Cyclosporine ophthalmic emulsions are colloidal oil-in-water dispersions with physicochemical properties that are sensitive to the manufacturing process/conditions. As such, it is critical that these properties, which include globule size distribution (GSD) and rheology, are adequately characterized using appropriate techniques. The adequate characterization of GSD can be used to ensure batch-to-batch product quality consistency and to evaluate generic-to-reference product sameness. The measurement of GSD can be challenging for polydisperse drug products. In addition, the presence of carbomer as a stabilizing agent and viscosity enhancer in the formulation can interfere with the size determination.. Our group developed an asymmetrical-flow field flow fractionation (AF4) method for determining the GSD of polydisperse emulsions. The purpose of this study was two-fold: 1) to further evaluate the developed AF4 method, and 2) to assess the interplay between GSD and formulation viscosity and their dependence on the manufacturing processes. Five formulations, that were qualitatively (Q1) and quantitatively (Q2) the same as the reference listed drug (RLD) (Restasis®) were manufactured. These formulations were generated with variations in the GSD and rheological properties by controlling the process variables, such as homogenization speed, microfluidization pressure, and temperature. The results showed that the microfluidization process was critical in controlling the GSD of the formulation where both higher temperatures and pressures were effective in producing smaller oil-globules. Furthermore, the carbomer was shear sensitive, and the formulation viscosity could be made to be higher, lower, or comparable to the RLD by simply changing the shear conditions. Lastly, the GSD determined by the AF4 method was more robust against changing formulation viscosities, when compared with other sizing techniques like dynamic light scattering. Our study demonstrated that AF4 is useful in assisting with the determination of the impact of manufacturing process on the critical characteristics of cyclosporine ophthalmic emulsions.

Asymmetric flow field flow fractionation to assess the impact of manufacturing process variables on the globule size distribution of cyclosporine ophthalmic emulsions

2019 Spring National Meeting

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