Highly Efficient Organic Solvent-Free Oiling-Out-DissolvingStrategy to Fabricate Aripiprazole Microcrystals for Long-Acting Antipsychotics

Specific-sized drug microcrystals (MCs) can be applied in the development of long-acting sustained-release formulations for intramuscular injection and have received increasing attention. However, due to the limitations of traditional production methods, which involve using complex equipment, high energy consumption, and high use of organic solvents, their large-scale application has been severely hindered. In this work, we have proposed an oiling-out-dissolving strategy to controllably synthesize the antipsychotic drug aripiprazole (APZ) Form III MCs through a simple heating–quenching–dissolving operation without the use of organic solvents or complex equipment. The obtained drug MCs have a size range of 1–5 μm, sharp-edge crystal morphology, good dispersibility, and a stable crystal structure without crystal transformation during the preparation process. The formation mechanism of APZ MCs inside spherical particles was revealed by measuring the crystallization induction time and characterizing the crystal structure of spherical particles with different APZ contents. The well-defined sharp-edge morphology induced a greater inflammatory response and endowed the as-prepared APZ-MCs LAI formulations with lower in vivo dissolution in the initial stage and less plasma concentration fluctuation compared with commercial Abilify Maintena. Combining pharmacokinetic and pathological analysis, the sustained release and absorption mechanism of APZ-MCs in rats were fully understood, paving the way for the design of drug sustained-release injection formulations.