CN107519135A - A kind of preparation method of high water-soluble florfenicol powder - Google Patents
A kind of preparation method of high water-soluble florfenicol powder Download PDFInfo
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- CN107519135A CN107519135A CN201710940638.7A CN201710940638A CN107519135A CN 107519135 A CN107519135 A CN 107519135A CN 201710940638 A CN201710940638 A CN 201710940638A CN 107519135 A CN107519135 A CN 107519135A
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- florfenicol
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- AYIRNRDRBQJXIF-NXEZZACHSA-N (-)-Florfenicol Chemical compound CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)C=C1 AYIRNRDRBQJXIF-NXEZZACHSA-N 0.000 title claims abstract description 108
- 229960003760 florfenicol Drugs 0.000 title claims abstract description 107
- 239000000843 powder Substances 0.000 title claims abstract description 78
- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- 239000011259 mixed solution Substances 0.000 claims abstract description 64
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 56
- 238000000034 method Methods 0.000 claims abstract description 55
- 238000003756 stirring Methods 0.000 claims abstract description 53
- 239000011812 mixed powder Substances 0.000 claims abstract description 29
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims abstract description 26
- 239000012452 mother liquor Substances 0.000 claims abstract description 23
- 238000001035 drying Methods 0.000 claims abstract description 18
- 238000005119 centrifugation Methods 0.000 claims abstract description 16
- 238000010792 warming Methods 0.000 claims abstract description 16
- 238000002156 mixing Methods 0.000 claims description 13
- 239000007788 liquid Substances 0.000 claims description 12
- AJKNNUJQFALRIK-UHFFFAOYSA-N 1,2,3-trifluorobenzene Chemical compound FC1=CC=CC(F)=C1F AJKNNUJQFALRIK-UHFFFAOYSA-N 0.000 claims description 10
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 229920000858 Cyclodextrin Polymers 0.000 abstract description 12
- 239000001116 FEMA 4028 Substances 0.000 abstract description 2
- 235000011175 beta-cyclodextrine Nutrition 0.000 abstract description 2
- 229960004853 betadex Drugs 0.000 abstract description 2
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 75
- 239000000243 solution Substances 0.000 description 16
- 150000001875 compounds Chemical class 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 229950005162 benexate Drugs 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000011265 semifinished product Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- GZCGUPFRVQAUEE-SLPGGIOYSA-N aldehydo-D-glucose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O GZCGUPFRVQAUEE-SLPGGIOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 238000007789 sealing Methods 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000005265 energy consumption Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000001125 extrusion Methods 0.000 description 3
- 239000008234 soft water Substances 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 229940121657 clinical drug Drugs 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000013049 sediment Substances 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 238000005563 spheronization Methods 0.000 description 2
- 238000001694 spray drying Methods 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000031295 Animal disease Diseases 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- 239000008118 PEG 6000 Substances 0.000 description 1
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- PZUUTJLAUKMLTH-UHFFFAOYSA-N [F].C1=CC=CC=C1 Chemical compound [F].C1=CC=CC=C1 PZUUTJLAUKMLTH-UHFFFAOYSA-N 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000003975 animal breeding Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000000889 atomisation Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- IAXUQWSLRKIRFR-SAABIXHNSA-N chembl2104696 Chemical compound C1C[C@@H](CNC(=N)N)CC[C@@H]1C(=O)OC1=CC=CC=C1C(=O)OCC1=CC=CC=C1 IAXUQWSLRKIRFR-SAABIXHNSA-N 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000010304 firing Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000007779 soft material Substances 0.000 description 1
- 239000011122 softwood Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000004552 water soluble powder Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a kind of preparation method of high water-soluble florfenicol powder, comprise the following steps：S1, the water of 400 500 parts by weight, the beta cyclodextrin of 200 250 parts by weight, the Florfenicol of 20 80 parts by weight are added in a kettle, stir and be warming up to 90 DEG C, 2 5h are incubated at being 90 95 DEG C in temperature, is kept stirring in insulating process, obtains the first mixed solution；S2, the first mixed solution is cooled to 10 DEG C, it is standby after being incubated 0.5 1h at being 0 15 DEG C in temperature, wherein, it is kept stirring in insulating process；S3, S2 is handled after the first mixed solution centrifugation, obtain the first mixed-powder and the first mother liquor, will the first mixed-powder drying after sieve, obtain the first florfenicol powder.The present invention provides a kind of a kind of preparation method of the high water-soluble florfenicol powder for the solubility that can effectively improve Florfenicol.
