A combined approach for full API particle size distribution characterization in nasal spray suspensions based on...

Determining the particle size distribution (PSD) of the active pharmaceutical ingredient (API) in nasal spray suspensions is a challenging task that usually requires the use of morphologically-directed Raman spectroscopy (MDRS). A dissolution-based modeling strategy was established to characterize the entire PSD of starting API in mometasone furoate nasal sprays using dissolution data of finished formulations, whereas MDRS measures API PSD in the final products. A dissolution-PSD model was built in-house to derive the API PSD from the dissolution data of target products, with model parameters estimated using test products with known raw API PSD and dissolution profiles. To obtain representative dissolution data that could better reflect the intrinsic API PSD characteristics of the formulation, different sample pretreatment procedures and dissolution approaches were investigated. The results suggested that the dissolution profile acquired by the paddle method following combined enzymatic hydrolysis and ultrasonication pretreatment was preferable for characterizing the starting API particle size features. Model predictions demonstrated that the commercial Nasonex® displayed a bimodal volume-weighted PSD and a relatively high Dv₉₀ of 15.8 μm, which differed from previous reports. A modified MDRS was applied for cross-checking, and the modeled Dv₉₀ was in agreement with the measured results. Cross-validation for the model using five test batches yielded prediction errors mostly <10%, indicating acceptable performance. For nasal suspension products that typically present complex PSD features, the present method may provide a feasible auxiliary tool for guiding formulation screening and optimizing manufacturing parameters in the preliminary development stage.