The majority of pharmaceutical powders are required to be less than 500 microns in size for ease of manufacture and biopharmaceutical performance. Powder behavior of particles in this size range spans cohesive to aeratable powders. Powder performance is not only dependent on the powder bulk density and micromeritic properties of individual particles, but also crucially the structuring of particles within the powder bed. Micromeritic assessment is also routinely performed using image analysis or particle sizing techniques such as laser diffraction analysis. However, there is a clear need for techniques that provide non-destructive microstructural information of pharmaceutical powder structures.
Microstructure (Q3) has emerged as an important topic of consideration in the regulatory science of topical drug products, opening alternative routes to demonstrate pharmaceutical equivalence between different batches of products or between brand and generic products. Yet the challenge in demonstrating equivalence of topical medicines is highlighted by Dry Powder Inhalers (DPI), where the pre-aerosolised formulation, DPI device and patients’ airflow all have an influence on the post-aerosolised formulation that is inhaled by the patient and reaches the lungs. Understanding how microstructure links to processing, properties and performance will enable the powder to be linked to efficacy, but a central part of this is the microstructural characterisation.
As part of the INFORM project, ZEISS and its partners have developed a non-destructive microstructural characterization technique using X-Ray microscopy for dry powder inhaler (DPI) formulations. XRM can provide unique microstructural insight at nano- and micro-scales, with a range of applications including complex inhalation blends. These techniques are showing promise to enable quantitative measurement of Q3 parameters of different blends and formulations in the asthma medication arena.
Dr Parmesh Gajjar
Henry Moseley X-ray Imaging Facility
The University of Manchester, UK
Read about the interview in our Blog
Read the Manchester Press Release about how the "New understanding of asthma medicines could improve future treatment"
Dr Ioanna Danai Styliari
Postdoctoral Research Fellow
School of Life and Medical Sciences
University of Hertfordshire, UK
Dr. Xizhong Chen
University of Cambridge, UK
3D X-ray microscopy reconstructed data shows the blend of lactose carrier particles (yellow) with an active pharmaceutical ingredient (red). The API in this case is Terbutaline Sulphate. The drug blend is commonly utilized in dry powder inhalers for treating asthma and other respiratory diseases. Using phase contrast microscopy and ZEISS proprietary phase identification software, the two drug components can be easily differentiated and quantified in 3D.
Tablets are one of the most frequent dosage forms of pharmaceutical drugs. Typically, the active pharmacological ingredient (API) and additional constituents (like diluents) are compressed or moulded into tablet form. Frequently, tablets will undergo surface coating to mask the taste of the ingredients, to facilitate swallowing of the tablet and to control release of the drug in the body. Surface roughness of tablets is a crucial design criterion in drug formulation: It has direct impact on the ease of swallowing tablets and thereby impacts the uptake and efficacy of the drug (tablets being rejected by patients, pre-mature release of the API by prolonged exposure to saliva in the patient’s mouth).
Our laser scanning microscope LSM 900 for Materials lends itself to a broad spectrum of micro-structural analyses on powders and tablets including measurements of the surface roughness and topography of tablets (coated and non-coated) during early development phases as well as for formulation optimization and quality control during the manufacturing process.
To ensure FDA 21 CFR Part 11 compliant workflows and reliable and reproducible data irrespective of the operator, LSM 900 is controlled via our ZEN core software suite with GxP data integrity module.
At ZEISS, ease-of-use and compliance are two sides of the same coin.
3D Characterisation of Dry Powder Inhaler Formulations: Developing X-ray Micro Computed Tomography Approaches
P. Gajjar, I. D. Styliari, T. H. Nguyen, J. Carr, X. Chen, J. A. Elliott, R. B. Hammond, T. L. Burnett, K. Roberts, P. J. Withers, D.Murnane
European Journal of Pharmaceutics and Biopharmaceutics, Vol 151, June 2020: pp 32-44. doi.org/10.1016/j.ejpb.2020.02.013
Powder bed packing and API content homogeneity of granules in single drop granule formation
Tianxiang Gao, Arun S.S. Singaravelu, Sarang Oka, Rohit Ramachandran, František Šteponek, Nikhilesh Chawla, Heather N. Emady
Powder Technology, Volume 366, 15 April 2020, Pages 12-21. Doi.org/10.1016/j.powtec.2020.02.039
The Effect of Inorganic Salt on Disintegration of Tablets with High Loading of Amorphous Solid Dispersion Containing Copovidone
Hanmi Xi, Jie Ren, Julie M. Novak, Eric Kemp, Gregory Johnson, Gerard Klinzing, Mary Ann Johnson & Wei Xu
Pharmaceutical Research volume 37, Article number: 70 (2020).
T.Leißner, A. Diener, E. Löwer, R. Ditscherlein, K. Krüger, A. Kwade, U.A. Peuker
Advanced Powder Technology, Volume 31, Issue 1, January 2020, Pages 78-86.
Glycine microparticles loaded with functionalized nanoparticles for pulmonary delivery
Amlan Chakrabortya, Simon G. Roycec, Magdalena Plebanski, Cordelia SelomulyaInternational Journal of Pharmaceutics
Volume 570, 30 October 2019, 118654. doi.org/10.1016/j.ijpharm.2019.11865
Multiscale Tomography: Probing The Nano-, Micro-, and Meso-Scale Resolution of Inhalation Powder Structure
Gajjar, P., Styliari, I. D., Burnett, T., Chen, X., Elliot, J. A., Ganley, W. J., Murnane, D.
RDD Europe 2019 (Vol. 1, pp. 155-168).
Computed Tomography for In Situ Detection of Precipitation in a Solution Pressurized Metered Dose Inhaler
Phil Cocks, Alexander D Slowey
Respiratory Drug Delivery 2018, Vol 2 (2018): pp 291-294
Application of X-ray microtomography for the characterisation of hollow polymer-stabilised spray dried amorphous dispersion particles
John F. Gamble, Masako Terada, Christian Holzner, Leah Lavery, Sarah J. Nicholson, Peter Timmins, Mike Tobyn
International Journal of Pharmaceutics, Volume 510, Issue 1, 20 August 2016, Pages 1-8.
ZEISS Microscopy is the world's only one-stop manufacturer of light, electron, X-ray and ion microscope systems and offers solutions for correlative microscopy. The portfolio comprises of products and services for life sciences, materials and industrial research, as well as education and clinical practice.
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