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High-purity polymyxin B1 sulfate crystal form and preparation method thereof

A polymyxin, high-purity technology, applied in the field of high-purity polymyxin sulfate B1 crystal form and its preparation, can solve the problems of large toxic and side effects, affecting the clinical use of polymyxin, etc. The effect of less species and total amount and uniform particle size distribution

Pending Publication Date: 2021-06-11
CHONGQING QIANTAI BIOLOGICAL MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the main impurities B3 and B1-I have relatively large toxic and side effects, which have seriously affected the clinical use of polymyxin. At present, the main method of medication is external use, and it is locally used for eye, ear, skin, mucous membrane infections and burns of sensitive bacteria. Bacterial infection, the European Pharmacopoeia EP and the United States Pharmacopoeia USP stipulate that the quality standards of polymyxin B sulfate are basically the same, requiring the sum of B1, B2, B3, and B1-1 to be ≤80.0%, impurities B3 to be ≤6.0%, and B1-I to be ≤15.0%
Impurities B3 and B1-I are very close to active ingredients B1 and B2 in structure (see formula I below), and conventional ultrafiltration, organic solvent extraction, nanofiltration, chromatographic column purification, precipitation and other methods are difficult to effectively remove. Wider promotion and use requires the use of new technologies to remove impurities with large toxic and side effects to obtain effective monomers

Method used

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  • High-purity polymyxin B1 sulfate crystal form and preparation method thereof
  • High-purity polymyxin B1 sulfate crystal form and preparation method thereof
  • High-purity polymyxin B1 sulfate crystal form and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Dissolve 100g of multi-component polymyxin sulfate B (components: B1=40%, B2=7.5%, B3=1%, B1-I=7%) in 1000ml purified water, prepare and separate on 100DAC, The filler is Daiso's SP-100-8-ODS-P, the mobile phase is 23% acetonitrile water, 8‰ sodium sulfate is added, the pH is adjusted to 2.5 with phosphoric acid, and the detection wavelength is 215mn. After collecting in sections, the polymyxin B1 components are combined. ≥99% of the components; the collected liquid was concentrated to 1 / 5 of the original volume by nanofiltration, after adding purified water with 4 times the volume of the concentrated liquid, adsorbed on SP825 macroporous adsorption resin, and washed the resin with 5 times the volume of purified water. 5 volumes of 70% ethanol, pH 5.0 ± 0.5, were hydrolyzed. Collect the desorbed solution, dilute it with an equal volume of purified water of the desorbed solution, and then concentrate to 500 ml by nanofiltration. Add 3000 ml of purified water in 5 times t...

Embodiment 2

[0035] Dissolve 100g of multi-component polymyxin sulfate B (components: B1=40%, B2=7.5%, B3=1%, B1-I=7%) in 1000ml purified water, prepare and separate on 100DAC, The filler is Daiso's SP-100-8-ODS-P, the mobile phase is 25% acetonitrile water, 4‰ sodium sulfate is added, the pH is adjusted to 2.0 with phosphoric acid, and the detection wavelength is 215mn. 99% of the components, the collected liquid was concentrated to 1 / 5 of the original volume by nanofiltration, after adding purified water with 4 times the volume of the concentrated liquid, adsorbed on the XAD1600N macroporous adsorption resin, and washed the resin with 5 times the volume of the resin. .0±0.5 of 60% acetone hydrolyzed by 5 volumes. Collect the desorbed liquid, dilute it with an equal volume of purified water, and then perform nanofiltration to concentrate to 500 ml. Add 3000 ml of purified water in five times to replace acetonitrile, and then concentrate to 500 ml. Add 4500 ml of acetone to the concentrate...

Embodiment 3

[0037] Dissolve 100g of multi-component polymyxin B sulfate (composition of each component: B1=40%, B2=7.5%, B3=1%, B1-I=7%) in 1000ml purified water, prepare and separate on 100DAC, The filler is Daiso's SP-100-8-ODS-P, the mobile phase is 90% acetonitrile water, 10‰ sodium sulfate is added, and the pH is adjusted to 3.5 with phosphoric acid. The detection wavelength is 215nm, and after collection in sections, the components with polymyxin B1 components ≥ 99% are combined. Concentrate the collected liquid by nanofiltration to 1 / 5 of the original volume, add purified water with 4 times the volume of the concentrated liquid, and then adsorb on HZ20SS macroporous adsorption resin, wash the resin with 5 times the volume of resin purified water, and use 50% of pH 5.0±0.5 Absorb 5 times the volume with acetonitrile hydrolysis. Collect the desorption liquid, dilute it with purified water equal to the volume of the desorption liquid, then conduct nanofiltration and concentrate to 50...

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PUM

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Abstract

The invention provides a preparation method of a high-purity polymyxin B1 crystal form, specifically, a DAC preparative column is adopted for separation, then macroporous resin desalination treatment is conducted, and then the polymyxin B1 sulfate crystal form is crystallized after nanofiltration concentration, the crystal form provided by the invention is uniform in particle size distribution and good in fluidity, preparation of a preparation is facilitated, the preparation method of the crystal form is simple, and the obtained crystal has high purity.

Description

technical field [0001] The present invention relates to the technical field of purification and crystallization of microbial fermentation products, in particular to a high-purity polymyxin sulfate crystal form and a preparation method thereof. Background technique [0002] Polymyxin B sulfate, also known as colistin B sulfate, is a polypeptide antibiotic composed of a variety of amino acids and fatty acids, including polymyxin B1, B2, B3, B1-1, among which B1 and B2 are the effective components, and B3 and B1-1 are the main impurities. It has a strong inhibitory or bactericidal effect on almost all Gram-negative bacteria, such as Escherichia coli, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Acidophilus, Bacillus pertussis and Shigella, etc., especially for green Pseudomonas has a significant effect. The drug has been approved for use as a feed additive in many countries around the world. [0003] The molecular formula of polymyxin B sulfate is: C 56 ...

Claims

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Application Information

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IPC IPC(8): C07K7/62C07K1/36C07K1/34C07K1/30C07K1/16
CPCC07K7/62
Inventor 周大国郭明张有理吴禄春袁建栋
Owner CHONGQING QIANTAI BIOLOGICAL MEDICINE
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