CN111592576B - 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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- CN111592576B CN111592576B CN202010391598.7A CN202010391598A CN111592576B CN 111592576 B CN111592576 B CN 111592576B CN 202010391598 A CN202010391598 A CN 202010391598A CN 111592576 B CN111592576 B CN 111592576B
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- lincomycin
- mother liquor
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- butanol
- lincomycin hydrochloride
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- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 title claims abstract description 79
- 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 57
- 229960001595 lincomycin hydrochloride Drugs 0.000 title claims abstract description 56
- 239000012452 mother liquor Substances 0.000 title claims abstract description 45
- 238000002425 crystallisation Methods 0.000 title claims abstract description 39
- 230000008025 crystallization Effects 0.000 title claims abstract description 39
- 238000000034 method Methods 0.000 title claims abstract description 26
- 238000011282 treatment Methods 0.000 title abstract description 14
- 239000007787 solid Substances 0.000 claims abstract description 44
- 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
- 239000007788 liquid Substances 0.000 claims abstract description 29
- 238000000855 fermentation Methods 0.000 claims abstract description 27
- 230000004151 fermentation Effects 0.000 claims abstract description 27
- 239000006228 supernatant Substances 0.000 claims abstract description 19
- 229910019142 PO4 Inorganic materials 0.000 claims abstract description 17
- 239000010452 phosphate Substances 0.000 claims abstract description 17
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims abstract description 17
- 238000004519 manufacturing process Methods 0.000 claims abstract description 15
- 238000001035 drying Methods 0.000 claims abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000012670 alkaline solution Substances 0.000 claims abstract description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 14
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 14
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 claims description 14
- 239000001963 growth medium Substances 0.000 claims description 12
- 239000000463 material Substances 0.000 claims description 8
- 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 claims description 7
- 229910021380 Manganese Chloride Inorganic materials 0.000 claims description 7
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 claims description 7
- 235000019764 Soybean Meal Nutrition 0.000 claims description 7
- 229920002472 Starch Polymers 0.000 claims description 7
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 7
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 7
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 7
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 7
- 239000008103 glucose Substances 0.000 claims description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 7
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 7
- 239000011565 manganese chloride Substances 0.000 claims description 7
- 235000002867 manganese chloride Nutrition 0.000 claims description 7
- 229940099607 manganese chloride Drugs 0.000 claims description 7
- 239000011780 sodium chloride Substances 0.000 claims description 7
- 239000004317 sodium nitrate Substances 0.000 claims description 7
- 235000010344 sodium nitrate Nutrition 0.000 claims description 7
- 239000004455 soybean meal Substances 0.000 claims description 7
- 239000008107 starch Substances 0.000 claims description 7
- 235000019698 starch Nutrition 0.000 claims description 7
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical group [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 6
- 238000009835 boiling Methods 0.000 claims description 5
- 238000011049 filling Methods 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- 230000001954 sterilising effect Effects 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 239000001488 sodium phosphate Substances 0.000 claims description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 2
- 239000012047 saturated solution Substances 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims 1
- 239000012467 final product Substances 0.000 claims 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 abstract description 21
- 102000004169 proteins and genes Human genes 0.000 abstract description 9
- 108090000623 proteins and genes Proteins 0.000 abstract description 9
- 238000011084 recovery Methods 0.000 abstract description 7
- 239000000126 substance Substances 0.000 abstract description 7
- 230000001105 regulatory effect Effects 0.000 abstract description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 11
- 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
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 8
- 235000019796 monopotassium phosphate Nutrition 0.000 description 8
- 238000001514 detection method Methods 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 6
- 235000019624 protein content Nutrition 0.000 description 6
- 239000000047 product Substances 0.000 description 4
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 229910052750 molybdenum Inorganic materials 0.000 description 3
- 239000011733 molybdenum Substances 0.000 description 3
- 239000011343 solid material Substances 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
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 description 2
- 235000011009 potassium phosphates Nutrition 0.000 description 2
- 235000011008 sodium phosphates Nutrition 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
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 241000187399 Streptomyces lincolnensis Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 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
- 230000015556 catabolic process Effects 0.000 description 1
- 229960002227 clindamycin Drugs 0.000 description 1
- 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 1
- 238000006731 degradation reaction Methods 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000007781 pre-processing Methods 0.000 description 1
- 238000001556 precipitation Methods 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
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 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 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
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- 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 treatment method of 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 regulating pH value to 7.0-11.0 with alkaline solution; standing for layering to obtain supernatant and lower turbid liquid, and separating; (2) centrifugally separating the turbid liquid to obtain liquid and solid; the supernatant is used for recovering lincomycin hydrochloride; drying the solid, directly discarding the solid generated by using EDTA and EDTA salt, and using the solid generated by using phosphate for fermenting and producing lincomycin. The invention can separate out protein substances from the butanol crystallization mother liquor of the lincomycin hydrochloride, the content of the lincomycin hydrochloride in the mother liquor after treatment is not reduced, and the butanol crystallization mother liquor after treatment is directly concentrated and crystallized or is subjected to other treatments, so that the recovery of the lincomycin hydrochloride in the mother liquor becomes simple, and the generated baked solid can be used for fermentation production of the lincomycin if the baked solid is produced by phosphate.
