CN111592576A - Treatment method of butanol crystallization mother liquor of lincomycin hydrochloride - Google Patents
Treatment method of butanol crystallization mother liquor of lincomycin hydrochloride Download PDFInfo
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- CN111592576A CN111592576A CN202010391598.7A CN202010391598A CN111592576A CN 111592576 A CN111592576 A CN 111592576A CN 202010391598 A CN202010391598 A CN 202010391598A CN 111592576 A CN111592576 A CN 111592576A
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- phosphate
- edta
- mother liquor
- lincomycin
- solid
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- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 title claims abstract description 78
- POUMFISTNHIPTI-BOMBIWCESA-N hydron;(2s,4r)-n-[(1r,2r)-2-hydroxy-1-[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-methylsulfanyloxan-2-yl]propyl]-1-methyl-4-propylpyrrolidine-2-carboxamide;chloride Chemical compound Cl.CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 POUMFISTNHIPTI-BOMBIWCESA-N 0.000 title claims abstract description 54
- 229960001595 lincomycin hydrochloride Drugs 0.000 title claims abstract description 53
- 239000012452 mother liquor Substances 0.000 title claims abstract description 50
- 238000002425 crystallisation Methods 0.000 title claims abstract description 36
- 230000008025 crystallization Effects 0.000 title claims abstract description 36
- 238000000034 method Methods 0.000 title claims abstract description 31
- 238000011282 treatment Methods 0.000 title claims description 17
- 239000007787 solid Substances 0.000 claims abstract description 51
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims abstract description 36
- OJMMVQQUTAEWLP-UHFFFAOYSA-N Lincomycin Natural products CN1CC(CCC)CC1C(=O)NC(C(C)O)C1C(O)C(O)C(O)C(SC)O1 OJMMVQQUTAEWLP-UHFFFAOYSA-N 0.000 claims abstract description 33
- 229960005287 lincomycin Drugs 0.000 claims abstract description 33
- OJMMVQQUTAEWLP-KIDUDLJLSA-N lincomycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 OJMMVQQUTAEWLP-KIDUDLJLSA-N 0.000 claims abstract description 33
- 238000000855 fermentation Methods 0.000 claims abstract description 30
- 230000004151 fermentation Effects 0.000 claims abstract description 30
- 239000007788 liquid Substances 0.000 claims abstract description 25
- 229910019142 PO4 Inorganic materials 0.000 claims abstract description 22
- 239000010452 phosphate Substances 0.000 claims abstract description 22
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims abstract description 22
- 238000001035 drying Methods 0.000 claims abstract description 19
- 239000006228 supernatant Substances 0.000 claims abstract description 19
- 238000004519 manufacturing process Methods 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000012670 alkaline solution Substances 0.000 claims abstract description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical class [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 11
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 9
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 9
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical class [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 9
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 239000012535 impurity Substances 0.000 claims description 4
- 239000013543 active substance Substances 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 2
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 2
- 229920000642 polymer Polymers 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 239000002244 precipitate Substances 0.000 claims description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- 235000011008 sodium phosphates Nutrition 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims description 2
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical group [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 claims description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims 1
- 239000012047 saturated solution Substances 0.000 claims 1
- 102000004169 proteins and genes Human genes 0.000 abstract description 11
- 108090000623 proteins and genes Proteins 0.000 abstract description 11
- 239000000126 substance Substances 0.000 abstract description 11
- 238000000926 separation method Methods 0.000 abstract description 7
- 239000001963 growth medium Substances 0.000 description 13
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 12
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 9
- 239000011574 phosphorus Substances 0.000 description 9
- 229910052698 phosphorus Inorganic materials 0.000 description 9
