Solution-Mediated Phase Transformation of Aripiprazole: Negating the Effect of Crystalline Forms on Dissolution and Oral Pharmacokinetics

• Published in: Journal of pharmaceutical sciences 2020-12, Vol.109 (12), p.3668-3677
• Main Authors: Chung, Sungyoon, Kim, Jongyeob, Ban, Eunmi, Yun, Jungmin, Park, Boosung, Kim, Aeri
• Format: Article
• Language: English
• Subjects: Aripiprazole; Dissolution rate; Hydrates; Pharmacokinetics; Polymorph; Solubility; Solution-mediated phase transformation
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1016/j.xphs.2020.09.031

We aimed to evaluate the effect of crystalline forms of aripiprazole, an antipsychotic drug for schizophrenia, on the dissolution rates and oral pharmacokinetics. Solubility, intrinsic dissolution rates, and tablet dissolution rates of the monohydrate (MA) and the anhydrous form (AA) were measured in various aqueous media while monitoring the phase transformation by ATR-FTIR. And their oral pharmacokinetics in dogs were compared. The intrinsic dissolution rate of MA was lower compared to AA, confirming its thermodynamic stability relative to AA in water. Phase transformations during the solubility measurement were media-dependent: In simulated gastric fluid, both AA and MA changed to HCl salt form, whereas AA and HCl salt form transformed to MA in simulated intestinal fluid. In vitro dissolution rates and dog oral pharmacokinetics of AA and MA tablets were similar. The results suggest that the solution-mediated transformation to HCl salt or MA negates the effect of different crystalline forms on dissolution rates in vivo and, consequently, on oral pharmacokinetics. We emphasize the importance of the dissolution tests employing various bio-relevant media for better prediction of in vivo performance and the selection of a solid form for development.