Faster to a New Medication

05/25/2023

Researchers from Rostock, Aachen and Würzburg have developed a new method that simulates the decomposition processes of drugs in just 15 minutes. This could significantly speed up the authorisation process.

Virtually all medicines contain excipients and carriers that can interact with the active ingredient. The photo shows colour changes after the forced decomposition of the drugs under investigation by grinding at high speed. (Image: LIKAT / Nordlicht)

Before being authorised, medicines must not only be tested for their efficacy and safety, but also for their stability, as they are usually stored for years in pharmacies and patients' private households and must not change during this time. In order to test their stability, a process is needed that decomposes the drug "in fast motion".

Such a process was recently developed by a team of scientists from the Leibniz Institute for Catalysis in Rostock (LIKAT), RWTH Aachen University and Julius-Maximilians-Universität Würzburg, supported by the company RD&C (Vienna, Austria). The research results have now been published at a high level in the journal ACS Central Science.

Additives Interact With the Active Ingredient

Background: Virtually all drugs are multi-component or multi-phase systems that are embedded in a matrix, i.e. they contain excipients and carriers, for example. These additives can interact with the active ingredient over time, for example during prolonged storage of the medicinal product, and impair the effect of the medicinal product. The pharmaceutical industry must disclose all stability data before authorising a new drug, which is why there is considerable interest in the development of reliable prediction tools to assess the safety of drugs.

However, the availability of such predictive tools for solid-state properties, particularly with regard to solid-state stability and degradation, is currently limited. In addition, the rate and decomposition products of solid-state degradation processes are unique for each compound, which makes the development of stability models very time-consuming and costly. There are prediction methods in an aqueous environment, but these lead to high error rates. As irrelevant degradation products are often formed under these conditions, these prediction methods represent a high financial and health development risk for the manufacturer of new drugs and for the customer.

Fast Results Thanks to the Vibrating Mill

Based on proof-of-concept studies successfully conducted by RD&C and the team, a unique and innovative experimental method for the prediction of stability profiles and degradation pathways in solid compounds, mixtures and matrices has now been developed. In the literature, the approach is referred to as "mechanochemistry". It involves treating the isolated active ingredient or marketed pharmaceutical product in a vibrating mill in the presence of a degradation-inducing reagent. Degradation processes can be observed within less than 15 minutes.

Everaldo Krake (LIKAT Rostock), first author of the study and newly graduated young scientist, explains: "We were able to demonstrate this with a series of structurally similar so-called thienopyridines, which are the drugs in the antiplatelet tablets. The collaboration with the group led by Carsten Bolm (RWTH Aachen University), a world-leading expert in the field of mechanochemistry, and the team led by Ulrike Holzgrabe (University of Würzburg), a renowned pharmaceutical chemist, was crucial to the success of the project.

A Paradigm Shift in Organic Chemistry

It was shown that the degradation profiles are identical for both the pure drug substance and the finished pharmaceutical product. This means that reproducible and relevant statements can be made for this class of drugs in short reaction times using the active ingredient alone. This would be of great importance for the accelerated authorisation of medicinal products.

According to the authors, this new approach represents a paradigm shift in the application of mechanochemical processes in organic chemistry. "In general, mechanochemical studies on the conversion of small organic molecules, especially drugs, are carried out with the aim of producing specific structural motifs. The new work that has now been published emphasises the potential of this approach to degrade specific structural motifs in a targeted manner," says Carsten Bolm.

This could be important not only for drug testing, but also for organic synthesis in general. "In the future, it will be interesting to transfer this mechanochemical approach to other drug families and to evaluate the role of other stimuli such as light or temperature for the forced degradation process," summarises Ulrike Holzgrabe.

Publication

E. F. Krake, L. Backer, B. Andres, W. Baumann, N. Handler, H. Buschmann, U. Holzgrabe, C. Bolm, T. Beweries, ACS Cent. Sci. 2023, DOI: 10.1021/acscentsci.3c00167.