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 and cycle of detection. The HPLC purity of the product is 99.53%. According to the national drug standard YBH02852011, the total impurities of related substances shall not exceed 1.5%. ASP 9 ‐Bivalirudin and D‐Phe 12 ‐Bivalirudin should not exceed 0.5%. The prepared bivalirudin API is close to 1 / 3 of the total impurity limit. Within 2 years of validity, long-term storage is likely to cause quality problems such as unqualified inspection items for related substances

[0014] The purification process of the above-mentioned bivalirudin raw material drug has low product yield, production capacity or low purity, and the freeze-drying process cannot ensure that the known impurity ASP is easy to be detected during the freeze-drying of the sample. 9 ‐Bivalirudin does not increase, so it is not conducive to the industrial production of kilogram-level bivalirudin raw materials that can ensure that the relevant substance inspection items pass the validity period

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