Drug-drug cocrystallization or salt formation as an alternative to combination drugs: a case study on clofazimine

PhD thesis defended by Laurie BODART (Prof. Johan WOUTERS) - 20/09/2021

Prof. Johan WOUTERS, UNamur, NARILIS

  • Prof. Yoann OLIVIER (département de Chimie, UNamur), président
  • Prof. Johan WOUTERS (département de Chimie, UNamur), secrétaire et promoteur
  • Dr Luc AERTS (UCB Pharma)
  • Prof. Tom LEYSSENS (Institute of Condensed Matter and Nanosciences, UCLouvain)
  • Dr Nikolay TUMANOV (département de Chimie, UNamur)
  • Prof. Carmela APRILE (département de Chimie, UNamur)

The problem of antibiotic resistance is a global public health issue that has been accompanied by the implementation of multi-therapies. In this context, the number of drugs simultaneously administered to patients is increasing. This may be associated to poor compliance and thus also to the development of new resistance. Drug combinations have emerged to facilitate treatment and improve patient compliance. However, parent drugs incompatibility (e.g., in terms of physico-chemical properties) can hamper their development. A viable option is the cocrystallization or salification of several drugs, which consists of combining them within the same crystal lattice (mixing of species at the molecular level). Cocrystallization/salt formation techniques further allow modulation of the physico-chemical properties of the drugs.

The objective of this thesis is to prepare salts or cocrystals combining several drugs, including clofazimine, a molecule known for its antileprotic and antituberculosis properties. These new solids are prepared in order to characterize their propensity to crystallize in solvated or non-solvated forms and their thermal stability, aqueous solubility and hygroscopicity. To this end, the ability of clofazimine to crystallize with solvents or other molecules (solvates, salt/cocrystals) has been studied. On the basis of these results, other drug molecules with functional groups potentially interacting with clofazimine, and which could be of benefit in the treatment of tuberculosis, were selected. The new crystalline phases were mainly prepared by mechanochemistry and/or by solvent crystallization. They were then characterized by X-ray diffraction on powder samples and on single-crystals, by thermogravimetric analysis and by differential scanning calorimetry. The aqueous solubility of the non-solvated salts or cocrystals was further characterized by HPLC or UV-visible methods. These results revealed how the preparation of multicomponent crystalline solids combining several drugs allows to modulate their physico-chemical properties.