Purpose: Appropriate and adequate physicochemical characterization of complex formulations is crucial to ensure product sameness of a generic product to a reference listed drug (RLD). This is particularly important if the product with a complex formulation has complex structures that are sensitive to manufacturing process changes. The current analytical techniques cover rather well on particle size, particle concentration, or in vitro drug release. However, limited information is available on existence of the morphological variations in a complex formulation, and more importantly the impact of morphology changes on product performance. Our previous work on propofol emulsions revealed some unique structures in the products, such as hybrid structures of oil droplets connected with lipid vesicles. The current investigation focused on understanding the impact of manufacturing process on changes in the relative percentage of various structures.
Methods: In-house manufacturing of propofol emulsions involves two-step processing: The generation of a coarse emulsion, followed by homogenization using a microfluidizer. The course emulsion was prepared by mixing the oil phase with the aqueous phase at various mixing speeds (500 and 1000 rpm) and temperatures (55, 65 and 75°C). The coarse emulsion was then subjected to microfluidization to reduce the particle size. During this step, various combinations of microfluidization pressures (10K, 20K and 30K psi) and temperatures (10, 20, and 30°C) were evaluated. Particle size and particle concentration were measured by dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA), respectively. Cryogenic transmission electron microscopy (cryo-TEM) was used to confirm particle size and determine particle morphology.
Results: Three distinct structures were found in propofol emulsions: Oil droplets, liposomes, and hybrid structures (oil droplets connected to liposomes) (Fig. 1A). A higher mixing speed (1000 rpm vs. 500 rpm) at the coarse emulsion stage led to the formation of smaller particles. However, mixing speed did not alter the relative percentage of the three structures or particle concentration. Higher temperature during both the coarse emulsion mixing and the microfluidization step yielded smaller particles, while neither led to substantial change in particle concentration. The microfluidization pressure (10K-30K psi) had a significant impact on both particle size and the relative percentage of various structures (Fig. 1B), with a higher pressure resulting in less percentage of liposome structures.
Conclusion: Manufacturing process parameters were found to have marked effects on the particle size, concentration and morphology of propofol emulsions. Measurement on particle size and concentration using DLS and NTA did not capture the changing populations of morphological variants. Only cryo-TEM could discern the particle morphology and the relative ratio of different structures such as oil droplets and lipid vesicles, in response to process changes. It is currently unclear whether process-induced morphological changes impact the drug distribution in the various structures in the formulation and whether such changes also influence the drug release. Further studies are needed to understand the impact of structural variations on the drug release characteristics of this complex formulation.
Wenchun Feng
– ORISE Fellow, US Food and Drug Administration, Silver SpringWenchun Feng
– ORISE Fellow, US Food and Drug Administration, Silver SpringYong Wu
– ORISE Fellow, US Food and Drug AdministrationLynn Chen
– ORISE Fellow, US Food and Drug AdministrationHaiou Qu
– ORISE Fellow, US Food and Drug Administration, MarylandDeval Patel
– ORISE Fellow, US Food and Drug Administration, MarylandXiaoming Xu
– Senior Staff Fellow, U. S. Food and Drug AdministrationStephanie Choi
– Chemist, US Food and Drug Administration, MarylandJiwen Zheng
– Chemist, US Food and Drug AdministrationJiwen Zheng
– Chemist, US Food and Drug AdministrationWenchun Feng
– ORISE Fellow, US Food and Drug Administration, Silver Spring378 Views