FULL PUBLICATION
“O-PTIR enables the measurement of API PSD, which is critical for formulators in developing nasal suspension products. This approach holds potential as an innovative complimentary analytical tool that could diminish the need for extensive clinical endpoint bioequivalence studies when evaluating the comparability of generic and brand-name nasal suspension products.”
Reporting in the International Journal of Pharmaceutics, researchers at The University of Sydney addressed a critical analytical challenge in pharmaceutical development. Evaluation of the particle size distribution (PSD) of active pharmaceutical ingredients (APIs) in nasal suspension products is challenging due to the presence of both API and excipients.
Existing techniques like morphology-directed Raman spectroscopy (MDRS) showed significant limitations, including inconsistencies between measurements, days-long analysis times, and inability to detect submicron particles due to insufficient spatial resolution.
The research team applied O-PTIR to analyze commercially available Nasonex® and generic Azonaire® nasal mometasone furoate suspensions. Simultaneous O-PTIR and Raman spectra, as well as IR chemical maps, were collected from the particles in both formulations. The technique successfully identified mometasone furoate (MM) particles using specific spectral peaks at 1727 cm⁻¹, 1661 cm⁻¹, and 1122 cm⁻¹, while distinguishing them from microcrystalline cellulose excipient particles.
The MM particle size distribution analysis for Nasonex® confirmed the D10 of 0.447 μm, D50 of 0.963 μm and D90 of 3.058 μm with a Span of 2.712. Similarly, the D10 of 0.447 μm, D50 of 1.045 μm and D90 of 4.575 μm with a Span of 3.951.
Critically, O-PTIR detected submicron particles that MDRS missed, with TEM imaging confirming the presence of particles ranging from nanometers to microns. The lower D50 value obtained from O-PTIR, accurately reflects the particle size distribution by incorporating particles smaller than 1 μm.
Additionally, because O-PTIR does not use morphology filters for identifying drug particles, the technique is unbiased and includes all particles that exhibit the characteristic chemical signatures of the drug molecules of interest. The spatial resolution of approximately 300 nm enabled comprehensive assessment of nanochemical composition and particle size distribution.
O-PTIR spectroscopy is able to discriminate between the insoluble API and excipient particles in the complex nasal suspension products. The technique represents a significant advancement for pharmaceutical development, offering automated analysis capabilities and potential to reduce reliance on extensive clinical bioequivalence studies.
Multiple FDA product-specific guidances for nasal suspension products recommend using advanced analytical techniques for active pharmaceutical ingredient-specific particle size analysis as an alternative to reduce clinical endpoint bioequivalence studies in the development and approval of generic nasal suspensions. Thus, O-PTIR is promising as a valuable complimentary tool to support the formulation and development of nasal generic suspensions.
Authors: Dipesh Khanal, Yue Cao, Waiting Tai, Hak Kim Chan
DOI: 10.1016/j.ijpharm.2024.124653
