CN114230639A - Preparation method of bacitracin methylene disalicylate - Google Patents
Preparation method of bacitracin methylene disalicylate Download PDFInfo
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- CN114230639A CN114230639A CN202111577667.4A CN202111577667A CN114230639A CN 114230639 A CN114230639 A CN 114230639A CN 202111577667 A CN202111577667 A CN 202111577667A CN 114230639 A CN114230639 A CN 114230639A
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- bacitracin
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- POMORUSPLDFVEK-PHXAWWDYSA-N (4r)-5-[[(2s,3s)-1-[[(2s)-6-amino-1-[[(2r)-5-amino-1-[[(2s,3s)-1-[[(2r)-1-[[(2s)-1-[[(2r)-1-[[(1s)-3-amino-1-carboxy-3-oxopropyl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-3-(1h-imidazol-5-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-methy Chemical compound OC1=CC=CC=C1C(=O)OCOC(=O)C1=CC=CC=C1O.C1SC(C(N)C(C)CC)=NC1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](CCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)CC1=CC=CC=C1 POMORUSPLDFVEK-PHXAWWDYSA-N 0.000 title claims abstract description 14
- 235000019783 Bacitracin Methylene Disalicylate Nutrition 0.000 title claims abstract description 14
- 229940032022 bacitracin methylene disalicylate Drugs 0.000 title claims abstract description 14
- 108010054309 bacitracin methylenedisalicylic acid Proteins 0.000 title claims abstract description 14
- CLKOFPXJLQSYAH-ABRJDSQDSA-N bacitracin A Chemical compound C1SC([C@@H](N)[C@@H](C)CC)=N[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]1C(=O)N[C@H](CCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2N=CNC=2)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCCCC1 CLKOFPXJLQSYAH-ABRJDSQDSA-N 0.000 claims abstract description 49
- 108010001478 Bacitracin Proteins 0.000 claims abstract description 48
- 229930184125 bacitracin Natural products 0.000 claims abstract description 48
- 229960003071 bacitracin Drugs 0.000 claims abstract description 48
- 238000002386 leaching Methods 0.000 claims abstract description 19
- 230000000536 complexating effect Effects 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 13
- 238000001035 drying Methods 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 18
- SWHSXWLSBBYLGM-UHFFFAOYSA-N 2-[(2-carboxyphenoxy)methoxy]benzoic acid Chemical compound OC(=O)C1=CC=CC=C1OCOC1=CC=CC=C1C(O)=O SWHSXWLSBBYLGM-UHFFFAOYSA-N 0.000 claims description 15
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 15
- 239000012043 crude product Substances 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 8
- 238000001694 spray drying Methods 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 6
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- JAPKSVAKWPKFRI-UHFFFAOYSA-N (2-hydroxybenzoyl)oxymethyl 2-hydroxybenzoate Chemical compound OC1=CC=CC=C1C(=O)OCOC(=O)C1=CC=CC=C1O JAPKSVAKWPKFRI-UHFFFAOYSA-N 0.000 abstract description 16
- 239000002904 solvent Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- FCLQHQCOKGKLHR-PPPWKGACSA-N (4R)-5-[[(2R,3R)-1-[[(3S,9R,12R,15R,18R,21R)-3-(2-amino-2-oxoethyl)-18-(3-aminopropyl)-12-benzyl-15-[(2R)-butan-2-yl]-6-(carboxymethyl)-9-(1H-imidazol-5-ylmethyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclopentacos-21-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-4-[[(2R)-4-methyl-2-[[2-[(2R)-2-methylbutanoyl]-1,3-thiazole-4-carbonyl]amino]pentanoyl]amino]-5-oxopentanoic acid Chemical compound CC[C@@H](C)[C@@H](NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@@H](CC(C)C)NC(=O)c1csc(n1)C(=O)[C@H](C)CC)C(=O)N[C@@H]1CCCCNC(=O)[C@H](CC(N)=O)NC(=O)C(CC(O)=O)NC(=O)[C@@H](Cc2cnc[nH]2)NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@H](NC(=O)[C@@H](CCCN)NC1=O)[C@H](C)CC FCLQHQCOKGKLHR-PPPWKGACSA-N 0.000 description 5
- XBWARDHGMLRCQP-UHFFFAOYSA-N 6-hydroxy-5-methylidenecyclohexa-1,3-diene-1-carboxylic acid Chemical compound OC1C(=C)C=CC=C1C(O)=O XBWARDHGMLRCQP-UHFFFAOYSA-N 0.000 description 5
- 108010016876 bacitracin F Proteins 0.000 description 5
- ABQNCKJDMKENIG-UHFFFAOYSA-N bacitracin F Natural products CCC(C)C(NC(=O)C(CCC(=O)O)NC(=O)C(CC(C)C)NC(=O)c1csc(n1)C(=O)C(C)CC)C(=O)NCCCCC2NC(=O)C(CC(=O)N)NC(=O)C(CC(=O)O)NC(=O)C(Cc3cnc[nH]3)NC(=O)C(Cc4ccccc4)NC(=O)C(NC(=O)C(CCCN)NC2=O)C(C)CC ABQNCKJDMKENIG-UHFFFAOYSA-N 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 230000004580 weight loss Effects 0.000 description 5
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- 230000001580 bacterial effect Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 238000002791 soaking Methods 0.000 description 4
