Improving Solubility of Poorly Soluble Abiraterone Acetate by Cocrystal Design Aided by In Silico Screening

摘要

Abiraterone acetate (ABI) is a BCS class IV (low solubility and low permeability) drug, and it was approved by the US FDA with brand name Zytiga in April 2011 for patients suffering from metastatic castration-resistant prostate cancer (mCRPC). ABI is administered orally at a high dosage of 1 g/day (four 250 mg tablets) and has an issue of poor solubility. The combination of high dose and poor aqueous solubility/dissolution properties make the compound a candidate for salt/cocrystal work. To date, there are no reports on solid-state modification (salts/cocrystals) of ABI using a crystal engineering approach. In this regard, we applied an in silico (COSMOtherm-X) method, as well as Delta pK(a) index, to identify suitable GRAS coformers (generally regarded as safe coformers approved by the US FDA) to form cocrystals with abiraterone acetate (ABI), which is used as a model drug compound in this study. Solvent assisted cogrinding and crystallization of abiraterone acetate (ABI) with high solubility coformers resulted in four cocrystals with succinic acid (SA), glutaric acid (GA), 4-hydroxy benzoic acid (4HBA), and 3,5-dihydroxy benzoic acid (35DHBA). The parent drug ABI and cocrystals ABI-SA (2:1), ABI-GA (1:1), ABI-4HBA (1:1), and ABI-35DHBA (1:1) were characterized using various techniques. Diffraction quality single crystals could be grown for cocrystals ABI-GA (1:1) and ABI-4HBA (1:1) for structure determination, while solid phase purity for the other two cocrystals was proven with powder indexing analysis using material studio. Incidentally, ABI-GA (1:1) forms a supercell (Z = 12 and Z' = 6). Moreover, it shows a highest dissolution rate of 31-fold as compared with the parent ABI (120 min interval) at pH 1.2 buffer conditions. Investigation of ABI-GA (1:1) high dissolution rate as compared with other cocrystals, stability studies (forced degradation), and reasons for supercell formation (ABI-GA (1:1)) are also discussed in detail.