Description
Technical field
The present invention relates to the preparation field of florfenicol powder.A kind of it is more particularly related to high water-soluble fluorobenzene
Buddhist nun examines the preparation method of powder.
Background technology
Florfenicol is a kind of antibacterials more conventional in animal-breeding production, safely, effectively, is widely used.But
It is that dissolubility of the Florfenicol in water is minimum, is not suitable for water-soluble administration, limits its application in Animal diseases treatment.Help
Solvent micropowder, beta-cyclodextrin inclusion compound, hydroxypropylβ-cyclodextrin inclusion, PVPK dispersions, PEG6000 dispersions, ultra micro, grinding
The methods of solubilization-aid effect it is generally undesirable, dissolution velocity is slow, dissolution rate is small, is difficult to meet the needs of preparation and concentrated compounding use.
Initial florfenicol powder technology of preparing is simply mixed by Florfenicol and starch or water-soluble starch or glucose etc.
Conjunction forms, and the florfenicol powder solubility being prepared is small, and in terms of effective ingredient Florfenicol, the solubility under normal temperature is about
300ppm, such product bioavilability are low.
Closely during the last ten years, the country has that research of the more producer to the water soluble preparation of Florfenicol is quite a lot of, in the market
There are the florfenicol powder or florfenicol soluble powder of polytype water-soluble, product quality differs greatly, and preparation side
Method is also not quite similar.Water-soluble preferable florfenicol powder, its preparation method are mainly dry by spraying on domestic market
Drying method is prepared, although the product water solubility prepared is greatly improved, by Main Ingredients and Appearance Florfenicol
Count, the solubility under normal temperature is about 1200-3000ppm, and is produced with the method, and production capacity is smaller, and energy consumption is higher.
CN102160854 describes a kind of preparation method of florfenicol powder, be the defects of this method include it is not thorough
Bottom, products obtained therefrom solubility and bioavilability are perfect not to the utmost, and the solubility of Florfenicol improves 4 times, about 1200ppm,
Differ larger with prior art；Second, being prepared using the method for oven drying, labor intensity is big, high energy consumption；Third, the method is also
Glucose need to be added to be mixed again.
CN104825400B equally also describes a kind of preparation method of florfenicol powder, Florfenicol prepared by this method
Powder solubility is enhanced, and can reach 3000ppm, and market is in a leading position level at home at present.The method remove with β-
Outside cyclodextrin, sorbefacient is also add, in addition, the preparation method that the patent provides is spray drying process, production capacity has necessarily
Limitation, energy consumption is higher.
Silica not soluble in water and a large amount of has been used in the preparation method for the florfenicol powder that CN105902497 is introduced
Citric acid, the solubility and bioavilability of products obtained therefrom must be by larger limitations.The maxima solubility introduced in the patent is about
For 1200ppm, differ larger with prior art.
CN106177983 describes a kind of technology of preparing of florfenicol powder, the shortcomings that this method one be add it is organic molten
Agent ethanol, lab scale preparation is only applicable to, during actual production, the recovery and processing of organic solvent must be considered；Second, preparation method
Complexity, need first to be made into two kinds of solution As and B respectively, then progressively mixed, in addition, to obtain product, will also be first in refrigerator cold-storage
24 hours, finally also washed with ethanol, preparation method is complicated and the cycle is oversize；Third, the inclusion rate and yield of this method are not
Ideal, inclusion is not thorough, and product solubility must be impacted；Fourth, this method is not suitable for large-scale production.
The content of the invention
It is an object of the invention to provide a kind of solubility that can effectively improve Florfenicol, the clinic of Florfenicol is improved
Curative effect and bioavilability, reduce a kind of preparation method of high water-soluble florfenicol powder of clinical drug dosage.
