Category: Formulation and Quality
Purpose: Particle size distribution (PSD) is a critical quality attribute of ophthalmic suspensions as it can affect not only the dose uniformity, physical stability, and dissolution properties of the product, but may also affect bioavailability and impact the determination of bioequivalence. To measure the PSD in ophthalmic suspensions, laser diffraction (LD) is the most commonly used particle sizing technique, as most of the commercial products exhibit size in the range of few hundred nanometers to a few microns. However, presence of heterogeneous polymeric excipients can interfere with the PSD analysis and lead to potentially erroneous interpretation of the results. Using two case studies (loteprednol and brinzolamide ophthalmic suspensions), we intend to demonstrate the challenges and nontypical solutions to eliminate the material influences to allow accurate and precise measurement of the PSD in ophthalmic suspensions.
Methods: Commercially available loteprednol and brinzolamide ophthalmic suspensions were used as model systems, as both products contain similar polyacrylic acid polymers (e.g., carbomer or polycarbophil). The impact of polymer on the LD measurement results was determined using one factor at a time experimental design approach whereas NIST traceable size standards were used as a reference. A Malvern Mastersizer 3000 equipped with a MV dispersion unit was used to measure sample PSD based on diffraction of both red and blue laser lights. Particle free water or a saturated solution of loteprednol or brinzolamide was used as a dispersant. Samples were dispersed using the built-in stirrer along with an external bath sonicator or the in situ sonicator. Image-based particle size analysis using polarized light microscopy (Olympus BX51) coupled with ImageJ software was used as an orthogonal technique to check the suitability of the developed method.
Results: Polyacrylic acid polymer, a viscosity enhancer, was found to interfere with the PSD analysis using LD technique. The diffraction pattern of polyacrylic acid was similar with that of particles, in the range of micrometers to hundred micrometers (Figure 1). Additionally, sodium chloride, a tonicity adjustor, exhibited an indirect influence on the measurement which reduced the size of the polyacrylic acid to that of suspension particles (Figure 2). As a result, the signal of the drug on the PSD histogram overlapped with or superimposed on that of the excipient, leading to false interpretation of particle size results. For the brinzolamide suspension, in addition to the impact of polyacrylic acid, the API dissolution during the measurement was found to result in underestimation of the particle size. A total background subtraction approach was developed to eliminate the interference of the excipients whereas a laser diffraction pattern of placebo dispersion was used as a background. Furthermore, for brinzolamide suspension, a saturated solution of API at fixed pH was used as a dispersant to prevent API particles from dissolving during the measurement.
Conclusion: The newly developed LD method successfully eliminated the interference of excipients, and thus allowed more reliable measurement of the PSD in ophthalmic suspensions. A similar strategy can also be applied to other heterogeneous dispersed systems where the excipients interferences could be of concern.
Disclaimer: This article reflects the views of the authors and should not be construed to represent FDA’s views or policies.
Anh Vo– Silver Spring, Maryland
Xin Feng– Staff Fellow, US Food and Drug Administration, Silver Spring, Maryland
Darby Kozak– Chemist (Lead), Untied States Food and Drug Administration, Silver Spring, Maryland
Yan Wang– Staff Fellow, United States Food and Drug Administration, Silver Spring, Maryland
Stephanie Choi– Chemist, US Food and Drug Administration, Silver Spring, Maryland