A Systematic Approach in the Development of the Morphologically-Directed Raman Spectroscopy Methodology for Characterizing Nasal Suspension Drug Products

Gonçalo Farias,Elizabeth Bielski,Robert Price,Bryan Newman,Jagdeep Shur

doi:10.1208/s12248-021-00605-w

Gonçalo Farias, Elizabeth Bielski + Show 3 more

Open Access

https://doi.org/10.1208/s12248-021-00605-w

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Abstract

Demonstrating bioequivalence (BE) of nasal suspension sprays is a challenging task. Analytical tools are required to determine the particle size of the active pharmaceutical ingredient (API) and the structure of a relatively complex formulation. This study investigated the utility of the morphologically-directed Raman spectroscopy (MDRS) method to investigate the particle size distribution (PSD) of nasal suspensions. Dissolution was also investigated as an orthogonal technique. Nasal suspension formulations containing different PSD of mometasone furoate monohydrate (MFM) were manufactured. The PSD of the MFM batches was characterized before formulation manufacture using laser diffraction and automated imaging. Upon formulation manufacture, the droplet size, single actuation content, spray pattern, plume geometry, the API dissolution rate, and the API PSD by MDRS were determined. A systematic approach was utilized to develop a robust method for the analysis of the PSD of MFM in Nasonex® and four test formulations containing the MFM API with different particle size specifications. Although the PSD between distinct techniques cannot be directly compared due to inherent differences between these methodologies, the same trend is observed for three out of the four batches. Dissolution analysis confirmed the trend observed by MDRS in terms of PSD. For suspension-based nasal products, MDRS allows the measurement of API PSD which is critical for BE assessment. This approach has been approved for use in lieu of a comparative clinical endpoint BE study [1]. The correlation observed between PSD and dissolution rate extends the use of dissolution as a critical analytical tool demonstrating BE between test and reference products.

Highlights

To demonstrate bioequivalence (BE) with its reference listed drug (RLD), a generic product must demonstrate an absence of a significant difference in the rate and extent of absorption of the active pharmaceutical ingredient (API) when administered at the same molar dose under similar experimental conditions, either single dose or multiple dose [2]
With the advent of the morphologically-directed Raman spectroscopy (MDRS) approach to measure the particle size of APIs in situ within locally acting nasal suspension drug products, it is important to determine if the technique is able to track the particle size of the API pre- and post-manufacture of a locally acting suspension nasal spray
It will be helpful to determine if particle size differences determined by MDRS are likely to result in similar trends seen in the dissolution kinetics

Summary

Introduction

To demonstrate bioequivalence (BE) with its reference listed drug (RLD), a generic product must demonstrate an absence of a significant difference in the rate and extent of absorption of the active pharmaceutical ingredient (API) when administered at the same molar dose under similar experimental conditions, either single dose or multiple dose [2]. For an abbreviated new drug application (ANDA) submitted under section 505(j) of the Federal Food, Drug, and Cosmetic Act, the FDA recommends a “weight-ofevidence” approach to help determine BE between test and reference products for locally acting nasal suspensions as presented in Fig. 1 [4, 6]. In line with the Generic Drug User Fee Amendments (GDUFA) program and the “weight-ofevidence” approach, the FDA has published a number of product-specific guidances (PSGs) for a series of nasal products [7, 8].

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