Toward the Development of an Injectable Dosage Form of Propofol: Preparation and Evaluation of Propofol–Sulfobutyl Ether 7‐β‐Cyclodextrin Complex

Abstract

The objectives of the present study were to undertake activities toward the development of an aqueous‐based formulation of propofol (2,6‐diisopropyl phenol), using sulfobutylether 7‐β‐cyclodextrin (SBECD). Preformulation studies, including high performance liquid chromatography (HPLC) method development and phase‐solubility evaluation in the presence of SBECD were conducted. It was determined that equilibrium solubility has been reached by 4‐day and 7‐day phase‐solubility analysis at 30°C and 37°C. The apparent binding constants and various thermodynamic parameters were calculated from this data. These results suggest that “nonclassical hydrophobic effects” are the driving forces for inclusion complex formation. Compounding and lyophilization of the formulation with 20% SBECD yielded a product with propofol concentration of 10 mg/mL. The formulation properties were probed by using techniques 4‐hat included modulated differential scanning calorimetry (MDSC) and Karl Fischer analysis. MDSC showed that propofol, SBECD, and the Propofol‐SBECD complex displayed thermal properties at widely varying temperatures, suggesting the formation of a new solid form. The active pharmaceutical ingredient in the liquid formulation and lyophilized product was determined by the newly developed and qualified HPLC method. Short‐term stability studies of the liquid formulation showed that they were stable for a month at 4°C. Short‐term stability studies of the freeze‐dried cakes showed that the product was stable for over a month at 4°C, 37°C, and 50°C. Based on these preliminary results, we believe that an aqueous based injectable formulation of propofol with sulfobutylether 7‐β‐cyclodextrin can be successfully developed.