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Disease and treatment

Innovative technology overcomes the barrier for fundamental understanding of active pharmaceutical ingredients

A new technology can potentially save the pharmaceutical industry resources in early research and reduce the risk of recalling drug products.

One key challenge when developing active pharmaceutical ingredients is ensuring that their response to environmental conditions (temperature and humidity) is well controlled and understood. This is done to ensure the safety and efficacy of the medicine.

If changes caused by temperature and humidity are not well understood, there can be catastrophic consequences if they happen in the hands of patients.

Until now, pharmaceutical companies have found that carrying out the necessary fundamental investigations to ensure that this does not happen can be both difficult and expensive.

However, this problem may soon be solved, since researchers from the Technical University of Denmark have developed a new technique that enables researchers to study how a single drug particle changes when it is heated and cooled.

“This is a new way of characterizing active pharmaceutical ingredients to determine how they react to temperature changes or to various levels of humidity. I think many people have had a headache pill lying in the bottom of a bag for a month that has been heated and cooled many times if they take the bag outside during the winter. This fluctuation may not be so important for headache pills but can strongly influence whether other types of medication work as they are designed to. Our technique can help to ensure that medicines are stable and remain effective,” explains a researcher behind the new study, Anja Boisen, Professor and Head of Section, Department of Health Technology, Technical University of Denmark.

The study has been published in Nature Communications.

Company recalled medicine because the properties changed

The problem with medicines that change when they are exposed to the real world is not just a theoretical exercise. Pharmaceutical companies have been severely affected.

One such example was ritonavir, a medicine for treating people living with HIV.

After it had been on the market for 2 years, researchers discovered that there was another drug form that had properties that differed from the marketed form.

“Recalling ritonavir was a very expensive exercise, not to mention the major reputational damage,” explains the first author, Peter Ouma Okeyo, Postdoctoral Fellow from the same department as Anja Boisen.

Cardboard illustrates such changes in physiochemical and mechanical properties. When cardboard is dry, it has different properties than when it is wet, and even after the cardboard dries again, it does not regain its original structure.

“Some of the existing and new medicines have metastable states that can be difficult to detect because they appear over very short time scales. They can be either crystalline or amorphous, and amorphous compounds dissolve extremely well but crystalline compounds do not necessarily. Methods are needed to identify whether the state of the active pharmaceutical ingredients changes in the hands of the patient,” says Anja Boisen.

Current methods are expensive and inadequate

Pharmaceutical companies are naturally working on this problem and use standard analytical techniques (such as differential scanning calorimetry and thermogravimetric analysis) to ensure that the properties of their medicines do not change during development, manufacturing and storage.

Pharmaceutical companies usually perform physical, chemical and mechanical studies on large amounts of active pharmaceutical ingredients. More sensitive methods have also been developed in recent years, using nano- and microelectromechanical systems (NEMS/MEMS), for characterizing tiny amounts of material. These systems are manufactured in cleanrooms, which are also used in manufacturing computer chips.

Both methods have limitations.

When researchers measure the physiochemical and mechanical properties of large amounts of an active pharmaceutical ingredient, they end up measuring the overall properties of this ingredient plus all the impurities (if present), of which there can be many in the initial stages of development.

The obvious disadvantage of fabricating microelectromechanical system devices is the huge cost of either constructing or renting the specially designed cleanrooms.

“Further, these methods cannot be used for measuring large-sized active pharmaceutical ingredient particles, as used in our study, and the user must account for the interaction between the active pharmaceutical ingredient and the fabricated device during thermal studies,” explains Peter Ouma Okeyo.

Plucking a tiny guitar string

To solve this problem, researchers at the Technical University of Denmark developed a new technique called particle mechanical thermal analysis (PMTA) that can analyse a single particle of the active pharmaceutical ingredient in the laboratory without using special premises.

Using microelectromechanical systems, researchers usually sprinkle the material on miniature guitar-like strings made of silicon nitride that are set in motion by placing them on a small plate that vibrates.

These guitar strings vibrate – or change keynote – with different patterns according to the physical and chemical properties of the active pharmaceutical ingredient. Particle mechanical thermal analysis works based on a principle called the resonance frequency, as illustrated by the guitar strings. Tracking the resonance frequency of the active pharmaceutical ingredient enables the fundamental changes related to its properties during thermal cycling to be understood.

The new discovery from the Technical University of Denmark replaces the guitar strings of silicon nitride with particles of the active ingredient. This eliminates the need for a specially designed cleanroom, and the experiment can take place in the laboratory.

“Nobody has been able to do this previously with an active pharmaceutical ingredient. Further, we can use this technique to investigate the metastable states of materials and determine how the properties of a material change when temperature or humidity changes,” says Anja Boisen.

The pharmaceutical industry is conservative

Peter Ouma Okeyo says that the pharmaceutical industry now has a non-destructive method it can use for investigating phase transitions in single particles of the active pharmaceutical ingredients (or excipients) but that more hurdles still need to be overcome before the technique is actually adopted.

The pharmaceutical industry is notoriously conservative, and researchers must show that they can identify and characterize the phase transitions in a wide range of materials, also quantitatively, before the new technique can gain a foothold.

“The pharmaceutical industry can be conservative in early research – and more so in manufacturing – and changing their mindset to use a new technique may be difficult. But this technique will probably become more interesting if we can give more examples using existing active pharmaceutical ingredients and provide additional information about the fundamental changes occurring that are almost impossible to obtain using standard techniques. Our hope is that such knowledge can be used to predict the behaviour of the active pharmaceutical ingredients and prevent unwanted changes,” says Peter Ouma Okeyo.

Single particles as resonators for thermomechanical analysis” has been published in Nature Communications. In 2017, the Novo Nordisk Foundation awarded a grant to co-author Anja Boisen for the project MIMIO – Microstructures, Microbiota and Oral Delivery.

Peter Ouma Okeyo
Postdoc
Peter Ouma Okeyo, who is a Postdoc in Professor Anja Boisen’s research centre IDUN at DTU Health Tech, has headed the development of a new method that is called Particle Mechanical Thermal Analysis (PMTA). PMTA bypasses the barrier described above, by using the drug material itself as a MEMS device. Hereby, it is possible to do analysis directly on a single particle of drug. This means that any impurities that may have been in the larger bulk of material that is needed for standard methods can now be filtered out and the analysis will can be done more accurately on a pure drug particle.
Anja Boisen
Head of Sections, Professor
Anja Boisen is working on micro- and nano sensor development and microdevices for drug delivery. The sensor projects are focusing on micro- and nanosensors as resonating strings, surface enhanced Raman scattering, electrochemistry on a disc and Raman spectroscopy. With these we can for example measure resonance frequency shifts of nanograms of material, perform rapid diagnostics and studies of molecular action of drugs and obtain finger-print spectra to identify unknown compounds. Furthermore, we are focusing on micrometer sized containers as an oral drug delivery system. The microcontainers are fabricated in polymeric material. Following the fabrication, the microcontainers are loaded with drug using methods such as embossing, inkjet printing and supercritical impregnation. The drug-loaded microcontainers are then coated with a polymeric lid, and the microcontainers are tested in vitro and in vivo for oral drug delivery of for example insulin, antibiotics and vaccines.