CN1590368A - Recovery method of demeclocy cline hydrochloride crystal mother liquor - Google Patents
Recovery method of demeclocy cline hydrochloride crystal mother liquor Download PDFInfo
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- CN1590368A CN1590368A CN 03143276 CN03143276A CN1590368A CN 1590368 A CN1590368 A CN 1590368A CN 03143276 CN03143276 CN 03143276 CN 03143276 A CN03143276 A CN 03143276A CN 1590368 A CN1590368 A CN 1590368A
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- demethylchlortetracyclini
- chloridum
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Abstract
A method for recovering the mecicline from its crystalline mother liquid includes low-temp natural deposition, filtering, using alkali solution to regulate pH, adding filtering aid, filtering, dissolving the filter cake in solution of oxalic acid, adding cleaning agent, filtering, extracting in solvent, cooling the liquid extract, adding urea, washing, crystallizing and drying.
Description
Technical field
The present invention relates to the preparation method of pharmaceutical raw material, specifically the recovery method of demethylchlortetracyclini chloridum crystalline mother solution.
Background technology
Demethylchlortetracyclini chloridum is a kind of Fourth Ring class Broad spectrum antibiotics, and most gram-positive microorganisms and Gram-negative bacteria are all had anti-microbial effect, and its antimicrobial spectrum and terramycin, tsiklomitsin are similar.Demethylchlortetracyclini chloridum still is the important starting raw material of synthesizing dimethylamine base tsiklomitsin.Demethylchlortetracyclini chloridum can and make through biological fermentation, acidifying filtration, one-tenth double salt, commentaries on classics salt, crystallization and drying.In the process of producing demethylchlortetracyclini chloridum, its crystalline mother solution generally all directly enters the sewage disposal operation without recovery at present.One ton of demethylchlortetracyclini chloridum of common every production produces ten tons of crystalline mother solutions approximately, and remaining cicloxin (it is tired and is about 4000-6000u/ml) is just wasted and loses in the mother liquor like this, also brings certain difficulty to sewage disposal simultaneously.At present, when producing other tetracycline antibioticses (as terramycin, tsiklomitsin etc.), have employing directly to efflux method to its crystalline mother solution, the employing solvent method or the precipitator method that also have reclaim.One ton of terramycin of general every production produces 100M approximately
3Crystalline mother solution, its crystalline mother solution adopt solvent extraction to reclaim.Because this method percentage extraction is low, and the decay of multi-stage solvent extraction partition ratio is fast, so be difficult to realize industrialization; One ton of tsiklomitsin of every production produces 150M approximately
3Crystalline mother solution, remaining tetracycline activity is about 750u/ml, and its crystalline mother solution adopts the magnesium salts precipitator method to reclaim.In actual production, these recovery methods all can't be used for the recovery of demethylchlortetracyclini chloridum crystalline mother solution.And the remaining quantity of demethylchlortetracyclini chloridum crystalline mother solution will be higher than the remaining quantity in terramycin and the abricycline crystal mother liquor far away.Thereby, seek a kind of recovery method of effective demethylchlortetracyclini chloridum crystalline mother solution, will reduce the production cost of demethylchlortetracyclini chloridum greatly, also can reduce waste and environmental pollution in the production process simultaneously.
Summary of the invention
Purpose of the present invention is exactly the recovery method that a kind of demethylchlortetracyclini chloridum crystalline mother solution will be provided, and this method reclaims yield height, good product quality, and can be used for suitability for industrialized production.
The objective of the invention is such realization: with demethylchlortetracyclini chloridum crystalline mother solution low temperature natural subsidence, under the weakly alkaline situation, through sedimentation and filtration, solvent extraction and urea double salt and salt acid crystal, from crystalline mother solution, reclaim demethylchlortetracyclini chloridum thereby finished.
This method may further comprise the steps:
A. with demethylchlortetracyclini chloridum crystalline mother solution low temperature natural subsidence, filter; To remove the part insoluble impurities.