In order to realize according to object of the present invention and further advantage, there is provided a kind of high water-soluble florfenicol powder
Preparation method, comprise the following steps：
S1, the water of 400-500 parts by weight, the beta-schardinger dextrin of 200-250 parts by weight, 20-80 weight are added in a kettle
Part Florfenicol, stir and be warming up to 90 DEG C, 2-5h is incubated in 90-95 DEG C of environment, is kept stirring for, obtains in insulating process
To the first mixed solution；
S2, first mixed solution is cooled to 10 DEG C, it is standby after being incubated 0.5-1h in 0-15 DEG C of environment, its
In, it is kept stirring in insulating process；
S3, S2 is handled after the first mixed solution centrifugation, the first mixed-powder and the first mother liquor are obtained, by described first
Sieved after mixed-powder drying, obtain the first florfenicol powder.
Preferably, in a kind of preparation method of described high water-soluble florfenicol powder, described first is mixed in S2
The method that solution is cooled to 10 DEG C is as follows：
After first mixed solution is cooled into less than 40 DEG C using recirculated water, reuses chilled water and mixed described first
Close solution and be cooled to 10 DEG C.
Preferably, it is further comprising the steps of in a kind of preparation method of described high water-soluble florfenicol powder：
S4, first mother liquor, the water of 50-100 parts by weight, the 200-250 for adding 400-500 parts by weight in a kettle
Beta-schardinger dextrin, the Florfenicol of 20-80 parts by weight of parts by weight, stir and be warming up to 90 DEG C, be incubated in 90-95 DEG C of environment
2-5h, it is kept stirring in insulating process, obtains the second mixed solution；
S5, second mixed solution is cooled to 10 DEG C, it is standby after being incubated 0.5-1h in 0-15 DEG C of environment, its
In, it is kept stirring in insulating process；
S6, S5 is handled after the second mixed solution centrifugation, the second mixed-powder and the second mother liquor are obtained, by described second
Sieved after mixed-powder drying, obtain the second florfenicol powder.
Preferably, in a kind of preparation method of described high water-soluble florfenicol powder, described second is mixed in S5
The method that solution is cooled to 10 DEG C is as follows：
After second mixed solution is cooled into less than 40 DEG C using recirculated water, reuses chilled water and mixed described second
Close solution and be cooled to 10 DEG C.
Preferably, it is further comprising the steps of in a kind of preparation method of described high water-soluble florfenicol powder：
S7, second mother liquor, the water of 50-100 parts by weight, the 200-250 for adding 400-500 parts by weight in a kettle
Beta-schardinger dextrin, the Florfenicol of 20-80 parts by weight of parts by weight, stir and be warming up to 90 DEG C, be incubated in 90-95 DEG C of environment
2-5h, it is kept stirring in insulating process, obtains the 3rd mixed solution；
S8, the 3rd mixed solution is cooled to 10 DEG C, it is standby after being incubated 0.5-1h in 0-15 DEG C of environment, its
In, it is kept stirring in insulating process；
S9, S8 is handled after the 3rd mixed solution centrifugation, the second mixed-powder and the second mother liquor are obtained, by described second
Sieved after mixed-powder drying, obtain trifluoro-benzene Buddhist nun and examine powder.
Preferably, in a kind of preparation method of described high water-soluble florfenicol powder, by the described 3rd mixing in S8
The method that solution is cooled to 10 DEG C is as follows：
After the 3rd mixed solution is cooled into less than 40 DEG C using recirculated water, reuses chilled water and mixed the described 3rd
Close solution and be cooled to 10 DEG C.
Preferably, it is further comprising the steps of in a kind of preparation method of described high water-soluble florfenicol powder：
S10, the trifluoro-benzene Buddhist nun for obtaining S9 examine powder and DEXTROSE ANHYDROUS and are well mixed according to any mass ratio, and mistake
After 80-100 mesh sieves, it is added to after mixing 0.5-1h in mixer, obtains phenyl tetrafluoride Buddhist nun and examine powder.
The beneficial effects of the invention are as follows：
(1) present invention carries out complete, sufficient inclusion, fluorine by beta-schardinger dextrin and Florfenicol in the case of being completely dissolved
In the cavity body for the hydrophobic lipophilic that benzene Buddhist nun's examination mark enters beta-schardinger dextrin molecule, Florfenicol-Benexate Hydrochloride is formed,
Then by the crystallization technique of uniqueness, inclusion compound is crystallized to precipitation from the aqueous solution, obtains Florfenicol-Benexate Hydrochloride
Crystalline solid, further increase the purity of Florfenicol inclusion compound.By such a physical process, using beta-schardinger dextrin compared with
Good dissolution characteristics, not only increase the solubility and stability of Florfenicol, but also because Florfenicol beta-schardinger dextrin network
The sustained release of compound and taste masking effect, improve the bioavilability of Florfenicol, reduce adverse reaction etc..
