Thought Leaders

Thermomechanical Analysis Using Single Particles as Resonators


Thought LeadersDr. Peter Ouma Okeyo
Dr. Peter Emil Larsen
Technical University of Denmark

Dr. Peter Ouma Okeyo and Dr. Peter Emil Larsen speak to AZoM about a new drug discovery technique using single particles as resonators for thermomechanical analysis.

What inspired your research into new methods of thermomechanical analysis?

The idea behind the new method was born from necessity. The original plan was to investigate the dehydration of drugs that have the ability to form hydrates (water-solid interactions) using our cleanroom fabricated microsensors.

During the initial stages, it became clear, however, that the drug crystals we were interested in were simply too large and heavy for our existing resonant MEMS sensors.

Why are current thermal characterization methods such as DSC and TGA often unsuitable for drug discovery?

The current thermal characterization are in general suitable and commonly used in drug discovery, as well as different stages of drug development. The challenge is that methods such as DSC and TGA require a minimum of a few milligrams of material for a single measurement and give an averaged thermal response.

This can be a problem for early-stage scientists when impurities (e.g. unwanted solid forms) are present in the drug after synthesis, thereby leaving the scientist with a limited amount of pure drug.

By using our newly developed method called Particle Mechanical Thermal Analysis (PMTA), it is now possible to simply isolate the desired pure drug particle via optical microscopy and directly characterize it.

Why can thermal analysis be problematic when analyzing biological samples such as proteins?

This can be related to the sensitivity of biological samples and especially proteins to temperature. PMTA makes it possible to using measure small amounts of sample (nano-microgram), and with a limited amount of sample we can get more information within just one heating run rather than going through cycles of heating and cooling as is the case with DSC for instance.

Why are current uses of NEMS/MEMS systems problematic?

Resonant NEMS/MEMS devices have shown tremendous potential in a wide range of fields ranging from quantum computing to material characterization and biomedical applications. However, widespread adoption of the underlying technology in commercial products remains elusive.

The main reason for this is the prohibitive cost of systems that fundamentally rely on clean room-based microfabrication.

Even putting the cost factor aside there are only a few places around the globe with state-of-the-art cleanroom facilities, which really limits the number of companies and scientists that can work on the development of such NEMS/MEMS systems.

Figure: PMTA schematic and operation.

Please explain the ‘Particle Mechanical Thermal Analysis (PMTA)’ method your team has developed.

The principle behind resonant MEMS sensors is easily explained when you imagine a musical instrument such as a guitar. When played they will vibrate at a clearly defined frequency that we can perceive as a certain note.

Any change to this system will result in a change in tone that can be measured. For example, going outside (change in temperature) will require the musician to retune his instrument (change in stress in the string).

In typical resonant MEMS sensors, the sample is placed onto a micro string and any change in resonant behavior (e.g. tone) can be attributed to a change in the sampled material. In PMTA, we avoid the need for a cleanroom fabricated sensor, by simply using the sample particle itself as a sensor.

Many of the investigated materials crystalize into needle-like structures that we can “listen” to, just like a tuning fork. Any change in tone can, just like before, be attributed to changes in the crystal structure of the analyzed material.

Please describe to us the experiments you carried out to test this method and its results.

We used a model drug called theophylline monohydrate (TP MH), that is used to treat respiratory illnesses such as asthma and is commonly used as a model drug in pharmaceutical research. The first step was to identify the drug-using x-ray powder diffraction. This step is critical because we had to ensure that we had the right solid form of the drug before further experimental investigations.

Upon confirmation, thermal analysis (DSC, TGA, and DMA) was performed on TP MH. With the thermal measurements, we were able to decipher where the main thermal transitions were and compare these results to those of PMTA.

The initial results from PMTA were in good agreement with the standard methods. To our surprise, the results also showed additional transitions that were not detected by the standard methods and this was more evident from the quality factor signals. More details can be found in our published article in Nature Communications.

Figure: Proof of concept for PMTA from a single experiment.

