Solid-State Characterization of Fluconazole Polymorphs: Temperature and Time-Triggered Analysis

Abstract

Background: An antifungal drug, fluconazole, was selected as a model drug in this study to comprehend the effect of temperature and moisture on polymorphic transformation.Materials and Methods: Three polymorphs of fluconazole namely, Polymorph I, Polymorph II and Polymorph III, were prepared by the single solvent crystallization method using acetone, methanol, and isopropyl alcohol. The polymorphs were characterized by FTIR, DSC, XRPD, and equilibrium solubility studies to illustrate the solid-state transformation. The effects of moisture {65 ± 5% Relative Humidity (RH) at 28 ± 2°C}, and the temperature, ranging from 30 to 100°C, on the polymorphic transformation was investigated. Results and Discussion:The three polymorphs showed an endotherm at 140.19°C, 142.53°C, and 142.04°C, respectively. The fluconazole polymorph I and polymorph II showed polymorphic transformation at 80°C and on the 10th and 29th days, respectively, at 65 ± 5% RH/28 ± 2°C. On the other hand, the polymorph III, having a melting point of 120 ± 2°C, underwent polymorphic transformation at 90°C and on the 19th day at 65 ± 5% RH/28 ± 2°C. The impact of moisture on polymorphic transformation was evidenced by the remarkable shift of FTIR absorption peaks along with changes in their melting point.Conclusion: In summary, energetic steps involving heating of the drug and exposure to moisture will bring about polymorphic transformation in fluconazole, which result in changes in its solubility and, hence, it’s biological performance.

Keywords: Crystal transformation; Fluconazole; Metastable; Polymorph; Solid-state transformation