Design and molecular insights of drug-active metabolite based co-amorphous formulation: A case study of toltrazuril-ponazuril co-amorphous

Co-amorphous supersaturated drug delivery systems are emerging as an alternative strategy to improve the water solubility of BCS II drugs. Typically, the supersaturation and stability of co-amorphous systems largely depend on the type of employed co-former. This study aims to assess the potential for active metabolites of drugs as co-former in drug-drug co-amorphous formulations. Toltrazuril (Tol) was chosen as the model drug, to which ponazuril (Pon) was added as co-former.

Highlights

Drug’s active metabolite was a potential co-former for drug-drug co-amorphous system.

Drug-drug combination with similar chemical structures exhibit homogeneity.

Heterodimer with complementary intermolecular interaction was more stable.

Solid-state stability and crystallization inhibition enhanced spring parachute effect.

Considering the importance of intermolecular interactions in co-amorphous systems, we performed highlighted investigations including molecular dynamics simulation and quantum mechanics calculations. The results indicated that Tol and Pon molecules were connected by N-H···O = C hydrogen bonds in the form of a complementary pairing of amide groups. Further, the solubility/dissolution and solid-state stability of the co-amorphous system were investigated. We found that co-amorphous Tol-Pon was stable for at least one month at 40 °C/75% RH, while amorphous materials underwent recrystallization within 10 days.

Moreover, both drugs in the co-amorphous system exhibited enhanced “spring parachute effect” during the dissolution process. This could be attributed to the noticeably increased solid-state stabilization as well as inhibition of Pon on the crystallization of Tol from a supersaturated state. In general, our study provides some useful information and molecular insights to guide the development of drug-active metabolite-based co-amorphous formulations.

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Article information: Bin Li, Yingyun Wang, Ying Feng, Dan Yuan, Renjie Xu, Cuiping Jiang, Xuecheng Xiao, Shan Lu,
Design and molecular insights of drug-active metabolite based co-amorphous formulation: A case study of toltrazuril-ponazuril co-amorphous, International Journal of Pharmaceutics, Volume 615, 2022. https://doi.org/10.1016/j.ijpharm.2022.121475.