2023 FDA Science Forum
Understanding Formulation Processes and Implications for Dosage Form Determination of Phytonadione Injectables
- Authors:
- Center:
-
Contributing OfficeCenter for Drug Evaluation and Research
Abstract
Phytonadione injection contains an oil-like immiscible drug substance, which is mixed with surfactant, then further dispersed in an aqueous phase. The Orange Book, product labeling, and USP monograph designated the dosage form of phytonadione injection using terminologies which represent subtly different dispersion states (injection, aqueous colloidal solution, and emulsion, respectively). Consequently, a lack of clarity about the dosage form(s) presented significant regulatory challenges, including the determination of appropriate characterizations and criteria for assessing product equivalence. To address these challenges, FDA conducted a study to compare how different sources of surfactant and manufacturing processes impact the formulation dispersion state, the particle size distribution (PSD), and the determination of the product’s dosage form. To help address these questions, critical formulation characteristics such as critical micelle concentration (CMC), micelle and formulation PSD, and processing behavior during the formulation procedure, were investigated using a combination of analytical techniques: dynamic light scattering (DLS), advanced separations like asymmetrical flow field-flow fractionation (AF4) with online multiangle light scattering (MALS) and DLS, and surface tension measurements. Low energy preparation processes (i.e., slow stirring at room temperature) readily produced a transparent homogeneous dispersion. Further investigation on the manufacturing process and formulation composition (surfactant to oil ratio, etc.) indicated that both can affect the initial intermediary dispersion state of the formulation (e.g., producing macro-, nano-, or micro- emulsions). These dispersion state variations represent transient states for the system, which are limited by kinetic constraints like surfactant lability. Given enough time and energy (thermal or mechanical) the phytonadione injection formulations reverted to the most energetically favored microemulsion dispersion state. Additional stability studies with varied storage duration and temperature further confirmed the phytonadione injection is a thermodynamically stabilized system, as opposed to a kinetically stabilized system. Lastly, a novel interface directed pseudo-ternary phase diagram was constructed to elucidate the role of interfacial areas (e.g., via changes in manufacturing processes) on the dispersion states, which helped to explain the difference in the initial dispersion states of phytonadione formulations caused by switching the order of mixing continuous and dispersed phases.
