CN109081844B - Method for extracting spectinomycin from fermentation culture - Google Patents
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- CN109081844B CN109081844B CN201811175836.XA CN201811175836A CN109081844B CN 109081844 B CN109081844 B CN 109081844B CN 201811175836 A CN201811175836 A CN 201811175836A CN 109081844 B CN109081844 B CN 109081844B
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Abstract
The invention provides a method for extracting spectinomycin from a fermentation culture. The spectinomycin is extracted by adopting the liquid ion exchanger, the sulfonic group in the liquid ion exchanger has good binding capacity with the spectinomycin, and the spectinomycin can be selectively, quickly and accurately extracted from a system containing a large amount of impurities. By adopting the method provided by the invention, the yield of the spectinomycin can reach more than 65%, the purity reaches 98%, the product quality is good, the product meets the quality standards of EP and USP, and the method has the advantages of short period, less pollution discharge, low production cost and the like.
Description
Technical Field
The invention relates to the technical field of spectinomycin extraction, in particular to a method for extracting spectinomycin from a fermentation culture.
Background
Spectinomycin is an aminoglycoside antibiotic produced by fermentation and extraction of Streptomyces spectabilis, has antibacterial activity against most gram-positive and gram-negative bacteria, is highly effective against the currently prevalent neisseria gonorrhoeae isolates, is highly sensitive to penicillin-and tetracycline-resistant gonococci, has the characteristics of outstanding curative effect, few side effects, safe use and the like in the aspect of clinical treatment of infection caused by neisseria gonorrhoeae and the like, and has become one of the first-choice medicines for treating gonorrhoea in China. In addition, the low toxicity and broad-spectrum antibacterial property of spectinomycin make the spectinomycin more and more widely applied in the fields of agriculture, animal husbandry and the like.
At present, the traditional extraction method of spectinomycin is usually a resin adsorption and desorption method, the yield is low, the extraction period is long, and a large amount of acid-base wastewater is generated.
Disclosure of Invention
The invention aims to provide a method for extracting spectinomycin from a fermentation culture, and the method provided by the invention has high yield and purity of spectinomycin and good product quality, and meets the quality standards of EP and USP; and has the advantages of short period, less sewage discharge and low production cost.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a method for extracting spectinomycin from a fermentation culture, which comprises the following steps:
adjusting the pH value of spectinomycin fermentation liquor to 3.0-4.0 by adopting an acidic reagent, then carrying out solid-liquid separation, and adjusting the pH value of the obtained liquid material to 6.0-7.0 by adopting an alkaline reagent to obtain a precursor solution;
mixing the precursor solution with a liquid ion exchanger and an organic solvent, carrying out ion exchange, and separating to obtain an organic phase containing spectinomycin; the liquid ion exchanger contains sulfonic acid groups;
mixing the organic phase containing the spectinomycin with an aqueous phase extractant, then carrying out water extraction, and separating to obtain an aqueous phase containing the spectinomycin;
and (3) decoloring the water phase containing the spectinomycin, and crystallizing to obtain the spectinomycin.
Preferably, the acidic reagent comprises hydrochloric acid, sulfuric acid or oxalic acid, and the concentration of the acidic reagent is 1.5-2.5 mol/L.
Preferably, the alkaline reagent comprises sodium hydroxide solution, potassium hydroxide solution or ammonia water, and the concentration of the alkaline reagent is 5-15 wt.%.
Preferably, the liquid ion exchanger comprises propyl naphthalene sulfonic acid or nonyl naphthalene sulfonic acid.
Preferably, the organic solvent comprises ethyl acetate, butyl acetate, propyl acetate, toluene or n-butanol.
Preferably, the volume ratio of the spectinomycin fermentation liquor to the liquid ion exchanger to the organic solvent is 5: (0.15-0.25): (0.75-0.85).
Preferably, the aqueous phase extractant comprises hydrochloric acid, an ammonium chloride solution or a sodium chloride solution, and the concentration of the aqueous phase extractant is 1.5-2.5 wt.%.
Preferably, the volume ratio of the organic phase containing spectinomycin to the aqueous phase extractant is (4-6): 1.
preferably, the crystallization comprises the steps of:
concentrating the decolorized solution obtained after decolorization, and cooling when crystals are separated out to obtain spectinomycin; wherein the concentration temperature is 65-75 ℃; the time of the cooling treatment is 3.5-4.5 h, and the final temperature of the cooling treatment is 5-10 ℃.
