Over the past decade, an increasing trend in weak base oral drug candidates has been observed. Their pH-dependent solubility often translates to lower oral bioavailability and poor clinical outcomes, especially in patients on treatment with acid reducing agents (ARAs), e.g., proton-pump inhibitors (PPI) that increase stomach pH. Traditional approaches to mitigate pH-dependent solubility challenges for weak bases are to enhance solubility with amorphous solid dispersion, utilize a co-crystal/salt form of the compound, or leverage a modified release formulation. In this study, an alternative approach, termed “enhanced conventional,” was investigated to solve the bioavailability challenge of weak base oral drug candidates under PPI conditions. This approach was demonstrated with the model Compound A, a BCS Class II weak base small molecule drug. An acidifier and an anti-nucleation polymer, selected through a high throughput screening method and excipient compatibility studies, were blended together with the crystal form of the weak base and other excipients to form the enhanced conventional formulation, which was compressed into tablets by direct compression. The enhanced conventional tablets were characterized for formulation properties, evaluated in disintegration test, PPI dissolution and physiological-based pharmacokinetic modeling and simulation (PBPK) modeling to assess and predict their bioperformance in vivo. Solid dispersion-based tablets were prepared as reference formulation. Ranging of acid and polymer levels in the formulation illustrated that acid amount is critical to enhance the dissolution performance by reducing local pH and the amount of acid needed varies by the buffer strength in dissolution studies. The polymer serves to extend supersaturation of the API at the higher pHs that would be seen in the upper intestines. PPI dissolution and modeling demonstrated that the enhanced conventional formulation has the potential to achieve even higher Cmax and %Fa (bioavailability) relative to the amorphous solid dispersion-based tablets, and stronger PPI mitigation capability with reduced developmental effort and cost. Based on the study results, it was concluded that enhanced conventional formulations may provide a promising route to address the bioavailability challenges commonly observed for weak base formulations, particularly in overcoming the PPI effect typically seen in elderly patient populations under ARA treatments.
Learning Objectives:
Upon completion, participant will be able to understand deeply of the challenges faced with oral formulation development of poorly soluble weak base drug molecules and the impact on patient access.
Upon completion, participants will learn what are the commonly used formulation approaches to address the bioavailability challenges of weak bases for patients, especially those on ARA treatments
Upon completion, participants will learn novel approaches of weak base crystalline formulation that can solve the bioavailibility challenge and mitigate ARA risks with reduced development effort and cost.
