Monitoring Degree of Agglomeration in Aqueous Suspensions Subjected to Various Environmental Conditions by Raman Imaging

By: Oksana Olkhovyk, Senior Scientist, Gateway Analytical, Gibsonia, PA, USA

Outsourcing the development and manufacturing of generic drug products is a very common strategy in today’s current global market. Because of this, some of the biggest generic manufacturers of orally inhaled and nasal drug products (OINDPs) are located overseas. As a result, evaluating out–of–specification issues, establishing batch–to–batch equivalency, addressing the stability of the products during scale-up, long–term storage, and shipping in varying environmental conditions has become of paramount importance for the industry and regulating agencies around the world.

For assessing product quality, establishing bioavailability, and proofing bioequivalence of generic OINDPs, the US FDA requires that the extent and size of drug particle agglomerates is determined, as well as the size and number of primary active pharmaceutical ingredients (API) particles. Gateway Analytical offers expert analytical solutions to help generic manufacturers obtain this information, and, as a result, helps them get their products to market faster. Among numerous analytical offerings for the analysis of pharmaceuticals, Gateway Analytical utilizes Raman Chemical Imaging (RCI) ^[1] for chemically specific analysis that can identify whether a product contains a significant amount of aggregates/agglomerates and whether observed agglomerates are combinations of multiple primary API particles, API-excipient particles, or multiple excipient particles.

The following concerns can be addressed by chemically-specific analysis: what conditions may trigger drug particles in the formulation to agglomerate, what is the chemical makeup of the agglomerates formed and whether the actuator device used is appropriate to warrant sufficient particles de-agglomeration. An increase in drug particle size distribution (PSD) will eventually change the drug dissolution rate and could void the product’s bioavailability. When drug particles significantly adhere to excipients which are larger in size (i.e. microcrystalline cellulose), such particles may not be able to reach the intended site of action (the mucous membrane/lungs). Thus, the final product may lose efficacy and fail stability testing.

Gateway Analytical collaborated with the FDA/CDER/Division of Pharmaceutical Analysis in St. Louis, Missouri to qualitatively and semi-quantitatively estimate the degree of agglomeration in nasal suspensions containing common corticosteroid as an active ingredient and microcrystalline cellulose as a solid excipient after various temperature treatments.

For this study, aqueous nasal spray suspension samples prepared in-house were subjected to temperature treatments that simulated mailing conditions that may occur in the US Midwest (room temperature (RT) (21-23 °C), 60°C, ^[2] and -20°C ^[3]) for 12-14 hours. They were then compared to commercial aqueous nasal spray suspension that were stored at room temperature. Figure 1 illustrates the procedure for agglomerates assessment based on RCI.

The field-of-view containing an API particle as confirmed by RCI ^[4] is visually compared to an optical microscopy/RCI fusion image. If the identified API particle is determined to be an agglomerate, based on visual inspection of the brightfield reflectance image, RCI fusion image and associated with each particle Raman spectrum, the size of the particle is retained and extent of agglomerates are assessed. Additionally, since the RCI method allows the extraction of a Raman spectrum from every pixel in the image (spatial resolution approaching 350nm can be achieved), all identified particles can be objectively grouped into three categories: stand-alone API particles; API-API agglomerates and API-excipient agglomerates, and their sizes can be precisely determined.

This collaborative study revealed that heating manifested the highest degree of API-excipient agglomeration and larger PSD values for API-API agglomerates. However, freezing did not significantly affect particle size and degree of agglomeration when compared to room temperature stored nasal sprays. Primary (stand-alone) API particles were estimated to have very similar PSD for all samples. It was observed that API-API agglomerates were comprised of small particles, which may be because smaller particles have larger surface area/volume ratio and stronger adhesion forces.

The above-mentioned study proved that the knowledge of the conditions promoting drug particles adhesion to each other or to excipients may aid in the understanding of OINDPs bioavailability, stability and efficacy. Chemically-specific particle sizing analysis can greatly benefit developers of nasal suspensions, dry powder inhalers and metered dose inhalers containing multiple APIs and/or excipients even prior pharmacokinetics (PK) bioequivalence studies.

For more information, visit Gateway Analytical at www.gatewayanalytical.com.

References

Doub, W.H. et al.: Pharm. Research 2007, 24 (5): 934-945.

Black, J.C., & Layloff, T. (1996). Summer of 1995-Mailbox Temperature Excursions in St. Louis. Pharmacopeial Forum, 22(6), 3305.

Typical low winter temperatures in St. Louis, MO range between 0 to -5 °F.

Priore, R.J., Olkhovyk, O., Klueva, O., and Fuhrman, M. Automation of Ingredient-Specific Particle Sizing Employing Raman Chemical Imaging, US Patent Publication No. 2010/0179770, filed on January 8, 2010.