Making the pill less bitter

How Chirality Affects Compliance for an Essential Bilharzia Drug

Background

Schistosomiasis, or Bilharzia, is a devastating parasitic tropical disease caused by flatworms called schistosomes. In 2018, it was estimated that approximately 230 million people required preventive treatment, and the principal option was praziquantel (Biltricide).

Only the (R)-enantiomer of praziquantel has antiparasitic activity. However, the drug is administered as the less expensive racemic mixture. Two serious drawbacks to this approach are the extremely bitter taste of the racemic compound and the large tablet with which it is dosed. This combination makes it extremely difficult to swallow, especially for children.

The active (R)-enantiomer is significantly less bitter than racemic praziquantel. A method to both reduce the dose and bitterness, without resorting to expensive taste-masking methods is desirable.[1] Therefore, the low-cost preparation of pure (R)-praziquantel has been assigned a key priority by the WHO’s Special Programme for Research and Training in Tropical Diseases. A classical resolution of praziquantel was developed earlier by Dr. Jean-Paul Seerden at Symeres, but, by its very nature, a classical resolution can give, at best, 50% yield.

The HORIZON Programme and the team

Symeres participates with six universities in the HORIZON Programme “Continuous Resolution and Deracemization of Chiral Compounds by Crystallization (CORE)”. Giulio Valenti worked on this programme at Symeres as part of his Ph.D. and received daily guidance from Prof. R. M. Kellogg and Dr. Michel Leeman. The chief producer of praziquantel, Merck (Germany), set its deracemization as a principal objective.

These involved projects required broad cooperation. To achieve the goal, we collaborated with Prof. Joop ter Horst, Director of the CORE Programme (University of Strathclyde), Dr. Wim Noorduin and Dr. I. Baglai (Amolf Institute, Amsterdam), Dr. Bernard Kaptein (Innosyn), and Dr. Paul Tinnemans (Radboud University).

What was achieved

Deracemization requires in situ racemization, together with a method of selective collection of the desired enantiomer. Giulio Valenti discovered a reversible Pd/C-catalyzed racemization at 130°C. Based on this, a flow system was developed to couple the catalyzed racemization with a deracemizing crystallization by cycled cooling between 15 and 5 °C. In this way, praziquantel was efficiently deracemized to the desired (R– enantiomer. If you want to read, in detail, how this process works, we refer you to the group’s publication in Angewandte Chemie International Edition (doi: 10.1002/ange.202013502).

[1] T. Meyer et al. PLoS Negl Trop Dis. 2009 Jan; 3(1): e357

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