- 239000007921 spray Substances 0.000 description 4
- 241000287828 Gallus gallus Species 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 235000013330 chicken meat Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 241000272525 Anas platyrhynchos Species 0.000 description 1
- 241000194108 Bacillus licheniformis Species 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241001112695 Clostridiales Species 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 108010016899 bacitracin A Proteins 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
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- 230000014759 maintenance of location Effects 0.000 description 1
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- 239000000376 reactant Substances 0.000 description 1
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
- 229930000044 secondary metabolite Natural products 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/50—Cyclic peptides containing at least one abnormal peptide link
- C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
- C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
- C07K7/58—Bacitracins; Related peptides
Abstract
The invention relates to a preparation method of bacitracin methylene disalicylate. The method comprises the steps of leaching from a bacitracin premix, concentrating, complexing, extracting, drying and adding salt. The method is simple, and the yield is greatly improved; the biological value of the prepared methylene disalicylate bacitracin reaches over 47u/mg, and the total yield of the methylene disalicylate bacitracin reaches over 90 percent. The solvent used in the process has low toxicity and low consumption, is easy to recycle and is convenient for industrial production.
Description
Technical Field
The invention relates to a method for preparing methylene disalicylate bacitracin,
background
The methylene salicylic acid bacitracin (methylene salicylic acid) is a reactant of bacillus licheniformis secondary metabolite bacitracin and methylene salicylic acid, and is a novel feed drug additive; the peptide is successfully developed by Simonoff et al in 1954, is popularized and used in the world in the 80 s, and the FDA in the United states successively approves the use regulation of the methylene salicylic acid bacitracin in the growth promotion and the prevention and control of clostridial enteritis of animals such as chickens, pigs, cattle and the like.
In 2013, the methylene salicylic acid bacitracin obtains the approval code of the drug additives of Ministry of agriculture, is formally popularized in China, and has the following approval code: the veterinary drug "Zedokuai" (2013)130012425, is approved for continuous use on chicken, pig and duck.
The pharmacopoeia has strict regulations on the content of each component of the medicinal methylene disalicylic acid bacitracin; wherein the content of bacitracin A (HPLC relative retention time is 1.0RT) is not less than 40%, the sum of peak areas of bacitracin B1, B2, B3 and A (0.7RT, 0.7RT, 0.8RT and 1.0RT) is not less than 70%, the sum of peak areas before bacitracin B1(0.7RT) is not more than 13%, the peak area of bacitracin F (2.4RT) is not more than 6%, the titer is more than 40u/mg, the ph is between 8 and 9.5, the MD content is between 26% and 32%, and the drying weight loss is less than 7.5.
At present, domestic research on the methylene disalicylate bacitracin is focused on application, and almost no methylene disalicylate bacitracin is prepared, so that reports of related processes of a pure methylene disalicylate bacitracin product are not available so far, most of the methylene disalicylate bacitracin premix has the content of only 50% at most, and the yield is between 60% and 70%; such as 50% soluble bacitracin methylenedisalicylate powder which is usually sold on the market, and the character is light yellow to light brown powder.
Therefore, the development of a preparation process of the methylenedisalicylate bacitracin, which has the advantages of simple process, high yield, low energy consumption and high content and also meets the pharmacopoeia standard, is an urgent problem to be solved at present.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a preparation method of bacitracin methylene disalicylate.
The biological value of the bacitracin methylene disalicylate prepared by the invention reaches more than 47u/mg, and the total yield of the bacitracin methylene disalicylate can reach more than 90%.
