Study on the Impurities and Preparation Process of Dexamethasone Sodium Phosphate Injection
|School||Zhejiang University of Technology|
|Keywords||dexamethasone sodium phosphate injection drug excipientcompatibility Impurity Ⅰ antioxidants qualitativeinvestigation pharmaceutical process|
Dexamethasone sodium phosphate (DSP) belongs to glucocorticoids, which has been commonly used pharmaceutical of great importance as named "the king of corticoid" for its low price and high effect in the area of anti-allergy and anti-autoimmunity inflammatory treatment.Dexamethasone sodium phosphate injection(DSPI) is sterile water solution. In recent years, it has been found flakes and precipitations in domestic drug products, as the import bulk drug was took place by the domestic one which has quite different craft and prone to hydrolyze to dexamethasone(Dex) which was practically insoluble in water and easily oxidized to change the color of the drug product. Manufacturers had attempted to improve the stability of the product by adjusting the prescription while few attentions had been paid to its related substances.The related substances test of DSPI was added into the pharmacopoeia of PRC(2012, part Ⅱ) in2012, which specified the limitations of Dex, Impurity I and other related substances. Institute for food and drug control had finished sampling inspect of DSPI in2012, the result showed that part of the samples were disqualification on related substances and assay tests, the content of Impurity I whose chemical structure, chemicophysical property and physiological toxicity were still unknown even exceeded the limitation for more than ten times in certain sample, greatly threatened the safety of the drug product.In this paper, the qualities of DSP and twelve batches of DSPI were examined according to ChP(2010), which proved that the Impurity I was not introduced from bulk drug but probably from pharmaceutical formulation or manufacture process. A series of force degradation tests were conducted to investigate the influence of the antioxidant sodium bisulfite(SB) to the stability of DSP, combined with the result on the structure analysis of Impurity I by HPLC-ESI-Q-TOF-MS, the results indicated that Impurity I was the product of the additive reaction from DSP and sodium bisulfite. Then Impurity I was roughly separated from additive reaction solution utilizing the solubility difference, and refined by pre-HPLC. The purity of Impurity I was up to96%calculated based on normalization method by HPLC. UV, IR, HPLC-ESI-Q-TOF-MS and NMR technologies were applied to make an all-round identification of Impurity I, and it had been shown possess no toxicity by animal tests.The relative response factor of Impurity I to DSP was also determined according to both USP and ChP and the results were with one accord, it was suggested that the relative correction factor should be considered in the calculation of the content of Impurity I.A method of making impurity I positioning solution for system suitability test was established by heat force from DSP and SB for improving the quality control ability. An in-lab preparation process which was analogical to practical industrial manufacture process was developed to investigate the key factors to the stability of DSPI, which indicated that other sulfite antioxidants besides SB could also reacted with DSP to produce Impurity I.It was proved that Dex could be absorbed by medicinal charcoal, propylene glycol could relieve the hydrolysis of the product and heating&filling nitrogen would affected the stability and the quality of DSPI. All work above could be beneficial references for optimizing the preparation process.