(T1030-09-57) Evaluating the Potential of X-Ray Microscopy (XRM) as a Non-destructive Technique for the Characterization of Dry Powder Inhaler (DPI) Formulations

Purpose: The performance of dry powder inhaler (DPI) formulations is dependent on the carrier and active pharmaceutical ingredient (API) particle size distribution, surface roughness, fine particle fraction, and flow properties that need accurate characterization. These features contribute to the microstructural and spatial organization of the particles. The introduction of microstructural equivalence (Q3) concept by FDA makes it important to characterize the microstructural details in addition to Q1 (qualitative) and Q2 (quantitative) bioequivalence studies between reference listed drug (RLD) and generics. However, conventional techniques such as laser diffraction (LD), scanning electron microscopy (SEM), optical microscopy (OM), and cascade impaction (CI) give information about the physical characteristic of DPI but they pose intrinsic limitations¹ such as being destructive in nature, representing small portion of whole sample and revealing just 2D information of the sample. To this end, X-ray computed tomography (XCT, or X-ray microscopy, XRM) has increasingly gained interest as a non-destructive technique to study the 3D microstructure of pharmaceutical formulations². Correlating the unique 3D microstructural insights of pre-aerosolized inhalation powders to the effect of the microstructure on the post-aerosolized powder behavior, can help the Agency to develop recommendations for brand and generic drug manufacturers to ensure consistent drug product quality. XRM technology is still in its early stage and thus this work will focus on optimizing method development for 3D imaging of DPI formulations, collecting quantitative 2D/3D data, and comparing the technique to conventional approaches such as SEM imaging.

Methods: As a case study, RLD and generic tiotropium bromide DPI formulations were used. The DPI formulations used to control symptoms of chronic obstructive pulmonary disease (COPD) and contains tiotropium bromide as API and lactose as carrier excipient. The DPI capsule was mounted as it as and it was scanned using Bruker 1272 micro-CT. The scanned DPI sample was reconstructed and quantified by using the provided software NRecon and CTAn respectively.

Results: Figure 1A shows the experimental workflow. The capsule was mounted and exposed to X-rays to acquire the projection image based on the density of the sample. The projection image was then reconstructed in NRecon, a single layer is shown in figure1A. Once the whole sample was reconstructed it was quantified in CTAn software to get 2D/3D information of the sample. Figure 1A (right) shows particle size distribution of a single layer. Once the workflow was streamlined, different parameters such as resolution, rotation steps and filters were tried to get the optimal image quality at a reasonable time while taking less disk space which is very important to consider for processing the data later for quantitative analysis. Figure 1B summarizes the effect of each parameter on time and disk space used. This optimization was also important in our case because the whole capsule is not packed with DPI rather just a small amount of DPI is at the bottom which gives it more space to move inside the capsule. It was found that using a 2K resolution, with 0.185-0.20 rotation step with an Aluminum filter (0.25 mm) gave optimal image quality and reduced the time and disk space to 4-4.2 hours and 6 GBs respectively. The pixel size for each experiment was 2.35 µm which was maximum that can be achieved without removing the DPI from capsule at 2K resolution. Finally, after optimization, the same parameters were used to scan the generic and Figure 1C and 1D shows the comparison of equivalent spherical diameter and form/sphericity between RLD and generic. Generic form has similar size distribution at larger sizes i.e., above 5 µm as compared to RLD however, it was found to have 9% more population of smaller particles ranging from 0-5 microns. As the particles gets smaller, they tend to have more spherical form, since generic was found to have higher population of smaller particles, it tends to have more spherical population as compared to RLD (Figure 1D).

Conclusion: XRM is a promising technique that reveals valuable information about the DPI formulations in 3D without disrupting them. Its potential can further be extended by utilizing artificial intelligence/machine learning to make it more robust for quantification. Future directions include, correlating the data obtained from XRM with SEM imaging and nano-IR for chemical characterization and applying the technique on other DPI and metered dose inhalers (MDIs).

References: (1) Zhang, S.; Wu, D.; Zhou, L. Characterization of Controlled Release Microspheres Using FIB-SEM and Image-Based Release Prediction. AAPS PharmSciTech 2020, 21 (5), 194. DOI: 10.1208/s12249-020-01741-w.
(2) Hancock, B. C.; Mullarney, M. P. X-ray microtomography of solid dosage forms. Pharmaceutical technology 2005, 29, 92-100.

Acknowledgements: These scientific results reflect the views of the authors and should not be construed to represent FDA’s views or policies.

Figure 1: A: Workflow of scanning the capsule. B: Optimization of time and disk space. C, D: ESD and form comparison between RLD and generic.