An Enabling Formulation of a Weakly Basic Compound Guided by Physiologically Based Biopharmaceutics Modeling (PBBM).

Area of Science:

• Pharmaceutical Sciences
• Biopharmaceutics
• Drug Delivery

Background:

• Weakly basic compounds risk precipitation in the intestine, reducing drug absorption and plasma exposure.
• This precipitation poses challenges for dose escalation in early clinical trials.
• In vitro studies and computational models assess and mitigate these biopharmaceutical risks.

Purpose of the Study:

• To guide formulation development and select excipients for a weakly basic compound.
• To minimize risks of poor intestinal absorption at higher doses.
• To reduce the time and effort in selecting enabling formulation excipients.

Main Methods:

• Utilized parameter sensitivity analysis and pH shift precipitation studies.
• Employed computational models to simulate drug behavior.
• Screened acidic excipients and polymers for supersaturation and precipitation retardation.

Main Results:

• Gastric pH and precipitation time significantly impact drug absorption, controllable via formulation.
• Particle size and gastric residence time showed minimal effect on absorption.
• Hydroxypropyl methylcellulose acetate succinate (HPMCAS) and para-toluene sulfonic acid were identified as optimal excipients.

Conclusions:

• Integrating in vitro testing with computational modeling accelerates excipient selection for challenging formulations.
• Formulation approaches can effectively manage supersaturation and control precipitation for improved drug absorption.
• This integrated approach is valuable for optimizing drug delivery of weakly basic compounds.