Study On The Tautomerism Of Benzimidazole Compounds And The Quantitative Determination Of Pantoprazole Sodium By Nuclear Magnetic Resonance

In this paper the tautomerism of benzimidazole compounds was studied by NMR.The quantitative nuclear magnetic resonance?qNMR?method was demonstrated to determine the content of pantoprazole sodium in its tablet formulation.First,NMR experiments combined density functional theory?DFT?theoretical calculations method was established to study the tautomerism of Omeprazole sulfide?R?-Lansoprazole and Omeprazole sulfone under different conditions.The results showed that the chemical shifts of the same compound in CDCl_3,DMSO-d₆ and CD₃OD were quite different.Among which the hydrogen proton signals of benzimidazole ring became wide and weak.Some carbon signals were so weak that even disappeared in the baseline.However well split spectra were obtained when the solvent was changed to DMSO-d₆+NaOD.This paper discussed the reason was that the tautomeric equilibrium of three compounds was effected by the nature of solvents and the formation of hydrogen bonds.Second the tautomerism of three compounds among the range of 203K-323 K was studied by variable temperature nuclear magnetic resonance?VT-NMR?experiments.The results showed that at 203 K the two tautomers of Omeprazole sulfide were separated and determined to be 6:4 and those of Omeprazole sulfone be 7:3.In contrast?R?-Lansoprazole presented only one tautomer at 203 K while the tautomerism was observed again when the temperature increased to 243 K.Their free energies of activation of the tautomeric interchange were 13.77 kcal/mol,13.47 kcal/mol and 13.06 kcal/mol,respectively.DFT simulations were demonstrated to calculate the energy of all the tautomers of three compounds.The preferred conformations of them were given.?R?-Lansoprazole had higher energy differences among the three compounds demonstrating only one preferred conformation existed at203K.At last the qNMR method combined method validation experiments were demonstrated for the determination of proton pump inhibitors?PPIs?pantoprazole sodium in its tablet formulation.The results showed that this method was in good liner among the range of 2.04-20.40 mg/mL?R²=0.9994?.The limit of detection?LOD?and limit of quantitative?LOQ?were 0.39 mg/mL and 1.21 mg/mL,respectively.The contents of pantoprazole sodium were tested to be 21.8%,which was in consistent with the result of HPLC?21.7%?.The method was easy,accurate and reproducible for determining the content of pantoprazole sodium.