Preferably, the crystallization further comprises:
and (3) carrying out solid-liquid separation on the system obtained after crystallization, and drying the obtained solid material to obtain the spectinomycin.
The invention provides a method for extracting spectinomycin from a fermentation culture, which comprises the steps of adjusting the pH value of a spectinomycin fermentation liquor to 3.0-4.0 by adopting an acidic reagent, carrying out solid-liquid separation, adjusting the pH value of an obtained liquid material to 6.0-7.0 by adopting an alkaline reagent, and obtaining a precursor solution; mixing the precursor solution with a liquid ion exchanger and an organic solvent, carrying out ion exchange, and separating to obtain an organic phase containing spectinomycin; the liquid ion exchanger contains sulfonic acid groups; mixing the organic phase containing the spectinomycin with an aqueous phase extractant, then carrying out water extraction, and separating to obtain an aqueous phase containing the spectinomycin; and (3) decoloring the water phase containing the spectinomycin, and crystallizing to obtain the spectinomycin. The spectinomycin is extracted by adopting the liquid ion exchanger, and the sulfonic group in the liquid ion exchanger has good binding capacity with the spectinomycin, so that the spectinomycin can be selectively extracted from a system containing a large amount of impurities quickly and accurately; in addition, after water extraction treatment, the liquid ion exchanger can restore activity and can be reused. By adopting the method provided by the invention, the yield of the spectinomycin can reach more than 65%, the purity reaches 98%, the product quality is good, the product meets the quality standards of EP and USP, and the method has the advantages of short period, less pollution discharge, low production cost and the like.
Detailed Description
The invention provides a method for extracting spectinomycin from a fermentation culture, which comprises the following steps:
adjusting the pH value of spectinomycin fermentation liquor to 3.0-4.0 by adopting an acidic reagent, then carrying out solid-liquid separation, and adjusting the pH value of the obtained liquid material to 6.0-7.0 by adopting an alkaline reagent to obtain a precursor solution;
mixing the precursor solution with a liquid ion exchanger and an organic solvent, carrying out ion exchange, and separating to obtain an organic phase containing spectinomycin; the liquid ion exchanger contains sulfonic acid groups;
mixing the organic phase containing the spectinomycin with an aqueous phase extractant, then carrying out water extraction, and separating to obtain an aqueous phase containing the spectinomycin;
and (3) decoloring the water phase containing the spectinomycin, and crystallizing to obtain the spectinomycin.
According to the invention, the pH value of spectinomycin fermentation liquor is adjusted to 3.0-4.0 by adopting an acidic reagent, then solid-liquid separation is carried out, and the pH value of the obtained liquid material is adjusted to 6.0-7.0 by adopting an alkaline reagent, thus obtaining a precursor solution. In the invention, the spectinomycin fermentation liquor is preferably obtained by culturing and fermenting a strain of streptomyces spectabilis; the specific operation method of the culture and fermentation of the strain is not particularly limited in the present invention, and a method well known to those skilled in the art may be used. In the invention, the content of spectinomycin in the spectinomycin fermentation liquor is preferably 3000-4500 u/mL, and more preferably 3500-4000 u/mL.
The acid reagent is not particularly limited, and the reagent which is well known by the technical personnel in the field and can adjust the pH value of the spectinomycin fermentation liquor to 3.0-4.0 can be adopted; in the invention, the acidic reagent preferably comprises hydrochloric acid, sulfuric acid or oxalic acid, and the concentration of the acidic reagent is preferably 1.5-2.5 mol/L, and more preferably 2 mol/L. The pH value of the spectinomycin fermentation liquor is adjusted to 3.0-4.0 by adopting an acidic reagent, so that the solid-liquid separation yield of subsequent fermentation liquor is improved, and the separation effect is improved.
The solid-liquid separation method of the present invention is not particularly limited, and a method known to those skilled in the art, such as filtration or centrifugation, may be used. Solid impurities such as fungus residues in the system are removed through solid-liquid separation, and a liquid material containing spectinomycin is obtained.
