Structural Diversity of Brexpiprazole and Related Analogues: Impact on Solubility and Drug Delivery

Abstract

Brexpiprazole (BPZ) is an atypical antipsychotic drug indicated for the treatment of schizophrenia and depression. Crystal form screening of BPZ resulted in the formation of three polymorphs (I, II, and III), two methanol solvates, a toluene hemisolvate, and a dihydrate. Thermal analysis and solvent-mediated conversion experiments of the three unsolvated polymorphs established that Form I is the thermodynamically stable form at ambient temperature. All three polymorphs are monotropically related, whereby Forms I and II are the most and least stable forms, respectively. Structural diversity of BPZ was compared with two chemically related analogues, aripiprazole (APZ) and its active metabolite dehydroaripiprazole (dAPZ). Like APZ and dAPZ, BPZ was shown to form a thermodynamically stable, hydrated crystal form when exposed to an aqueous environment; however, while APZ and dAPZ were characterized as monohydrates, BPZ is a dihydrate. The crystal structure of BPZ dihydrate (S 2H 2 O ) showed two water molecules connecting two BPZ molecules, with hydrogen bonding occurring between both the piperazine nitrogen and the oxygen of the carbonyl moiety with different water molecules. Despite the chemical similarity of BPZ, APZ, and dAPZ, comparison of all accumulated crystal structures reveals wide structural diversity, with a significant impact on physicochemical properties. In particular, the solubility of BPZ is significantly lower in water across the physiologically relevant pH range. Implications to drug delivery of these findings are discussed.

Industry-Oriented Route Evaluation and Process Optimization for the Preparation of Brexpiprazole

“…1,2 Brexpiprazole is considered to be a possible successor of Otsuka's top-selling antipsychotic drug aripiprazole. 3 Many synthesis strategies have been reported for the preparation of 1; 1,2,4−10 however, as commented on recently by Micro Labs Ltd., 11 most of the reported synthesis routes were feasible from an academic perspective but were of limited practical value. We herein report our results from the R&D campaign of route evaluation and the process optimization in pursuit of a commercially viable process.…”

“…Brexpiprazole ( 1 ), discovered by Otsuka Pharmaceutical Co., Ltd. and approved by the FDA in 2015, is an antipsychotic drug for the treatment of schizophrenia and is also used as an adjunctive therapy for the treatment of major depressive disorder (MDD). , Brexpiprazole is considered to be a possible successor of Otsuka’s top-selling antipsychotic drug aripiprazole …”

Polymorph screening and solubility characterization of lercanidipine hydrochloride

“…Brexpiprazole and aripiprazole hydrated forms solubility were evaluated by the shake-flask method in the pH range from 2 to 8 at 37 °C. While brexpiprazole form I and dihydrate have not shown a significant difference in solubility in the pH range studied, aripiprazole form III and monohydrate presented a variation of about 20 mg·mL -1 for solubility at the interval 2-5 pH, what promotes solubility (ZEIDAN et al, 2018).…”