Ketoconazole-Fumaric Acid Pharmaceutical Cocrystal: From Formulation Design for Bioavailability Improvement to...

Area of Science:

• Pharmaceutical Sciences
• Crystal Engineering
• Drug Delivery

Background:

• Poorly water-soluble drugs like Ketoconazole present formulation challenges.
• Cocrystal formation is a strategy to improve solubility and bioavailability.
• Crystal engineering offers a route to stable solid forms with enhanced properties.

Purpose of the Study:

• To develop a controlled cocrystallization process for a 1:1 Ketoconazole-Fumaric acid cocrystal.
• To evaluate the physicochemical, in vitro, and in vivo performance of the developed cocrystal.
• To investigate the molecular interactions of the cocrystal with its target enzyme.

Main Methods:

• Controlled cocrystallization by cooling using meta-stable zone width determination.
• Laboratory scale-up and characterization using powder X-ray diffraction.
• In vitro biological assays on cell lines, in vivo pharmacokinetic studies in rats, and molecular docking simulations.

Main Results:

• A stable, single-phase 1:1 Ketoconazole-Fumaric acid cocrystal was successfully produced with high yield (up to 90%).
• The cocrystal exhibited improved in vitro efficacy against human dermal fibroblasts and hepatocarcinoma cells.
• In vivo studies showed enhanced oral bioavailability of Ketoconazole from the cocrystal in rats, with no significant liver toxicity or skin sensitization in mice.

Conclusions:

• Cocrystal formation is an effective strategy to enhance the bioavailability and efficacy of Ketoconazole.
• The Fumaric acid coformer improves the binding affinity of Ketoconazole to the target enzyme CYP51.
• This cocrystal formulation represents a promising approach for treating fungal infections caused by poorly soluble drugs.