Description
Technical Field
The invention relates to the technical field of pharmacy, in particular to a treatment method of butanol crystallization mother liquor of lincomycin hydrochloride.
Background
Lincomycin, referred to as Lincomycin (Lincomycin), also known as Lincomycin, is a lincolamine basic antibiotic produced by lincoln variant Streptomyces lincolnensis of streptomyces lincoleus. Lincomycin and its chemical semisynthetic downstream product Clindamycin are high-efficiency broad-spectrum antibiotics with obvious curative effect, similar to erythromycin, and strong action on gram positive bacteria and gram negative bacteria, and can be used for osteomyelitis, septicemia, respiratory system and soft tissue infection. The product has strong penetrability to bones, and is the first choice for osteomyelitis.
Lincomycin hydrochloride (molecular formula: C) 18 H 34 N 2 O 6 S·HCl·H 2 O) having a molecular weight of 461.02 and a molecular structural formula as follows. The crystallization of lincomycin hydrochloride butanol utilizes the azeotropic principle of butanol and water, and comprises the following specific steps: decolorizing lincomycin hydrochloride back-extraction liquid, adding 3-5 times of butanol, heating to 60-65 deg.C under vacuum, boiling, distilling, and cooling for crystallization. Crystallization of lincomycin hydrochloride butanol is carried outThe butanol mother liquid is obtained by solid-liquid separation, and the mother liquid contains lincomycin hydrochloride not less than 3mg/ml, contains a small amount of water, and contains residual protein substances and trace inorganic salts.
The recovery of lincomycin hydrochloride in the mother liquor generally adopts re-concentration crystallization or solvent extraction back extraction procedure. Because the protein substances exist in the lincomycin hydrochloride butanol crystallization mother liquor, no matter which method is adopted in the prior art to treat the lincomycin hydrochloride butanol crystallization mother liquor is difficult, the protein substances have 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 of ordinary skill in the art.
Disclosure of Invention
The invention aims to provide a treatment method of butanol crystallization mother liquor of lincomycin hydrochloride, which can enable the butanol crystallization mother liquor of lincomycin hydrochloride to be directly concentrated for crystallization and enable solids produced by separation to be dried and then used for fermentation production of lincomycin.
In order to achieve the above object, the present invention provides a method for treating a butanol crystallization mother liquor of lincomycin hydrochloride, comprising the steps of:
(1) Adding any one of EDTA, EDTA salt or phosphate into butanol crystallization mother liquor of lincomycin hydrochloride, then adding water, and then 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 supernatant and lower turbid liquid, and then separating; (2) Centrifugally separating the separated turbid liquid to obtain liquid and solid, and directly discarding the solid generated by using EDTA and EDTA salt; the supernatant is used for recovering lincomycin hydrochloride; (3) And (3) drying the solid obtained in the step (2), wherein the obtained solid dried matter is used for producing lincomycin by fermentation.
The EDTA, EDTA salt or phosphate forms complex with inorganic and organic impurities in the mother liquor or forms precipitation with polymer, and the EDTA, EDTA salt or phosphate is easy to obtain and can be reused later. Since the impurities remaining in the mother liquor are all acid soluble, the pH is adjusted to 7.0-11.0 with an alkaline solution, but if the alkaline exceeds ph=11.0, degradation of the intended active substance is caused.
In a preferred embodiment, the EDTA salt is EDTA sodium salt.
In a preferred embodiment, the phosphoric acid is selected from one of potassium phosphate and sodium phosphate.
In a preferred embodiment, the potassium phosphate salt is selected from any one 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 solution of phosphate.
In a preferred embodiment, 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.
In a preferred embodiment, in step (1), the pH is 7.5 to 9.5.
