CN103145594B - Method for preparing florfenicol microcrystal - Google Patents
Method for preparing florfenicol microcrystal Download PDFInfo
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- CN103145594B CN103145594B CN201310099557.0A CN201310099557A CN103145594B CN 103145594 B CN103145594 B CN 103145594B CN 201310099557 A CN201310099557 A CN 201310099557A CN 103145594 B CN103145594 B CN 103145594B
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Abstract
The invention discloses a method for preparing florfenicol microcrystal, and belongs to the technical field of florfenicol preparation methods. According to the method, the florfenicol microcrystal is prepared by using an anti-solvent sediment method, thereby increasing the solubility of the florfenicol microcrystal in water and accelerating the florfenicol microcrystal to be dissolved. The method comprises the following steps of: dissolving the florfenicol into methanol, dropping a florfenicol methanol solution into a water solution with a stabilizer under the stirring ice-bath condition, and through selecting appropriate process condition, precipitating out the florfenicol so as to obtain the florfenicol microcrystal with good solubility property. According to the method, the chemical structure of the florfenicol is not changed, no other cosolvents are used, and the florfenicol as the raw powder can be made into a variety of dosage forms. The particle size of the florfenicol microcrystal prepared by using the method is greatly reduced, the crystal structure is greatly damaged, the solubility of the florfenicol in water is increased to 3960 mu g/ml from 1350 mu g/ml, and the result shows that the solubility property of the florfenicol is remarkably enhanced because of the florfenicol microcrystal, so that the florfenicol can be further popularized and applied.
Description
Technical field
The invention belongs to florfenicol preparation method technical field, particularly a kind of method preparing florfenicol microcrystal.
Background technology
Florfenicol is the thiamphenicol derivative of synthetic, for animal specific chloromycetin Broad spectrum antibiotics, can be used for the bacteriosis of ox, pig, fowl etc. and mycoplasma and aquatic products medication, evident in efficacy to the Animal diseases caused by sensitive organism, be the drug of first choice for the treatment of Corynebacterium diphtheriae, paratyphosum Bacterium, salmonellal various infection.Compare with thiamphenicol with similar paraxin, florfenicol has the features such as has a broad antifungal spectrum, good absorption, distribution in vivo be wide, safe and efficient, and without potential induced aplastic anemia, teratogenesis, carcinogenic and mutagenesis, particularly paraxin is forbidden in food animal owing to there being the untoward reaction of serious induced aplastic anemia, therefore, in food animal diseases prevention and treatment, florfenicol has broad application prospects.But florfenicol is insoluble in water, the solubleness in water is only 1350 μ g/ml, and this not only affects the oral absorption of florfenicol, and affects its bioavailability further.
In order to solve the problem of indissoluble in florfenicol water, researchist starts with from solvent, is proposed a lot of florfenicol injection and oral dedicated solvent.Though this improves its solvability to a certain extent, in use still there are some problems.If as there being water to exist in dissolution process, florfenicol will be separated out.And injection liquid is owing to applying inconvenience, is difficult to large-scale application in scale livestock farming.And current most of injection liquid is all with preparations such as organic solvent dimethyl formamide and propylene glycol, easily cause local excitation and toxic reaction, security is unreliable.
In view of the foregoing, the problem solving the solubility property difference of florfenicol in water is the focus of field of veterinary research always.The raising florfenicol water soluble method seeing report at present has two large classes: one is physical method, comprise Benexate Hydrochloride, hydroxy propyl-Beta cyclodextrin inclusion compound and prepare solid dispersion etc., but this class methods solubilization-aid effect is general not good, dissolution rate is slow, dissolution rate is little, and complex process, need a large amount of special auxiliary material, be difficult to the demand meeting preparation and Clinical practice; Another kind is chemical process, non-activity prodrug is made by florfenicol, entering metabolism after in animal body is that florfenicol plays a role, and it is characterized in that water-solublely being far longer than physical method, but the characteristics of pharmacokinetics that can change medicine due to structural changes produces some unforeseen effects.
According to Noyes-Whitney equation, drug particle is less, and specific surface area is larger, and the stripping of medicine is better.This theory of bibliographical information has been successfully applied to Azythromycin, irbesartan, atorvastatincalcuim, cefuroxime axetil, the medicines such as nifedipine, and existing 5 kinds of products utilizing this technology to produce go on the market in the U.S., comprise sirolimus (trade(brand)name Rapamune, 2000 listing), aprepitant (trade(brand)name Emend, 2003 listing), fenofibrate (trade(brand)name Tricor, 2004 listing; Trade(brand)name Triglide, listing in 2005) and megestrol (trade(brand)name Megace, listing in 2005).Below all absolutely prove that the method is insoluble in the solubleness of water medicine practical in raising.
