Crude drug bivalirudin purification process

Abstract

The invention belongs to the field of pharmaceutical synthesis and particularly relates to a crude drug bivalirudin purification process. According to the bivalirudin purification and drying process, two purification systems are combined to complete bivalirudin purification, a chromatographic system for first-time purification (coarse purification) consists of a mobile phase A, namely 0.025%-0.2% of heptafluorobutyric acid solution, and a mobile phase B, a chromatographic column filler is an octadecyl silane bonded silica gel filler with the particle diameter ranging from 45 microns to 75 microns, the purity can be up to 99.8% after gradient elution, a chromatographic system for second-time purification (refine purification) consists of a mobile phase A, namely 0.01%-0.05% of trifluoroacetic acid solution, and a mobile phase B, a chromatographic column filler is an octadecyl silane bonded silica gel filler with 10-microns particle diameter, and the purity of a concentrated solution can be up to 99.8% after gradient elution and twice purification.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a purification process of bivalirudin crude drug. Background technique [0002] Bivalirudin is a direct thrombin inhibitor (DTI), derived from hirudin derivatives, and is a synthetic short peptide consisting of 20 amino acids. Bivalirudin is an effective, highly selective and reversible inhibitor that not only inhibits free and bound thrombin, but also inhibits thrombin-mediated platelet activation and aggregation. Bivalirudin has fast drug effect, short half-life, does not combine with plasma proteins and red blood cells in the body, and has no risk to heparin-induced thrombocytopenia and heparin-induced thrombosis-thrombocytopenia syndrome (HIT / HITTS). , In the treatment, there is no need to combine antithrombin and other cofactors, and there is no need to activate platelets. These characteristics make bivalirudin an ideal heparin substitute. [0003] Bivalirudin (al...

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Problems solved by technology

[0008] Chinese patent CN200910028793.7 only describes the purification of bivalirudin primary peptide by HPLC method and freeze-drying. There is no detailed description of the purification process and freeze-drying process, and the product purity can only reach 98.5%, according to the national drug standard YBH02852011. Substances should not exceed 1.5%, the prepared bivalirudin API is close to the impurity limit, within 2 years of validity, long-term storage is likely to cause unqualified inspection items of related substances

This method only uses a chromatographic purification system, and the elution gradient has not been described in detail. During the purification process, 25% DMSO (dimethyl sulfoxide) solution was used to dissolve the crude peptide, while for the raw material drug used in the preparation of injection , In the quality control system of raw materials, DMSO needs to be controlled for residual solvents, which increases the cost an

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