Fasted intestinal solubility limits and distributions applied to the biopharmaceutics and developability...

Area of Science:

• Biopharmaceutical Sciences
• Drug Solubility Analysis
• In Vitro Assays

Background:

• Drug solubility in intestinal fluid is crucial for oral bioavailability and estimating biopharmaceutical parameters.
• Current in vitro methods using fasted human intestinal fluid (HIF) or simulated intestinal fluid (SIF) provide single solubility values, limiting their predictive power.
• The position of this single value within the fasted intestinal solubility envelope is unknown, hindering comprehensive analysis.

Purpose of the Study:

• To develop and validate a nine-point equilibrium solubility determination method in SIF for a wider range of drugs.
• To assess if this multi-dimensional approach provides a more accurate representation of intestinal drug solubility compared to single-point measurements.
• To evaluate the utility of the determined solubility envelope for risk-based biopharmaceutical calculations and quality by design.

Main Methods:

• A nine-point fasted equilibrium solubility determination was performed in SIF for seven model drugs.
• The method was based on a multi-dimensional analysis of fasted human intestinal fluid composition.
• Solubility data was analyzed and plotted using the developability classification system to assess drug behavior and dose/solubility ratios.

Main Results:

• The nine-point method generated a solubility envelope encompassing literature values in both HIF and SIF, confirming its validity.
• Three drugs exhibited narrow solubility ranges, a feature missed by single-point methods.
• The lowest solubility values from the envelope proved useful for worst-case scenario risk-based biopharmaceutical calculations.

Conclusions:

• The novel multi-dimensional approach provides greater in vitro detail on drug solubility behavior.
• This method enhances the ability to apply risk-based analysis to biopharmaceutical performance and drug development.
• Further studies are needed to expand the drug range and correlate in vitro findings with in vivo outcomes.