阅读说明：本技术 盐酸林可霉素的丁醇结晶母液的处理方法 (Treatment method of butanol crystallization mother liquor of lincomycin hydrochloride ) 是由 张宏周 刘俭国 朱德育 赖珅 刘守强 陈中刚 张增辉 李磊 谢书琴 王雪洁 王鑫 于 2020-05-11 设计创作，主要内容包括：本发明公开了一种盐酸林可霉素的丁醇结晶母液的处理方法,步骤包括：(1)在盐酸林可霉素的丁醇结晶母液中加入EDTA、EDTA盐或磷酸盐中的任意一种,加水,用碱性溶液调节pH值至7.0-11.0；静置分层,得到上清液和下层浑浊液,分离；(2)将浑浊液离心分离,得到液体和固体；上清液用于回收盐酸林可霉素；将固体烘干,使用EDTA、EDTA盐产生的固体直接废弃,使用磷酸盐产生的固体用于发酵生产林可霉素。本发明能够从盐酸林可霉素的丁醇结晶母液中分离出蛋白类物质,处理后母液的盐酸林可霉素含量不降低,且处理后的丁醇结晶母液以直接浓缩结晶或进行其他处理,使母液中盐酸林可霉素回收变得简单,产生的烘干固体如果是使用磷酸盐产生的还可用于林可霉素发酵生产。(The invention discloses a method for treating butanol crystallization mother liquor of lincomycin hydrochloride, which comprises the following steps: (1) adding any one of EDTA, EDTA salt or phosphate into butanol crystallization mother liquor of lincomycin hydrochloride, adding water, and adjusting the pH value to 7.0-11.0 by using an alkaline solution; standing for layering to obtain supernatant and lower turbid liquid, and separating; (2) carrying out centrifugal separation on the turbid liquid to obtain liquid and solid; the supernatant is used for recovering lincomycin hydrochloride; and drying the solid, directly discarding the solid generated by EDTA and EDTA salt, and using the solid generated by phosphate for fermentation production of lincomycin. The method can separate protein substances from the butanol crystallization mother liquor of the lincomycin hydrochloride, the lincomycin hydrochloride content of the processed mother liquor is not reduced, and the processed butanol crystallization mother liquor is directly concentrated and crystallized or subjected to other processing, so that the lincomycin hydrochloride in the mother liquor is easy to recover, and the generated dried solid can be used for lincomycin fermentation production if phosphate is used.)

1. A treatment method of butanol crystallization mother liquor of lincomycin hydrochloride is characterized by comprising the following steps:

(1) adding any one of EDTA, EDTA salt or phosphate into butanol crystallization mother liquor of lincomycin hydrochloride, then adding water, and adjusting the pH value to 7.0-11.0 by using alkaline solution, wherein the volume ratio of the butanol crystallization mother liquor to the EDTA, the EDTA salt or the phosphate is 100:1-8, and the volume ratio of the butanol crystallization mother liquor to the water is 1: 0.2-1; stirring uniformly, standing for layering to obtain a supernatant and a lower-layer turbid liquid, and then separating;

EDTA, EDTA salt or phosphate forms a complex with inorganic and organic impurities in the mother liquor or polymer forms precipitates, and the EDTA, EDTA salt or phosphate is easy to obtain and can be reused subsequently.

Since impurities remaining in the mother liquor are all acid-soluble, the pH is adjusted to 7.0 to 11.0 using an alkaline solution, but if the alkalinity exceeds the pH of 11.0, the target active substance is degraded.

(2) Centrifugally separating the separated turbid liquid to obtain liquid and solid, and directly discarding the solid obtained by using EDTA \ EDTA salt; using phosphate, and entering the step (3).

(3) And (3) drying the solid obtained in the step (2), and using the dried solid for fermentation production of lincomycin.

2. The process according to claim 1, characterized in that the EDTA salt is EDTA sodium salt.

3. The method according to claim 1, wherein the phosphoric acid is one selected from potassium phosphate salts and sodium phosphate salts.

4. The method according to claim 3, wherein the potassium phosphate salt is any one selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate and potassium phosphate.

5. The method according to claim 3, wherein the sodium phosphate salt is any one selected from the group consisting of sodium dihydrogen phosphate, disodium hydrogen phosphate, and sodium phosphate.

6. The treatment process according to claim 1, characterized in that the phosphate is a phosphate saturated solution.

7. The process of claim 1, wherein the volume ratio of butanol crystallization mother liquor to EDTA, EDTA salt or phosphate is 100: 2-5; preferably, the volume ratio of the butanol crystallization mother liquor to EDTA, EDTA salt or phosphate is 100: 3-4.

8. The treatment process according to claim 1, characterized in that said alkaline solution is a sodium hydroxide solution.

9. The process according to claim 1, wherein in step (1), the pH is 7.5 to 9.5.

10. The process according to claim 1, wherein the supernatant is further treated 1 to 2 times by the above step (1).

Technical Field

The invention relates to the technical field of pharmacy, in particular to a method for treating butanol crystallization mother liquor of lincomycin hydrochloride.