(2) present invention prepare high water-soluble florfenicol powder raw material it is simple, in addition to beta-schardinger dextrin, it is not necessary to add again
Other any auxiliary materials, Florfenicol is only included completely using beta-schardinger dextrin, obtains Florfenicol-Benexate Hydrochloride, i.e. fluorine
Benzene Buddhist nun examines powder, and product quality is stable, uniform, and solubility is good, is not required to other cosolvents or sorbefacient.
(3) present invention, using the method for crystallisation by cooling, obtains fluorobenzene Buddhist nun after Florfenicol cyclodextrin inclusion compound is formed
- Benexate Hydrochloride, i.e. florfenicol powder are examined, relative to conventional spray drying process, its production capacity is big, cost is relatively low, more
Economic value.
(4) present invention prepares caused Florfenicol-Benexate Hydrochloride during high water-soluble florfenicol powder
Mother liquor, it is environment-friendly on the one hand without discharging of waste liquid to its recycled, meet national environmental protection policy；On the other hand, mother is passed through
The recycled of liquid, the yield of Florfenicol Benexate Hydrochloride is effectively increased, effectively reduces production cost.
Further advantage, target and the feature of the present invention embodies part by following explanation, and part will also be by this
The research and practice of invention and be understood by the person skilled in the art.
Embodiment
It should be noted that experimental method described in following embodiments, is conventional method unless otherwise specified, institute
Reagent and material are stated, unless otherwise specified, is commercially obtained.
<Embodiment 1>
A kind of preparation method of high water-soluble florfenicol powder, comprises the following steps：
S1, the purified water for adding 400 parts by weight in a kettle, the beta-schardinger dextrin of 200 parts by weight, the fluorobenzene of 20 parts by weight
Buddhist nun examines, and stirs and is warming up to 90 DEG C, 2h is incubated in 90 DEG C of environment, is kept stirring in insulating process, it is molten to obtain the first mixing
Liquid；
S2, after first mixed solution is cooled into less than 40 DEG C using recirculated water, chilled water is reused by described
One mixed solution is cooled to 10 DEG C, standby after being incubated 0.5h in 0 DEG C of environment, wherein, it is kept stirring in insulating process；
S3, S2 is handled after the first mixed solution centrifugation, the first mixed-powder and the first mother liquor are obtained, by described first
Sieved after mixed-powder drying, obtain the first florfenicol powder.
S4, first mother liquors of 400 parts by weight, the purified water of 50 parts by weight, 200 parts by weight are added in a kettle
The Florfenicol of beta-schardinger dextrin, 20 parts by weight, stir and be warming up to 90 DEG C, be incubated 2h in 90 DEG C of environment, in insulating process
It is kept stirring for, obtains the second mixed solution；
S5, after second mixed solution is cooled into less than 40 DEG C using recirculated water, chilled water is reused by described
Two mixed solutions are cooled to 10 DEG C, standby after being incubated 0.5h in 0 DEG C of environment, wherein, it is kept stirring in insulating process；
S6, S5 is handled after the second mixed solution centrifugation, the second mixed-powder and the second mother liquor are obtained, by described second
Sieved after mixed-powder drying, obtain the second florfenicol powder.
S7, second mother liquors of 400 parts by weight, the purified water of 50 parts by weight, 200 parts by weight are added in a kettle
The Florfenicol of beta-schardinger dextrin, 20 parts by weight, stir and be warming up to 90 DEG C, be incubated 2h in 90 DEG C of environment, in insulating process
It is kept stirring for, obtains the 3rd mixed solution；
S8, after the 3rd mixed solution is cooled into less than 40 DEG C using recirculated water, chilled water is reused by described
Three mixed solutions are cooled to 10 DEG C, standby after being incubated 0.5h in 0 DEG C of environment, wherein, it is kept stirring in insulating process；
S9, S8 is handled after the 3rd mixed solution centrifugation, the second mixed-powder and the second mother liquor are obtained, by described second
Sieved after mixed-powder drying, obtain trifluoro-benzene Buddhist nun and examine powder.