- 238000001514 detection method Methods 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- 235000010469 Glycine max Nutrition 0.000 description 6
- 244000068988 Glycine max Species 0.000 description 6
- 229910021380 Manganese Chloride Inorganic materials 0.000 description 6
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 6
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 6
- 235000011130 ammonium sulphate Nutrition 0.000 description 6
- 229910000019 calcium carbonate Inorganic materials 0.000 description 6
- 239000008103 glucose Substances 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- 239000011565 manganese chloride Substances 0.000 description 6
- 235000002867 manganese chloride Nutrition 0.000 description 6
- 229940099607 manganese chloride Drugs 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 239000004317 sodium nitrate Substances 0.000 description 6
- 235000010344 sodium nitrate Nutrition 0.000 description 6
- 239000008107 starch Substances 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- 238000009835 boiling Methods 0.000 description 4
- 229960002227 clindamycin Drugs 0.000 description 4
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 description 4
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 229910052750 molybdenum Inorganic materials 0.000 description 3
- 239000011733 molybdenum Substances 0.000 description 3
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 3
- 235000019624 protein content Nutrition 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- 206010031252 Osteomyelitis Diseases 0.000 description 2
- 241000187399 Streptomyces lincolnensis Species 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/14—Acyclic radicals, not substituted by cyclic structures attached to a sulfur, selenium or tellurium atom of a saccharide radical
- C07H15/16—Lincomycin; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Biotechnology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
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.
Description
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.
Example 1
The treatment method of the butanol crystallization mother liquor of lincomycin hydrochloride comprises the following steps:
(1) adding 200ml of saturated sodium phosphate into 10000ml of butanol crystallization mother liquor of lincomycin hydrochloride, then adding 5000ml of water, and then adjusting the pH value to 8.4 by using sodium hydroxide; fully and uniformly stirring, standing for 1 hour, layering to obtain a supernatant and a lower-layer turbid liquid, and then separating;
(2) carrying out centrifugal separation on the separated turbid liquid to obtain liquid and solid; detecting lincomycin hydrochloride in the supernatant by using a high performance liquid chromatography, wherein the detection result is shown as the lincomycin hydrochloride content in the mother liquor in the table 1, and the supernatant is used for recovering the lincomycin hydrochloride; and
(3) drying the solid obtained in the step (2), drying the solid in an oven at 95 ℃ and normal pressure in a small trial run, drying the solid in a boiling drying mode in production, determining the content of phosphorus in the dried solid by adopting a molybdenum blue method, determining the content of protein by adopting a formaldehyde method, and determining the detection results as shown in the content of phosphorus and protein in the recovered solid in table 2; and (3) then using the solid drying object with the detected phosphorus and protein contents for producing lincomycin by shaking flask fermentation, and using the liquid obtained in the step (2) for recovering butanol.
The method for producing lincomycin by shaking flask fermentation comprises the following steps:
control group: filling 50ml of prepared culture medium into a 500ml triangular flask, counting 20 bottles in total, wrapping the bottle mouth by eight layers of gauze, keeping the temperature of a sterilization pot at 121-; inoculating lincomycin strains into a shake flask for shake culture in a sterile room, wherein the rotation speed of the shake flask is 200 plus or minus 240rpm, the temperature is 30.0 +/-1.0 ℃, the humidity is 40-70%, and the culture time is 180 h; then, filtering, and detecting lincomycin hydrochloride by adopting a high performance liquid chromatography.
The mixing ratio of the shake flask fermentation culture medium is calculated according to the volume of each 1000 ml: 80g of glucose, 25g of soybean cake powder, 20g of starch, 6g of sodium chloride, 8g of ammonium sulfate, 8g of sodium nitrate, 8g of calcium carbonate, 0.5g of manganese chloride, 0.7g of magnesium sulfate and 0.4g of monopotassium phosphate.
