Large‐Scale Production of Fluconazole Para‐Hydroxy Benzoic Acid Cocrystal by Milling Technique

ABSTRACT Pharmaceutical cocrystals are emerging as a promising strategy to modify the physicochemical properties of the API (Active Pharmaceutical Ingredient). Solvent‐based cocrystallization techniques involve the use of a large quantity of organic solvent and energy consumption, making continuous manufacturing challenging. The current research aimed to manufacture Fluconazole cocrystals via a mechanochemical process. The kilogram scale batch of fluconazole (FLZ) and para‐hydroxy benzoic acid (PHBA) cocrystals is prepared using neat grinding and liquid‐assisted grinding. Results suggested liquid‐assisted grinding to be the ideal cocrystallization technique, where complete cocrystals are developed within 90 min of processing time. The FLZ‐PHBA CC showed good flow characteristics with improved compressibility, tabletability, and compactibility properties. The Cocrystals showed a reduced elastic recovery rate, which is favourable for powder compression. The Heckel and Kawakita analysis of FLZ‐PHBA cocrystals resulted in reduced P k and P y, depicting more plastic deformation and particle rearrangement. Moreover, the cocrystal presented better hygroscopic and accelerated stability than FLZ alone. The in vivo pharmacokinetic parameters of FLZ, FLZ‐BA CC, and FLZ‐PHBA CC are studied in Wistar rats. The study revealed that after cocrystallization, no significant change is observed in the pharmacokinetic parameters of FLZ.