S10, the trifluoro-benzene Buddhist nun for obtaining S9 examine powder and DEXTROSE ANHYDROUS and are well mixed according to any mass ratio, and cross 80
After mesh sieve, it is added to after mixing 0.5h in mixer, obtains phenyl tetrafluoride Buddhist nun and examine powder.
<Embodiment 2>
A kind of preparation method of high water-soluble florfenicol powder, comprises the following steps：
S1, the deionized water for adding 460 parts by weight in a kettle, the beta-schardinger dextrin of 224 parts by weight, the fluorine of 50 parts by weight
Benzene Buddhist nun examines, and stirs and is warming up to 90 DEG C, 3h is incubated in 92 DEG C of environment, is kept stirring in insulating process, obtains the first mixing
Solution；
S2, after first mixed solution is cooled into less than 40 DEG C using recirculated water, chilled water is reused by described
One mixed solution is cooled to 10 DEG C, standby after being incubated 0.5h in 7 DEG C of environment, wherein, it is kept stirring in insulating process；
S3, S2 is handled after the first mixed solution centrifugation, the first mixed-powder and the first mother liquor are obtained, by described first
Sieved after mixed-powder drying, obtain the first florfenicol powder.
S4, first mother liquor of 390 parts by weight, the deionized water of 80 parts by weight, 215 parts by weight are added in a kettle
Beta-schardinger dextrin, the Florfenicol of 50 parts by weight, stir and be warming up to 90 DEG C, 5h, insulating process are incubated in 92 DEG C of environment
In be kept stirring for, obtain the second mixed solution；
S5, after second mixed solution is cooled into less than 40 DEG C using recirculated water, chilled water is reused by described
Two mixed solutions are cooled to 10 DEG C, standby after being incubated 0.5h in 7 DEG C of environment, wherein, it is kept stirring in insulating process；
S6, S5 is handled after the second mixed solution centrifugation, the second mixed-powder and the second mother liquor are obtained, by described second
Sieved after mixed-powder drying, obtain the second florfenicol powder.
S7, second mother liquor of 400 parts by weight, the deionized water of 70 parts by weight, 215 parts by weight are added in a kettle
Beta-schardinger dextrin, the Florfenicol of 50 parts by weight, stir and be warming up to 90 DEG C, 4h, insulating process are incubated in 92 DEG C of environment
In be kept stirring for, obtain the 3rd mixed solution；
S8, after the 3rd mixed solution is cooled into less than 40 DEG C using recirculated water, chilled water is reused by described
Three mixed solutions are cooled to 10 DEG C, standby after being incubated 0.5h in 7 DEG C of environment, wherein, it is kept stirring in insulating process；
S9, S8 is handled after the 3rd mixed solution centrifugation, the second mixed-powder and the second mother liquor are obtained, by described second
Sieved after mixed-powder drying, obtain trifluoro-benzene Buddhist nun and examine powder.
It is 1 that S10, the trifluoro-benzene Buddhist nun for obtaining S9, which examine powder and DEXTROSE ANHYDROUS according to mass ratio,:1 is well mixed, and mistake
After 80-100 mesh sieves, it is added to after mixing 0.5h in mixer, obtains phenyl tetrafluoride Buddhist nun and examine powder.
<Embodiment 3>
A kind of preparation method of high water-soluble florfenicol powder, comprises the following steps：
S1, the soft water for adding 500 parts by weight in a kettle, the beta-schardinger dextrin of 250 parts by weight, the fluorobenzene Buddhist nun of 80 parts by weight
Examine, stir and be warming up to 90 DEG C, 5h is incubated in 95 DEG C of environment, is kept stirring in insulating process, obtains the first mixed solution；
S2, after first mixed solution is cooled into less than 40 DEG C using recirculated water, chilled water is reused by described
One mixed solution is cooled to 10 DEG C, standby after 15 DEG C are incubated 1h, wherein, it is kept stirring in insulating process；
S3, S2 is handled after the first mixed solution centrifugation, the first mixed-powder and the first mother liquor are obtained, by described first
Sieved after mixed-powder drying, obtain the first florfenicol powder.