The alkaline reagent is not particularly limited, and the reagent which is well known to a person skilled in the art and can adjust the pH value of the liquid material obtained after solid-liquid separation to 6.0-7.0 can be adopted; in the present invention, the alkaline agent preferably includes a sodium hydroxide solution, a potassium hydroxide solution, or ammonia water, and the concentration of the alkaline agent is preferably 5 to 15wt.%, and more preferably 10 wt.%. According to the invention, the pH value of the liquid material obtained after solid-liquid separation is adjusted to 6.0-7.0 by adopting an alkaline reagent, so that the subsequent ion exchange is facilitated.
After a precursor solution is obtained, the precursor solution is mixed with a liquid ion exchanger and an organic solvent for ion exchange, and an organic phase containing spectinomycin is obtained by separation; the liquid ion exchanger contains sulfonic acid groups. In the present invention, the liquid ion exchanger preferably includes propyl naphthalene sulfonic acid or nonyl naphthalene sulfonic acid; the organic solvent preferably includes ethyl acetate, butyl acetate, propyl acetate, toluene, or n-butanol. In the present invention, the volume ratio of the spectinomycin fermentation broth, the liquid ion exchanger and the organic solvent is preferably 5: (0.15-0.25): (0.75 to 0.85), more preferably 5: 0.2: 0.8.
in the present invention, the precursor solution is preferably mixed with a liquid ion exchanger and an organic solvent by mixing the precursor solution with an organic solution of a liquid ion exchanger.
In the invention, the time of the ion exchange is preferably 25-35 min, and more preferably 30 min; the temperature is preferably 20 to 30 ℃, and more preferably 25 ℃. In the present invention, the ion exchange is preferably carried out under stirring conditions; the stirring rate is not particularly limited in the present invention, and a stirring rate known to those skilled in the art may be used.
According to the invention, the precursor solution is subjected to ion exchange by adopting a liquid ion exchanger, and the sulfonic group in the liquid ion exchanger has good binding capacity with spectinomycin, so that the spectinomycin can be selectively, quickly and accurately extracted from a system containing a large amount of impurities; in addition, after subsequent water extraction treatment, the liquid ion exchanger can recover the activity and can be reused.
The separation is not particularly limited in the present invention, and the separation method well known to those skilled in the art can be adopted, and the separation is preferably performed by standing for layering or by using a high-speed disk centrifuge.
After obtaining the organic phase containing the spectinomycin, the invention mixes the organic phase containing the spectinomycin with the aqueous phase extractant, then carries out water extraction, and separates to obtain the aqueous phase containing the spectinomycin. In the present invention, the aqueous phase extractant preferably comprises hydrochloric acid, an ammonium chloride solution or a sodium chloride solution, and the concentration of the aqueous phase extractant is preferably 1.5 to 2.5wt.%, more preferably 2 wt.%. In the invention, the volume ratio of the organic phase containing spectinomycin to the aqueous phase extractant is preferably (4-6): 1, more preferably 5: 1.
In the invention, the water extraction time is preferably 25-35 min, and more preferably 30 min; the temperature is preferably 20 to 30 ℃, and more preferably 25 ℃. In the present invention, the aqueous extraction is preferably carried out under stirring conditions; the stirring rate is not particularly limited in the present invention, and a stirring rate known to those skilled in the art may be used.
The invention adopts the water phase extractant to carry out water extraction on the organic phase containing the spectinomycin, and aims to transfer the spectinomycin into the water phase for subsequent purification and simultaneously recover the activity of the liquid ion exchanger, thereby facilitating subsequent recycling.
The separation is not particularly limited in the present invention, and a separation technique known to those skilled in the art may be adopted, and the separation is preferably performed after standing and layering.
After obtaining the water phase containing the spectinomycin, the invention decolors the water phase containing the spectinomycin and then carries out crystallization to obtain the spectinomycin. In the invention, the decolorizing reagent adopted for decolorizing is preferably activated carbon, and specifically, the water phase containing spectinomycin is mixed with activated carbon for decolorizing, filtered and then the obtained decolorized solution is subjected to subsequent crystallization. The specific operating conditions for the decolorization in the present invention are not particularly limited, and the decolorization technique known to those skilled in the art may be used.