The invention is realized by the following technical scheme:
a preparation method of bacitracin methylene disalicylate comprises the following steps:
1) leaching: leaching the bacitracin premix by using an organic solvent;
2) concentration: concentrating the leaching solution;
3) complexing: adding methylene disalicylic acid into the concentrated solution obtained in the step 2) for complexing;
4) and (3) extraction: extracting the concentrated solution after complexing with acid water;
5) and (3) spray drying: drying the extracted acid water to obtain a crude product;
6) adding salt: and adding salt into the crude product to adjust the pH value to obtain a finished product of the bacitracin methylene disalicylate.
Preferably, in step 1), the organic solvent is ethyl acetate or n-butanol.
Preferably, in step 1), the amount of the organic solvent added is 6-8 times of the mass of the bacitracin premix, and the leaching time is 3-8 h.
Preferably, in step 1), the bacitracin premix has a bacitracin content of 18-30%.
Preferably, in the step 2), the concentration temperature is 60-75 ℃, and the concentration is carried out until the volume of the leaching liquor is 1/6-1/10.
Preferably according to the invention, in step 2), the concentrate is carried out to 1/8% of the volume of the leach liquor.
Preferably, in step 3), the methylene disalicylic acid is dissolved by using 1 time of the extracted organic solvent before being added, and then is added into the concentrated solution.
Preferably, in step 3), the amount of methylene disalicylic acid added is 0.3-0.8 times of the total hundred million bacitracin in the bacitracin premix.
Preferably, in step 3), the amount of methylene disalicylic acid added is 0.4-0.6 times of the total hundred million bacitracin in the bacitracin premix.
Preferably, according to the invention, in step 3), the complexing time is from 1 to 6 hours.
Preferably, in step 4), the acid water is citric acid or tartaric acid.
Preferably, in step 4), the concentration of the acid water is 0.3 to 0.5 mol/L.
Preferably, in step 4), the mass-to-volume ratio of methylenedisalicylic acid to acid water is: (3-6): (10-20), unit: kg/L.
Preferably, in step 5), the drying is spray drying, and the pH is adjusted to 7 to 8 with caustic soda flakes before spray drying.
Spray drying is carried out according to the prior art.
Preferably according to the invention, in step 6), the salt added is a mixture of sodium carbonate and sodium bicarbonate, the mass ratio of sodium carbonate to sodium bicarbonate being 1: (6-9).
Preferably, according to the invention, in step 6), the salt is added in an amount of 6 to 9% by mass of the crude product.
The invention has the technical characteristics and advantages that:
1. the preparation method provided by the invention is simple and rapid to operate, has short treatment time, effectively reduces the degradation of active components, greatly improves the purity of bacitracin, well retains various active components, and ensures that the proportion of each component reaches the standard of United states Pharmacopeia.
2. The biological value of the bacitracin methylene disalicylate prepared by the invention reaches more than 47u/mg, and the total yield of the bacitracin methylene disalicylate is as high as more than 90%. The solvent used in the process has low toxicity and low consumption, is easy to recycle and is convenient for industrial production.
Drawings
FIG. 1 is a liquid chromatogram of a finished product of bacitracin methylenedisalicylate.
Detailed Description
The following examples are merely illustrative of the methods of carrying out the invention and are not to be construed as limiting the invention. All modifications and variations that come within the spirit of the invention are to be considered within the scope of the invention.
The experimental materials used in the examples are all technical grade materials unless otherwise specified; analytical column Hypersil GOLD C18, 5 μm, 4.6X 250mm was obtained from Agilent, Inc., the organic solvent used in the extraction was obtained from Tianjin chemical reagent, Inc., and both acid and base reagents were commercially available. The chromatographic solvent was purchased from kang scientific technologies, ltd, Tianjin.
Example 1
A preparation method of methylene disalicylate bacitracin comprises the following steps:
taking 50kg of bacitracin premix, soaking the bacitracin premix with n-butyl alcohol of 8 times for 4 hours, wherein the content of the bacitracin is 20 percent; filtering out bacterial residues through two-in-one, collecting leaching liquor, heating to 65 ℃, concentrating to 50L, dissolving 4kg of methylene disalicylic acid with 4L of n-butyl alcohol, adding into the concentrated solution, complexing for 3 hours, and extracting for three times with 15L of 0.4mol/L citric acid; the acid water was combined three times, and the pH was adjusted to 7.6 with 1kg of caustic soda flakes to obtain an alkaline aqueous phase containing the target compound, which was then dried by a spray dryer to obtain 13.8kg of crude product.