In a preferred embodiment, the supernatant is further treated 1-2 times by the step (1).
Compared with the prior art, the invention has the following beneficial effects:
according to the invention, substances such as phosphate and EDTA are used for preprocessing the butanol crystallization mother liquor of the lincomycin hydrochloride, so that protein substances can be separated from the butanol crystallization mother liquor of the lincomycin hydrochloride, the content of the lincomycin hydrochloride in the processed mother liquor is not reduced, and the processed butanol crystallization mother liquor can be directly concentrated and crystallized or subjected to other treatments, so that the recovery of the lincomycin hydrochloride in the mother liquor is simplified, and the quality of the obtained lincomycin hydrochloride product meets the requirements of the quality of new edition pharmacopoeia; the phosphate treatment is used to produce stoving solid containing mainly phosphate and protein matter, and the stoving solid may be used in fermentation to replace phosphate, such as potassium dihydrogen phosphate, in culture medium.
Detailed Description
The following detailed description of specific embodiments of the invention is, but it should be understood that the invention is not limited to specific embodiments.
Example 1
A method for treating a butanol crystallization mother liquor of lincomycin hydrochloride, the method comprising:
(1) Adding 200ml of saturated sodium phosphate into 10000ml of butanol crystallization mother liquor of lincomycin hydrochloride, then adding 5000ml of water, and then regulating the pH value to 8.4 by sodium hydroxide; fully and uniformly stirring, standing for 1 hour, layering to obtain supernatant and lower turbid liquid, and then separating;
(2) Centrifugally separating the separated turbid liquid to obtain liquid and solid; detecting lincomycin hydrochloride in the supernatant by high performance liquid chromatography, wherein the detection result is shown as the content of the lincomycin hydrochloride in the mother liquor in table 1, and the supernatant is used for recovering the lincomycin hydrochloride; and
(3) Drying the solid obtained in the step (2), wherein a small test is dried by adopting an oven at the temperature of 95 ℃ and the normal pressure, and the production can be carried out by adopting boiling drying, the determination of the phosphorus content in the obtained solid dried material adopts a molybdenum blue method, the protein content adopts a formaldehyde method, and the detection result is shown as the phosphorus and protein content in the recovered solid material in the table 2; and (3) then using the solid drying matters with the detected phosphorus and protein contents in shake flask fermentation to produce lincomycin, and using the liquid obtained in the step (2) in butanol recovery.
The method for producing lincomycin by shake flask fermentation comprises the following steps:
control group: filling 50ml of the assembled culture medium into 500ml triangular bottles, 20 bottles in total, binding bottle mouths with eight layers of gauze, and maintaining the temperature of a sterilizing pot at 121-123 ℃ for 30 minutes; inoculating lincomycin strain into shake flask for shake cultivation in sterile room, wherein the rotation speed of shake flask is 200-240rpm, the temperature is 30.0+ -1.0deg.C, the humidity is 40-70%, and the cultivation time is 180h; then, the solution is filtered, and the lincomycin hydrochloride is detected by adopting high performance liquid chromatography.
The proportion of the shake flask fermentation medium is calculated according to the volume of each 1000 ml: 80g of glucose, 25g of soybean meal, 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 group: the shake flask fermentation adopts the same culture conditions as the control group, and adopts shake flask 1, shake flask 2 and shake flask 3 for fermentation culture, and the only difference is that: the culture medium ratio adopted when the solid dried matter is used for producing lincomycin by fermenting shake flasks is calculated according to the volume of each 1000 ml: 80g of glucose, 25g of soybean meal, 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 solid dried material obtained in example 1. Namely, the experimental group uses the recovered solid dried matter to replace the monopotassium phosphate in the original culture medium. The results are shown in Table 3.
TABLE 1
According to the data, there was substantially no loss of lincomycin content before and after treatment.
TABLE 2
TABLE 3 Table 3
According to the results, the obtained solid is used for shake flask fermentation production of lincomycin, can reach a control level, and can be used for fermentation production of lincomycin.
