Multicomponent crystals of anti-tuberculosis drugs: a mini-review

Abstract

Tuberculosis (TB) is the leading cause of death from a single infectious agent globally. Some of the early research on TB treatment indicated drug resistance as one of the key challenges in fighting this disease. The discovery that administering two or more drugs simultaneously could lead to much more effective treatment, with reduced drug resistance and shorter periods of chemotherapy, was, therefore, a very significant breakthrough in TB drug research. Pursuant to this discovery, the World Health Organisation (WHO) recommended TB treatment employing fixed-dose combinations (FDCs) containing first line anti-TB drugs; rifampicin, isoniazid, pyrazinamide, streptomycin and ethambutol. Regardless, certain challenges associated with FDCs remain and these include chemical instability and reduced bioavailability of rifampicin. Therefore, some research effort has been directed towards finding ways to deal with these challenges. One such effort involves the use of pharmaceutical co-crystals of the active pharmaceutical ingredients. Consequently, several pharmaceutical co-crystals of isoniazid and pyrazinamide have been reported. This paper aims at reviewing the multicomponent crystal structures of two first-line anti-TB drugs; isoniazid and pyrazinamide. The review will first set out a brief history of the disease, milestones in TB chemotherapy and the challenges associated with current treatment regimens. This will then be followed by a brief introduction to pharmaceutical co-crystals and how they can improve the physical and chemical properties of the active pharmaceutical ingredients. Secondly, multicomponent crystals of the two active pharmaceutical ingredients will be analysed by manual inspection for common supramolecular synthons between the drug molecules as well as between drug molecules and co-formers. Lastly; stability, solubility and dissolution experiments carried out on the pharmaceutical co-crystals of pyrazinamide and isoniazid will be analysed to gain insights into progress made with regards to improving stability and solubility of the active pharmaceutical ingredients.