B. transfer pH to 7.0-10.0 with basic solution filtrate, press 1%-5% (w/v) and add flocculating aids, stir, filter;
Transfer pH to 7.0-10.0 with basic solution, make demethylchlortetracyclini chloridum form condensation product; Add flocculating aids, condensation product is easily filtered, and can effectively remove the part soluble impurity.
Basic solution can be selected ammoniacal liquor, 20% yellow soda ash, but preferentially selects ammoniacal liquor for use.
Flocculating aids can be selected perlite for use, also can select diatomite for use.But preferably select perlite for use, to guarantee better rate speed.
C. with the oxalic acid solution dissolving of filter cake, continue to add excessive oxalic acid solution and make pH reach 1.0-3.0, add scavenging agent with 3% (w/v), the filtration that stirs, filtrate is diluted to tiring of Ledermycining with purified water and is 1300-1800u/ml;
Filter cake dissolves with the oxalic acid solution of 3% (w/v).At this moment, flocculating aids all swims in the upper strata of liquid, adds excessive oxalic acid and makes the pH value of solution be 1.0-3.0, and the demethylchlortetracyclini chloridum unit that wraps in the filter cake is all discharged, and adds scavenging agent, further removes the impurity such as foreign protein in the solution, filters.
Scavenging agent can be inorganic salt (as zinc sulfate, the Tripotassium iron hexacyanides), also can be organism (as cicloxin fermented liquid resulting wet mycelium after acidifying is filtered).But preferably select the Tripotassium iron hexacyanide of 0.3-0.4% or the zinc sulfate of 0.3-0.4% for use.Because of its higher, better effects if of yield of comparing with the organism scavenging agent, and recrystallization again.
D. diluent transfers pH to 7.0-10.0 with basic solution, carries out solvent extraction with the mixed solution of higher alcohols or higher alcohols and acetic ester, and extraction liquid cools off, transfer pH1.0-2.0 with the vitriol oil, add 40% (w/v) aqueous solution of urea, stirred 2-3 hour, left standstill 1-3 hour, and separated;
Higher alcohols can be selected butanols, octanol, isooctyl alcohol etc. for use.The mixed solution solvent of higher alcohols and acetic ester can be selected butanols for use: (weight part ratio is 5-50 to N-BUTYL ACETATE: 95-50), or inositol: vinyl acetic monomer (5-50: 95-50), or inositol: N-BUTYL ACETATE (5-50: 95-50), but the mixed solution of butanols and N-BUTYL ACETATE preferably.Multistage alcohol mixture can be as 8-11 carbon alcohol (having commercially available).
The dosage of extraction solvent is decided by the potency unit of the cicloxin in the diluent in this step, preferably counts 8-11% (v/v) by diluent, makes it obtain good effect of extracting.
The add-on of aqueous solution of urea also is to decide on the potency unit of cicloxin in the extraction liquid in this step, and it is water-soluble preferably to add 0.25-5.5 milliliter 40% urea by 100 unit cicloxin in the extraction liquid, guarantees that cicloxin all forms double salt precipitation.
When carrying out solvent extraction, preferably add the chlorinated dodecane base leucoaurin of 5-10% or the sodium-chlor of chloro-hexadecane yl pyridines and 0.4-0.8% simultaneously.Can impel demethylchlortetracyclini chloridum to form mixture like this, accelerate the solvent layering, shorten the extraction time.
E. the urea complex salt crystal is with washing with acetone, dissolved in distilled water, with salt acid crystal, drying.
The important innovations part of the inventive method is earlier cicloxin crystalline mother solution natural subsidence, remove the part insoluble impurities in the crystalline mother solution, then under the situation of pH7.0-10.0, make the special albumen in cicloxin and the mother liquor form condensation product, further remove impurity in the mother liquor, carry out solvent extraction on this basis again, can remove a large amount of impurity in the mother liquor, thereby improved the extraction efficiency of solvent greatly; Adopt the urea complex salt crystal in the method and change crystal of hydrochloride, can effectively improve the demethylchlortetracyclini chloridum quality of recovery.
