Objective: To establish a in vitro research method for consistency evaluation of aripiprazole oral disintegrating tablets by using computer modelling and parallel artificial membrane permeation model, to provide methods and data support for the screening of key process parameters in poorly-soluble drug preparations. Methods: In vitro dissolution methods for aripiprazole oral collapsing tablets was established. The model for in vivo absorption of aripiprazole oral collapsing tablets was established using GastroplusTM software. The in vitro/in vivo correlation of the dissolution methods was analyzed to find the physiological correlated dissolution method. The particle size range of the generic product was designed via the parameter sensitivity analysis of computer modelling. The dissolution curves of the generics product with different particle sizes and the reference preparation were compared to determine the particle size range. Parallel artificial membrane permeability assay was conducted to simulate the bioequivalence between the generic products and the reference product, thus to investigate the relationship between the particle size and the in vivo absorption of the drug. Bioequivalence prediction was validated through clinical trial results. Results: Aripiprazole is a poorly-soluble drug and shows a pH-relevant solubility. The dissolution profiles of aripiprazole oral collapsing tablets were different in pH 1.2, pH 4.0 and pH 4.5 media, with the fastest dissolution in pH 1.2 medium and the slowest dissolution in pH 4.5 medium. The dissolution in pH 4.5 medium showed the highest correlation coefficient with the simulated in vivo release curve (Y=0.005 3X2+0.404 1X-0.068 5, r=0.998 7). The dissolution curves of generic products meet the similarity requirement with the reference product(f2>50). A batch of generic products within the particle size range was used for clinical trials, and the results showed that it was bioequivalent with the reference product. Conclusion: A dissolution method with high in vitro and in vivo correlation was established by computer modelling combined with parallel artificial membrane permeation. This method successfully guided the drug particle size screening, and determined the drug particle size range in the process parameters. This method provides data support for the screening of generic drug prescription process quickly and effectively. It reduces the time spent in the research and development of generic products, reduces the cost and improves the success rate of bioequivalence of generic products.
GUO Zhiyuan, ZHOU Rui, FENG Wen, ZHU Qiang, XIE Hua, YANG Lei
. Appilcation of computer modelling and the parallel artificial membrane permeability assay in the study of aripiprazole oral collapsing tablets formulation process*[J]. Chinese Journal of Pharmaceutical Analysis, 2023
, 43(6)
: 982
-990
.
DOI: 10.16155/j.0254-1793.2023.06.09
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