(T1130-06-34) Impact of Formulation Processes on Dosage Form Determination of Phytonadione Injectables

Purpose: 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 label, and USP monograph designated the dosage form of phytonadione injection using subtly different terminologies (injection, aqueous colloidal solution, and emulsion, respectively). Consequently, difference in dosage form necessitates different characterization and criteria for demonstrating equivalence. The objectives of this study were to compare how different sources of polyethylene glycol (PEG)-n castor oil (surfactant) and manufacturing processes give rise to similarities/differences in key excipient properties and to determine the dosage form of the product.

Methods: The impact of manufacturing process conditions (e.g., stir rate, shear, mixing equipment, directionality) on formulation dispersion state and particle size distribution (PSD) were examined. PSD of formulations were measured by batch mode dynamic light scattering (DLS) (Wyatt Technology, DynaPro Plate Reader II) and compared to PSD as determined by asymmetrical flow field-flow fractionation with online multiangle light scattering and DLS (Wyatt Technology, Eclipse). A commercially available phytonadione injection product was used for PSD comparison. Three different PEG-n castor oil surfactants were used for formulation comparison (n = 30, 35, and 40). In addition, the surface tension and critical micelle concentrations (CMC) for these surfactants were determined by pendant drop analysis using a drop-shape analyzer (Kruss Scientific, DSA-100). Particle-free water and phosphate buffered saline were used as dispersants.

Results: The CMCs of three PEG-n castor oils (n=30, 35, and 40) were determined to be in the same range (approximately 1 mg/mL) with no significant difference (p >0.05). For all three PEG-n castor oils, although low energy preparation process (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). Notably, both appearance (turbidity) and more quantitatively PSD were found to be useful surrogates for distinguishing nanoemulsions (broad PSD, turbid) and microemulsions (monodispersed PSD, translucent) (Figure 1). Additional stability studies with varied storage duration and temperature further confirmed the phytonadione dispersion is ultimately 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 (Figure 2), 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.

Conclusion: The three PEG-n castor oils (n=30, 35, and 40) have similar properties and can be considered qualitatively similar. For the formulation composition of phytonadione injection investigated in the current study, varying processing conditions produced a spectrum of dispersion states at the initial phase. 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 will revert to the most energetically favored microemulsion dispersion state.

Acknowledgements: Drs. Smith and Liu were supported in part by the Oak Ridge Association of Universities (ORAU) and the Oak Ridge Institute of Science and Education (ORISE), through an agreement between the U.S. Department of Energy and the U.S. FDA.
Disclaimer: This abstract reflects the views of the authors and should not be construed to represent FDA’s views or policies.


Figure 1. Particle sizes for four formulations (at initial stage) of identical compositions (molar ratio of surfactant to oil phase) produced using various mixing strategies (stir bar at 300 and 600 rpm or homogenizer at 3000 rpm) and mixing directionality either dispersed phase into continuous phase (O2A, green) or continuous phase into dispersed phase (A2O, orange), and respective images for the formulations.


Figure 2. a) Pseudo-ternary phase diagram for two formulations of identical compositions exhibiting different initial dispersion states (microemulsion -left- and nanoemulsion -right-) based on mixing directionality, with representative image. b) A 2-dimensional projection of interface-directed pseudo-ternary phase diagram at a fixed surfactant to oil ratio (W: water, O: oil, PIC: phase inversion composition).