S4, first mother liquors of 500 parts by weight, the soft water of 100 parts by weight, 250 parts by weight are added in a kettle
The Florfenicol of beta-schardinger dextrin, 80 parts by weight, stir and be warming up to 90 DEG C, 5h are incubated at 95 DEG C, are kept stirring in insulating process,
Obtain the second mixed solution；
S5, after second mixed solution is cooled into less than 40 DEG C using recirculated water, chilled water is reused by described
Two mixed solutions are cooled to 10 DEG C, standby after being incubated 1h in 15 DEG C of environment, wherein, it is kept stirring in insulating process；
S6, S5 is handled after the second mixed solution centrifugation, the second mixed-powder and the second mother liquor are obtained, by described second
Sieved after mixed-powder drying, obtain the second florfenicol powder.
S7, second mother liquors of 500 parts by weight, the soft water of 100 parts by weight, 250 parts by weight are added in a kettle
The Florfenicol of beta-schardinger dextrin, 80 parts by weight, stir and be warming up to 90 DEG C, be incubated 5h in 95 DEG C of environment, in insulating process
It is kept stirring for, obtains the 3rd mixed solution；
S8, after the 3rd mixed solution is cooled into less than 40 DEG C using recirculated water, chilled water is reused by described
Three mixed solutions are cooled to 10 DEG C, standby after 15 DEG C are incubated 1h, wherein, it is kept stirring in insulating process；
S9, S8 is handled after the 3rd mixed solution centrifugation, the second mixed-powder and the second mother liquor are obtained, by described second
Sieved after mixed-powder drying, obtain trifluoro-benzene Buddhist nun and examine powder.
S10, the trifluoro-benzene Buddhist nun for obtaining S9 examine powder and DEXTROSE ANHYDROUS and are well mixed according to any mass ratio, and mistake
After 100 mesh sieves, it is added to after mixing 1h in mixer, obtains phenyl tetrafluoride Buddhist nun and examine powder.
<Comparative example 1>
A kind of method for the Florfenicol quick-releasing type water-soluble powder preparation for preparing inclusion cyclodextrin, comprises the following steps：
(1) inclusion reaction：Using saturated water solution method, deployed Florfenicol, cyclodextrin and water are put into stainless
Steel drum is stirred with traveling agitator, there is provided mixing speed is 50 revs/min, is placed on after stirring on electric furnace or other
Firing equipment is heated and continues to stir, and heating-up temperature is since 80 DEG C and timing, heat time are 45 minutes to 60 minutes,
The Florfenicol cyclodextrin inclusion compound of liquid state is prepared；
(2) dry：It is uniform that Florfenicol cyclodextrin inclusion compound is poured into drip pan middle berth, being put into baking oven, persistently to dry 3.5 small
When, during which once, drying temperature is 105 DEG C to turn-over, obtains powdered Florfenicol cyclodextrin inclusion compound；
(3) natural cooling；
(4) 60 mesh sieves are crossed：Florfenicol cyclodextrin inclusion compound powdered after cooling is crossed into 60 mesh sieves, contained with bucket is contained
Connect；
(5) hybrid detection：Sieving is pumped into sampling after mixer carries out multiple batches of be well mixed with feeder and passes through height
Effect liquid phase chromatogram instrument detects, testing goal：Whether checking Florfenicol can be with meeting legal mark by the front and rear content of inclusion
Quasi- method is detected；
(6) auxiliary material dilutes：Glucose is used as in auxiliary material addition mixer and prepared Florfenicol ring by feeder
Cyclodextrin inclusion compound is mixed together uniformly, and the component of the glucose of addition is about 1.5-4 times of Florfenicol cyclodextrin inclusion compound, most
Good value is 4 times (to be specifically made semi-finished product, adds glucose, most Florfenicol content is diluted to and advised in product at last on demand
Fixed content)；
(7) semi-finished product detect：With high performance liquid chromatograph to semi-finished product sample detect, by qualified semi-finished product racking machine,
Sealing machine dispenses；
(8) qualified semi-finished product are dispensed with racking machine, packaging bag is sealed with sealing machine；Semi-finished product tinning will have been dispensed, used
Tin seamer sealed cans, by canned case, with sealing compound joint sealing and with baling press the step such as pack by finished product packing, finished product sampling is used again
High performance liquid chromatograph detects, qualified storage.
