Topography of Simulated Intestinal Equilibrium Solubility

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Physical Chemistry
• Formulation Science

Background:

• Oral drug absorption depends on dissolution in the gastrointestinal tract, which is influenced by intestinal fluid properties like pH and amphiphile content.
• Simulated intestinal fluids are used to model this behavior, but a comprehensive understanding of factor interactions is lacking.

Purpose of the Study:

• To investigate the topographical and statistical overview of drug solubility in simulated intestinal fluids.
• To analyze the impact of pH, total amphiphile concentration, and specific amphiphiles (bile salt, phospholipid, oleate, monoglyceride) on the solubility of acidic, basic, and neutral drugs.
• To identify complex factor interactions affecting drug solubility and variability.

Main Methods:

• Utilized a four-component mixture design (4CMD) across three pH values and three total amphiphile concentrations.
• Studied three model drugs: indomethacin (acidic), carvedilol (basic), and fenofibrate (neutral).
• Measured equilibrium solubility and analyzed topographical and statistical effects of individual amphiphiles and their interactions.

Main Results:

• Drug solubility generally increased with higher pH and total amphiphile concentration.
• Each drug exhibited unique solubility topographies influenced by amphiphile type and concentration.
• Identified significant three- and four-way interactions between bile salt, phospholipid, pH, and total amphiphile concentration.
• Solubility variability was minimized in systems containing all four amphiphiles.

Conclusions:

• The four-component mixture design provides a novel overview of intestinal solubility topography and factor impacts.
• The study highlights the critical role of amphiphile composition and interactions in determining drug solubility.
• Results can inform the development of intestinal solubility windows for physiologically based pharmacokinetic (PBPK) modeling.