Summary of the invention
The object of this invention is to provide a kind of method preparing florfenicol microcrystal, it is characterized in that: former for florfenicol powder is dissolved in methyl alcohol, be mixed with the methanol solution of florfenicol, by the aqueous solution be made into containing stablizer soluble in water for stablizer, wherein, the concentration of methanol solution of florfenicol is 40mg/ml-70mg/ml, concentration containing the aqueous solution of stablizer is 3mg/ml-5mg/ml, stablizer adopts Vltra tears, polyvinylpyrrolidone, PLURONICS F87, Macrogol 4000, tween-80, the mixture of PLURONICS F87 and Vltra tears, the mixture of PLURONICS F87 and tween-80, any one in the mixture of Vltra tears and tween-80, , the volume ratio of methyl alcohol and water is 1:(1-3), under stirring and 4 DEG C of condition of ice bath, the methanol solution of florfenicol is slowly added drop-wise in the aqueous solution containing stablizer, churning time is 15min-30min, florfenicol slowly separates out formation suspension, by this suspension suction filtration, drying florfenicol microcrystal powder.
In aforesaid method, the preferred 40mg/ml of concentration of methanol solution of florfenicol.
In aforesaid method, the preferred 4mg/ml of the concentration containing the aqueous solution of stablizer.
In aforesaid method, the preferred Vltra tears of stablizer.
In aforesaid method, the preferred 1:2 of volume ratio of methyl alcohol and water.
In aforesaid method, the preferred 15min of churning time.
In aforesaid method, stirring can adopt magnetic force or electric stirring.
The present invention provides a kind of most preferred method preparing florfenicol microcrystal further, former for florfenicol powder is dissolved in methyl alcohol, be mixed with the methanol solution of florfenicol, by the aqueous solution be made into containing stablizer soluble in water for stablizer, wherein, the concentration of methanol solution of florfenicol is 40mg/ml, concentration containing the aqueous solution of stablizer is 4mg/ml, stablizer adopts Vltra tears, the volume ratio of methyl alcohol and water is 1:2, under stirring and 4 DEG C of condition of ice bath, the methanol solution of florfenicol is slowly added drop-wise in the aqueous solution containing stablizer, churning time is 15min, florfenicol slowly separates out formation suspension, by this suspension suction filtration, drying florfenicol microcrystal powder.
Beneficial effect of the present invention is:
In order to improve the dissolving out capability of florfenicol in water, thus improve florfenicol in GI absorption to improve its bioavailability.The present invention adopts anti-solvent nanoprecipitation legal system for florfenicol microcrystal.The particle diameter of the florfenicol microcrystal that the method that the present invention provides obtains obviously reduces, and crystalline structure obviously destroys, and the solubleness of florfenicol in water can bring up to 3960 μ g/ml by 1350 μ g/ml.Result illustrates, florfenicol microcrystal makes the dissolving out capability of florfenicol obviously strengthen, can further genralrlization application.
The present invention uses intermediate processing to prepare florfenicol microcrystal to increase its solubleness in water and accelerate its stripping thus improve its bioavailability, by screening suitable recrystallization condition, to obtain the good florfenicol microcrystal of solubility property, and the preparation technology using the solubleness of microcrystal and dissolution rate as judgement criteria to microcrystal is optimized.The method does not change medicines structure, does not apply other solubility promoters, can make multiple formulation as former powder.