In the present invention, the crystallization preferably comprises the steps of:
concentrating the decolorized solution obtained after decolorization, and cooling when crystals are separated out to obtain spectinomycin; wherein the concentration temperature is 65-75 ℃; the time of the cooling treatment is 3.5-4.5 h, and the final temperature of the cooling treatment is 5-10 ℃.
In the invention, the concentration is preferably vacuum concentration, and the temperature of the vacuum concentration is preferably 65-75 ℃, and more preferably 70 ℃.
In the invention, the temperature reduction treatment is a process of realizing crystallization through slow temperature reduction, and the time of the temperature reduction treatment is preferably 3.5-4.5 h, and more preferably 4 h; the final temperature of the temperature reduction treatment is preferably 5-10 ℃. The cooling rate in the cooling treatment process is not specially limited, and the temperature is uniformly cooled from 65-75 ℃ to 5-10 ℃ after 3.5-4.5 hours.
The spectinomycin in the system is fully separated out through crystallization, wherein the slow cooling is adopted to avoid the phenomenon that the crystal is separated out too fast to cause the product to contain impurities, the crystal form of the product is stable and uniform, and the product quality is improved.
After the crystallization is completed, the solid-liquid separation is preferably carried out on the system obtained after the crystallization, and the obtained solid material is dried to obtain the spectinomycin, so that the spectinomycin is obtained. The solid-liquid separation mode is not particularly limited in the invention, and the technical scheme of solid-liquid separation known to those skilled in the art, such as filtration, can be adopted. The drying method is not particularly limited, and the technical scheme of drying which is well known to those skilled in the art is adopted to ensure that the materials are sufficiently dried.
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Taking 5L of spectinomycin fermentation liquor (the content of spectinomycin is 3780u/mL), adjusting the pH value to 3.5 by using hydrochloric acid with the concentration of 2mol/L, carrying out solid-liquid separation, and collecting 4.8L of filtrate; adjusting the pH value of the filtrate to 6.5 by using a sodium hydroxide solution with the concentration of 10 wt.%, adding 1L of an ethyl acetate solution (prepared by propyl naphthalene sulfonic acid and ethyl acetate according to the volume ratio of 1: 4) of propyl naphthalene sulfonic acid, carrying out ion exchange for 30min under the stirring condition, standing for layering, and collecting an organic phase containing spectinomycin; adding 200mL of 2 wt.% ammonium chloride solution, carrying out water extraction for 30min under the stirring condition, standing for layering, and collecting 450mL of a water phase containing spectinomycin; adding activated carbon for decolorization, filtering, vacuum concentrating the decolorized solution at 70 deg.C, cooling when crystal is separated out (uniformly cooling to 10 deg.C for 4 hr), filtering, and drying the obtained crystal to obtain spectinomycin 18.60g, with yield of 63.6% and purity of 97.6%.
Example 2
Taking 100L of spectinomycin fermentation liquor (the content of spectinomycin is 3960u/mL), adjusting the pH value to 4.0 by using sulfuric acid with the concentration of 2mol/L, carrying out solid-liquid separation, and collecting 97L of filtrate; adjusting the pH value of the filtrate to 7.0 by using a potassium hydroxide solution with the concentration of 10 wt.%, adding 20L of n-butanol solution (prepared by nonyl naphthalene sulfonic acid and ethyl acetate according to the volume ratio of 1: 4) of nonyl naphthalene sulfonic acid, carrying out ion exchange for 30min under the stirring condition, standing for layering, and collecting an organic phase containing spectinomycin; adding 4L of 2 wt.% hydrochloric acid solution, performing water extraction for 30min under stirring, standing for layering, and collecting 9L of water phase containing spectinomycin; adding activated carbon for decolorization, filtering, vacuum concentrating the obtained decolorized solution at 75 deg.C, cooling when crystal is separated out (uniformly cooling to 15 deg.C for 4 hr), filtering, and drying the obtained crystal to obtain spectinomycin 363.20g with yield of 64.3 and purity of 97.8%.