Experimental groups: the shake flask fermentation adopts the same culture conditions as the control group, and adopts shake flasks 1, 2 and 3 for fermentation culture, the only difference is that: the proportion of the culture medium adopted when the solid dried substance is used for producing lincomycin by fermenting and shaking the flask is calculated according to the volume of each 1000ml as follows: 80g of glucose, 25g of soybean cake powder, 20g of starch, 6g of sodium chloride, 8g of ammonium sulfate, 8g of sodium nitrate, 8g of calcium carbonate, 0.5g of manganese chloride, 0.7g of magnesium sulfate and 0.4g of a solid dried product obtained in example 1. Namely, the experimental group used the recovered dried solid instead of potassium dihydrogen phosphate in the original culture medium. The results obtained are shown in Table 3 for the fermentation shake flask.
TABLE 1
According to the data, the lincomycin content is basically not lost before and after the treatment.
TABLE 2
TABLE 3
The results show that the obtained solid is used for producing lincomycin by shaking flask fermentation, can reach the control level, and can be used for producing lincomycin by fermentation.
Example 2
The treatment method of the butanol crystallization mother liquor of lincomycin hydrochloride comprises the following steps:
(1) adding 600ml of saturated sodium phosphate into 20000ml of butanol crystallization mother liquor of lincomycin hydrochloride, then adding 20000ml of water, and then adjusting the pH value to 9.0 by using sodium hydroxide; fully and uniformly stirring, standing for 1 hour, layering to obtain a supernatant and a lower-layer turbid liquid, and then separating;
(2) carrying out centrifugal separation on the separated turbid liquid to obtain liquid and solid; detecting lincomycin hydrochloride in the supernatant by using a high performance liquid chromatography, wherein the detection result is shown as the lincomycin hydrochloride content in the mother liquor in the table 4, and the supernatant is used for recovering the lincomycin hydrochloride; and
(3) drying the solid obtained in the step (2), drying the solid in an oven at 95 ℃ and normal pressure in a pilot plant, drying the solid in a boiling drying mode in production, determining the content of phosphorus in the dried solid by adopting a molybdenum blue method, determining the content of protein by adopting a formaldehyde method, and determining the detection results as shown in the content of phosphorus and protein in the recovered solid in a table 5; and (3) then using the solid drying object with the detected phosphorus and protein contents for producing lincomycin by shaking flask fermentation, and using the liquid obtained in the step (2) for recovering butanol.
The method for producing lincomycin by shaking flask fermentation comprises the following steps:
control group: filling 50ml of prepared culture medium into a 500ml triangular flask, counting 20 bottles in total, wrapping the bottle mouth by eight layers of gauze, keeping the temperature of a sterilization pot at 121-; inoculating lincomycin strains into a shake flask for shake culture in a sterile room, wherein the rotation speed of the shake flask is 200 plus or minus 240rpm, the temperature is 30.0 +/-1.0 ℃, the humidity is 40-70%, and the culture time is 180 h; then, filtering, and detecting lincomycin hydrochloride by adopting a high performance liquid chromatography.
The mixing ratio of the shake flask fermentation culture medium is calculated according to the volume of each 1000 ml: 80g of glucose, 25g of soybean cake powder, 20g of starch, 6g of sodium chloride, 8g of ammonium sulfate, 8g of sodium nitrate, 8g of calcium carbonate, 0.5g of manganese chloride, 0.7g of magnesium sulfate and 0.4g of monopotassium phosphate.
Experimental groups: the shake flask fermentation adopts the same culture conditions as the control group, and adopts shake flasks 1, 2 and 3 for fermentation culture, the only difference is that: the proportion of the culture medium adopted when the solid dried substance is used for producing lincomycin by fermenting and shaking the flask is calculated according to the volume of each 1000ml as follows: 80g of glucose, 25g of soybean cake powder, 20g of starch, 6g of sodium chloride, 8g of ammonium sulfate, 8g of sodium nitrate, 8g of calcium carbonate, 0.5g of manganese chloride, 0.7g of magnesium sulfate and 0.4g of a solid dried substance obtained in the example. Namely, the experimental group used the recovered dried solid instead of potassium dihydrogen phosphate in the original culture medium. The results obtained are shown in Table 6 for the fermentation flasks.