Accompanying drawing explanation
Fig. 1 is the impact of different stabilizers on florfenicol microcrystal stripping;
Fig. 2 is the impact of florfenicol solution concentration on microcrystal dissolution rate;
Fig. 3 is the electron photomicrograph (electron photomicrograph of gained microcrystal when A represents that florfenicol concentration of methanol solution is 50mg/ml in figure that florfenicol solution different concns obtains microcrystal, the electron photomicrograph of gained microcrystal when B represents that florfenicol concentration of methanol solution is 80mg/ml in figure, the electron photomicrograph of gained microcrystal when C represents that florfenicol concentration of methanol solution is 100mg/ml in figure);
Fig. 4 is the impact of stablizer different concns on microcrystal dissolution rate;
Fig. 5 is microcrystal microscopic morphology figure (the microcrystal microscopic morphology figure obtained when A represents that stabilizer concentration is 1mg/ml in figure that stablizer different concns obtains; Microcrystal microscopic morphology figure obtained when B represents that stabilizer concentration is 3mg/ml in figure, microcrystal microscopic morphology figure obtained when C represents that stabilizer concentration is 4mg/ml in figure);
Fig. 6 is that solvent and anti-solvent ratio are on the impact of microcrystal stripping;
Fig. 7 is the dissolution rate curve of florfenicol microcrystal;
Fig. 8 is the microscopic morphology (in figure, A is the microscopic morphology of the former powder of florfenicol, and B is the microscopic morphology of florfenicol microcrystal) of florfenicol microcrystal prepared by the former powder of florfenicol and embodiment 1.
Embodiment
The following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way.
In embodiment, material therefor, instrument, performance measurement method etc. are as follows:
1, primary drug and reagent
Florfenicol raw material medicine (Hubei pharmaceutcal corporation, Ltd of Zhong Mu HTC, lot number: 20110805 content 99.8%); Vltra tears (Anhui Shanhe Medical Accessary Material Co., Ltd., 20110321), PLURONICS F87 (Nanjing WeiEr chemical engineering Co., Ltd lot number:, lot number 20101201), tween-80, Macrogol 4000, methyl alcohol, polyvinylpyrrolidone be analytical pure, Chengdu Ke Long Chemical Co., Ltd. produces.
2, key instrument
Magnetic stirring apparatus: HJ-4 type and HJ-5 type, Changzhou Guohua Electric Appliance Co., Ltd.'s product; Spectrophotometer: UV-2102P type, UNICO's product; Electronic analytical balance: Shenyang Longteng Electronic Co., Ltd.'s product; Electric drying oven with forced convection: 101A-4 type, Shanghai laboratory apparatus factory produces; Constant temperature oscillation water-bath: HZS-H type, Dongming, Harbin City Medical Instruments factory product.
3, the mensuration of florfenicol microcrystal solubleness and dissolving out capability
It is appropriate that the mensuration precision of 3.1 determined wavelength takes the former powder of florfenicol, be placed in 25ml volumetric flask, adding proper amount of methanol makes it dissolve, by methanol constant volume to scale marks, make the solution of 200 μ g/ml, separately get not containing the methyl alcohol of florfenicol as negative controls, in the interscan of 200 ~ 400nm wavelength region, result florfenicol solution has maximum absorption band at 266nm place.And methyl alcohol at 266nm place without absorbing, on the uv-absorbing of florfenicol without impact, therefore use 266nm as the mensuration wavelength of florfenicol.
The determination precision of 3.2 typical curves takes florfenicol standard substance in right amount, is placed in 50ml volumetric flask, adds proper amount of methanol and make it dissolve, by methanol constant volume to scale marks, make the solution that concentration is 1000 μ g/ml.Respectively precision measure above-mentioned solution 1,1.5,2.0,2.5,3.0,3.5,4.0ml is in 10ml volumetric flask, with methanol constant volume to scale marks, make the florfenicol solution that concentration is 100,150,200,250,300,350,400 μ g/ml, then absorbancy is measured at maximum absorption wavelength, repeat 3 times, get its mean value.Absorbancy is carried out linear regression to florfenicol concentration, and obtaining regression equation is A=0.002C-0.01(r=0.999).Wherein, A is absorbancy, and C is concentration, and r is relation conefficient, and namely florfenicol is in 100 μ g/ml ~ 400 μ g/ml concentration ranges, absorbancy and drug level linear relationship good.
3.3 precision and determination of recovery rates
3.3.1 rate of recovery experiment precision takes florfenicol sample and is placed in 50ml volumetric flask in right amount, scale is settled to distilled water again with after dissolve with methanol, measure absorbancy at 266nm wavelength place, calculate florfenicol content with the typical curve of gained, calculate the rate of recovery.Its average recovery rate of result is 98.93%, illustrates that the method accuracy is higher.
3.3.2 Precision Experiment compound concentration be 150 μ g/ml, the methanol solution containing florfenicol of 200 μ g/ml, 350 μ g/ml the 0.5th, 1,1.5,2,3h measures absorbancy respectively, investigates the precision of the method.The precision of three kinds of different concns is respectively 0.4%, 0.27%, 0.2% as a result, illustrates that the method is more stable.