What are the benefits of PMTA? How do single particle micromechanical resonators eliminate the need for cleanroom fabrication?

One main advantage is of course that there is no need for cleanroom fabrication as discussed previously. However, there is another advantage: In traditional resonant MEMS sensors (if there is such a thing) there is always a need to contemplate the effects of the sensor itself.

There are still phenomena in thin films (such as their response to temperature changes) that are not fully understood. In PMTA the sensor is simultaneously the sample. Thereby, any measured changes stem from the material of interest.

Other benefits include the ability to work on pure single crystals without contaminations and to investigate the effects of the single-particle geometry.

What additional transitions can PMTA detect and why is this such an important factor within drug discovery?

The additional transitions that were detected using PMTA were seen with the signals from the resonance frequency and the quality factor. However, this was clearly more evident with the quality factor and this is because this signal is linked to the internal dampening that is happening in the TP MH particle as it changes its crystal structure to an anhydrous form.

We still do not fully understand what implications detecting these additional transitions could have within drug discovery, as this method is the first of its kind and is in its early stages.

However, our results are indicating that complex thermal transitions are occurring on the surface of these single particles that are linked to mechanical changes that have not been detected up to now using such organic materials.

Figure: Comparison of standard thermal methods to PMTA.

How can PMTA be combined with other methods to give more information?

In principle, PMTA can be combined with other spectroscopic techniques such as near-infrared (NIR) to provide a fingerprint of the particle during its phase transitions.

What materials is PMTA applicable to?

Based on the measurement principle of PMTA, a wide variety of materials can be measure, from food particles to inorganic materials.

The most important factor is to ensure that the material being measured can vibrate to the extent that its resonance frequency can be measured and/or tracked during thermal cycling.

How could this method influence the future of drug discovery? Could the method influence other industries within the science and medical sector?

Researchers and companies that perhaps do not have access to cleanroom facilities due to the high cost of use would benefit from this method because such measurements can be performed in a lab environment.

One of the goals for us was to show that there is a method that can allow for the thermomechanical characterization of single particles of organic materials without the need for cleanroom fabricated devices.

Image Credit: Syda Productions/Shutterstock.com

How could the possibility of monitoring unique features of individual particles lead to further developments in material science?

I think this method has the potential to open the door to a deeper understanding of mechanical changes occurring in materials.

By comparing PMTA to the standard methods, the goal is that with a certain amount of measurements using single particles, bulk properties of materials can be predicted. This could help small to large-sized companies that have limited amounts of pure materials for analysis.

What is the next step for your research?

We need more diverse examples to demonstrate the versatility of the method and provide more information about the materials parameters.

Where can readers find more information?

https://www.nature.com/articles/s41598-019-43959-0 

https://pharmacy.ku.dk/news/news-2020/organic-hydrates-in-nature-communications/

About Dr. Peter Ouma Okeyo

Peter Ouma Okeyo is a postdoctoral researcher at the Technical University of Denmark, Department of Health Technology. He is a member of the IDUN research group. He is currently developing methods that can be used for monitoring the quality of medicines using sensor-based technologies and spectroscopic techniques such as Raman spectroscopy.

He obtained his BSc and MSc at Kingston University London. He has worked at Novartis AG and Medicines for Malaria Venture (MMV) in Switzerland. Peter completed his Ph.D. at the University of Copenhagen in the Department of Pharmacy in 2020. He has published in Nature Communications and Scientific Reports.

About Dr. Peter Emil Larsen

Peter Emil Larsen holds an MSc in Mechanical Engineering from the University of Bremen. After 2 years of working for the Institue of Metrology, Automation and Quality Science, he moved to Copenhagen to complete his Ph.D. at Institute for Micro- and Nanotechnology of the Technical University of Denmark.

Subsequently, Dr. Larsen worked as a Postdoc for three more years having the privilege to co-supervise four Ph.D. projects on the interface to other scientific fields. Currently, he works at Radiometer Medical as a R&D Engineer.

 

 

 

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