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Separation and purification method of tacrolimus

A tacrolimus, separation and purification technology, applied in the field of biopharmaceuticals, can solve problems such as high cost and difficult industrial production, and achieve the effect of improving purity and high yield

Active Publication Date: 2022-01-11
NEW FOUNDER HLDG DEV LLC +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In recent years, there are more and more methods for the research and separation and purification of tacrolimus, mainly focusing on the extraction of fermented mycelia, separation of macroporous resins, silica gel chromatography, high-speed countercurrent chromatography, reversed-phase column chromatography, Silver salt modified silica gel or resin chromatography, normal phase column preparation, etc. However, these methods will undoubtedly use high-cost fillers and complex mixed solvent systems, and some even use acetonitrile, tetrahydrofuran and other toxic solvents , only suitable for laboratory research, difficult to apply to industrial production

Method used

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  • Separation and purification method of tacrolimus
  • Separation and purification method of tacrolimus
  • Separation and purification method of tacrolimus

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] The separation and purification method of tacrolimus in this embodiment comprises the following steps:

[0063] 1) Use a ceramic membrane to filter 30L tacrolimus fermentation broth (the content of tacrolimus in the fermentation broth is 1.054mg / mL, as determined by HPLC, the fermentation broth contains 31.62g of tacrolimus, and the tacrolimus in the fermentation broth The purity is 63.45%), and use 90L of water to wash the filter cake to obtain ceramic membrane dope 10L. Wherein, the pore diameter of the ceramic membrane is 50 nm.

[0064] 2) Add ethanol to the ceramic membrane dope until the volume concentration of ethanol in the dope is 30%, then add 3 L of Huazhen HZ806 resin, stir for 2 hours and then filter, rinse the filtered resin with a small amount of water, and wash the 3 L of Huazhen Pack the column with Zhen HZ806 resin to get the first resin column, then use 6L Huazhen HZ806 resin to pack the column to get the second resin column, and then use 15L Huazhen...

Embodiment 2

[0071] The separation and purification method of tacrolimus in this example is basically the same as that in Example 1, except that:

[0072] In step 1), the tacrolimus content in the tacrolimus fermentation broth used was 1.07 mg / mL, the fermentation broth contained 32.1 g of tacrolimus, and the tacrolimus purity in the fermentation broth was 64.12%.

[0073] In step 2), ethanol with a volume concentration of 50% is used as the eluent to elute the series resin column.

[0074] Finally, 22.1 g of tacrolimus was obtained with a purity of 99.09% and a total yield of 68.56%.

Embodiment 3

[0076] The separation and purification method of tacrolimus in this example is basically the same as that in Example 1, except that:

[0077] In step 1), the content of tacrolimus in the tacrolimus fermentation broth used was 1.01 mg / mL, the fermentation broth contained 30.3 g of tacrolimus, and the purity of tacrolimus in the fermentation broth was 63.77%.

[0078] In step 2), ethanol with a volume concentration of 45% is used as the eluent to elute the series resin column.

[0079] Finally, 20.75 g of tacrolimus was obtained with a purity of 99.59% and a total yield of 68.48%.

[0080] In this example, after obtaining the crude product of tacrolimus chromatography, the resin in the first resin column was regenerated with absolute ethanol, the regenerated solution appeared red, and the regenerated resin returned to white.

[0081] figure 1 It is the pure product liquid phase chromatogram of tacrolimus of embodiment 3, to figure 1 The relevant information in Table 1 can be ...

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Abstract

The invention provides a separation and purification method of tacrolimus. The method comprises the following steps: 1) filtering tacrolimus fermentation liquor by using a ceramic membrane to obtain concentrated fermentation liquor; 2) adding ethanol into the concentrated fermentation liquor to obtain a mixed system, and then adding resin into the mixed system for adsorption; 3) eluting the adsorbed resin by using an ethanol solution to obtain a chromatographic crude product of tacrolimus; and 4) sequentially carrying out primary crystallization, preparative column separation and secondary crystallization on the chromatographic crude product of tacrolimus to obtain a pure tacrolimus product. The separation and purification method is simple to operate and low in cost, and high-purity high-yield tacrolimus can be obtained.

Description

technical field [0001] The invention belongs to the field of biopharmaceuticals and relates to a method for separating and purifying tacrolimus. Background technique [0002] Tacrolimus, also known as FK506, is a fermentation product isolated from Streptomyces. It is a macrolide antibiotic and a powerful new immunosuppressant, mainly by inhibiting interleukin-2 (IL -2), thereby comprehensively inhibiting T lymphocytes, and its immunosuppressive activity is 10-100 times that of the traditional immune agent cyclosporin A. Although the total synthesis method of tacrolimus has been reported in the literature, the steps are cumbersome, costly, and difficult, and it is difficult to apply it to industrial production. [0003] At present, tacrolimus is mainly obtained by isolation and extraction from fermentation broth, but most of the strains capable of producing tacrolimus will also produce ascomycin and some other macrolide impurities during the fermentation process, which are r...

Claims

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Application Information

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IPC IPC(8): C07D498/18
CPCC07D498/18Y02P20/10
Inventor 赵燕何勇崴张葵
Owner NEW FOUNDER HLDG DEV LLC
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