Adding 1.11kg of a mixture of sodium carbonate and sodium bicarbonate into the crude product, and uniformly mixing, wherein the mass ratio of the sodium carbonate to the sodium bicarbonate is 1: 8; 14.91kg of finished product of the methylene disalicylate peptide is obtained. The bacitracin F impurity is 4%, the potency is 50u/mg, the ph is 8.8, the MD content is 29%, and the drying weight loss is 5.3. The yield thereof was found to be 97%.
Example 2
A preparation method of methylene disalicylate bacitracin comprises the following steps:
taking 50kg of bacitracin premix with 20% of bacitracin content, soaking for 4 hours by using 6 times of n-butanol, filtering out bacterial residues through two-in-one, collecting leaching liquor, heating to 65 ℃, and concentrating to 37.5L. Dissolving 3.8kg of methylene disalicylic acid by using 3.6L of n-butyl alcohol, adding the dissolved solution into the concentrated solution, complexing for 2 hours, and extracting for three times by using 12L of 0.4mol/L citric acid; the acid water was combined three times, and the pH was adjusted to 7.6 with 1kg of caustic soda flakes to obtain an alkaline aqueous phase containing the target compound, which was then dried by a spray dryer to obtain 13.3kg of crude product.
Adding 1.06kg of a mixture of sodium carbonate and sodium bicarbonate into the crude product, and uniformly mixing, wherein the mass ratio of the sodium carbonate to the sodium bicarbonate is 1: 8; 14.36kg of finished product of the methylene disalicylate peptide is obtained. The bacitracin F impurity is 4.6%, the titer is 47u/mg, the ph is 8.7, the MD content is 28.8%, the drying weight loss is 6.1, and the yield is 95%.
Example 3
A preparation method of methylene disalicylate bacitracin comprises the following steps:
taking 50kg of bacitracin premix with 20% of bacitracin content, soaking the bacitracin premix in 6 times of ethyl acetate for 4 hours, filtering out bacterial residues through two-in-one, collecting leaching liquor, heating the leaching liquor to 65 ℃, and concentrating the leaching liquor to 37.5L. Dissolving 3.6kg of methylene disalicylic acid with 3.6L of ethyl acetate, adding into the concentrated solution, and complexing for 1-3 hours. Extracting for three times by using 12L of 0.4mol/L citric acid; the acid water was combined three times, and the pH was adjusted to 7.8 with 1kg of caustic soda flakes to obtain an alkaline aqueous phase containing the target compound, which was then dried by a spray dryer to obtain 12.6kg of crude product.
Adding 1.01kg of a mixture of sodium carbonate and sodium bicarbonate into the crude product, and uniformly mixing, wherein the mass ratio of the sodium carbonate to the sodium bicarbonate is 1: 8; 13.61kg of finished product of the methylene disalicylate peptide is obtained. The bacitracin F impurity is 5.2%, the titer is 47u/mg, the ph is 8.6, the MD content is 28.6%, the drying weight loss is 6.2, and the yield is 90%.
Example 4
A preparation method of methylene disalicylate bacitracin comprises the following steps:
taking 50kg of bacitracin premix with 20% of bacitracin content, soaking the bacitracin premix in 8 times of ethyl acetate for 4 hours, filtering out bacterial residues through two-in-one, collecting leaching liquor, heating the leaching liquor to 65 ℃, and concentrating the leaching liquor to 50L. Dissolving 3.9kg of methylene disalicylic acid with 3.9L of ethyl acetate, adding into the concentrated solution, and complexing for 1-3 hours. Extracting for three times by using 15L of 0.4mol/L citric acid; the acid water was combined three times, and the pH was adjusted to 7.5 with 1kg of caustic soda flakes to obtain an alkaline aqueous phase containing the target compound, which was then dried by a spray dryer to obtain 13.65kg of crude product.
Adding 1.09kg of a mixture of sodium carbonate and sodium bicarbonate into the crude product, and uniformly mixing, wherein the mass ratio of the sodium carbonate to the sodium bicarbonate is 1: 8; 14.74kg of finished product of the methylene disalicylate peptide is obtained. The bacitracin F impurity is 5.4%, the potency is 49u/mg, the ph is 8.7, the MD content is 29.1%, and the drying weight loss is 5.7; the yield thereof was found to be 97.5%.