The mensuration of 3.4 sample solubility takes the florfenicol microcrystal for preparing in right amount in the beaker being added with appropriate distilled water, this beaker is put into the constant temperature oscillation water-bath of 37.0 DEG C, rotating speed is set to 80r/min, get solution in beaker after 24h and also use filtering with microporous membrane in right amount, get filtrate and in 10ml volumetric flask, add methanol constant volume in right amount, measure absorbancy at maximum wavelength place, absorbancy is substituted into regression equation, the solubleness of calculation sample.Be measured in the same method the solubleness of the former powder of florfenicol.
The mensuration of 3.5 sample dissolution rates takes a certain amount of microcrystal samples in the beaker being added with appropriate distilled water, and be placed in by beaker on multifunctional table-type thermostatic mixer, temperature is set to 37.0 DEG C, and rotating speed is set to 100r/min.Respectively the 5th, 10,15,20,30,45,60,90min sample thief from beaker is appropriate, and with filtering with microporous membrane, get appropriate filtrate constant volume in 10ml volumetric flask, then ultraviolet determination is carried out, absorbancy is substituted into regression equation and obtain the stripping situation of sample at different time, finally draw stripping curve figure.
4, the observation of florfenicol microcrystal form is got florfenicol microcrystal sample and is added in the small beaker being added with appropriate distilled water in right amount, this beaker is placed in Ultrasonic Cleaners ultrasonic disperse 20min.Dip the sample suspension after dispersion on slide glass with glass stick, be placed on observed under electron microscope after adding cover glass and take pictures.
Embodiment 1
A kind of method preparing florfenicol microcrystal, the method is as follows: be dissolved in methyl alcohol by former for florfenicol powder, be mixed with the methanol solution of florfenicol, by the aqueous solution be made into containing stablizer soluble in water for stablizer, wherein, the concentration of methanol solution of florfenicol is 40mg/ml, concentration containing the aqueous solution of stablizer is 4mg/ml, stablizer adopts Vltra tears, the volume ratio of methyl alcohol and water is 1:2, under stirring and 4 DEG C of condition of ice bath, the methanol solution of florfenicol is slowly added drop-wise in the aqueous solution containing stablizer, churning time is 15min, florfenicol slowly separates out formation suspension, by this suspension suction filtration, drying florfenicol microcrystal powder.
The solubleness of florfenicol microcrystal in water prepared by the method can reach 3960 μ g/ml.
Embodiment 2 different stabilizers is on the impact of florfenicol microcrystal stripping
Florfenicol microcrystal preparation method is with embodiment 1, but change the kind of stablizer, investigate stablizer and use Vltra tears respectively, polyvinylpyrrolidone, tween-80, PLURONICS F87, Macrogol 4000, the mixture (PLURONICS F87-tween 80) of PLURONICS F87 and tween-80, the mixture (PLURONICS F87-Vltra tears) of PLURONICS F87 and Vltra tears, the impact (in said mixture, the mass ratio of two kinds of materials is 1:1) that the mixture (Vltra tears-tween 80) of Vltra tears and tween-80 is formed florfenicol microcrystal.
In florfenicol microcrystal forming process, stablizer stops the gathering of drug molecule in order to avoid form thick drug particles on the one hand, also enables the crystal stable existence of formation on the other hand.According to Fig. 1, the kind of stablizer has obvious impact to the solubleness of microcrystal and dissolution rate, wherein the solubilizing effect of Vltra tears is best, the effect of polyvinylpyrrolidone is poor, but all former than florfenicol powder stripping quickening, other stablizers to the improvement of stripping all at Vltra tears and polyvinylpyrrolidone therebetween, analyzing reason may be relevant with the hydroxyl contained in stablizer structure, containing a hydroxyl in florfenicol molecule, therebetween hydrogen bond may be formed, drug molecule and stablizer may be made like this to have better avidity, more be conducive to stablizer to play a role.The viscosity of the water-soluble rear increase solution of Simultaneous Stabilization agent, the motion of the drug molecule that slows down avoids drug molecule to be gathered into big particle, and therefore Vltra tears is the stablizer of optimum as preparation florfenicol microcrystal.