<Comparative example 2>
A kind of method for preparing Florfenicol inclusion quick releasing formulation, comprises the following steps：
Formula is as follows：Florfenicol 27.5g, beta-schardinger dextrin 106g, microcrystalline cellulose 6.62g, sodium carboxymethylcellulose
0.66g, Sulisi E-7-19040,21.33g, hydroxypropyl cellulose E5,0.26g；
(1) take appropriate purified water to be heated to 80 DEG C, add beta-schardinger dextrin stirring and dissolving, add Florfenicol, stir
30min, form Florfenicol inclusion solution；
(2) 160 DEG C of adjustable spraying drier EAT, 80 DEG C, pressure 0.3MPa of leaving air temp, by above-mentioned Florfenicol
Inclusion solution is spray-dried, and obtains florfenicol soluble powder；
(3) the above-mentioned florfenicol soluble powders of 66.25g, microcrystalline cellulose, sodium carboxymethylcellulose mixing are taken, is added
26.47g water, mix softwood processed；
(4) it is 25Hz to adjust extrusion spheronization machine extrusion frequency, and round as a ball frequency is 30Hz, round as a ball time 4min, will be above-mentioned soft
Material extrusion spheronization obtains wet granular, 60 DEG C of baking 2h, the particle of screening 40-60 mesh；
(5) Sulisi E-7-19040 is diluted with water and is well mixed to form coating solution with hydroxypropyl cellulose E5 again；Take
(4) the inclusion inner core 56g being prepared, it is placed in fluid bed and fluidizes, even application obtains in capsule core surface after coating solution atomization
Florfenicol includes controlled release preparation.
<Comparative example 3>
A kind of preparation method of Florfenicol-Benexate Hydrochloride, comprises the following steps：
A. 35ml distilled water is added into 0.005mol beta-schardinger dextrin, saturated solution A is made after heating for dissolving；
B. 13ml ethanol is added into 0.005mol Florfenicol, is prepared into solution B；
C. solution A is placed on magnetic stirring apparatus, under the conditions of 80 DEG C of heated at constant temperature, under 500r/min constant rotational speed,
Solution B is gradually dropped, obtains including liquid；Lasting stirring, after stopping heating, the container for filling inclusion liquid is placed in stirred in water bath
To room temperature, the water-bath initial temperature is room temperature；
D. sediment will be obtained after suction filtration after the inclusion liquid refrigeration 24h of cooling, and with 5-7ml ethanol washing precipitate,
Then dry sediment under the conditions of 55 DEG C, obtains Florfenicol-Benexate Hydrochloride.
<Contrast experiment>
In order to illustrate the effect of the preparation method of the high water-soluble florfenicol powder of the present invention, the applicant is respectively according to reality
Apply a 1-3 and prepare high water-soluble florfenicol powder, correspond to group 1-3 respectively and the performance to high water-soluble florfenicol powder is carried out
Detection, while in order to increase contrast effect, prepares florfenicol powder according to comparative example 1-3 respectively, corresponds to group 4-6 and right respectively
The performance of florfenicol powder is detected, and experimental result is shown in Table 1：
The florfenicol powder of table 1 maxima solubility in water is tested
As shown in Table 1, the data of 1-3 groups, high water-soluble florfenicol powder maxima solubility in water of the invention are
3800ppm, minimal solubility 3640ppm, and the maxima solubility of the middle florfenicol powder of 4-6 groups is 3000ppm, and remove
Outside 5th group, other two groups maxima solubilities are only 1200ppm, differ larger with the data of 1-3 groups, Gao Shui of the invention
Molten type florfenicol powder can effectively improve the solubility of Florfenicol, improve the clinical efficacy and biological utilisation of Florfenicol
Degree, reduce clinical drug dosage.
Although embodiment of the present invention is disclosed as above, it is not restricted in specification and embodiment listed
With it can be applied to various suitable the field of the invention completely, can be easily for those skilled in the art
Other modification is realized, therefore under the universal limited without departing substantially from claim and equivalency range, it is of the invention and unlimited
In specific details and shown here as the embodiment with description.
