challenges during its drug product development. In this contribution, a conjugate acid–base (CAB) cocrystal and a salt hydrate of FC were obtained with an artificial sweetener, acesulfame (AH), in molar ratios of 2 : 1 (FCAH21) and 1 : 1 (FCAH11), respectively. The resulting products were characterized by a variety of analytical methods, including single-crystal and powder X-ray diffraction (XRD), differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR), and dynamic vapor sorption (DVS). ¹³C and ¹⁵N solid-state NMR spectra provide solid evidence for the CAB cocrystal/salt formation. At room temperature, moisture sorption data show that the new forms are nonhygroscopic/slightly hygroscopic and resistant to FC hydrate formation under high RH conditions (>80%). FCAH21 has a higher FC content and presents more favorable thermal stability than FCAH11, which make it more attractive for further pharmaceutical application.