Example 3
Taking 500L of spectinomycin fermentation liquor (the content of the spectinomycin is 4060u/mL), adjusting the pH value to 3.0 by using sulfuric acid with the concentration of 2mol/L, carrying out solid-liquid separation, and collecting 480L of filtrate; adjusting the pH value of the filtrate to 5.0 by using an ammonia water solution with the concentration of 10 wt.%, adding 96L of a butyl acetate solution of nonylnaphthalenesulfonic acid (prepared from nonylnaphthalenesulfonic acid and ethyl acetate according to the volume ratio of 1: 4), carrying out ion exchange for 30min under the stirring condition, standing for layering, and collecting an organic phase containing spectinomycin; adding 20L of sodium chloride solution with the concentration of 2 wt.%, performing water extraction for 30min under the stirring condition, standing for layering, and collecting 46L of water phase containing spectinomycin; adding activated carbon for decolorization, filtering, vacuum concentrating the decolorized solution at 65 deg.C, cooling when crystal is separated out (uniformly cooling to 5 deg.C for 4 hr), filtering, and drying the obtained crystal to obtain spectinomycin 1.81kg, with yield of 65.2% and purity of 98.1%.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (4)
1. A method for extracting spectinomycin from a fermentation culture, comprising the steps of:
adjusting the pH value of spectinomycin fermentation liquor to 3.0-4.0 by adopting an acidic reagent, then carrying out solid-liquid separation, and adjusting the pH value of the obtained liquid material to 6.0-7.0 by adopting an alkaline reagent to obtain a precursor solution; the acid reagent is hydrochloric acid or sulfuric acid, and the concentration of the acid reagent is 1.5-2.5 mol/L; the content of the spectinomycin in the spectinomycin fermentation liquor is 3000-4500 u/mL; the alkaline reagent comprises a sodium hydroxide solution, a potassium hydroxide solution or ammonia water, and the concentration of the alkaline reagent is 5-15 wt.%;
mixing the precursor solution with a liquid ion exchanger and an organic solvent, carrying out ion exchange, and separating to obtain an organic phase containing spectinomycin; the liquid ion exchanger contains sulfonic acid groups and comprises propyl naphthalene sulfonic acid or nonyl naphthalene sulfonic acid; the volume ratio of the spectinomycin fermentation liquor to the liquid ion exchanger to the organic solvent is 5: (0.15-0.25): (0.75 to 0.85);
mixing the organic phase containing the spectinomycin with an aqueous phase extractant, then carrying out water extraction, and separating to obtain an aqueous phase containing the spectinomycin;
the aqueous phase extracting agent comprises hydrochloric acid, an ammonium chloride solution or a sodium chloride solution, and the concentration of the aqueous phase extracting agent is 1.5-2.5 wt.%;
decolorizing the aqueous phase containing spectinomycin, and crystallizing, wherein the crystallization comprises the following steps:
concentrating the decolorized solution obtained after decolorization, and cooling when crystals are separated out to obtain spectinomycin; wherein the concentration temperature is 65-75 ℃; the cooling treatment time is 3.5-4.5 h, and the final temperature of the cooling treatment is 5-10 ℃ to obtain the spectinomycin.
2. The method of claim 1, wherein the organic solvent comprises ethyl acetate, butyl acetate, propyl acetate, toluene, or n-butanol.
3. The method according to claim 1, wherein the volume ratio of the organic phase containing spectinomycin to the aqueous phase extractant is (4-6): 1.
4. the method of claim 1, further comprising, after said crystallizing:
and (3) carrying out solid-liquid separation on the system obtained after crystallization, and drying the obtained solid material to obtain the spectinomycin.
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| CN111705092B (en) * | 2020-07-20 | 2022-03-08 | 山东齐发药业有限公司 | Feed supplement for improving fermentation titer of spectinomycin and preparation method and use method thereof |
| CN112390806A (en) * | 2020-10-27 | 2021-02-23 | 河北圣雪大成制药有限责任公司 | Method for improving extraction yield of spectinomycin |
| CN115594687A (en) * | 2021-06-28 | 2023-01-13 | 黑龙江联顺生物科技有限公司（Cn） | Method for extracting and purifying spectinomycin |
| CN113861212A (en) * | 2021-10-11 | 2021-12-31 | 河北圣雪大成唐山制药有限责任公司 | Method for improving turbidity of spectinomycin hydrochloride product |
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| CN101012246B (en) * | 2006-12-20 | 2012-07-04 | 福州大学 | Ion exchange purifying method of aminoglycoside antibiotics |
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