Demethylchlortetracyclini chloridum crystalline mother solution recovery method provided by the present invention can make the demethylchlortetracyclini chloridum content of recovery reach more than 80%, and potency unit reaches more than the 900u/ml, reclaims yield and reaches more than 50%.The inventive method has effectively been avoided the waste that discarded cicloxin crystalline mother solution is caused in the demethylchlortetracyclini chloridum production process, can save production cost 5%, has also reduced the environmental pollution in the production process simultaneously.
Embodiment
Embodiment 1
When producing demethylchlortetracyclini chloridum, obtain the demethylchlortetracyclini chloridum crystalline mother solution, the potency unit of cicloxin is 4000-6000u/ml in this mother liquor.With crystalline mother solution 20 ℃ of following natural subsidence 8 hours, separate its clear liquid, transfer pH7.0-9.5 with ammoniacal liquor, add 5% perlite, stir, filter, filter cake with the dissolving of 0.3% oxalic acid solution after, continue to add excessive oxalic acid, making pH value of solution is 1.0-3.0, adds scavenging agent (0.3% zinc sulfate), and stirring is left standstill, filter, filtrate is 1500u/ml with the potency unit that purified water is diluted to cicloxin, transfers pH7.0-10.0 with ammoniacal liquor, and add the butanols of 8-11% (v/v): N-BUTYL ACETATE mixed solution (butanols and N-BUTYL ACETATE are formulated by 5: 95 weight part ratio in this mixed solution) stirs evenly, extraction, the potency unit of cicloxin is at 13000-18000u/ml in the extraction liquid.Extraction liquid is cooled to 5-10 ℃, is 1.0-2.0 with the vitriol oil (for the commercially available prod) adjust pH, adds 40% aqueous solution of urea (by 0.45 milliliter/100 units), stirs 2-3 hour, leaves standstill 1 hour, filters twice of washing with acetone of urea complex salt crystal.With purified water dissolved urea complex salt crystal, make the potency unit of cicloxin become 100000u/ml, add 6M hydrochloric acid by 1/10 of complex salt solution volume, stirred 2-3 hour, left standstill 1 hour, filter crystallizing and washing, drying.Gained demethylchlortetracyclini chloridum content is more than 80%, and more than the potency unit 900u/ml, the rate of recovery is more than 50%.
Embodiment 2
When producing demethylchlortetracyclini chloridum, obtain the demethylchlortetracyclini chloridum crystalline mother solution, crystalline mother solution total titer unit is 5184u/ml, with crystalline mother solution 18 ℃ of natural subsidence 5 hours, separate its clear liquid, 20% sodium carbonate solution is transferred pH8.5, add 2% diatomite, stir, filter, filter cake dissolves with the oxalic acid solution of 3% (w/v), continue to add excessive oxalic acid, making pH value of solution is 2, adds the wet mycelium that Ledermycins and goes into 0.3% the Tripotassium iron hexacyanide of 30% (w/v) and 0.3% zinc sulfate, and stirring is left standstill, filter, it is 1500u/ml that filtrate makes the potency unit of cicloxin with the purified water dilution, transfers pH9.5 with 20% sodium carbonate solution, adds the butanols of 10% (v/v); The N-BUTYL ACETATE weight part ratio is (15: 85) mixing, and the chloro tridecyl leucoaurin aqueous solution to the emulsion layer of adding 10% disappears, and adds 0.5% sodium-chlor, stir, static, make its abundant layering, separate, the potency unit of cicloxin is 18000u/ml in the extraction liquid.Extraction liquid is cooled to 5 ℃, is 1.4 with the vitriol oil (for the commercially available prod) adjust pH, adds 40% aqueous solution of urea, and 0.45 milliliter/100 units stirred 2 hours, left standstill 1 hour, filtered twice of washing with acetone of urea complex salt crystal.With purified water dissolved urea complex salt crystal, the potency unit that makes cicloxin is 100000u/ml, adds 6M hydrochloric acid by 1/10 of complex salt solution volume, stirs 2-3 hour, leaves standstill 1 hour, filters crystallizing and washing, drying.Gained demethylchlortetracyclini chloridum content is 89.73%, and potency unit 917.3u/ml reclaims yield 56%.
