The Development Of Ibuprofen Injection

Ibuprofen oral(Tread name, Brufen) was manufactured by the British Boots Company, UK, in 1968, for the treatment of mild to moderate pain and fever. It has been widely used in clinic for over 40 years and proved safety. Based on its good curative effect and less side effects, many countries have approved the ibuprofen for the OTC use. Ibuprofen is one of the most used antipyretic and analgesic medicines, which has the most dosage forms in China.In June 11, 2009, ibuprofen injection(Caldolor) of Cumberland pharmaceuticals Co. Ltd. was approved by the U.S. Food and Drug Administration(FDA). It was the first intravenous formulation for the treatment of pain and fever. Compared with ibuprofen oral, the safety and effectiveness of the injection are same, but it takes effect more quickly, and can be administered for the patients intolerant of oral administration, such as endotracheal intubation, coma, gastric motility decreased, nausea, just had surgery, or the patients who cannot ingest, digest, or absorb oral medication due to the other factors. In this study will make a comprehensive research on the imitation of ibuprofen injection, to fill the market vacancy of ibuprofen in our country. Part one Establish refining process of ibuprofen APIObjective: Establish the ibuprofen API refining process. Pilot test is done to ensure the technical feasibility, and provide stable source of API for ibuprofen injection.Methods: Use the impurity content, loss on drying or bacterial endotoxin as the indicators, optimize the concentration and dosage of the refined solvent, the dosage and decarbonization time of the activated carbon, the temperature and time of crystallization and drying.Results: In the refining process, 70% ethanol as the solvent refining, 60℃ as dissolved temperature,0.5% activated carbon, 30 min as decarbonizati--on time,stirring crystallization among 0~4℃, 3~4 hours of drying at 50 ℃, all the above were selected.Conclusion: Through the influence factors test, the pilot product was determined to be sealed for storage. The accelerated stability test for 6 months proved the total impurities content of the pilot products does not exceed 0.023%; the long term stability test for 6 months proved the total impurities of products does not exceed 0.020%. All the other indicators were also in line with the API internal control standards, the quality of product was stable. Part two Establish preparation technology of ibuprofen injectionObjective: Because the ibuprofen is difficult to dissolve in water, so adding arginine, one of alkaline cosolvent, can increase its water solubility, which made it more easily into injection form. Establish and optimize the preparation technology of ibuprofen injection, prepare six batch samples(2 specifications) in the pilot scale, observe the stability of product, and verify the superior and inferior of the process.Methods: Use ibuprofen: arginine =1:1(molar ratio) as prescription, product impurities, content, p H value and so on as indicators, the temperature, dosage of activated carbon and sterilization method of ibuprofen solution were optimized.Results: In the preparation technology, dissolving raw materials by the 60℃water for injection, adding 0.1% activated carbon, eliminating pyrogen for 15 minutes at 60℃, sterilizing at 121 ℃for 12 min, all the above were selected.Conclusion: Based on the influence factors test of pilot products, shady and cool was determined to be the storage condition. The accelerated stability test for 6 months proved the total impurities content of pilot products does not exceed 0.009%; The long term stability test for 9 months, proved the scaled total impurities of products does not exceed 0.010%, All the other indicators were also in line with the preparation quality specification. Part three Establishment ibuprofen injection quality standardsObjective: To establish the quality standard of ibuprofen injection, and ensure product quality.Methods: Establish a method for determination of known impurities and unknown impurities, and other amino acids, ibuprofen, arginine content, and carry on methodology validation about the method including the linear, durability, intermediate precision, recovery and repeatability.Results: The standard is tentatively scheduled for that 2-(4-isobutyrylph--rnyl) propionic acid(ibuprofen impurity A) should be no more than 0.2%, 4- isobutyl benzoic acid(ibuprofen impurity B) should be no more than 0.1%, 4- isobutyl acetophenone should be no more than 0.2%. 2-(4-formylphenyl) pro--pionic acid(EP impurity K) are not included in the quality standard. Sodium methylparaben(ibuprofen impurity C) and 2-(4-butylphenyl) propionic acid(EP impurity B) are not synthetic intermediates and byproducts, also not degradation products, and will not be produced in the process of stability research, so excluded from the quality standard. HPLC method is used to test the ibuprofen content, which determined the product is limited to 90% ~ 110%, is on the quality standard.Conclusion: In this study established comprehensive ibuprofen injection quality standards, which is better than other ibuprofen relevant standards at home and abroad now, and more appropriate for products determination.