Study On The Process Improvement Of Mecobalamin API

Mecobalamin, also called methyl vitamin B12, is one of the four kinds of vitamin B12 (cyanocobalamin, methylcobalamin, adenosylcobalamin and hydroxocobalamine) in the current international market. It is a very effective drug for anti peripheral neuropathy, participates in body metabolism, and therefore it is called cobamamide coenzyme B12. It is used to maintain the morphology and function of cells in the body by methyl conversion and used for nervous system disease, diabetic polyneuropathy etc. especially obvious effect on numbness, paralysis and pain in clinic. This product can promote the synthesis of nucleic acid and protein, promote the axon of axial and axonal regeneration, promote myelination of axons, and reduce the transmission delay of neurotransmitters and recovery. Methylation test of acute and subacute and chronic toxicity of inorganic mercury shows that methylcobalamin is a low toxic drug, and safe in clinical application. Mecobalamin has been listed in the "national basic drugs directory".In recent years, the number of patients who have diabetes increased at an alarming rate year by year. Diabetes has been listed as the third major diseases which is seriously harmful to human followed cancer and cardiovascular disease. Peripheral neuropathy is one of the common complications of diabetes mellitus. About 2/3 of non-insulin dependent diabetic patients have peripheral nerve and autonomic neuropathy, which cause sharp pain, numbness, movement disorders and even cause gangrene and amputation. Mecobalamin is an effective drug for clinical treatment of the diabetic according to Beijing, Shanghai clinical cooperation group studies. Mecobalamin has a good effect in the treatment of diabetic neuropathy. Therefore, It's of great practical significance to carry out the Mecobalamin API process technology research, improvment and production, as it can not only minimize the costs, improve the product quality, reduce environmental pollution, but also facilitate domestic patient use, to meet the needs of clinical medicine.The study found Cyanocobalamin is used as starting materials in traditional synthesis of Mecobalamin API. Add the reducing agent sodium borohydride into the mixed solution at 30±2 ?and add FeSO4 as Catalyzer, then add CH3I methanol solution or trimethylsulfoxonium iodidein the solution. Methylation reaction occurs lasting about 1 hours. After the reaction completed, the solution is filtered, evaporated, extracted by macroporous adsorption resin. The reaction solution are extracted by crystallization and finally finished Mecobalamin is obtained. This kind of preparation process, easy to produce by-products and waste during reduction reaction, irritant gases are produced during methylation reaction which pollute environment and finished product has high impurities and low chromatographic purity. Mecobalamin yield is only 80-90%.According to the shortcomings and deficiencies of the above process, we have made improvement studies on process technology of Mecobalamin.The main research contents and achievements are briefly introduced as follows:(1) This study optimized the process conditions of reducing reaction and catalyst. The reduction rate is well controlled, which can restrain trivalent cobalt being reduced to one cobalt, reduce the occurrence of side effects.(2) Because of the use of another type of catalyst in reduction reaction stage, it can not only make the reducing agent hydrolysis completely, but also make the catalyst reused, and reduce the environmental pressure.(3) The methylation reagent is optimized in this study, which is easy soluble in water, strong methylation ability and no odor material is produced. It effectively alleviate the environmental pressure of API production, while conducive to protecting the health of employees.(4) This study optimized the purification medium which is dedicated for Mecobalamin, this purification medium has strong specificity, effectively reduce the related substances of Mecobalamin, capable of producing high purity Mecobalamin which can greatly improve the drug safety of clinical medication.(5) Optimize the production process conditions, improve the quality and yield of products, reduce the cost.After studying small-scale process for a long time, the process and the control parameters of the production of Mecobalamin have been improved, which can produce high purity qualified products. The optimized process is started with Cyanocobalamine, optimized methylating agent, reducing agent catalyst and limiting reagent mixing in the reactor, add of sodium borohydride dilute alkali solution dropwise after removing oxygen by introducing high purity nitrogen oxygen into solution, followed by reductive methylation reaction which Mecobalamin is produced within one synthesis step. In this optimized process of Mecobalamin production, Cyanocobalamin isalsoused as starting materials; Mecobalamin is produced within one-step synthesis process, which is a simple production process with convenient production conditions and no need of equipment modificationand less requirements on facilities. Due to the optimized process reagent and conditions and optimization of refining medium dedicated for Mecobalamin, we can produce this product of good quality and high yield of about 93%. A small amount of pollutants generated in the production process which has the prospection of wide application.