Flutamide degradation driven by sulfonic acids: unforeseen salts and salt polymorphs of a degraded flutamide impurity†

Abstract

Flutamide, marketed as Eulexin, is a nonsteroidal anti-androgen primarily used in the treatment of advanced prostate cancer, particularly in B2-C and D2 metastatic disease stages. The present study investigated the salts derived from a degraded flutamide impurity (Flu·D). Initially, the research aimed to develop novel multicomponent systems of flutamide. To achieve this, flutamide was crystallized with various coformers; however, all attempts resulted in physical mixtures. Single crystals were obtained by forming salts of Flu·D. with sulfonic acid derivatives (methanesulfonic acid, ethanesulfonicacid, benzenesulfonic acid, and para-toluenesulfonic acid). The high acidity of these sulfonic acids led to the degradation of flutamide, resulting in the formation of eight new salts of Flu·D: Flu·D–MSA (1 : 1), Flu·D–MSA (2 : 2), Flu·D–ESA (2 : 2), Flu·D–BSA (1 : 1), Flu·D–BSA (2 : 2), Flu·D–BSA (6 : 6), Flu·D–PTSA (2 : 2) and Flu·D–PTSA–H₂O (1 : 2 : 3). The MSA and BSA salts of Flu·D crystallized in multiple polymorphic forms, while PTSA resulted in both anhydrous and hydrate structures, as evidenced by SCXRD analysis. Comprehensive stress studies of flutamide revealed its degradation behavior. A UHPLC method was successfully employed to isolate the degradation products. NMR and FT-IR spectroscopy were performed to confirm the degradation and salt formation. DSC and TGA were utilized to study the thermal properties of the salts. Equilibrium solubility studies were conducted in two different media (water and pH 1.2), demonstrating enhanced solubility of Flu·D and its salts compared to flutamide. Among all the salts, Flu·D–PTSA (2 : 2) exhibited superior dissolution profiles in both media. This comprehensive study characterizes the degradation products of flutamide, providing an effective strategy for impurity profiling and testing the chemical stability of the drug.