Embodiment 3
When producing demethylchlortetracyclini chloridum, obtain the demethylchlortetracyclini chloridum crystalline mother solution, recording crystalline mother solution total titer unit is 4636u/ml, with crystalline mother solution 18 ℃ of natural subsidence 3 hours, separate its clear liquid, transfer pH9.5 with ammonia soln, add 5% perlite, stir, filter, filter cake continues to add excessive oxalic acid with the oxalic acid solution dissolving of 3% (w/v), and making pH value of solution is 3, add 0.4% iron Repone K, stirring is left standstill, and filters, and filtrate is 1300u/ml with the potency unit that purified water is diluted to cicloxin, ammonia soln is transferred pH8.5, the butanols that adds 10% (v/v): N-BUTYL ACETATE (15: 85) mixing, the chloro-hexadecane yl pyridines aqueous solution to the emulsion layer of adding 10% disappears, and adds 0.8% (w/v) sodium-chlor, stir, static, make its abundant layering, separate, the potency unit that Ledermycins in the extraction liquid is 15000u/ml.Extraction liquid is cooled to 5 ℃, is 1.3 with the vitriol oil (for the commercially available prod) adjust pH, adds 40% aqueous solution of urea (in 0.45 milliliter/100 units), stirs 2 hours, leaves standstill 1 hour, filters washing with acetone three times of urea complex salt crystal.With purified water dissolved urea complex salt crystal, making the potency unit that Ledermycins is 100000u/ml, adds 6M hydrochloric acid by 1/10 of complex salt solution volume, stirs 2-3 hour, leaves standstill 1 hour, filters crystallizing and washing, drying.It is 86.73% that gained hydrochloric acid removes to add the mould cellulose content of fund, and potency unit 907.8u/ml reclaims yield 54%.
Claims (8)
1, a kind of demethylchlortetracyclini chloridum crystalline mother solution recovery method is characterized in that it may further comprise the steps:
A. with demethylchlortetracyclini chloridum crystalline mother solution low temperature natural subsidence, filter;
B. transfer pH to 7.0-10.0 with basic solution filtrate, press 1%-5% (w/v) and add flocculating aids, stir, filter;
C. with after the oxalic acid solution dissolving of filter cake with 3% (w/v), continue to add excessive oxalic acid solution and make pH reach 1.0-3.0, add scavenging agent, the filtration that stirs, filtrate is 1300-1800u/ml with the potency unit that purified water is diluted to cicloxin;
D. diluent transfers pH to 7.0-10.0 with basic solution, carries out solvent extraction with the mixed solution of higher alcohols or higher alcohols and acetic ester, and extraction liquid cools off, transfer pH1.0-2.0 with the vitriol oil, add 40% (w/v) aqueous solution of urea, stirred 2-3 hour, left standstill 1-3 hour, and separated;
E. the urea complex salt crystal is with washing with acetone, dissolved in distilled water, with salt acid crystal, drying.
2, demethylchlortetracyclini chloridum crystalline mother solution recovery method according to claim 1, its feature is an ammoniacal liquor at said basic solution.
3, demethylchlortetracyclini chloridum crystalline mother solution recovery method according to claim 1 and 2, the flocculating aids of its feature in said b step is perlite.
4, demethylchlortetracyclini chloridum crystalline mother solution recovery method according to claim 1 and 2, the scavenging agent of its feature in said c step is the Tripotassium iron hexacyanide of 0.3-0.4% or the zinc sulfate of 0.3-0.4%.