Example 2
A method for treating a butanol crystallization mother liquor of lincomycin hydrochloride, the method comprising:
(1) 600ml of saturated sodium phosphate is added into 20000ml of butanol crystallization mother liquor of lincomycin hydrochloride, then 20000ml of water is added, and the pH value is regulated to 9.0 by sodium hydroxide; fully and uniformly stirring, standing for 1 hour, layering to obtain supernatant and lower turbid liquid, and then separating;
(2) Centrifugally separating the separated turbid liquid to obtain liquid and solid; detecting lincomycin hydrochloride in the supernatant by high performance liquid chromatography, wherein the detection result is shown as the content of the lincomycin hydrochloride in the mother liquor in table 4, and the supernatant is used for recovering the lincomycin hydrochloride; and
(3) Drying the solid obtained in the step (2), wherein a small test is dried by adopting an oven at the temperature of 95 ℃ and the normal pressure, and the production can be carried out by adopting boiling drying, the determination of the phosphorus content in the obtained solid dried material adopts a molybdenum blue method, the protein content adopts a formaldehyde method, and the detection result is shown in the content of phosphorus and protein in the recovered solid material in the table 5; and (3) then using the solid drying matters with the detected phosphorus and protein contents in shake flask fermentation to produce lincomycin, and using the liquid obtained in the step (2) in butanol recovery.
The method for producing lincomycin by shake flask fermentation comprises the following steps:
control group: filling 50ml of the assembled culture medium into 500ml triangular bottles, 20 bottles in total, binding bottle mouths with eight layers of gauze, and maintaining the temperature of a sterilizing pot at 121-123 ℃ for 30 minutes; inoculating lincomycin strain into shake flask for shake cultivation in sterile room, wherein the rotation speed of shake flask is 200-240rpm, the temperature is 30.0+ -1.0deg.C, the humidity is 40-70%, and the cultivation time is 180h; then, the solution is filtered, and the lincomycin hydrochloride is detected by adopting high performance liquid chromatography.
The proportion of the shake flask fermentation medium is calculated according to the volume of each 1000 ml: 80g of glucose, 25g of soybean meal, 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 group: the shake flask fermentation adopts the same culture conditions as the control group, and adopts shake flask 1, shake flask 2 and shake flask 3 for fermentation culture, and the only difference is that: the culture medium ratio adopted when the solid dried matter is used for producing lincomycin by fermenting shake flasks is calculated according to the volume of each 1000 ml: 80g of glucose, 25g of soybean meal, 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 solid dried material obtained in the example. Namely, the experimental group uses the recovered solid dried matter to replace the monopotassium phosphate in the original culture medium. The results are shown in Table 6.
TABLE 4 Table 4
According to the data, there was substantially no loss of lincomycin content before and after treatment.
TABLE 5
TABLE 6
According to the results, the obtained solid is used for shake flask fermentation production of lincomycin, can reach a control level, and can be used for fermentation production of lincomycin.
Example 3
A method for treating a butanol crystallization mother liquor of lincomycin hydrochloride, the method comprising:
(1) 800ml of saturated sodium phosphate is added into 20000ml of butanol crystallization mother liquor of lincomycin hydrochloride, 15000ml of water is then added, and the pH value is adjusted to 7.5 by sodium hydroxide; fully and uniformly stirring, standing for 1 hour, layering to obtain supernatant and lower turbid liquid, and then separating;
(2) Centrifugally separating the separated turbid liquid to obtain liquid and solid; detecting lincomycin hydrochloride in the supernatant by high performance liquid chromatography, wherein the detection result is shown as the content of the lincomycin hydrochloride in the mother liquor in table 7, and the supernatant is used for recovering the lincomycin hydrochloride; and
(3) Drying the solid obtained in the step (2), wherein a small test is dried by adopting an oven at the temperature of 95 ℃ and the normal pressure, and the production can be carried out by adopting boiling drying, the determination of the phosphorus content in the obtained solid dried material adopts a molybdenum blue method, the protein content adopts a formaldehyde method, and the detection result is shown in the content of phosphorus and protein in the recovered solid material in the table 8; and then the solid dried matter with the content of phosphorus and protein detected is used for producing lincomycin by shake flask fermentation.
The method for producing lincomycin by shake flask fermentation comprises the following steps:
control group: filling 50ml of the assembled culture medium into 500ml triangular bottles, 20 bottles in total, binding bottle mouths with eight layers of gauze, and maintaining the temperature of a sterilizing pot at 121-123 ℃ for 30 minutes; inoculating lincomycin strain into shake flask for shake cultivation in sterile room, wherein the rotation speed of shake flask is 200-240rpm, the temperature is 30.0+ -1.0deg.C, the humidity is 40-70%, and the cultivation time is 180h; then, the solution is filtered, and the lincomycin hydrochloride is detected by adopting high performance liquid chromatography.
