Quality by design approach for the preparation of fat-soluble vitamins lipid injectable emulsion.

Abstract

The fat-soluble vitamins lipid injectable emulsion, a parenteral supplement, commonly used for hospitalized patients to meet daily requirements of fat-soluble vitamins. This study attempts to reduce risk, improve the stability and safety of fat-soluble vitamins lipid injectable emulsion using a Quality by Design (QbD) approach. The quality target product profile and critical quality attributes were defined based on a comprehensive understanding of fat-soluble vitamins lipid injectable emulsions. The emulsions were prepared using a high-pressure homogenization method. Critical quality attributes (CQAs) were identified using risk assessment tools such as fishbone diagram and risk estimation matrix. The assay, mean droplet size, polydispersity index, zeta potential, and the volume-weighted percentage of fat greater than 5 μm (PFAT5) were identified as CQAs. Accordingly, three critical formulation and process parameters for the emulsions were the percentage of emulsifier, homogenization pressure, and homogenization recirculation. The design space was obtained via a design of experiment (DoE), and an optimum formulation was successfully prepared. All physicochemical attributes of the optimal formulation were within the design space (i.e., droplet size: 217.2 ± 0.37 nm; polydispersity index: 0.115 ± 0.012; PFAT5: less than 0.05%; zeta potential: -34.6 ± 1.09 mV; and viscosity: 20.95 mPa at 0.1 s-1). The optimal formulation remained acceptable physicochemical stability at 25 ± 2 °C/60% RH ± 5% RH over a 12-month period. Safety of the optimal emulsion was evaluated as acceptable through the determination of lysophospholipid content and an in vitro hemolysis assay. In conclusion, an optimal lipid injectable emulsion for fat-soluble vitamins was successfully prepared using a QbD approach.