CN104418767A

CN104418767A - Demeclocycline extraction process

Info

Publication number: CN104418767A
Application number: CN201310380480.4A
Authority: CN
Inventors: 刘俭国; 毛全贵; 焦龙; 孟新梅; 祝立新; 王九; 唐慧慧; 牛景丽; 孟利沙; 王媛; 王雪洁; 谢书琴; 万丹; 刘丽杰; 王丹
Original assignee: TIANFANG PHARMACEUTICAL CO Ltd HENAN
Current assignee: TIANFANG PHARMACEUTICAL CO Ltd HENAN
Priority date: 2013-08-28
Filing date: 2013-08-28
Publication date: 2015-03-18

Abstract

The invention provides a demeclocycline extraction process which comprises the following technical steps: adding an antioxidant into demeclocycline fermentation liquor, adjusting the pH to 1.0-4.0 by an acid, micro-filtering to separate mycelia and other solid impurities, and decolorizing the filtrate; concentrating the decolorized filtrate by using a nanofiltration organic film to obtain a demeclocycline concentrated solution; adjusting the pH of the concentrated solution to 4.5-8.5 by an alkali, carrying out crystallization and sedimentation, and carrying out solid-liquid separation on precipitate to obtain a demeclocycline crude product; and refining the demeclocycline crude product by using a double salt method to obtain a demeclocycline hydrochloride finished product. Compared with the original solvent extraction process, the process provided by the invention avoids use of organic solvents or greatly reduces use of organic solvents, so that discharge of three wastes is less and the environmental pollution is reduced. The process is stable in product yield and quality and suitable for industrial production and has a very high practical value. The obtained product meets EP and USP standards.

Description

Cicloxin extraction process

Technical field

The present invention relates to the preparation of medicine, particularly relate to a kind of novel technology for extracting of cicloxin.

Background technology

Cicloxin, another name Demethylchlortetracycline, demethyl Uromycin etc., be the tetracycline antibiotics produced by streptomyces aureus fermentation, similar to duomycin for its antimicrobial spectrum of bulk drug, antibacterial effect is stronger than tsiklomitsin, stablizes than duomycin.Along with derivative Minocycline HCl and Tigecycline are gone on the market and the Persisting exploitation of other derivatives in succession, the market outlook of cicloxin are more and more wide.

Traditional cicloxin fermentative production extracting method is filter after cicloxin fermented liquid is carried out pre-treatment, sheet frame, filtrate uses N-BUTYL ACETATE and butanols to extract, then use hydrochloric acid to strip and concentrate recrystallize, oven dry obtains cicloxin hydrochloride, traditional technology uses a large amount of N-BUTYL ACETATEs and butanols, and two solvents all have very high water-soluble, so three waste discharge is serious, environmental treatment cost increases; And due to the complicacy of fermented liquid and organic solvent extraction limitation, cause extraction difficulty, quality product and yield are all subject to Different Effects.

Summary of the invention

The present invention is intended to overcome the above problems, and spy provides a kind of cicloxin extraction process, and it comprises following processing step;

A, in cicloxin fermented liquid, add oxidation inhibitor, through acid for adjusting pH=1.0-4.0, micro-filtration, isolates mycelium and other solid impurities, and filtrate is decoloured;

B, destainer concentrate through nanofiltration organic membrane, obtain cicloxin concentrated solution;

C, concentrated solution is regulated pH=4.5-8.5 through alkali, crystalline deposit, to precipitate after solid-liquid separation to obtain cicloxin crude product;

D, cicloxin double salt method to be refined, obtain cicloxin hydrochloride finished product.

Wherein antioxidant is 0.05-0.5wt% S-WAT, and wherein acid is hydrochloric acid or oxalic acid, and wherein use ceramic membrane to carry out micro-filtration, wherein filtrate is decoloured through decolorizing resin.

Wherein nanofiltration organic membrane molecular weight cut-off is 100-500 dalton, and wherein alkali is NaOH solution or the ammoniacal liquor of 0.1-2M.

Wherein cicloxin uses urea double salt method or calcium magnesium double salt method to refine.

Compared with traditional solvent extraction method, the present invention uses ceramic membrane filter, resin decolorization, organic membrane filter concentrated, then NaOH solution or ammoniacal liquor is directly used by concentrated solution to regulate pH to carry out crystalline deposit, re-use urea double salt method or calcium magnesium double salt method carries out being refined into cicloxin hydrochloride, thus avoid or greatly reduce with an organic solvent, greatly reduce environmental pollution, thus produce good economic benefit and social benefit.And decolouring is concentrated is physical means, and quality product and yield all have stable guarantee.

Embodiment

Below in conjunction with embodiment, the invention will be further described.