TABLE 4
According to the data, the lincomycin content is basically not lost before and after the treatment.
TABLE 5
TABLE 6
The results show that the obtained solid is used for producing lincomycin by shaking flask fermentation, can reach the control level, and can be used for producing lincomycin by fermentation.
Example 3
The treatment method of the butanol crystallization mother liquor of lincomycin hydrochloride comprises the following steps:
(1) adding 800ml of saturated sodium phosphate into 20000ml of butanol crystallization mother liquor of lincomycin hydrochloride, then adding 15000ml of water, and then adjusting the pH value to 7.5 by using sodium hydroxide; fully and uniformly stirring, standing for 1 hour, layering to obtain a supernatant and a lower-layer turbid liquid, and then separating;
(2) carrying out centrifugal separation on the separated turbid liquid to obtain liquid and solid; detecting lincomycin hydrochloride in the supernatant by using a high performance liquid chromatography, wherein the detection result is shown in the content of the lincomycin hydrochloride in the mother liquor in the table 7, and the supernatant is used for recovering the lincomycin hydrochloride; and
(3) drying the solid obtained in the step (2), drying the solid in an oven at 95 ℃ and normal pressure in a small trial run, drying the solid in a boiling drying mode in production, determining the content of phosphorus in the dried solid by adopting a molybdenum blue method, determining the content of protein by adopting a formaldehyde method, and determining the detection results as shown in the content of phosphorus and protein in the recovered solid in a table 8; and then the solid drying object with the detected phosphorus and protein contents is used for producing lincomycin by shaking flask fermentation.
The method for producing lincomycin by shaking flask fermentation comprises the following steps:
control group: filling 50ml of prepared culture medium into a 500ml triangular flask, counting 20 bottles in total, wrapping the bottle mouth by eight layers of gauze, keeping the temperature of a sterilization pot at 121-; inoculating lincomycin strains into a shake flask for shake culture in a sterile room, wherein the rotation speed of the shake flask is 200 plus or minus 240rpm, the temperature is 30.0 +/-1.0 ℃, the humidity is 40-70%, and the culture time is 180 h; then, filtering, and detecting lincomycin hydrochloride by adopting a high performance liquid chromatography.
The mixing ratio of the shake flask fermentation culture medium is calculated according to the volume of each 1000 ml: 80g of glucose, 25g of soybean cake powder, 20g of starch, 6g of sodium chloride, 8g of ammonium sulfate, 8g of sodium nitrate, 8g of calcium carbonate, 0.5g of manganese chloride, 0.7g of magnesium sulfate and 0.4g of monopotassium phosphate.
Experimental groups: the shake flask fermentation adopts the same culture conditions as the control group, and adopts shake flasks 1, 2 and 3 for fermentation culture, the only difference is that: the proportion of the culture medium adopted when the solid dried substance is used for producing lincomycin by fermenting and shaking the flask is calculated according to the volume of each 1000ml as follows: 80g of glucose, 25g of soybean cake powder, 20g of starch, 6g of sodium chloride, 8g of ammonium sulfate, 8g of sodium nitrate, 8g of calcium carbonate, 0.5g of manganese chloride, 0.7g of magnesium sulfate and 0.4g of a solid dried product obtained in example 1. Namely, the experimental group uses the recovered solid drying substance to proportionally replace the potassium dihydrogen phosphate in the original culture medium. The results obtained are shown in Table 9 for the fermentation flasks.
TABLE 7
According to the data, the lincomycin content is basically not lost before and after the treatment.
TABLE 8
TABLE 9
The results show that the obtained solid is used for producing lincomycin by shaking flask fermentation, can reach the control level, and can be used for producing lincomycin by fermentation.
