The Study On2-[4-(2-methyl-1-propenyl)Phenyl]Propionic Acid In Ibuprofen And Its Analytical Method

2-[4-(2-Methyl-l-propenyl) phenyl] propionic Acid is a impurity that has been found recently in the analysis of ibuprofen by Shandong Xinhua pharm.ltd. Many customers of Xinhua ibuprofen pay more attention to the impurity. But Pharmacopeias do not include the impurity, and customers neither do related research, Fourthermore, they have no quantitation method about the impurity which could lead to a lot of trouble and adverse effort on sample reception, and bring considerable workload and difficulties to quality control. We carried out analysis from starting material of ibuprofen, then prepared the impurity by preparative chromatography, and confirmed the source of the impurity. Moreover, we prepared the impurity by chemical synthesis and performed chemistry structure analysis. Finally, the structure of the impurity was determined. Next, analytical method for the impurity was inverstigated. An excellent chromatographic condition was found and corresponding method was also validated. The Ibuprofen samples were tested randomly in order to prove whether the method was suitable for the determination of2-[4-(2-Methyl-l-propenyl) phenyl] propionic Acid in ibuprofen. After development of HPLC method for analysis of the impurity, relevant technological route for eliminating and reducing the impurity quantity was also investigated, and a suitable process route was achieved to improve the quality of ibuprofen.In the present paper, the source of the impurity by preparative chromatography was firstly found. Secondly, the impurity by chemical synthesis method was prepared, an d the structure was identified with HPLC、MS、Nuclear magnetic resonance (NMR). After that, a HPLC method of quantification of2-[4-(2-Methyl-1-propenyl) phenyl] propionic acid in ibuprofen and ibuprofen was developed. An internal standard met hod and corrected area normalization method were simultaneously employed to quanti fy the ibuprofen and2-[4-(2-Methyl-1-propenyl) phenyl] propionic acid, respectivel y. In the process of building method, the test conditions, including column, mobile p hase, wavelength and so on were optimized. To confirm the developed method, mean while, method validation including specialization, accuracy, precision, linearity and ran ge, LOD, LOQ and so on was also perfromed. The best HPLC conditions were as f ollows:wavelength:254nm; column:ODS C18,4.6X250mm,5μm; mobilephase:1%chloroacetic acid (adjust pH to3.0with ammonium hydroxide)-acetonitrile=40:60. The results showed that all the items above met requirement. The experiment on stor e time of ibuprofen solution also meet requirement, demonstrating ibuprofen solution was very stable and suitable to determine the2-[4-(2-Methyl-l-propenyl) phenyl] p ropionic acid.The method referring to the subject was not only used for controlling the2-[4-(2-Methyl-1-propenyl) phenyl] propionic acid, but also controlling the ibuprofen quantit y by internal standard method accurately. The established method was high sensitive, simple, conveninent and time-saving, which was valuable significance on quality contr ol of ibuprofen.Through our study on the synthesis of one of the ibuprofen starting material, isobutyl benzene, combined with analysis by gas chromatography and mass spectrometry,2-methyl-1-phenyl propylene in isobutyl benzene was identified. The generation principle of2-methyl-1-phenyl propylene by synthesis of isobutyl benzene and the source and mechanism of2-[4-(2-Methyl-1-propenyl) phenyl] propionic acid in ibuprofen were revealed.According to the structure and chemical properties of the impurity, we investigated how to eliminate and reduce the impurity quantity in ibuprofen. Different schemes, for example, the selection of oxidizing agent and determination of its concentration and quantity, were tried through a series of contrast and repeated experimental data. Finally, we found the suitable process route of reducing the impurity. The implementation of this technology would lay a solid foundation on improving ibuprofen quality, reducing production cost, improving customer satisfaction.