In Vitro/In vivo evaluation of aripiprazole long-acting injectable microsuspension and development of IVIVC

Aripiprazole microcrystalline suspensions with varying particle sizes were prepared by wet media milling and characterized and compared with a Reference listed drug (RLD); The particle-size related properties were assessed by zeta potential, laser diffraction, and dynamic particle imaging, while morphology and solid-state properties were characterized by scanning electron microscopy (SEM), powder X-ray diffraction (XRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and Raman spectroscopy to provide a robust quality control. Because the paddle method from the FDA dissolution database lacked sufficient discriminability, a flow-through cell dissolution method (USP Apparatus 4) was developed and optimized to markedly improve discrimination among samples with different particle sizes and process conditions. Pharmacokinetic profiles of several formulations were evaluated in a rat model, and in vitro dissolution data were obtained using the flow-through method were evaluated in relation to in vivo performance to explore potential in vitro-in vivo correlations. The results indicate that the resulting model is capable of reasonably capturing burst-release behavior associated with differences in particle size and morphology, supporting formulation and process optimization.