X-ray microscopy reveals unique insights of pre-aerosolized materials
The 2018 Global Asthma Report estimates that as many as 339 million people are affected by asthma with approximately 1000 people per day dying from this affliction. Inhalers are used every day by people with asthma as well as those with other chronic lung diseases. The creation of generic inhaler medications is essential for supplying cost effective medications to these people.
In order to create generic inhaler medications, companies must demonstrate bioequivalence (BE) between the candidate and reference product. This means that there is no significant difference between the two products in terms of the drug reaching the point of action. It has been difficult to set standards for BE for inhaled medications as both the patient’s airflow and the microstructure of the medicinal formulation have an influence on the aerosolization and thus on the drug reaching the lungs. Yet despite the importance of formulation microstructure, there is still much to be scientifically understood.
Dr. Parmesh Gajjar
We spoke with Dr. Parmesh Gajjar of the University of Manchester, United Kingdom, about his upcoming digital conference talk “Unlocking the Microstructure of Inhalation Blends Using X-Ray Microscopy” to be presented at Respiratory Drug Delivery (RDD) 2020 in April. He will show his recent work that shows how X-ray microscopy can provide unique microstructural insight of pre-aerosolized material.
What led you to this line of research – using X-ray microscopy to investigate inhalation blends?
X-ray computed tomography (XCT) has become a popular tool in materials science due to its non-destructive but fully 3-dimensional nature. As far back as 2005, researchers began exploring whether XCT could help understand the structure of inhalation medicines, but the particle sizes were too small for the machine resolution at that time. ZEISS’ development of X-ray microscopes with increased contrast and resolution revived interest to see whether analysis of inhalation powders was now possible. This has become a central part of the INFORM 2020 project, funded by the UK Engineering and Physical Sciences Research Council (EPSRC). Led by Professor Darragh Murnane at the University of Hertfordshire, the project also involves the Universities of Manchester, Leeds and Cambridge with the support of AstraZeneca, 3M, GlaxoSmithKline, Malvern Panalytical and ZEISS.
Dr. Gajjar working with the ZEISS Xradia Ultra 810 X-ray microscope.
Could you summarize, in layman’s terms, the key discoveries in your work?
X-ray microscopy has allowed unparalleled insight into the microstructure of dry powder inhaler medicines. Fine particles in the medicines tend to stick together to form agglomerates, or large ‘pseudo’-particles. Using the ZEISS Xradia Ultra 810 X-ray microscope, we have been able to quantify the size distribution of constituent particles within an agglomerate. This is important for understanding how the agglomerate will break up when the patient inhales. The ZEISS Xradia Versa 520 X-ray microscope has also allowed us uniquely distinguish drug and non-drug particles within a powder blend.
Left: A 3D visualization of a blend of carrier lactose (grey) and the drug Terbutaline Sulphate (green). Right: A 3D visualisation of an agglomerate (‘pseudo’-particle) formed of micronized lactose particles, with each particle colored by its size. Images reproduced with permission from RDD Online / Virginia Commonwealth University.
When doing this work, were there any data that surprised you or that you are particularly excited about?
For three years there has been strong interest to examine an inhalation medicine blend with realistic particle sizes, but I was constantly worried that the small particle sizes of the drug (less than 5 microns) would be beyond the capabilities of the machine. Yet, the results (to be revealed during the talk) have been absolutely mind-blowing and beyond all expectations.
Learn more
Watch Dr. Gajjar’s talk online at RDD 2020 digital, the conference starts on April 26.
Get more information on ZEISS X-ray microscopes.