Study On Related Substances Of Prednisolone Sodium Phosphate

Prednisolone is a corticosteroid drug with predominant glucocorticoid and low mineralocorticoid activity, making it useful for the treatment of a wide range of inflammatory and auto-immune conditions such as asthma, rheumatoid arthritis, ulcerative colitis, vasculitis, acute lymphoblastic leukemia, autoimmune hepatitis and systemic lupus erythematosus. It can also be used as an immunosuppressive drug for organ transplants. Prednisolone has a low solubility in water and for advanced bioavailability the prednisolone sodium phosphate was prepared, which can be formulated for both parenteral and topical administration. In the processing of synthesis and producing of preparation, some by-products yield to affect the quality and safety in clinical therapy. Therefore identifying the related substances of prednisolone sodium phosphate (PSP) is essential for marketing authorization.EU and USP pharmacopeias both provide standard of quality control for related substances. The given chemical structures are mostly produced in the proceedings of synthesis of PSP, the degraded products fron PSP preparation in manufacture progress have not been reported, especially the thermal degradants. John SE has reported that Prednisolone sodium phosphate is believed to undergo hydrolysis of the phosphate ester group in water.We analyze the bulk drug of PSP to find seven impurities that more than 1‰. According to reference data, five impurities were deduced by HPLC-MS analysis: 11β,17-dihydroxy-21-nor-3,20-dioxopregna-1,4-diene(1-2), 11β-hydroxyl-3-oxoandrosta-1,4-diene-17-carboxylic acid (1-3), 11β,17a-Dihydroxy-3,20-dioxopregna-1,4-dien-21-oic acid (1-4), 17α-formyloxy-11β-hydroxy-1,4-androstadien-17β-carboxylic Acid (1-5).Furthermore, five impurities were isolated from impurity fraction of PSP by using HSCCC and preparative HPLC methods, their structures were identified by 1H-,13C-NMR,2D NMR spectra and X-ray analysis as follow: (17S*,20S*)-11β,20-dihydroxy-3-oxopregna-1,4-diene-21-oil acid (2-1), (17S*,20R*)-11β,20-dihydroxy-3-oxopregna-1,4-diene-21-oil acid (2-2), (17R*,20R*)-11β,20-dihydroxy-3-oxopregna-1,4-diene-21-oil acid (2-3) 11β,17α-dihydroxy-3-oxoandrosta-1,4-diene-17β-carboxylic acid (2-4), 11,17α,21-trihydroxy-1,4-pregnadien-3,20-dione (2-5, prednisolone). In addition, the above compounds were assigned to that of PSP impurities by HPLC method in chromatographic condition of EU pharmacopeia.