Analyzing ophthalmic suspension particle size distributions using laser diffraction: Placebo background subtraction method.

The current study demonstrated that the presence of excipients can interfere with the measurement of particle size distribution (PSD), a critical quality attribute of ophthalmic suspensions, by laser diffraction (LD) and that a placebo background subtraction approach can eliminate the impact of excipients on the PSD measurement. Commercially available loteprednol etabonate and brinzolamide ophthalmic suspensions were used as model suspensions. The impact of excipients in these formulations on the LD measurements was determined using a one-factor-at-a-time experimental design approach, using National Institute of Standards and Technology (NIST) traceable polystyrene particle size standards as references. Among the evaluated excipients, polymers containing polyacrylic acid were found to interfere with the PSD analysis by creating the LD signals correspond to particles ranging from a few micrometers to a hundred micrometers in size. As a result, the measured PSD of active pharmaceutical ingredient (API) particles in the formulation overlapped with or superimposed on the excipient PSD signal, leading to erroneous interpretation of the API particle size. Additionally, dispersion of brinzolamide particles in unsaturated solutions led to rapid dissolution of brinzolamide particles during the measurement, resulting in underestimation of the particle size range. Here, a placebo background subtraction approach was developed to eliminate the interference of the excipients. This newly developed LD method was also evaluated using orthogonal methods, including polarized light microscopy and scanning electron microscopy (SEM). The strategy used in this study to eliminate the interference of excipients may also be useful for other heterogeneous dispersions where excipient interference may be of concern.