The concentration of embodiment 3 florfenicol in methyl alcohol is on the impact of microcrystal stripping
Florfenicol microcrystal preparation method with embodiment 1, but changes the concentration of methanol solution of florfenicol, and the methanol concentration investigating florfenicol is respectively the impact that 30mg/ml, 50mg/ml, 80mg/ml, 100mg/ml are formed microcrystal.Can find out the increase of the concentration of methanol solution along with florfenicol from the result of Fig. 2 and table 1, the solubleness of microcrystal reduces.Accelerate this is because concentration crosses ambassador's nucleation rate, and then to cause in system moment density of solid particles is excessive causing gathering.In addition, in liquid phase-granular system, exist between particle and interact, when 2 intergranular distances narrow down to critical range, intergranular reactive force, based on gravitation, which results in intermolecular reunion.Intergranular reunion makes particle diameter increase, specific surface area reduces thus makes the stripping of microcrystal slack-off.Also can obviously be found out by the aspect graph of florfenicol microcrystal, when florfenicol solution concentration is 50mg/ml, the particle diameter (particle diameter about 20 μm) of particle is significantly less than concentration is 80mg/ml(particle diameter about 200 μm) and 100mg/ml(particle diameter about 300 μm) time particle diameter (as shown in Figure 3).But florfenicol concentration is too low, because it has certain solubility in the mixed system of first alcohol and water, make florfenicol not easily form microcrystal and cause yield too low, such as, when florfenicol concentration is 30mg/ml, the rate of recovery of microcrystal is only 11%.
Table 1 florfenicol solution concentration is on the impact of microcrystal yield and solubleness
The concentration of the embodiment 4 stablizer aqueous solution is on the impact of microcrystal stripping
Florfenicol microcrystal preparation method with embodiment 1, but changes the concentration of aqueous solution containing stablizer, investigates stablizer Vltra tears concentration and is set to 1mg/ml, 2mg/ml, 3mg/ml, 4mg/ml, 5mg/ml impact on microcrystal respectively.Along with the increase of stabilizer concentration, the solubleness of microcrystal and dissolution rate first increase rear minimizing, and result as shown in Figure 4.Because stablizer can hinder the gathering of molecule, therefore when stabilizer concentration is lower, it can hinder molecular aggregates to form macrobead, along with the rising mixing solutions viscosity of concentration increases, molecular motion reduced capability and make Molecule Set be polymerized to particle, hinders and drug particles will be made to become large during molecular aggregates effect when this effect is greater than it and affect stripping.By also can see microcrystal particles difference in size that different concns stablizer obtains significantly (gained microcrystal particle diameter about 350 μm when stabilizer concentration is 1mg/ml to the morphologic observation of microcrystal, gained microcrystal particle diameter about 300 μm when stabilizer concentration is 3mg/ml, gained microcrystal particle diameter about 35 μm when stabilizer concentration is 4mg/ml), as shown in Figure 5.
The volume ratio of embodiment 5 solvent and anti-solvent is on the impact of microcrystal stripping
Florfenicol microcrystal preparation method with embodiment 1, but changes solvent (methyl alcohol) and the ratio of anti-solvent (water), has investigated solvent (methyl alcohol) and anti-solvent (water) than the impact on microcrystal when being respectively 2:1,1:1,1:2,1:3,1:4,1:5.Result does not have crystallize out than when being 1:5 in system at solvent and anti-solvent, illustrates that the solubleness of florfenicol in this mixing solutions is large.The dissolving power of the mixing solutions that solvent and anti-solvent mix in varing proportions to florfenicol is different, thus makes florfenicol degree of supersaturation in system different, and degree of supersaturation is to the granular size of crystallize out, and nucleation speed plays a crucial role.Compare through the stripping result (as shown in Figure 6) of contrast different solvents than crystal obtained under condition, the methyl alcohol of this experimental selection and the volume ratio of water are 1:2.
Embodiment 6 churning time is on the impact of microcrystal stripping
Florfenicol microcrystal preparation method with embodiment 1, investigate churning time be 10,20,30,40,50min is on the impact of microcrystal.Churning time is short, and drug molecule and stabiliser solution can not mix, and are unfavorable for that stablizer plays a role, and the long meeting of churning time causes nucleus further growth, causes particle to become the improvement being unfavorable for greatly drug dissolution energy.The present embodiment investigated respectively churning time be 10,20,30,40,50min time the stripping situation of microcrystal that obtains, the corresponding solubleness of different time is respectively 1775,1985,1810,1790,1680 μ g/ml, and the microcrystal solubleness formed during obvious 20min is larger.