Embodiment one

By the fermented liquid containing 6.0g/L cicloxin 35 liters, adjust the temperature to 5-10 DEG C and add 0.05wt% S-WAT 35g, adjust the temperature to 10 DEG C, oxalic acid is used to regulate pH=1.5 ± 0.2, stir 20 minutes, use Nanjing for a long time my company's ceramic membrane filter, pottery membrane flux 30 ls/h; Obtain filtrate 70 liters;

Filtrate is crossed 122 resins, flow velocity 2BV/h, use the tap water top of pH=6.8-7.0 to wash 0.5 hour after completing, obtain destainer 72 liters;

Destainer being crossed molecular weight cut-off is 150 GE company of daltonian U.S. organic nanofiltration membrane assemblies, pressure 1.5mpa, and temperature keeps 5-10 DEG C; Obtain concentrated solution 4 liters;

By under concentrated solution agitation condition, regulate temperature 5-8 DEG C, use the ammoniacal liquor of 0.1M to regulate pH=6.5 ± 0.2, be precipitated suspension, continue stirring 30 minutes, leave standstill 30 minutes, solid-liquid separation obtains cicloxin crude product;

Used by cicloxin crude product urea double salt method to refine to obtain cicloxin finished product, dry to obtain cicloxin hydrochloride 152g, total recovery 72.38%; Finished product censorship meets EP, USP standard.

Embodiment two

By the fermented liquid containing 7.5g/L cicloxin 30 liters, add 0.5wt% S-WAT 150g, adjust the temperature to 5-10 DEG C, hydrochloric acid is used to regulate pH=2.5 ± 0.2, stir 20 minutes, use Xiamen three to reach company's ceramic membrane filter, pottery membrane flux 24.5 ls/h; Obtain filtrate 65 liters;

Filtrate is crossed LX-200 resin decolorization, flow velocity 3BV/h, use the tap water top of pH=6.8-7.0 to wash 0.5 hour after completing, obtain destainer 70 liters;

Destainer being crossed molecular weight cut-off is 150 GE company of daltonian U.S. organic nanofiltration membrane assemblies, pressure 1.5mpa, and temperature keeps 5-10 DEG C; Obtain concentrated solution 3.8 liters;

By under concentrated solution agitation condition, regulate temperature 5-8 DEG C, use the NaOH aqueous solution of 2M to regulate pH=8.2 ± 0.2, be precipitated suspension, continue stirring 30 minutes, leave standstill 30 minutes, solid-liquid separation obtains cicloxin crude product;

Used by cicloxin crude product urea double salt method to refine to obtain cicloxin finished product, dry to obtain cicloxin hydrochloride 166g, total recovery 73.78%; Finished product censorship meets EP, USP standard.

Embodiment three

By the fermented liquid containing 5.8g/L cicloxin 30 liters, adjust the temperature to 5-10 DEG C, add 0.1wt% S-WAT 30g, oxalic acid is used to regulate pH=3.8 ± 0.2, stir 20 minutes, use Nanjing for a long time my company's ceramic membrane filter, pottery membrane flux 28.5 ls/h; Obtain filtrate 70 liters;

Filtrate is crossed ROHM AND HAAS decolorizing resin, flow velocity 4BV/h, use the tap water top of pH=6.8-7.0 to wash 0.5h after completing, obtain destainer 75 liters;

Destainer being crossed molecular weight cut-off is 100 GE company of daltonian U.S. organic nanofiltration membrane assemblies, pressure 1.8mpa, and temperature keeps 5-10 DEG C; Obtain concentrated solution 4.5 liters;

By under concentrated solution agitation condition, regulate temperature 5-8 DEG C, use the ammoniacal liquor of 1M to regulate pH=4.8 ± 0.2, be precipitated suspension, continue stirring 30 minutes, leave standstill 30 minutes, solid-liquid separation obtains cicloxin crude product;

Used by cicloxin crude product calcium magnesium double salt method to refine to obtain cicloxin finished product, dry to obtain cicloxin hydrochloride 127g, total recovery 72.98%; Finished product censorship meets EP, USP standard.

Claims

1. a cicloxin extraction process, is characterized in that comprising following processing step;

2. cicloxin extraction process as claimed in claim 1, wherein antioxidant is 0.05-0.5wt% S-WAT.

3. cicloxin extraction process as claimed in claim 1, wherein acid is hydrochloric acid or oxalic acid.

4. cicloxin extraction process as claimed in claim 1, wherein carries out micro-filtration by ceramic membrane.

5. cicloxin extraction process as claimed in claim 1, wherein the molecular weight cut-off of nanofiltration organic membrane is 100-500 dalton.

6. cicloxin extraction process as claimed in claim 1, wherein alkali is NaOH solution or the ammoniacal liquor of 0.1-2M.

7. cicloxin extraction process as claimed in claim 1, wherein cicloxin uses urea double salt method or calcium magnesium double salt method to refine.

8. cicloxin extraction process as claimed in claim 1, wherein filtrate is decoloured through decolorizing resin.