Separation and purification method of high-purity vancomycin hydrochloride

一种盐酸万古霉素、分离纯化的技术，应用在肽的制备方法、化学仪器和方法、有机化学等方向，能够解决色谱纯度不能一次性达到99%以上、残留溶剂不能有效去除、达不到残留溶剂要求等问题，达到易于处理和溶剂的回收、产品颜色外观提升、简单浓缩处理的效果

Active Publication Date: 2015-05-13
ZHE JIANG MEDICINE CO LTD XINCHANG PHARMA FAB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The process involved in this patent has some defects, especially for the commercial expansion of production. First, different solvents are used in the mobile phase and eluent in this method, and there are certain difficulties in solvent recovery; second, because the process Through reverse-phase purification, the chromatographic purity cannot reach more than 99% at one time, so two steps of solvent crystallization are required, and finally the finished product is obtained by vacuum drying. However, the common problem of solvent crystallization is that the residual solvent cannot be effectively removed, and the ICH cannot be achieved. Requirements for residual solvents; finally, the method is not ideal in product yield due to many steps
[0007] Therefore, from the current literature, due to various defects, there is not yet a method for producing vancomycin hydrochloride suitable for commercial production with high purity (chromatographic purity reaching more than 99%) on the market, and in view of vancomycin hydrochloride Mycin drug safety, need a kind of method for preparing high-purity vancomycin hydrochloride

Method used

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  • Separation and purification method of high-purity vancomycin hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0027] Embodiment 1: Preparation of vancomycin hydrochloride solution with vancomycin B content not less than 95%

[0028] Dissolve 250 g of vancomycin crude product in 2.0 L of purified water in a beaker, stir well, and filter it with a filter membrane with a pore size of 0.2 μm after completely dissolving, then add water to dilute, and finally obtain 3.0 L of vancomycin hydrochloride crude product solution, The concentration is 43.6mg / ml, the chromatographic purity is 90.2%, see figure 1 .

[0029] Take 3000ml of the above-mentioned vancomycin hydrochloride crude product solution, pass it through the 8cm*60cm glass chromatography column equipped with dextran Sephadex CM-25, the column volume is about 4% of the column volume, and the adsorption method is to put the column volume liquid and 1 / 5 of the chromatography filler, and then put the mixture directly on the column, and then wash it with purified water at a flow rate of 1.5 times the column volume / hour. After washing 6 ...

Embodiment 2

[0031] Embodiment 2: Preparation of high-purity vancomycin hydrochloride finished product

[0032] Take 680ml of the concentrated solution prepared in Example 1, pass through a preparative column (15cm*30cm) equipped with a C18 silica gel filler with a particle size of 30 μm, adjust pH=4.0 with hydrochloric acid, and contain 0.2% NH 4 Cl(W / V) and 8% methanol aqueous solution (V / V) were used as the mobile phase for pre-washing 100mim, the flow rate was 5BV / h, and then the proportion of methanol in the mobile phase was increased to 12% for elution, and the flow rate was 5BV / h h, online detection wavelength λ=280, when the absorption value starts to rise rapidly, start to collect the eluate, collect one bottle per 2.5L, collect about 10 bottles in total, detect the vancomycin B content of each bottle, the chromatographic purity is greater than 98.5% were mixed to obtain a total of 12.5 L of mixed chromatography solution with a concentration of 6.8 mg / ml, and the pH was adjusted t...

Embodiment 3

[0034] Example 3: Concentration effect comparison of nanofiltration membranes with different apertures

[0035] Select nanofiltration membrane tubes with different pore diameters, the pore diameters are 100Da, 200Da, 400Da and 800Da respectively, and the filtration area is 0.32m 2 , installed in turn on the small nanofiltration membrane equipment in the laboratory (model LNG-NF-101), take 8000ml of concentrated solution containing 10% vancomycin hydrochloride, divide it into 4 parts, first take one part for nanofiltration concentration, and the circulation pump pressure Control at 10bar. At the beginning of concentration, take a dialysis sample for potency testing, and record the flow rate. When the volume of the circulating fluid is 1000ml, take a dialysis sample for potency testing, and record the dialysis flow rate. After each use Clean the equipment and replace the next nanofiltration membrane tube with another concentrated solution for testing. The test results are as fo...

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Abstract

Provided is a separation and purification method for vancomycin hydrochloride of a high purity. The method comprises the following steps: (1) obtaining a vancomycin hydrochloride solution from a crude vancomycin product by ion exchange chromatography and obtaining a concentrate by nanofiltration desalination and concentration; (2) adjusting the concentrate with a hydrochloric acid solution and then performing a column chromatography using a reverse chromatography column for the adjusted concentrate; (3) collecting the chromatographic solution of vancomycin to obtain a mixed chromatographic solution; (4) adjusting the mixed chromatographic solution, and separating the solution and the salts by nanofiltration desalination and concentration to obtain a concentrate; and (5) obtaining a vancomycin dry powder with a chromatographic purity of up to 99% and a pure white appearance by dehydrating and drying the concentrate of step (4), or by solvent crystallization or salting-out crystallization.

Description

technical field [0001] The invention relates to a method for separating and purifying high-purity vancomycin hydrochloride. The method uses crude vancomycin with a chromatographic purity of about 90% as a raw material, firstly carries out chromatography on a Sephadex column with saline-water as the mobile phase, collects vancomycin hydrochloride with a chromatographic purity greater than 95%, and Carry out nanofiltration desalting and concentration to 100mg / ml-200mg / ml, then pass through a reversed-phase C18 silica gel chromatography column or a reversed-phase polymer chromatography column, and use methanol aqueous solution or ethanol aqueous solution containing ammonium salt as the mobile phase to elute, and collect the chromatographic purity More than 98.5% vancomycin hydrochloride, then remove the solvent by nanofiltration, and then concentrate to 150mg / ml-250mg / ml for freeze-drying, to obtain vancomycin hydrochloride with a chromatographic purity of 99% and a pure white ap...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K9/00C07K1/14C07K1/18
CPCA61K38/14A61P31/04C07K9/008C07K1/18C07K1/20C07K1/34C07K1/36
Inventor 李恩民庄逸云王珏孙新强劳学军江必旺
Owner ZHE JIANG MEDICINE CO LTD XINCHANG PHARMA FAB
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