In the method for the invention, containing the concentration of aqueous solution of stablizer and the impact of the concentration of methanol solution of florfenicol on microcrystal dissolved corrosion the most remarkable.On the one hand the height of the concentration of methanol solution of florfenicol affects the florfenicol molecule number in nucleation rate and unit volume, and concentration of aqueous solution containing stablizer then plays obstruction molecular aggregates and becomes oarse-grained effect.These two factors have impact on the committed step that microcrystal is formed, so have remarkably influenced to result.
In Vitro Dissolution curve and the crystal microscopic morphology of the florfenicol microcrystal that the technique (embodiment 1) after optimizing is obtained and the former powder of florfenicol are shown in Fig. 7 and Fig. 8 respectively. as can be seen from the figure, florfenicol under stabilizer function after recrystallization its form obviously regular, and prepare microcrystal particle diameter (particle diameter about 10 μm) obviously reduction (about 400 μm, the former powder footpath of florfenicol) under this condition, so its In Vitro Dissolution strengthens greatly, solubleness reaches 3960 μ g/ml, more former powder improves nearly 2 times, dissolution rate in vitro also obviously strengthens, this is for strengthening absorption of florfenicol oral administration and improving its bioavailability and have vital role.
The above; be only the present invention's preferably embodiment, but protection scope of the present invention is not limited thereto, is anyly familiar with those skilled in the art in the technical scope that the present invention discloses; the change that can expect easily or replacement, all should be encompassed within protection scope of the present invention.Therefore, protection scope of the present invention should be as the criterion with the protection domain of claim.
Claims (6)
1. prepare the method for florfenicol microcrystal for one kind, it is characterized in that: former for florfenicol powder is dissolved in methyl alcohol, be mixed with the methanol solution of florfenicol, by the aqueous solution be made into containing stablizer soluble in water for stablizer, wherein, the concentration of methanol solution of florfenicol is 40mg/ml-70mg/ml, concentration containing the aqueous solution of stablizer is 3mg/ml-5mg/ml, stablizer adopts Vltra tears, the volume ratio of methyl alcohol and water is 1:(1-3), under stirring and 4 DEG C of condition of ice bath, the methanol solution of florfenicol is slowly added drop-wise in the aqueous solution containing stablizer, churning time is 15min-30min, florfenicol slowly separates out formation suspension, by this suspension suction filtration, drying florfenicol microcrystal powder.
2. the method preparing florfenicol microcrystal according to claim 1, is characterized in that: the concentration of methanol solution of florfenicol is 40mg/ml.
3. the method preparing florfenicol microcrystal according to claim 1, is characterized in that: the concentration containing the aqueous solution of stablizer is 4mg/ml.
4. the method preparing florfenicol microcrystal according to claim 1, is characterized in that: the volume ratio of methyl alcohol and water is 1:2.
5. the method preparing florfenicol microcrystal according to claim 1, is characterized in that: adopt magnetic force or electric stirring.
6. the method preparing florfenicol microcrystal according to claim 1, it is characterized in that: former for florfenicol powder is dissolved in methyl alcohol, be mixed with the methanol solution of florfenicol, by the aqueous solution be made into containing stablizer soluble in water for stablizer, wherein, the concentration of methanol solution of florfenicol is 40mg/ml, concentration containing the aqueous solution of stablizer is 4mg/ml, stablizer adopts Vltra tears, the volume ratio of methyl alcohol and water is 1:2, under stirring and 4 DEG C of condition of ice bath, the methanol solution of florfenicol is slowly added drop-wise in the aqueous solution containing stablizer, churning time is 15min, florfenicol slowly separates out formation suspension, by this suspension suction filtration, drying florfenicol microcrystal powder.
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| CN109053506B (en) * | 2018-08-16 | 2020-05-08 | 天津大学 | Method for preparing florfenicol nano crystal |
| CN109553556B (en) * | 2018-12-31 | 2020-08-18 | 京山瑞生制药有限公司 | Novel preparation method for preparing florfenicol crystal |
| CN109528659B (en) * | 2018-12-31 | 2021-07-06 | 京山瑞生制药有限公司 | Preparation method of florfenicol superfine powder |
| CN109851536B (en) * | 2018-12-31 | 2021-01-05 | 京山瑞生制药有限公司 | Method for preparing florfenicol |
| CN114209655B (en) * | 2021-12-31 | 2023-11-28 | 瑞孚信江苏药业股份有限公司 | Preparation method of dolutegravir micropowder |
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