A method for efficiently removing residual organic solvents in insulin aspart

Abstract

The invention relates to the field of biomedicine, in particular to a method for efficiently removing solvent residues in the crystallization and drying process of insulin aspart. The insulin aspart crystallization drying process of the present invention adopts preliminary vacuuming to remove most of the organic solvents; then add water to keep the moisture and keep the pressure, during which temperature control and timely turning are required, so that the solvent crystals of insulin aspart are transformed into crystal water; Vacuumize, control the temperature and turn the material in time to further remove the difficult-to-remove residual organic solvents; repeat the moisturizing and pressure-holding and vacuuming steps to allow the wet solids to fully contact with water vapor, and ensure the stability of the sample on the basis of reducing solvent residues. The residual ethanol solvent in the kilogram-level insulin finished product prepared by the invention is less than 3000 ppm, and the product purity reaches more than 99%. It solves the problems of high solvent residue, unstable quality, high equipment requirements, high amplification cost and unsuitability for large-scale production existing in the prior art.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a method for efficiently removing solvent residues in the crystallization and drying process of insulin aspart. Background technique [0002] Insulin aspart is an effective drug for diabetes treatment produced by gene recombination technology. In the drying process of insulin aspart produced by gene recombination technology, normal temperature vacuum drying or freeze drying technology is generally used. In the traditional insulin production process, insulin crystallization uses a large amount of organic solvents to dehydrate and vacuum dry. This drying process not only has the risk of organic solvent residues, but also dries at room temperature, and the drying time is long. During the drying period, the temperature and drying time It also affects the biological activity and purity of insulin. CN103709244B adopts n-propanol to rinse and rinse the insulin aspart crystal to remove the h...

AI Technical Summary

Problems solved by technology

In the traditional insulin production process, insulin crystallization uses a large amount of organic solvents to dehydrate and vacuum dry. This drying process not only has the risk of organic solvent residues, but also dries at room temperature, and the drying time is long. During the drying period, the temperature and drying time Also affects the biological activity and purity of insulin

CN103709244B adopts n-propanol to rinse and rinse the insulin aspart crystal to remove the highly toxic resorcinol organic impurities, then remove the introduced organic solvent n-propanol by freeze-drying, but the freeze-drying process increases the production cost, and the equipment requirements are relatively high. High, and not conducive to industrial amplification

CN108929376A uses a hollow fiber system to wash insulin crystals or insulin analog crystals, collect the crystals, and freeze-dry. In the process, an ultrafiltration process is added to increase the production cycle. At the same time, the freeze-drying process is used, which has high cost and high equipment requirements

Although in today’s insulin production process, organic solvents are used for insulin crystallization, most of the solvent residues can be removed by washing and freeze-drying, but it is still impossible to lower the solvent residues in the finished product. The types of solvents used in the process Mainly ethanol, acetonitrile, isopropanol or toluene (there may be benzene impurities introduced into the toluene raw material), the current 2020 version of the Chinese Pharmacopoeia has limit requirements for these solvents, which are not more than (NMT) 5000 ppm, 410 ppm and 5000 ppm respectively and 890 ppm, of which the residual limit of benzene solvent is NMT 2 ppm, these residual solvents will bring certain risks to the quality of the final product

[0003] At the same time, using the freeze-drying process, although the quality requirements can be guaranteed to a certain extent, the requirements for equipment are relatively high, and the cost of process amplification is relatively high, which is mainly reflected in the cost of equipment. A freeze-drying line needs to invest tens of millions of funds. The electricity and maintenance costs required for later use are also relatively high; and most of them are freeze-dried in aqueous solution systems, and the obtained is amorphous solids, which cannot obtain more stable insulin crystals. During the later storage process, its related substances grow faster. The product is unstable

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