Product, process and packaging optimization for development of stable oral capsule formulation of second-line anti-tubercular drug

Objectives: Cycloserine (CS) is a second-line anti-tubercular drug. It is an analog of d-alanine amino acid which directly interfere with peptidoglycan formation and bacterial cell wall synthesis in susceptible strains of Mycobacterium tuberculosis. Stability of CS and flowability of its final blend are the two major problems in formulation development of CS capsules. The main objective of the present investigation was to develop stable and commercially viable robust formulation of CS at affordable price. Materials and Methods: For product formula finalization, selection of appropriate grade of diluent and quantitative optimization of glidant, anti-adherent, lubricant and alkalizer (s) was done. For process parameter optimization; processing environmental condition, slugging, filling process and packaging material optimization were done. Results: Avicel® PH 200 was selected as a diluent due to its higher particle size, hence better flow property. Addition of magnesium oxide and sodium carbonate as an alkalizer mixture increased the micro-environmental pH of formulation and prevented auto-aminolysis of CS. Slugging (Dry Granulation) was the suitable technique of choice because CS is a moisture sensitive API. Flowability of blend was further augmented by sodium stearyl fumarate, purified talc and colloidal silicone dioxide. In packaging material study, it was concluded that capsules packed in fompack Alu-Alu blister displayed better performance as compared to HDPE bottle with CRC closure at 25° ± 2°C /60 ± 5%RH and 30° ± 2°C /65 ± 5%RH in long term stability study. Conclusion: The formulation developed in our lab is stable and cost effective, which can be easily afforded by people of developing or least developed countries. Key words Tuberculosis; Cycloserin; Alkalize; Stability; Flow improvement; Dry Granulation; Slugging; Packaging; Alu-Alu blister