NMR-based Quality Control Of Fosfomycin Drugs

Fosfomycin is a new broad-spectrum of antibiotics with little side effect and can eliminate most of the gram-negative bacteria and Gram-positive bacteria. Now most fosfomycin is manufactured with synthetic methods. Fosfomycin has a unique chemical structure, similar with phosphoenolpyruvate（PEP）. Fosfomycin kill bacteria by competing with PEP which is an intermediate in the synthesis of bacterial cell wall. Fosfomycin specific antibacterial mechanism makes it shows no cross-resistance, no antagonism and a synergistic effect with other antibacterial drugs in combination. Fosfomycin application in clinical practice is very widespread.Fosfomycin（（2）-（1R,2S）-（1,2-epoxypropyl）phosphonic acid）, the epoxy ring is readily open, to generate（1,2-dihydroxypropyl）phosphonate（impurity A） which is needed to control in fosfomycin drugs. These compounds all have a simple chemical structure and strong polarity, and they have poor UV-Vis absorption or fluorescence response, these physico-chemical characteristics led to difficult separation and determination with directly chromatography or reversed-phase high-performance liquid chromatography with UV detection. With the rapid socio-economic development, people pay more attention to drug safety issues, so for the quality control of drugs fosfomycin is the most fundamental task of pharmacy workers. With the continuous development of analytical instruments, the analytical methods of fosfomycin drugs is ever-changing.Quantitative NMR analysis with quantitative and qualitative in one of the technologies used in pharmaceutical analysis has been greatly improved. Compared with other methods, NMR analysis is fast, accurate, and specific characteristics. Quantitative NMR analysis is analyzed by characteristic absorption peak area. As long as one or two relatively strong characteristic absorption peaks in the test compoundcan be quantitatively analyzed. Fosfomycin drugs contain only one phosphorus atom,³¹P-NMR peaks relatively simple, more specific. Compared with 1H-NMR, ³¹P-NMR can avoid the influence of other complex matrices. We only need a standard to make a criterion standard curve to calculate the content of the sample in external standard measurement.A method of quantitative ³¹P-NMR for simultaneous determination of fosfomycin and its impurity A in pharmaceutical products of fosfomycin sodium or calcium was developmented. In this method, trimethyl phosphate chemically stable was used as an external standard reagents evenly injected into the capillary coaxially inserted into the NMR tube in every ³¹P-NMR experiments. Standards are fosfomycin calcium. Compared to fosfomycin sodium hygroscopic characteristics, fosfomycin calcium can ensure the accuracy of the standard solution concentration. Criterion standard curve was manufactured by standard solution concentration as the horizontal and the ratio of phosphorus signal of standard solution with phosphorus signal of external standard reagent trimethyl phosphate as vertical axis. And the accuracy, precision and robustness of the analytical method were verified. Compared with other analytical methods, ³¹P-NMR determination of fosfomycin and impurity A is quite simple and accurate and there are good prospects in quality control of fosfomycin drugs.