Improving the dissolution behaviors and bioavailability of abiraterone acetate via multicomponent crystal forms

Abstract

Abiraterone acetate (ABA), the first-line drug for the treatment of metastatic castration resistant prostate cancer (mCRPC), is administered at a high daily dosage of 1000 mg due to its poor solubility, and its fasted absolute oral bioavailability is estimated to be less than 10%. In this work we have focused on developing multicomponent forms with improved dissolution behaviors and bioavailability. Two salts of ABA with malonic acid (ABA-MA) and saccharin (ABA-SAC), and five cocrystals with trans-aconitic acid (ABA-TAA), 1-hydroxy-2-naphthoic acid (ABA-1HNA), pyrocatechol (ABA-PCA), resorcinol (ABA-RES) and hydroquinone (ABA-HDE) were successfully obtained. Their crystal structures were elucidated by single crystal X-ray diffraction, and these multicomponent forms were fully characterized by powder X-ray diffraction, thermal analysis and Fourier Transform Infrared spectra. Among them, ABA-TAA cocrystal shows substantial enhancements both in the solubility and intrinsic dissolution rates in different buffer solutions. In the meantime, we unexpectedly found the gelation of ABA-MA salt and ABA-SAC salt in pH 2.0 buffer solution. The gel-like materials generated on the surface of drug will suppress the release of ABA. Moreover, in vivo pharmacokinetic study on beagle dogs was conducted for ABA-TAA cocrystal preparation and ABA commercial product, and ABA-TAA cocrystal preparation shows enhanced absorption. These advantages in dissolution behaviors and bioavailability demonstrate the potential of ABA-TAA cocrystal to be a better candidate for the treatment of mCRPC compared with ABA.

Keywords: Abiraterone acetate; Bioavailability; Cocrystal; Crystal structure; Dissolution.