Diffusion and Flux Improvement of Drugs through Complexation.

Area of Science:

• Crystal engineering
• Supramolecular chemistry
• Pharmaceutical sciences

Background:

• Improving drug solubility and permeability is crucial for developing effective medicines, especially for Biopharmaceutics Classification System (BCS) class IV drugs.
• Cocrystallization and salt formation are key strategies in crystal engineering to enhance drug bioavailability.
• Recent research focuses on pharmaceutical cocrystals and salts to overcome permeability challenges.

Purpose of the Study:

• To review the fundamentals of drug permeability mechanisms.
• To present examples of pharmaceutical cocrystals and salts designed to enhance drug diffusion and permeability.
• To understand structural factors modulating drug flux and transport across semipermeable membranes.

Main Methods:

• Review of existing literature on pharmaceutical cocrystals and salts.
• Analysis of approximately 50 examples of drug cocrystals/salts.
• Examination of drug flux and transport across semipermeable membranes.
• Evaluation of transepithelial electrical resistance (TEER) values.

Main Results:

• Two primary phenomena enhance drug permeability: survival of hydrogen-bonded heterosynthons leading to supersaturation and higher drug flux, and coformers/cocrystals reducing transepithelial electrical resistance (TEER) by impairing lipid monolayer tight junctions.
• These mechanisms facilitate drug passage and improve diffusion/permeability.
• The principles can guide the de novo design of high-permeability coformers.

Conclusions:

• Pharmaceutical cocrystals and salts enhance drug solubility and permeability without altering the drug's molecular structure.
• These supramolecular complexes address the poor bioavailability challenge for BCS class II and IV drugs.
• The findings support the use of cocrystallization for developing high-bioavailability medicines.