The proportion of the shake flask fermentation medium is calculated according to the volume of each 1000 ml: 80g of glucose, 25g of soybean meal, 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 group: the shake flask fermentation adopts the same culture conditions as the control group, and adopts shake flask 1, shake flask 2 and shake flask 3 for fermentation culture, and the only difference is that: the culture medium ratio adopted when the solid dried matter is used for producing lincomycin by fermenting shake flasks is calculated according to the volume of each 1000 ml: 80g of glucose, 25g of soybean meal, 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 solid dried material obtained in example 1. Namely, the experimental group uses the recovered solid dried matter to replace the monopotassium phosphate in the original culture medium in proportion. The results are shown in Table 9.
TABLE 7
According to the data, there was substantially no loss of lincomycin content before and after treatment.
TABLE 8
TABLE 9
According to the results, the obtained solid is used for shake flask fermentation production of lincomycin, can reach a control level, and can be used for fermentation production of lincomycin.
Example 4
A method for treating a butanol crystallization mother liquor of lincomycin hydrochloride, the method comprising:
(1) Adding 500ml of saturated EDTA into 10000ml of butanol crystallization mother liquor of lincomycin hydrochloride, then adding 10000ml of water, and then regulating the pH value to 8.0 by sodium hydroxide; fully and uniformly stirring, standing for 1 hour, layering to obtain supernatant and lower turbid liquid, and then separating;
(2) Centrifugally separating the separated turbid liquid to obtain liquid and solid; detecting lincomycin hydrochloride in the supernatant by high performance liquid chromatography, wherein the detection result is shown as the content of the lincomycin hydrochloride in the mother liquor in table 10, and the supernatant is used for recovering the lincomycin hydrochloride; the solids are discarded.
Table 10
The foregoing descriptions of specific exemplary embodiments of the present invention are 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 the specific principles of the invention and its practical application to thereby enable one skilled in the art to make and utilize the invention in various exemplary embodiments and with various 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 (3)
1. A method for treating butanol crystallization mother liquor of lincomycin hydrochloride, which is characterized by comprising the following steps:
(1) Adding phosphate into butanol crystallization mother liquor of lincomycin hydrochloride, then adding water, and then adjusting the pH value to 7.5-9.5 by using alkaline solution, wherein the volume ratio of the butanol crystallization mother liquor to the phosphate is 100:2-4, and the volume ratio of the butanol crystallization mother liquor to the water is 1:0.5-1; stirring uniformly, standing for layering to obtain supernatant and lower turbid liquid, and then separating;
wherein, the butanol crystallization mother liquor of lincomycin hydrochloride is: decolorizing lincomycin hydrochloride back-extraction liquid, adding 3-5 times of butanol, boiling and distilling at 60-65deg.C under vacuum, cooling for crystallization, crystallizing lincomycin hydrochloride butanol, and performing solid-liquid separation to obtain the final product; the phosphate is sodium phosphate saturated solution;
(2) Centrifugally separating the separated turbid liquid to obtain liquid and solid;
(3) Drying the solid obtained in the step (2), wherein the obtained solid dried matter is used for producing lincomycin by fermentation;
the specific method for producing lincomycin by using the solid baking material for fermentation comprises the following steps:
filling 50ml of the assembled culture medium by adopting a 500ml triangular flask, binding a bottle mouth by using eight layers of gauze, and maintaining the temperature of a sterilizing pot at 121-123 ℃ for 30 minutes; inoculating lincomycin strain into shake flask for shake cultivation in sterile room, wherein the rotation speed of shake flask is 200-240rpm, the temperature is 30.0+ -1.0deg.C, the humidity is 40-70%, and the cultivation time is 180h; then, filtering;
wherein the culture medium ratio is calculated according to the volume of each 1000 ml: 80g of glucose, 25g of soybean meal, 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 solid dried material.
2. The process according to claim 1, wherein the alkaline solution is sodium hydroxide solution.
3. The process according to claim 1, wherein the supernatant is further treated 1-2 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.安徽化工.2003,(第5期),20. * |
| 李华 等.林可霉素发酵工艺优化降低B组分.山东化工.2016,第45卷(第8期),63-64. * |
| 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.中国抗生素杂志.2002,第27卷(第6期),332-336. * |
| 毛全贵 等.林可霉素发酵后期的工艺改进.国外医药(抗生素分册).2014,第35卷(第6期),265-267,S19. * |
| 牛宗亮 等.微生物学核心理论及发酵技术.中国原子能出版社,2019,152-153. * |
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