(T1430-06-34) Chemical Imaging by Raman Spectroscopy: A Powerful Analytical Technique for Surface Morphology Investigation of Inhaled Products

Purpose: Particle interactions are of great importance where the dispersion of active pharmaceutical ingredient (API) particles from carrier particles is critical for lung deposition. Poorer API homogeneity is unfavourable since homogenous drug content is essential to achieve uniform metering doses by the patient during inhalation. Moreover, the adhesion force must be strong enough to maintain the blend homogeneity during manufacturing process whereas it must allow detachment by inhalation to effectively deposit fine API into the lung. Thus, blending active pharmaceutical ingredient (API) with carrier is a critical stage that determines the blend homogeneity and is the first step towards obtaining the final quality of the powder blend. Raman spectroscopy and its powerful chemical imaging capability enables to understand many of these key attributes for inhaled formulations. In this study, two marketed inhaler products, used for the treatment of exacerbated COPD, were compared by Chemical Imaging using Raman spectroscopy. Chemical Imaging is a method that consists of a collection of responses to the illumination at multiple wavelengths of positions spatially distributed across the sample surface. As a result, each mapped sample point (pixel) contains a wealth of information, and the recorded signal reflects chemical and physical properties such as ingredient identity, concentration, crystallinity, orientation, domain size and particle size. The components of inhaled formulations (API, carrier & excipients) are usually micronised and/or processed, to allow for the successful transportation down into the deep lung. Therefore, this needs to be monitored during sample processing and formulating. Chemical imaging by Raman spectroscopy is being used to understand distribution of formulation components, to quantify and compare content uniformity/homogeneity, to analyse raw materials and determine the API physical form and batch to batch variation. The aim of this study was to demonstrate whether chemical imaging by Raman spectroscopy could detect any variation in product content in two different marketed products (Fobumix 320μg/9μg^® and WockAIR 320μg/9μg ^®). In addition, the percentage of each component present in each product and particle size distribution of respective components remained key interests in this research.

Methods: The chemical imaging of the two different marketed inhaler products was carried out using RA802 Pharmaceutical Analyser (Renishaw, UK). A thin layer of product was placed onto a mirror slide using the powder contained in 5 capsules (lactose monohydrate, budesonide, and formoterol fumarate dihydrate) for each marketed inhaler. LiveTrack focus-tracking ensures optimum focus was maintained over the rough split surface of the powder. Renishaw’s fast mapping technique Streamline Image Acquisition was used with LiveTrack to acquire Raman images of the surface of the powder. Three maps were chemically imaged in random areas of the sample preparation. Spectra were previously acquired of reference materials: Lactose monohydrate, Budesonide and Formoterol. Multivariate data analysis technique, using reference spectra for the powder components, were used to acquire the spectrum dataset. Non-Negative Least Squares (NNLS) component analysis was used to generate the chemical images and quantify the content of the materials within the powder layer. Images are based on NNLS scores, which indicate the correlation between each map spectrum and each reference spectrum. NNLS component analysis was performed using reference spectra for Lactose monohydrate, Budesonide and Formoterol.

Results: Both formulations showed similar homogeneity and PSD based on the mapping data obtained here in Tables 2, 3 and 4. However, the particle size of Budesonide is higher than the particle size of Formoterol Fumarate Dihydrate in both formulations. Finally, there is a degree of variance in the content of these two marketed inhalers. Fobumix 320µg/9µg® presented a ca. 2% less of Lactose monohydrate, ca. 2% more of Budesonide and ca. 0.04% less of Formoterol Fumarate Dihydrate compared to WockAIR 320µg/9µg®.

Conclusion: The results obtained in this study show that chemical imaging by Raman spectroscopy is a powerful technique to analyse and monitor inhalation formulations with great accuracy. A lot of important information can be obtained by this technique which would allow scientists to develop a better inhaled products with a control over distribution (matrix), particle size etc.

Acknowledgments: No conflict of interest

Chemical Images obtained by Raman Spectroscopy. White = Lactose monohydrate; Red = Budesonide; Green = Formoterol Fumarate Dihydrate.



Particle Size Distribution Data for WockAIR 320µg/9µg® and Fobumix 320µg/9µg®.



% of components for WockAIR 320µg/9µg® and Fobumix 320µg/9µg®.