Claims (10)
1. A preparation method of bacitracin methylene disalicylate comprises the following steps:
1) leaching: leaching the bacitracin premix by using an organic solvent;
2) concentration: concentrating the leaching solution;
3) complexing: adding methylene disalicylic acid into the concentrated solution obtained in the step 2) for complexing;
4) and (3) extraction: extracting the concentrated solution after complexing with acid water;
5) and (3) spray drying: drying the extracted acid water to obtain a crude product;
6) adding salt: and adding salt into the crude product to adjust the pH value to obtain a finished product of the bacitracin methylene disalicylate.
2. The method according to claim 1, wherein in step 1), the organic solvent is ethyl acetate or n-butanol; the adding amount of the organic solvent is 6-8 times of the mass of the bacitracin premix, and the leaching time is 3-8 h.
3. The method according to claim 1, wherein in step 1), the bacitracin premix has a bacitracin content of 18-30%.
4. The preparation method according to claim 1, wherein in the step 2), the concentration temperature is 60-75 ℃, and the concentration is carried out until the volume of the leaching solution is 1/6-1/10; preferably, it is concentrated to 1/8 of the volume of the leach liquor.
5. The preparation method according to claim 1, wherein in step 3), the methylene disalicylic acid is dissolved by using 1 time of the extracted organic solvent before being added, and then is added into the concentrated solution; the addition amount of methylene disalicylic acid is 0.3-0.8 times of the total hundred million bacitracin in the bacitracin premix; preferably, the addition amount of methylene disalicylic acid is 0.4-0.6 times of the total hundred million bacitracin in the bacitracin premix.
6. The method according to claim 1, wherein the complexing time in step 3) is 1 to 6 hours.
7. The method according to claim 1, wherein the acid water is citric acid or tartaric acid in the step 4), and the concentration of the acid water is 0.3 to 0.5 mol/L.
8. The preparation method according to claim 1, wherein in the step 4), the mass-to-volume ratio of the methylenedisalicylic acid to the acid water is as follows: (3-6): (10-20), unit: kg/L.
9. The process according to claim 1, wherein the drying in step 5) is spray drying, and the pH is adjusted to 7 to 8 with caustic soda flakes before spray drying.
10. The preparation method according to claim 1, wherein in the step 6), the salt is a mixture of sodium carbonate and sodium bicarbonate, and the mass ratio of the sodium carbonate to the sodium bicarbonate is 1: (6-9); preferably, in step 6), the amount of salt added is 6-9% of the mass of the crude product.
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| CN202111577667.4A CN114230639B (en) | 2021-12-22 | 2021-12-22 | Preparation method of bacitracin methylene disalicylate |
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| CN202111577667.4A CN114230639B (en) | 2021-12-22 | 2021-12-22 | Preparation method of bacitracin methylene disalicylate |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2609324A (en) * | 1949-10-12 | 1952-09-02 | Commericial Solvents Corp | Recovery of bacitracin |
| GB770248A (en) * | 1954-05-21 | 1957-03-20 | Pfizer & Co C | Improvements in or relating to the preparation of bacitracin |
| US3966699A (en) * | 1975-02-07 | 1976-06-29 | Commercial Solvents Corporation | Reduced bacitracin |
| CN102153633A (en) * | 2010-12-27 | 2011-08-17 | 江苏九阳生物制药有限公司 | Method for extracting and separating bacitracin |
| CN102627554A (en) * | 2012-03-21 | 2012-08-08 | 浦城绿康生化有限公司 | Preparation method of methylene disalicylic acid |
| CN113248571A (en) * | 2021-06-30 | 2021-08-13 | 华东理工大学 | Method for separating and purifying bacitracin by utilizing thermal response polymer NPE-108 |
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2609324A (en) * | 1949-10-12 | 1952-09-02 | Commericial Solvents Corp | Recovery of bacitracin |
| GB770248A (en) * | 1954-05-21 | 1957-03-20 | Pfizer & Co C | Improvements in or relating to the preparation of bacitracin |
| US3966699A (en) * | 1975-02-07 | 1976-06-29 | Commercial Solvents Corporation | Reduced bacitracin |
| CN102153633A (en) * | 2010-12-27 | 2011-08-17 | 江苏九阳生物制药有限公司 | Method for extracting and separating bacitracin |
| CN102627554A (en) * | 2012-03-21 | 2012-08-08 | 浦城绿康生化有限公司 | Preparation method of methylene disalicylic acid |
| CN113248571A (en) * | 2021-06-30 | 2021-08-13 | 华东理工大学 | Method for separating and purifying bacitracin by utilizing thermal response polymer NPE-108 |
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