Background

Lincomycin, also called Lincomycin (Lincomycin) abroad, also called Lincomycin, is a lincomamine-type alkaline antibiotic produced by Streptomyces lincolnensis of Streptomyces lincolnensis. Lincomycin and a downstream product Clindamycin (Clindamycin) which is chemically semi-synthesized by lincomycin are high-efficiency broad-spectrum antibiotics which are widely applied in clinic for many years and have obvious curative effects, the action of the Clindamycin is similar to that of erythromycin, skin test is not needed, the effects on gram-positive bacteria and gram-negative bacteria are strong, and the Clindamycin is used for osteomyelitis, septicemia, infection of respiratory systems and soft tissues and the like. The product has strong penetration capability to bones, and is a preferred good medicine for osteomyelitis.

Lincomycin hydrochloride (molecular formula: C)₁₈H₃₄N₂O₆S·HCl·H₂O), its molecular weight is 461.02, molecular structural formula as follows. The lincomycin hydrochloride butanol crystallization utilizes the azeotropic principle of butanol and water, and comprises the following specific steps: decolorizing lincomycin hydrochloride back extraction liquid, adding butanol of 3-5 times, heating to 60-65 deg.c in vacuum state for boiling distillation, and cooling to crystallize. And (3) carrying out solid-liquid separation after the lincomycin hydrochloride butanol is crystallized to obtain butanol mother liquor, wherein the mother liquor contains lincomycin hydrochloride of not less than 3mg/ml, a small amount of water, residual protein substances and trace inorganic salts.

The lincomycin hydrochloride in the mother liquor is generally recovered by adopting re-concentration crystallization or entering a solvent extraction back-extraction procedure. Because the lincomycin hydrochloride butanol crystallization mother liquor contains the protein substances, the lincomycin hydrochloride butanol crystallization mother liquor is difficult to treat by any method in the prior art, and the protein substances cause great influence in various recovery treatment processes of the mother liquor, so that the recovery rate of the lincomycin hydrochloride is very low, and the product quality cannot be ensured.

The information disclosed in this background section is only for enhancement of understanding of the general background of the invention and should not be taken as an acknowledgement or any form of suggestion that this information forms the prior art already known to a person skilled in the art.

Disclosure of Invention

The invention aims to provide a method for treating a butanol crystallization mother liquor of lincomycin hydrochloride, which can directly concentrate and crystallize the butanol crystallization mother liquor of the lincomycin hydrochloride, and dry a solid generated by separation and then use the solid for fermentation production of the lincomycin.

In order to achieve the aim, the invention provides a method for treating a butanol crystallization mother liquor of lincomycin hydrochloride, which comprises the following steps:

(1) adding any one of EDTA, EDTA salt or phosphate into butanol crystallization mother liquor of lincomycin hydrochloride, then adding water, and adjusting the pH value to 7.0-11.0 by using alkaline solution, wherein the volume ratio of the butanol crystallization mother liquor to the EDTA, the EDTA salt or the phosphate is 100:1-8, and the volume ratio of the butanol crystallization mother liquor to the water is 1: 0.2-1; stirring uniformly, standing for layering to obtain a supernatant and a lower-layer turbid liquid, and then separating; (2) centrifugally separating the separated turbid liquid to obtain liquid and solid, and directly discarding the solid generated by EDTA and EDTA salt; the supernatant is used for recovering lincomycin hydrochloride; (3) and (3) drying the solid obtained in the step (2), and using the dried solid for fermentation production of lincomycin.

The EDTA, EDTA salt or phosphate and inorganic and organic impurities in the mother liquor form a complex or a polymer to form precipitate, and the EDTA, EDTA salt or phosphate is easy to obtain and can be reused subsequently. Since impurities remaining in the mother liquor are all acid-soluble, the pH is adjusted to 7.0 to 11.0 using an alkaline solution, but if the alkalinity exceeds the pH of 11.0, the target active substance is degraded.

In a preferred embodiment, the EDTA salt is EDTA sodium salt.

In a preferred embodiment, the phosphoric acid is one selected from potassium phosphate salts and sodium phosphate salts.

In a preferred embodiment, the potassium phosphate salt is any one selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate and potassium phosphate.

In a preferred embodiment, the sodium phosphate salt is selected from any one of sodium dihydrogen phosphate, disodium hydrogen phosphate, and sodium phosphate.

In a preferred embodiment, the phosphate is a saturated phosphate solution.

In a preferred embodiment, the volume ratio of the butanol crystallization mother liquor to EDTA, EDTA salt or phosphate is 100: 2-5; preferably, the volume ratio of the butanol crystallization mother liquor to EDTA, EDTA salt or phosphate is 100: 3-4.

In a preferred embodiment, in step (1), the pH is 7.5 to 9.5.

In a preferred embodiment, the supernatant is further treated 1 to 2 times in the step (1).

Compared with the prior art, the invention has the following beneficial effects:

according to the invention, the butanol crystallization mother liquor of the lincomycin hydrochloride is pretreated by using substances such as phosphate, EDTA and the like, protein substances can be separated from the butanol crystallization mother liquor of the lincomycin hydrochloride, the lincomycin hydrochloride content of the mother liquor after treatment is not reduced, and the butanol crystallization mother liquor after treatment can be directly concentrated and crystallized or subjected to other treatments, so that the lincomycin hydrochloride in the mother liquor is simply recovered, and the quality of the obtained lincomycin hydrochloride product meets the quality requirement of new pharmacopoeia; using phosphate treatment, the dried solids produced by the process contain primarily phosphate and proteinaceous matter, and can be used in lincomycin fermentation production in place of phosphate in the culture medium, such as potassium dihydrogen phosphate.

Detailed Description

The following detailed description of specific embodiments of the invention is provided, but it should be understood that the scope of the invention is not limited to the specific embodiments.