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

Area of Science:

• Pharmaceutical Sciences
• Drug Delivery
• Formulation Development

Background:

• Improving oral bioavailability of poorly water-soluble compounds is crucial in drug development.
• Chemical stability challenges can be overlooked during formulation technology screening.
• A balanced approach considering both pharmacokinetics and stability is essential for successful drug formulation.

Purpose of the Study:

• To evaluate formulation enabling technologies for enhancing the bioavailability of a poorly water-soluble, weakly basic compound.
• To assess the chemical stability of different formulation approaches alongside their pharmacokinetic performance.
• To identify optimal strategies for overcoming bioavailability and stability issues in drug formulation.

Main Methods:

• Initial screening included pH modification, lipid-based formulation (LBF), and amorphous solid dispersion (ASD).
• Pharmacokinetic (PK) performance and stability were assessed in dogs.
• Further evaluation involved nanosizing and cyclodextrin complexation, with stability studies under accelerated conditions (40°C/75%RH).

Main Results:

• pH modification showed no PK improvement.
• LBF and ASD increased AUC0-24 by 40-50% but exhibited significant chemical degradation (>25% for LBF).
• Nanosizing and cyclodextrin complexation yielded >2-fold increases in Cmax and AUC0-24 with excellent chemical stability.

Conclusions:

• While LBF and ASD enhance PK exposure, their chemical instability limits their application.
• Nanosizing and cyclodextrin complexation offer superior bioavailability enhancement and robust chemical stability.
• Simultaneous optimization of drug exposure and chemical stability is critical for effective formulation development.