The Effect of Drug Loading on the Properties of Abiraterone–Hydroxypropyl Beta Cyclodextrin Solid Dispersions Processed by Solvent Free KinetiSol® Technology

Abiraterone is a poorly water-soluble drug used in the treatment of prostate cancer. In our previous study, we reported that KinetiSol® processed solid dispersions (KSDs) based on hydroxypropyl β-cyclodextrin (HPBCD) showed improved dissolution and pharmacokinetics of abiraterone. However, the nature of abiraterone-HPBCD interaction within the KSDs or the effect of drug loading on the physicochemical properties and in vivo performance of HPBCD-based KSDs remain largely unknown.

Highlights

10 to 50% drug loaded KinetiSol® processed solid dispersions (KSDs) were developed.

KinetiSol, solvent free technology formed abiraterone-HPBCD complexes within KSDs.

As drug loading increased, the in-vitro and in-vivo performance of KSDs decreased.

10% drug loading was optimal, showing a dissolution enhancement of 15.7-fold.

10% drug loaded KSD, enhanced abiraterone bioavailability by 3.9-fold over Zytiga.

We hypothesize that KinetiSol technology can prepare abiraterone-HPBCD complexes within KSDs and that increasing the drug loading beyond an optimal point reduces the in vitro and in vivo performance of these KSDs. To confirm our hypothesis, we developed KSDs with 10–50% w/w drug loading and analyzed them using X-ray diffractometry and modulated differential scanning calorimetry. We found that KSDs containing 10–30% drug were amorphous. Interestingly, two-dimensional solid-state nuclear magnetic resonance and Raman spectroscopy indicated that the abiraterone-HPBCD complexes were formed. At elevated temperatures, the 10% and 20% drug-loaded KSDs were physically stable, while the 30% drug-loaded KSD showed recrystallization of abiraterone. In vitro dissolution and in vivo pharmacokinetic performances improved as the drug loading decreased; we attribute this to increased noncovalent interactions between abiraterone and HPBCD at lower drug loadings.

Overall, the 10% drug loaded KSD showed a dissolution enhancement of 15.7-fold compared to crystalline abiraterone, and bioavailability enhancement of 3.9-fold compared to the commercial abiraterone acetate tablet Zytiga®. This study is first to confirm that KinetiSol, a high-energy, solvent-free technology, is capable of forming abiraterone-HPBCD complexes. Furthermore, in terms of in vitro and in vivo performance, a 10% drug load is optimal.

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Article information: Urvi H. Gala, Dave A. Miller, Yongchao Su, Angela Spangenberg, Robert O. Bill Williams. The Effect of Drug Loading on the Properties of Abiraterone–Hydroxypropyl Beta Cyclodextrin Solid Dispersions Processed by Solvent Free KinetiSol® Technology, European Journal of Pharmaceutics and Biopharmaceutics, 2021. https://doi.org/10.1016/j.ejpb.2021.05.001.