CSIR-NCL Develops an Anti-TB Co-crystal 4-FDC Drug with Improved Stability

Tuberculosis (TB) is an airborneinfectious disease caused by a species of pathogenic bacteria Mycobacterium Tuberculosis. It is one of the top ten leading causes of death worldwide. According to the World Health Organization (WHO) in 2015 an estimated 10.4-mn people developed TB and 1.8-mn died from the disease, including 0.4-mn deaths among HIV-positive people.

WHO recommends the use of four drugs for treating TB – Rifampicin, Isoniazid (INH), pyrazinamide, and ethambutol dihydrochloride. In 1994, WHO and the International Union against Tuberculosis and Lung Disease (IUATLD), recommended the use of Fixed Drug Combinations (FDCs) (2-drug, 3-drug and 4-drug), and in 1999, the 4-drug FDC tablet, comprising all four drugs, was included in the WHO Model List of Essential Drugs.

But the 4-FDC tablets had quality and stability issues, including poor bioavailability of rifampicin and instability during storage. This raised serious concerns on its utility.

Now scientists from the CSIR-National Chemical Laboratory (CSIR-NCL), Pune have come up with an anti-TB co-crystal drug having improved stability. The research, published in the Journal of Pharmaceutical Sciences, by Prof. Ashwini Kumar Nangia and team at the CSIR-NCL and the School of Chemistry, University of Hyderabad has cleared the way for development of a stable formulation of 4-FDC for TB.

Five-fold improvement in stability

The team studied the cause for the instability of the 4-FDC drug and discovered a pharmaceutically stable co-crystal by applying crystal engineering principles to inhibit the cross-reaction between INH and rifampicin, thereby overcoming the formation of inactive by-products. The team showed that the pharmaceutically stable co-crystal of INH (INH-Caffeic Acid and INH-vanillic acid) is able to improve the stability more than five-fold compared to the current 4-FDC drugs. The co-former additives, which stabilize the formulation, are pharmaceutically accepted excipients. “Stable co-crystal drug with longer shelf-life will improve the prospects of transport logistics and inventory management of TB drugs,” Prof. Nangia said. In the next phase, longer-term stability data on 4-FDC will be validated with suitable excipients and polymeric additives to develop the tablet formulation.