Study On The Quality Of Ferric Citrate Hydrate

Ferric citrate is the treatment of chronic kidney disease(Chronic kidney disease,CKD),It is used for the treatment of patients with iron deficiency anemia and hyperphosphatemia,used as a food iron fortifier,nutritional supplement,and as a radioactive drug to check iron metabolism abnormalities and hematopoietic function.In recent years,relevant studies have shown that ferrophos binding agent can reduce blood phosphorus levels in patients with chronic kidney disease,and can improve anemia to some extent.This experiment involves a medicinal grade iron citrate,medicinal grade iron citrate contains a certain amount of organic acid and a certain amount of iron.Iron citrate has been reported to maintain calcium and phosphorus stability by reducing serum fibroblast growth factor-23(FGF-23)while improving kidney and heart function.Ferric citrate was first developed by Taiwan’s Panion & BF company,which was first approved in Japan in January2014 under the trade name Riona,for improving hyperphosphatemia in patients with chronic kidney disease.However,the Chinese Pharmacopoeia on Ferric citrate has not been included,and there is almost no relevant literature report,mostly about the application of synthetic routes.This paper mainly develops and establishes a complete set of quality control standards and separation analysis methods for ferric citrate,so as to achieve the purpose of effectively controlling the quality of drugs and provide detection methods for the synthesis of this API.Develop methods for detecting ferric citrate-related substances,contents,and solvent residues,and conduct methodological verification.Liquid chromatography related substance analysis method conditions:the column selection is Ultimate AQ-C18 5μm,4.6mm*250mm;The mobile phase was selected for isocratic elution of 45mmol/L ammonium dihydrogen phosphate;The wavelength selection is210nm;The flow rate is selected as 1.0m L/min;The column temperature was selected as 30℃;The injection volume was selected as 30 μL;The content of known impurities was calculated by external standard method,and the content of unknown impurities was calculated by the main component self-dilution control method,and the duration was 30 min.The conditions for the analysis method of related substances in ion chromatography were: the column selection was Dionex Ionpac TM ASS11-HC RFIC TM ANALYTICAL(4*250 mm);The eluent was selected for 50 mmol/L potassium hydroxide gradient elution;The detector is selected as a conductivity detector;The flow rate is selected as 1.0m L/min;The column temperature was selected as 30℃;The injection volume was selected as 20 μL;The content of impurities was calculated by external standard method,and the duration was 65 min.The conditions for the separation and analysis of the eight related substances in ion chromatography were: the column selection was Dionex Ionpac TM ASS11-HC RFIC TM ANALYTICAL(4*250 mm);The eluent was selected for 50 mmol/L potassium hydroxide gradient elution;The detector is selected as a conductivity detector;The flow rate is selected as 1.0m L/min;The column temperature was selected as 30℃;The injection volume was selected as 20 μL;The content of impurities was calculated by external standard method,and the duration was 70 min.The conditions for liquid chromatography content analysis method are: the column selection is Ultimate AQ-C18 5μm,4.6mm*250mm;The mobile phase was selected for isocratic elution of 45mmol/L ammonium dihydrogen phosphate;The wavelength selection is210nm;The flow rate is selected as 1.0m L/min;The column temperature was selected as 30℃;The injection volume was selected as 20 μL;The content was calculated by the external standard method,and the duration was 25 min.The conditions of the gas chromatography solvent residue analysis method are: nitrogen as the carrier gas and air as the auxiliary gas;Select the FID detector;Shunt ratio 10:1;The inlet temperature is 200℃;Detector temperature 250 ℃;The heating rate is60℃ at the starting temperature,held for 5 min,and maintained at 20℃/min to 200℃ for 3 min.The results show that the analytical method established in this paper is durable,accurate and reproducible,and meets the ICH standards for API.In addition,the properties of ferric citrate were investigated from many aspects such as appearance,melting point,hygroscopicity,acidity and etc;Ferric citrate was identified from liquid phase,infrared spectrum,specific surface area,ferric iron identification and other aspects.Determination of general impurities of ferric citrate from moisture and chloride detection;Detection of heavy metals present in ferric citrate from inductively coupled plasma;The relevant substances,contents and solvent residues in the three batches of ferric citrate samples were detected;The stability of ferric citrate was investigated by forced degradation,light stability and other experiments.It provides a reliable reference for the commerical value and industrial production of Ferric Citrate API.