Example 4
The treatment method of the butanol crystallization mother liquor of lincomycin hydrochloride comprises the following steps:
(1) adding 500ml of saturated EDTA into 10000ml of butanol crystallization mother liquor of lincomycin hydrochloride, then adding 10000ml of water, and then adjusting the pH value to 8.0 by using sodium hydroxide; fully and uniformly stirring, standing for 1 hour, layering to obtain a supernatant and a lower-layer turbid liquid, and then separating;
(2) carrying out centrifugal separation on the separated turbid liquid to obtain liquid and solid; detecting lincomycin hydrochloride in the supernatant by using a high performance liquid chromatography, wherein the detection result is shown in the content of the lincomycin hydrochloride in the mother liquor in the table 10, and the supernatant is used for recovering the lincomycin hydrochloride; the solids are discarded.
Watch 10
The foregoing descriptions of specific exemplary embodiments of the present invention have been presented for purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed, and obviously many modifications and variations are possible in light of the above teaching. The exemplary embodiments were chosen and described in order to explain certain principles of the invention and its practical application to enable one skilled in the art to make and use various exemplary embodiments of the invention and various alternatives and modifications as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the claims and their equivalents.
Claims (10)
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).
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102746348A (en) * | 2011-04-19 | 2012-10-24 | 上海医药工业研究院 | Method for separation of lincomycin |
| CN103173508A (en) * | 2011-12-23 | 2013-06-26 | 重庆药友制药有限责任公司 | Method for cleaning and producing lincomycin |
| CN103830172A (en) * | 2014-03-05 | 2014-06-04 | 刘飞飞 | Preparation method of lincomycin hydrochloride injection |
| CN104164462A (en) * | 2014-08-12 | 2014-11-26 | 天方药业有限公司 | Method for reducing lincomycin B components in fermentation process |
| CN104478973A (en) * | 2014-11-27 | 2015-04-01 | 天方药业有限公司 | Method for reducing impurities of spiramycin by recrystallization |
| CN109942646A (en) * | 2019-04-29 | 2019-06-28 | 宜昌东阳光药业股份有限公司 | A kind of extracting method of Lincomycin Hydrochloride |
| CN109971692A (en) * | 2019-05-16 | 2019-07-05 | 华东理工大学 | Str. lincolnensis (Streptomyces lincolnensis) and cultural method and application |
-
2020
- 2020-05-11 CN CN202010391598.7A patent/CN111592576B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102746348A (en) * | 2011-04-19 | 2012-10-24 | 上海医药工业研究院 | Method for separation of lincomycin |
| CN103173508A (en) * | 2011-12-23 | 2013-06-26 | 重庆药友制药有限责任公司 | Method for cleaning and producing lincomycin |
| CN103830172A (en) * | 2014-03-05 | 2014-06-04 | 刘飞飞 | Preparation method of lincomycin hydrochloride injection |
| CN104164462A (en) * | 2014-08-12 | 2014-11-26 | 天方药业有限公司 | Method for reducing lincomycin B components in fermentation process |
| CN104478973A (en) * | 2014-11-27 | 2015-04-01 | 天方药业有限公司 | Method for reducing impurities of spiramycin by recrystallization |
| CN109942646A (en) * | 2019-04-29 | 2019-06-28 | 宜昌东阳光药业股份有限公司 | A kind of extracting method of Lincomycin Hydrochloride |
| CN109971692A (en) * | 2019-05-16 | 2019-07-05 | 华东理工大学 | Str. lincolnensis (Streptomyces lincolnensis) and cultural method and application |
Non-Patent Citations (5)
| Title |
|---|
| 周晓荣: "混合醇回收结晶母液中活性成分林可霉素的研究" * |
| 李华 等: "林可霉素发酵工艺优化降低B组分" * |
| 武斌 等: "混合醇萃取用以降低林可霉素产品中B组分含量的工艺研究" * |
| 毛全贵 等: "林可霉素发酵后期的工艺改进" * |
| 牛宗亮 等, 中国原子能出版社 * |
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