Ingredient-Specific Particle Sizing of Aerosolized Nasal Spray* Using Widefield Raman Chemical Imaging
ChemImage Corporation, 7301 Penn Avenue, Pittsburgh, PA 15208, USA
Tel: +1 412 241 7335 info@chemimage.com www.chemimage.com
INTRODUCTION
Intra-nasal drug delivery is an attractive delivery method for a broad range of pharmaceuticals that treat a variety of diseases. This patient-friendly delivery method can provide multiple benefits like the reduction in potential side effects and increased compliance of the drug treatment.
Creating the correct nasal formulation is both challenging and critical. Particle size directly correlates to active pharmaceutical ingredient (API) bioavailability and drug effectiveness. Nasal sprays formulated as suspensions typically contain micronized API in the presence of multiple excipient materials. Although particle size distribution (PSD) of the drug can be easily determined prior to the formulation, it has been a challenge to determine ingredient-specific PSD in the finished product.
Particle sizing techniques based on laser scattering, cascade impaction or optical image analysis cannot discriminate between particles of API and those of an excipient or a surfactant. Multi-stage cascade impaction followed by extraction and HPLC analysis is an option but can be extremely time consuming, labor-intensive and is not very reproducible. In vitro methods are frequently preferred over in vivo methods, which are often costly, time consuming and inconclusive. Consequently, the development of an efficient ingredient-specific approach is essential for ensuring that all ingredients fall into the proper size range, particularly during the early stage of product development.
ChemImage conducts on-going studies using the FALCON II widefield Raman chemical imaging system to determine chemical identity and particle size distribution (PSD) of micronized drug substances in aqueous suspension nasal spray formulations. These studies are performed in collaboration with the FDA with the long-term goal of establishing a fully validated in vitro particle sizing method for measuring bioequivalence of nasal drug delivery products or batch comparison.
EXPERIMENTAL INFORMATION
Samples of a nasal spray formulation were prepared on aluminum-coated glass microscope slides. Raman spectra, brightfield images, polarized light and Raman chemical images were obtained using a FALCON II System with 532 nm excitation. For the formulated nasal spray samples, Raman chemical images were collected and analyzed until at least 100 API particles were counted analyzing areas ranging from 200 x 200 to 900 x 900 mm2 in size. The time required for imaging a single sample varied on the total number of frames and the integration time per frame. Images were analyzed using ChemImage Xpert software.
RESULTS AND DISCUSSION
The FALCON II system measured the PSD of an API and the excipient in a nasal spray suspension. Figure 1 illustrates the ability to identify ingredient specific particles based on unique Raman spectra.
The fusion of the Raman chemical and optical images shown in Figure 1a is made up of 14,745,600 individual spectra collected at a rate of >700 spectra per second. The histograms (Figures 1b and 1c) show the full distribution of 313 API and 90 excipient particles, respectively, in 225 fields of views. D50 and D90 statistics were obtained for both API and the excipient potassium sorbate. Note that the widefield imaging approach displays both individual and aggregated particles.  |
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Figure 1a: Raman / brightfield image fusion of API (green) and excipient (blue) particle distribution in droplet of a nasal spray suspension. |
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| Figure 1b: Drug-specific particle sizing; PSD histogram for API only, measured a total of 313 API particles. Histogram provides PSD, D50 and D90 |
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Figure 1c: Excipient-specific particle sizing; PSD histogram for potassium sorbate; measured a total of 96 potassium sorbate particles. Histogram provides PSD, D50, and D90. |
CONCLUSIONS
Widefield Raman chemical imaging is able to distinguish API in formulated products, count and measure only API particles, and confirm the particle identity with Raman spectra.
The FALCON II System is able to differentiate between and identify the chemical makeup of multiple components in complex mixtures. API particles are clearly distinguishable from those of excipients where RCI displays both solitary and aggregated API particles.
FALCON II efficiently collects millions of spectrally unique data points at sub-micron spatial resolution. Acquisition rates surpass the speed of competing point and line mapping systems. The substantial time and labor savings are ultimately transformed into cost savings and a reduced time to market.
For more details, please refer to: Doub, W. H. et al. Raman Chemical Imaging for Ingredient-Specific Particle Size Characterization of Aqueous Suspension Nasal Spray Formulations. Pharm. Research, Vol 24, No 15, pp 934-945, 2007.
* Work performed in collaboration with the US Food and Drug Administration.* This application note represents the personal opinions of ChemImage Corp. and does not necessarily represent the views or policies of the US Food and Drug Administration.
