(303b) Strategies to Develop IV Formulations of Poor Water-Soluble Compounds and Their in Vitro Evaluation

Although a drug might be developed and formulated for oral delivery, the same compound is commonly administered as a solution via an IV injection/infusion in order to determine absolute bioavailability to support early development. A common challenge to develop IV formulation is the low solubility of drug candidates, risking phlebitis due to precipitation upon injection. Other parameters that need attention include the pH variation (too high or too low) that can cause irritation, and osmolality differences that may cause significant fluid shifts between the intracellular and extracellular spaces. Thus, the development of a stable and safe IV formulation requires an adequate selection of solubilizers and evaluation of the safety of the solution prior to administration.

In this study, a weak acid drug with poor water-solubility required a minimum of 40-fold increase in aqueous solubility for IV delivery. To achieve increased aqueous solubility, multiple strategies were assessed including screening of solvents and co-solvents, in situ salt, and pH control. Phlebitis risk was evaluated by in vitro static dilution using surrogate plasma and observation of flocculation in rat plasma by optical microscopy. In conclusion, a pH-buffered solution containing in situ sodium salt allowed for up to 133-fold increase in aqueous solubility of the compound showing no risk of precipitation while complying with pH and tonicity requirements for IV administration.