Category: Formulation and Quality
Purpose: The purpose of the present research is to study the impact of antioxidants such as Butyl hydroxyl anisole and sodium ascorbate in impurity profile control of Rifapentine tablets at initial time and stability conditions. The formulations were analyzed for its tableting properties, in vitro dissolution behavior and impurity profiles.
Methods: Rifapentine is a rifamycin antimycobacterial indicated for the treatment of pulmonary tuberculosis caused by Mycobacterium tuberculosis in combination with one or more antituberculosis drugs. Rifapentine is having poor aqueous solubility across the physiological pH range and it is very sensitive to the environmental conditions like temperature, oxygen and moisture. The development of Rifapentine Tablets is quiet challenging with its impurity profiles. On storage conditions the impurity profiles are drastically increases and it may impact on the therapeutic efficacy of the product. Hence, the present study focuses to control the impurities of Rifapentine tablets by incorporating antioxidants. The major impurities present in the Rifapentine tablets are Rifapentine N-Oxide, 3-formyl rifamycin and Rifapentine quinone. The formulations were prepared by wet granulation method using different granulating liquids such as water and isopropyl alcohol. Formulations were designed 1) without antioxidants 2) with Butyl hydroxyl anisole 3) with sodium ascorbate. The common inactive ingredients used in the study are microcrystalline cellulose, Pregelatinized starch, Sodium starch glycolate, Disodium EDTA, Hydroxypropyl cellulose, Sodium ascorbate and Calcium Stearate. The final tablets were coated with Opadry brown coating material. Tablets were evaluated for tableting properties such as weight variation, hardness, thickness, disintegration time, friability and dissolution behavior. All the formulations were analyzed for impurity profiles at initial condition and at accelerated conditions (40°C/75%RH for 1, 2 and 3 months).
Results: The lubricated blend was evaluated for flow properties (Compressibility Index, Hausner’s ratio and angle of repose) and particle size distribution. The results indicated that the lubricated blend was good flow and having good compression properties. All the formulations were evaluated for in vitro dissolution behavior in pH 7.0 Phosphate buffer + 0.8 % SLS, USP II, 900 mL, 50 rpm. The results were compared with reference product, Priftin® (Rifapentine) Tablets. The similarity factor (f2) with reference product was found >60% in all the formulations. The impurity profiles were analyzed for all the above formulations. The major impurities present in the Rifapentine tablets are Rifapentine N-Oxide, 3-formyl rifamycin and Rifapentine quinone. Rifapentine N-oxide and Rifapentine quinone impurities obtain by oxidation of the active ingredient. Whereas 3-formyl rifamycin impurity is obtains by hydrolysis. The formulation prepared without antioxidant produced Rifapentine N-Oxide (1.2%), 3-formyl rifamycin (0.02%) and Rifapentine quinone impurities (2.5%) at initial period. The formulation contains Butyl hydroxyl anisole exhibited Rifapentine N-Oxide (0.8%), 3-formyl rifamycin (0.1%) and Rifapentine quinone impurities (1.4%) at initial time. The formulation contains sodium ascorbate exhibited Rifapentine N-Oxide (0.8%), 3-formyl rifamycin (0.1%) and Rifapentine quinone impurities (0.7%). The formulation contains Butyl hydroxyl anisole unable to control the impurities during stability studies. The formulations made with sodium ascorbate controls the impurities better compared with Butyl hydroxyl anisole.
Conclusion: The flow properties for the granules obtained by aqueous granulation were good. The physicochemical properties of tablets were meeting all the specification limits of official compendia. There was a significant enhancement in the Rifapentine quinone impurity during stability studies. Rifapentine undergoes oxidation and produces Rifapentine Quinone and Rifapentine N-oxide. The formulation contains Sodium Ascorbate converts the Rifapentine Quinone to Rifapentine better than Butyl hydroxyl anisole. Hence, sodium ascorbate based formulation controls rifapentine quinone based on other anti-oxidant. The impurity 3-formyl rifamycin is obtained by hydrolysis of Rifapentine and there is not much enhancement in its values during stability conditions. Finally, it was concluded that sodium ascorbate is better antioxidant in controlling the impurity profiles of Rifapentine tablets.