Impact of jet pulverization and wet milling techniques on properties of aripiprazole long-acting injection and absorption mechanism research in vivo.

This study aims to explore the influence of wet milling and jet pulverization on the aripiprazole microcrystalline long-acting injection. Crystal form and particle size distribution were taken as inspection indicators in vitro, and process parameters were optimized. The formulation prepared by wet milling (AMLAI-WM) was shown to undergo a slight conversion of crystal form by DSC, PXRD, TG, FT-IR and have a wider particle size distribution with D50 and Span values of 2.967 μm and 3.457 compared to the formulation fabricated by jet pulverization (AMLAI-JP) with 2.887 μm and 2.258 respectively. In addition, the in vitro release of AMLAI-WM was faster, whereby the pharmacokinetic data indicated that AMLAI-WM was absorbed more quickly within five days with AUC of 5243.7 μg·L·h and 4818.28 μg·L·h, respectively. Furthermore, no statistically significant differences in C t and AUC between AMLAI-JP and the commercial formulation (Abilify Maintena™) were found. The absorption mechanism was studied and showed a 1.4-fold later T after depletion of macrophages and significantly lower C and AUC after inhibiting angiogenesis, indicating inflammatory granuloma could facilitate drug plasma exposure. Overall, we demonstrated that jet pulverization was a good strategy for long-acting microcrystalline injection, and that the absorption behavior was affected by both particle size distribution and inflammatory granuloma.