10th International Aerosol Conference September 2 - September 7, 2018 America's Center Convention Complex St. Louis, Missouri, USA
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Improving Single Particle Aerosol Mass Spectrometry (SPAMS) Inhalation Analytics Performance through Rapid Particle Tracking and Sizing
Martin Jetzer, Bradley Morrical, DAVID FERGENSON, Georgios Imanidis, Novartis Pharma AG
Abstract Number: 1638 Working Group: Aerosols in Medicine
Abstract The two primary challenges in the analysis of inhalational pharmaceuticals and their associated devices (inhalation analytics) are the determination of the aerodynamic particle size distribution (APSD) of the active pharmaceutical ingredients (APIs) and, in the case of combination products, their co-association at the level of the individual aerosol particles. Additional challenges include formulation optimization (via excipient addition or process alteration) and the analysis of device and formulation performance under varying physiological conditions. A unique requirement for any inhalation analytical method is that it must handle a very large load of particles over a very short period of time. Multiple APIs in different combinations and the presence of non-API carrier particles require the composition of individual aerosol particles to be determined, rendering conventional particle counter/sizers substantially ineffective. The preferred method for determining the APSD of orally inhaled pharmaceutical aerosols according to the compendial literature is cascade impaction (for example the Next Generation Impactor, NGI, Copley Scientific, UK) followed by high performance liquid chromatography (HPLC). While highly quantitative for the total concentration of API delivered, this technique does not yield any information regarding the co-associations between the various product components (APIs and excipients) within the formulation. Single Particle Aerosol Mass Spectrometry (SPAMS) was initially applied to inhalation analytics to address this issue.
A SPAMS instrument collects a dual polarity mass spectrum from up to 250 individual particles per second and records the aerodynamic diameter of each particle as well. Unlike predecessor instruments, which froze or returned nonsensical data under heavy particle loads, a SPAMS continues to acquire up to 250 randomly sampled aerosol mass spectra per second under essentially arbitrary aerosol conditions. Because a SPAMS uses a single, square tracking laser that is roughly 1 mm tall, even under very high particle concentrations only a single particle will typically be in the tracking region at a time. The light scatter trace is acquired over a period of ~100 microseconds for each particle so it is also possible to verify that the particle was alone in the mass spectrometer.
However, until now there was no way to estimate the degree of particle load saturation occurring in a SPAMS measurement. Lacking this information, it was necessary to parametrically calibrate SPAMS data versus an NGI/HPLC analysis or a conventional counter/sizer such as a TSI 3321 Aerodynamic Particle Sizer. We have now developed a firmware upgrade to SPAMS, Survey Mode, specifically for inhalation analytics, which is similar to Fast Scatter Mode on the TSI Aerosol Time-of-Flight Mass Spectrometer but with significant additional capabilities. In Survey Mode, a SPAMS observes all aerosol scattering events that occur within the tracking laser over a full second. This allows the SPAMS not only to determine the absolute numbers and the sizes of the particles entering the instrument but also to determine the fraction of the time that any particles are found within the tracking laser, ensuring the integrity of the mass spectra that are acquired in the surrounding times.
We report the analyses of several combination inhalational pharmaceutical products in alternating Survey and mass spectrometric acquisition modes. We observe the progress of the SPAMS from saturation to non-saturation conditions and scale the mass spectrometric data to the total observed aerosol. Simultaneous measurements were made using a TSI 3321 APS to verify the linearity of the SPAMS survey mode. Scaling factors were determined for the SPAMS data, which are expected to be durable across many different aerosol systems.