Development and validation of a stability-indicating HPLC method to determine the impurity profile of fosaprepitant dimeglumine in the injection formulation.

Fosaprepitant dimeglumine, an injectable phosphorylated prodrug of aprepitant, has been approved for preventing chemotherapy-induced nausea and vomiting. A novel stability-indicating HPLC method was designed and validated to determine process- and degradation-related impurities of fosaprepitant dimeglumine in an injection formulation. Chromatographic separation was done on a NanoChrom C18 (250 mm×4.6 mm, 5µm) column at a column oven temperature of 35°C. Mobile phase A had 0.5 M ammonium dihydrogen phosphate solution (pH fixed to 2.2 with orthophosphoric acid) and acetonitrile at 80:20 ratio and mobile phase B had methanol and acetonitrile at 70:30 ratio. The formulations underwent forced degradation conditions, like acidic, basic, thermal oxidation and photolytic conditions. The designed HPLC approach was validated per International Conference of Harmonization (ICH) guidelines, including limit of detection (LOD), specificity, limit of quantitation (LOQ), accuracy, linearity, precision and robustness. The results showed that this method is specific, sensitive, precise, accurate and robust.

Simultaneous Determination of Four Related Substances in Olmesartan Medoxomil Hydrochlorothiazide Tablets by HPLC-Principal Component Self-Control with Correct Factor / 中国药房

OBJECTIVE： To establish the method for simultaneous determination of four known related substances （olmesartan，olmesartan ester dimer ，olmesartan ester alkene ，benzothiadiazine impurity ，called impurity A ，B，C，D for short ）in Olmesartan medoxomil hydrochlorothiazide tablets. METHODS ：HPLC-principal component self-control with correction factor were adopted. The determination was performed on YMC-Triart C 8 column with mobile phase A consisted of acetonitrile- 0.015 mol/L potassium dihydrogen phosphate solution （pH adjusted to 2.8 with phosphoric acid ）（70 ∶ 30，V/V），mobile phase B consisted of acetonitrile-0.015 mol/L potassium dihydrogen phosphate solution （pH adjusted to 2.8 with phosphoric acid ）（15 ∶ 85，V/V）at the flow rate of 0.8 mL/min（gradient elution ）. The detection wavelength was set at 265 nm，and column temperature was 25 ℃. The temperature of injector was 4 ℃；the injection volume was 10 μL. RESULTS：The correction factors of impurity A ，B，C，D were 1.42，1.17，0.89，0.92，respectively. The linear range of olmesartan medoxomil ，hydrochlorothiazide and impurity A ，B，C，D were 0.252 7-7.580 0，1.152 1-4.562 9，0.244 0-18.299 0，0.244 7-3.670 8，0.265 2-3.978 3 and 0.149 9-4.497 3 μg/mL（r≥ 0.999 7），respectively. The limits of detection were 0.084 2，0.050 7，0.081 3，0.081 6，0.088 4，0.050 0 μg/mL，respectively. The quantitative limits were 0.252 7，0.152 1，0.244 0，0.244 7，0.265 2 and 0.149 9 μg/mL，respectively. The results of intermediate precision ，stability（24 h）and repeatability tests all met the relevant requirements. The average recovery rates were 104.00％-108.04％，102.00％-104.94％，100.99％-106.89％，92.00％-95.18％，102.00％-105.06％，103.90％-107.00％（n＝3）， respectively. The contents of impurity A ，B and D in 3 batches of Olmesartan medoxomil hydrochlorothiazide tablets were 0.90％ -1.00％ ，0-0.11％ ，0.16％ -0.24％ ，respectively. The impurity C and other impurities were not detected. There is no significant difference between the results measured by the established method and by the external standard method. CONCLUSIONS：The method has been proved to be highly sensitive and reproducible. It can be used to simultaneously determine four known substances in Olmesartan medoxomil hydrochlorothiazide tablets.