IriSys was challenged to develop an intravenous formulation of a neutral, poorly water soluble compound at a high dose. IriSys was requested to improve an existing cyclodextrin-drug formulation where a 30% cyclodextrin component provided the high dose concentration requirement. However, there was concern about the toxicity of the high percentage of cyclodextrin increasing potential for a regulatory approval delay. A backup formulation without cyclodextrin and based on surfactants and organic co-solvents was developed. IriSys performed a multivariate solubility and compatibility study in which the variables were co-solvent type, co-solvent concentration, surfactant type, and surfactant concentration. Binary, ternary, and quaternary systems were studied and prototype formulations prepared that were subsequently tested for solubility, pH value, osmolality, and chemical stability. During the study it became apparent that process parameters influenced solubility and stability. These were studied and modified, as appropriate. IriSys successfully eliminated the cyclodextrin from the formulation and was able to increase the drug concentration by 100%.

IriSys was requested to develop a hard gelatin liquid-filled capsule formulation to reduce intersubject bioavailability variability of a poorly water soluble, high dose compound.  Preformulation studies were performed.  Based on the physical chemical characteristics of the compound, excipient compatibility studies were conducted.  A saturation solubility study in lipophilic excipients showed that there were no individual solvents that provided sufficient solubility or that were compatible with hard gelatin capsules.  The study was expanded to include binary and ternary excipient systems that would provide adequate solubility and be compatible with hard gelatin capsules.  A formulation was selected and studied for stability.  The final formulation of the hard gelatin liquid-filled capsule was stable and over time demonstrated compatibility with the non-active components.  Dissolution testing showed complete release in 30 minutes.