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The investigation of semisolid ophthalmic ointments is challenging due to their complex physicochemical properties and the unique anatomy of the human eye. Using Lotemax as a model ophthalmic ointment, three different manufacturing processes and two excipient sources (Fisher (OWP) and Fougera (NWP)) were used to prepare loteprednol etabonate ointments that were qualitatively and quantitatively the same across the manufactured formulations. Physicochemical properties including drug content and uniformity, particle size and distribution, as well as rheological parameters (onset point, crossover modulus, storage modulus and Power law consistency index) were investigated. In addition, USP apparatus 2 with enhancer cells was utilized to study the in vitro drug release characteristics of the ophthalmic ointments. Both manufacturing processes and excipient sources had a significant influence on the physicochemical attributes and the in vitro drug release profiles of the prepared ointments. Ointments prepared via the hot melt processes exhibited higher rheological parameters and lower drug release rates compared to ointments prepared without hot melting. Ointments prepared with OWP demonstrated higher rheological parameters and lower in vitro drug release rates compared to ointments prepared with NWP. A strong correlation between the rheological parameters and in vitro drug release rate was shown using logarithmic linear regression. This correlation may be useful in predicting in vitro drug release from measured physicochemical properties, and identifying the critical quality attributes during the development of ointment formulations.

It is essential as well as challenging to develop a reliable in vitro release testing method for determining whether differences in release profiles exist between qualitatively and quantitatively equivalent ophthalmic ointment formulations. There is a lack of regulatory guidance on in vitro release testing methods for ophthalmic formulations. Three different in vitro release testing methods 1) USP apparatus 4 with semisolid adapters; 2) USP apparatus 2 with enhancer cells; and 3) Franz diffusion cells were investigated. Qualitatively and quantitatively equivalent ointments were prepared via hot melting and simple mixing methods using four different sources of excipients (i.e. white petrolatum). The ointment formulations were characterized for content uniformity, particle size, and rheological parameters. All the formulations showed adequate content uniformity and similar particle size. The ointments prepared via the hot melting processes showed higher rheological parameters, as did the ointments prepared using 'white' petrolatum that exhibited a yellowish color. The three in vitro release testing methods were compared and evaluated for reproducibility, discriminatory capability, and correlation with the rheological parameters. Compared with the compendial methods, the non-compendial method (Franz diffusion cells) showed poorer reproducibility. All three methods possessed the ability to discriminate between the ophthalmic ointments with manufacturing differences. However, the USP apparatus 4 method displayed the largest margin of discrimination between the release profiles of the different ophthalmic ointments. In addition, the in vitro release rate obtained using the USP apparatus 4 method showed the strongest logarithmic linear correlation with the rheological parameters (Power law consistency index (K value) and crossover modulus) compared to the other two methods.

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