Mitigating chemical degradation in amorphous and lipid-based formulations through cyclodextrin complexation and...

To evaluate formulation enabling technologies for improving bioavailability of a poorly water-soluble, weakly basic compound with inherent chemical stability challenges.

While exposure enhancement is a key objective in developing poorly soluble compounds, chemical stability liabilities may be overlooked during technology screening. A balanced assessment of pharmacokinetics (bioavailability) and stability is critical for successful formulation development.

Initial screening evaluated pH modification, lipid-based formulation (LBF), and amorphous solid dispersion (ASD) technologies. Stability and pharmacokinetic (PK) performance were assessed in dogs and compared with conventional crystalline formulation. Due to chemical stability challenges, additional technology screening using nanosizing and cyclodextrin complexation was conducted. Chemical stability studies were performed under accelerated conditions (40 °C/75%RH).

The pH-modified formulation showed no PK improvement. LBF and ASD provided a 40-50% increase in AUC_0-24, indicating enhanced exposure in the amorphous state. However, all three approaches exhibited chemical degradation, with LBF showing >25% degradation after 3 weeks at 40 °C/75%RH. The addition of antioxidants did not improve stability. Nanosizing and cyclodextrin complexation resulted in >2-fold increases in C_max and AUC_0-24. Importantly, both approaches demonstrated excellent chemical stability under accelerated conditions.

Although LBF and ASD improved PK exposure, chemical instability limited their suitability. Nanosizing and cyclodextrin complexation provided superior bioavailability enhancement with robust stability, highlighting the importance of simultaneously optimizing exposure and chemical stability during formulation development.