Making drugs cheaper doesn’t always require pricey investments. A joint initiative by researchers from TU Eindhoven, the Dutch company Syncom BV and the Antoni van Leeuwenhoek hospital proves just that. What started out as a Bachelor project at TU/e laid the foundation for a much cheaper production of the promising cancer drug Z-endoxifen.

Tamoxifen is known world-wide as a blockbuster chemotherapeutic drug for the treatment of breast cancer, but it is not always effective. Before it can exert its healing effect, the patient’s body must first convert it into the active component Z-endoxifen. Unfortunately, the conversion depends on the patient’s genes, which can lead to a variable therapeutic response in patients. By not administering Tamoxifen but Z-endoxifen directly, this genetic dependence is circumvented and the medicine therefore becomes more effective and less toxic due to lower dosing. This has also been demonstrated by clinical trials in the US.

The application of Z-endoxifen had quite a hurdle to overcome: the drug’s production was only feasible in small amounts, which led to the exorbitant price of about ten thousand euros per gram. Researchers from TU/e and Syncom have now overcome this hurdle with an improved method to produce Z-endoxifen. During a Bachelor project attentive researchers from TU/e recognized that the HPLC purification method (high-pressure liquid chromatography) used was not at all necessary. Especially on a larger scale HPLC can be particularly expensive.

The existing production method yields two variants (Z- and E-stereo isomers) of endoxifen in a 70:30 ratio, of which the latter is undesired. HPLC was necessary to remove the unwanted 30%. The researchers from Eindhoven made the seredipitous discovery that the ratio one step earlier in the process could be increased to 95:5 in favour of the preferred Z-isomer. At this purity a chemical process known as trituration is possible, which enables removal of the the remaining 5% unwanted E-isomer by paper filter, not unlike filtering coffee granules from your morning coffee. The Dutch company Syncom showed this to be the case, andtook the project to the next level by scaling up the production and rendering the synthesis more robust using a tailored protective group on the molecule. Finally, Prof Jos Beijnen’s group in Amsterdam proved that this new approach did indeed produce pure Z-endoxifen and that the alternative method of purification is effective.

Read more at Eindhoven University of Technology