Project summary

The goal of the proposed project is to create a young, multidisciplinary research team capable to promote new solid forms/formulations of the antifungal Ketoconazole (KTZ) active pharmaceutical ingredient (API) with market potential.

Invasive fungal infections (IFIs) are a major cause of morbidity and mortality in premature infants, immuno-compromised patients or in those with acquired immunodeficiency syndrome. Recent estimates suggest that IFIs cause at least as many deaths as malaria and tuberculosis.  Azole antifungal agents are the most important drugs used in clinical treatment of fungal infections, KTZ being the first broad-spectrum oral antifungal Active Pharmaceutical Ingredient (API) approved by U.S. FDA in 1981.

 Ketoconazole is a class II drug, with low solubility and high permeability. It’s very low aqueous solubility, 0.017 mg/mL limits its bioavailability, the drug being eliminated from the gastrointestinal tract before it is completely dissolved, reducing its absorption into the blood circulation. Thus, finding new solid forms/formulations of KTZ with enhanced solubility and bioavailability can be the basis of a better product in order to maximize its therapeutic efficacy.

My research experience in APIs new solid forms development will be expanded with the knowledge about API-PAMAM dendrimer encapsulation, antifungal activity and biocompatibility studies.

For two new co-crystals, KTZ-Adipic Acid and KTZ-Sorbic Acid, with 100 and 40-fold increased solubility compared to commercial KTZ and for an KTZ-PAMAM complex, as APIs in optimized antifungal products with oral/topical administration,  the research team will strengthen their market potential. For the co-crystals we will complete the preliminary preformulation information with specific studies/assessment: compatibility with pharmaceutical excipients, in vitro and in vivo biocompatibility tests, and a protocol for co-crystallization process at grams scale necessary in pharmaceutical industry for developing a successful industrial co-crystallization process.