Claims (7)
1. a kind of preparation method of high water-soluble florfenicol powder, it is characterised in that comprise the following steps：
S1, the water of 400-500 parts by weight, the beta-schardinger dextrin of 200-250 parts by weight, 20-80 parts by weight are added in a kettle
Florfenicol, stir and be warming up to 90 DEG C, 2-5h is incubated in 90-95 DEG C of environment, is kept stirring in insulating process, obtains
One mixed solution；
S2, first mixed solution is cooled to 10 DEG C, it is standby after being incubated 0.5-1h in 0-15 DEG C of environment, wherein, protect
It is kept stirring for during temperature；
S3, S2 is handled after the first mixed solution centrifugation, obtain the first mixed-powder and the first mother liquor, described first mixed
Sieved after powder drying, obtain the first florfenicol powder.
2. a kind of preparation method of high water-soluble florfenicol powder as claimed in claim 1, it is characterised in that in S2 by described in
The method that first mixed solution is cooled to 10 DEG C is as follows：
After first mixed solution is cooled into less than 40 DEG C using recirculated water, chilled water is reused the described first mixing is molten
Liquid is cooled to 10 DEG C.
3. a kind of preparation method of high water-soluble florfenicol powder as claimed in claim 1, it is characterised in that also including following
Step：
S4, first mother liquor, the water of 50-100 parts by weight, 200-250 weight for adding 400-500 parts by weight in a kettle
Part beta-schardinger dextrin, the Florfenicol of 20-80 parts by weight, stir and be warming up to 90 DEG C, 2- is incubated in 90-95 DEG C of environment
5h, it is kept stirring in insulating process, obtains the second mixed solution；
S5, second mixed solution is cooled to 10 DEG C, it is standby after being incubated 0.5-1h in 0-15 DEG C of environment, wherein, protect
It is kept stirring for during temperature；
S6, S5 is handled after the second mixed solution centrifugation, obtain the second mixed-powder and the second mother liquor, described second mixed
Sieved after powder drying, obtain the second florfenicol powder.
4. a kind of preparation method of high water-soluble florfenicol powder as claimed in claim 3, it is characterised in that in S5 by described in
The method that second mixed solution is cooled to 10 DEG C is as follows：
After second mixed solution is cooled into less than 40 DEG C using recirculated water, chilled water is reused the described second mixing is molten
Liquid is cooled to 10 DEG C.
5. a kind of preparation method of high water-soluble florfenicol powder as claimed in claim 3, it is characterised in that also including following
Step：
S7, second mother liquor, the water of 50-100 parts by weight, 200-250 weight for adding 400-500 parts by weight in a kettle
Part beta-schardinger dextrin, the Florfenicol of 20-80 parts by weight, stir and be warming up to 90 DEG C, 2- is incubated in 90-95 DEG C of environment
5h, it is kept stirring in insulating process, obtains the 3rd mixed solution；
S8, the 3rd mixed solution is cooled to 10 DEG C, it is standby after being incubated 0.5-1h in 0-15 DEG C of environment, wherein, protect
It is kept stirring for during temperature；
S9, S8 is handled after the 3rd mixed solution centrifugation, obtain the second mixed-powder and the second mother liquor, described second mixed
Sieved after powder drying, obtain trifluoro-benzene Buddhist nun and examine powder.
6. a kind of preparation method of high water-soluble florfenicol powder as claimed in claim 5, it is characterised in that in S8 by described in
The method that 3rd mixed solution is cooled to 10 DEG C is as follows：
After the 3rd mixed solution is cooled into less than 40 DEG C using recirculated water, chilled water is reused the described 3rd mixing is molten
Liquid is cooled to 10 DEG C.
7. the preparation method of a kind of high water-soluble florfenicol powder as described in claim 5 or 6, it is characterised in that also include
Following steps：
S10, the trifluoro-benzene Buddhist nun for obtaining S9 examine powder and DEXTROSE ANHYDROUS and are well mixed according to any mass ratio, and cross 80-100
After mesh sieve, it is added to after mixing 0.5-1h in mixer, obtains phenyl tetrafluoride Buddhist nun and examine powder.
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| CN112641730A (en) * | 2021-02-19 | 2021-04-13 | 山东鲁抗舍里乐药业有限公司高新区分公司 | Preparation method of soluble florfenicol powder |
| CN112716902A (en) * | 2021-02-04 | 2021-04-30 | 广州市和生堂动物药业有限公司 | Florfenicol powder and preparation method thereof |
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