5, demethylchlortetracyclini chloridum crystalline mother solution recovery method according to claim 3, it is characterized in that the higher alcohols in the said d step and the mixed solution of acetic ester are the mixed solution of butanols and N-BUTYL ACETATE, the weight part ratio of each component is 5-50: 95-50 in the mixed solution.
6, demethylchlortetracyclini chloridum crystalline mother solution recovery method according to claim 3, its feature extract the dosage of solvent and count 8-11% (v/v) by diluent in said d step.
7, demethylchlortetracyclini chloridum crystalline mother solution recovery method according to claim 3 is characterized in that adding 0.25-5.5 milliliter 40% aqueous solution of urea by per 100 unit demethylchlortetracyclini chloridums in the extraction liquid in the said d step.
8, demethylchlortetracyclini chloridum crystalline mother solution recovery method according to claim 3, its feature during solvent extraction, add the chlorinated dodecane base leucoaurin of 5-10% or the sodium-chlor of chloro-hexadecane yl pyridines and 0.4-0.8% simultaneously in said d step.
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| CN 03143276 CN1226278C (en) | 2003-09-04 | 2003-09-04 | Recovery method of demeclocy cline hydrochloride crystal mother liquor |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102993043A (en) * | 2012-12-04 | 2013-03-27 | 天津大学 | Method for preparing high-purity tetracycline hydrochloride |
| CN103467344A (en) * | 2013-09-26 | 2013-12-25 | 宁夏启元药业有限公司 | Method for recovering urea from tetracycline urea compound salt crystallization mother liquor and recycling urea |
| CN103755577A (en) * | 2014-01-17 | 2014-04-30 | 浙江浙邦制药有限公司 | Method for recovering ambroxol base from ambroxol hydrochloride refined mother solution |
| CN104418767A (en) * | 2013-08-28 | 2015-03-18 | 河南天方药业股份有限公司 | Demeclocycline extraction process |
| CN108191692A (en) * | 2017-12-25 | 2018-06-22 | 安徽永生堂药业有限责任公司 | A kind of process for separation and purification of tetracycline antibiotics |
-
2003
- 2003-09-04 CN CN 03143276 patent/CN1226278C/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102993043A (en) * | 2012-12-04 | 2013-03-27 | 天津大学 | Method for preparing high-purity tetracycline hydrochloride |
| CN102993043B (en) * | 2012-12-04 | 2015-03-04 | 天津大学 | Method for preparing high-purity tetracycline hydrochloride |
| CN104418767A (en) * | 2013-08-28 | 2015-03-18 | 河南天方药业股份有限公司 | Demeclocycline extraction process |
| CN103467344A (en) * | 2013-09-26 | 2013-12-25 | 宁夏启元药业有限公司 | Method for recovering urea from tetracycline urea compound salt crystallization mother liquor and recycling urea |
| CN103755577A (en) * | 2014-01-17 | 2014-04-30 | 浙江浙邦制药有限公司 | Method for recovering ambroxol base from ambroxol hydrochloride refined mother solution |
| CN103755577B (en) * | 2014-01-17 | 2015-11-18 | 浙江浙邦制药有限公司 | A kind of method reclaiming Transbroncho alkali from Ambroxol HCl refinement mother liquor |
| CN108191692A (en) * | 2017-12-25 | 2018-06-22 | 安徽永生堂药业有限责任公司 | A kind of process for separation and purification of tetracycline antibiotics |
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| CN1226278C (en) | 2005-11-09 |
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Assignee: Huabei Pharmaceutical Co., Ltd. Assignor: Huabei Pharmaceutical Group Co., Ltd. Contract fulfillment period: 2008.10.15 to 2013.10.15 contract change Contract record no.: 2008130000142 Denomination of invention: Recovery method of demeclocy cline hydrochloride crystal mother liquor Granted publication date: 20051109 License type: Exclusive license Record date: 2008.12.4 |
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