Absorption-excipient-pH classification gradient maps: sparingly soluble drugs and the pH partition hypothesis

Area of Science:

• Pharmaceutical Sciences
• Drug Delivery
• Physical Chemistry

Background:

• Sparingly soluble drugs often exhibit poor oral absorption due to factors like pH and aqueous boundary layers.
• Excipients are commonly used to enhance drug solubility and bioavailability.
• Understanding the complex interplay between drug properties, excipients, and absorption is crucial for drug development.

Purpose of the Study:

• To investigate the impact of pH and aqueous boundary layers on drug absorption.
• To evaluate the efficacy of single excipients in mitigating absorption challenges for sparingly soluble drugs.
• To apply a novel visualization tool for high-throughput screening of excipient-drug interactions.

Main Methods:

• Measured drug solubility and artificial-membrane permeability (PAMPA) across different pH values.
• Incorporated factors like aqueous boundary layer resistance and drug aggregation into a flux function.
• Utilized a self-organized data visualization tool to identify promising excipient-drug combinations.

Main Results:

• Most drugs formed aggregates in excipient-free solutions.
• Excipients generally increased solubility more than they decreased permeability.
• Clotrimazole, griseofulvin, and progesterone showed the most significant absorption improvement with excipients.
• Hydroxypropyl-beta-cyclodextrin (HP-beta-CD) effects aligned with pharmacokinetic Cmax trends for certain drugs.

Conclusions:

• The classical pH Partition Hypothesis can be inverted for sparingly soluble compounds.
• A novel visualization tool effectively identifies beneficial excipient-drug combinations for enhanced absorption.
• Excipient selection is critical for optimizing the absorption potential of poorly soluble drugs.