CN105017281A - Salt of antofloxacin salt and preparation method and application thereof - Google Patents
Salt of antofloxacin salt and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a salt of antofloxacin as shown in the formula I and a preparation method and an application in the preparation of antibacterial drugs. The salt of antofloxacin contains benzene sulfonate, tosilate, malate, sulfate, phosphate, nitrate, fumarate, mesylate, citrate or maleate, etc. of antofloxacin. Experiments confirm that the above salt of antofloxacin has excellent water solubility.
Description
Technical field
The invention belongs to field of pharmacology, relate to medicinal chemistry art, more specifically, relate to salt of a kind of Antofloxacin hydrochlorid and preparation method thereof and the purposes in preparation treatment infectious disease medicament.
Background technology
Flouroquinolone drugs is the very important extensive pedigree antibiotic of a large class, and they obtain immense success clinically, and one that is described as field of medicaments eighties great progressive.Flouroquinolone drugs has the advantages such as antimicrbial power is strong, toxic side effect is little, convenient drug administration, low cost of manufacture.Have at present and be widely used in clinical more than 20 kinds, developed into the second largest class antibacterials being only second to cynnematin, and its current growth momentum is obviously faster than cynnematin.More than 10 years since 2000-2011, in 9 complete synthesis antibacterials of whole world listing, 8 (comprising antofloxacin hydrochloride) is fluoroquinolones [Mark S Butler and Matthew ACooper, Antibiotics in the clinical pipeline in2011, The journal of antibiotics, 2011,1-13].
Fluoroquinolones is different according to physico-chemical property, can in a salt form or the form listing of free alkali or acid, and listing formulation is also varied, mainly based on oral preparation, injection.Oral dosage form such as Tablet and Capsula is used for low-grade infection, non-hospital use etc., and injection type is mainly used in serious, acute, can not be oral patient.Therefore good water-soluble very important to physical and chemical properties of drugs, but, because flouroquinolone drugs major part is amphoteric substance, water-soluble generally not ideal, use is restricted because poorly water-soluble is difficult to make aqueous injection for some medicines such as norfloxicin, Prulifloxacin, Ciprofloxacin, gemifloxacin, Ofloxacine USP 23 etc.Therefore improve flouroquinolone drugs macromolecule water-solubility to have great importance, when particularly needing large bolus injection, be water-solublely greater than 50mg/mL advantageously.
Antofloxacin hydrochlorid, fluoro-2,3-dihydro-3-methyl-8-amino-7-oxo-7H-pyrido ［ 1,2,3-de ］ ［ Isosorbide-5-Nitrae ］ benzoxazine-6-carboxylic acid [the Chinese patent ZL97106728.7 of (S)-9-; Yang Yushe, Ji Ruyun, Hu Zengjian, Chen Kaixian, Wu Jimin.The synthesis of laevo-rotation ofloxacin analogue and structure activity relationship thereof, Acta Pharmaceutica Sinica, 1999,34(3), 197-202], be a kind of novel Development of Fluoroquinolone Antibacterials, 2009 with the form of hydrochloride in Discussion on Chinese Listed, popular name antofloxacin hydrochloride.It has potent, broad-spectrum antimicrobial, fungicidal activity.External to clinical separation 1080 strain pathogenic bacterium effect 2 ~ 4 hours, the bacterium of more than 99% can be killed.No matter oral, subcutaneous or intravenously administrable, all has very strong provide protection, ED to the mouse of abdominal cavity infection staphylococcus aureus, escherichia coli, Pseudomonas aeruginosa, streptococcus pneumoniae, Klebsiella Pneumoniae
50between 1.43 ~ 12.74mg/kg, its interior curative effect is better than market mainstream similar drugs Ciprofloxacin and Ofloxacine USP 23.Antofloxacin hydrochloride has excellent metabolic characteristic, it has the longest human body transformation period (20 hours), minimum protein binding rate (17%) and good oral administration biaavailability (96%), every day only takes 1 time, is long-acting quinolone medicine truly.Antofloxacin hydrochloride security is good.Suppressing hERG potassium current may cause QT interval prolongation, is the most worrying side effect of xacin-series medicine, this product to the inhibit activities of IKr than clinical safest Levofloxacin also weak 10 times.Antofloxacin hydrochloride III phase clinical treatment respiratory tract, urinary tract and skin soft-tissue infection, total effective rate 95.2%, bacteria clearance 96.7%, determined curative effect, untoward reaction is few.
But antofloxacin hydrochloride is water-soluble not ideal, listing is oral tablet at present, makes it develop large bolus injection agent and is restricted.As one of water miscible method of increase medicine, salify is often adopted, such as Moxifloxacin hydrochloride, levofloxacin hydrochloride etc.Now, extensively studied by series and screen, being surprised to find the special new salt of a kind of Antofloxacin hydrochlorid has well water-soluble, the requirement of preparation various forms of Antofloxacin hydrochlorid injection can be met completely, what new salt was surprising provides a large amount of advantage used on effective preparation with water-soluble significantly with stability, completes the present invention on this basis.
Summary of the invention
Therefore, an object of the present invention is to provide a kind of salt of Antofloxacin hydrochlorid, it has well water-soluble.
Another object of the present invention is to provide the preparation method of the salt of above-mentioned Antofloxacin hydrochlorid.
It is the pharmaceutical composition of activeconstituents containing above-mentioned salt that the present invention also provides a kind of.
The purposes of the salt also having an object to be to provide above-mentioned Antofloxacin hydrochlorid of the present invention in preparation antibacterials.
The invention provides the salt of Antofloxacin hydrochlorid shown in formula I, comprise benzene sulfonate, tosilate, malate, vitriol, phosphoric acid salt, nitrate, fumarate, mesylate, citrate, maleate etc.
Present invention also offers the preparation method of above-mentioned salt, described method comprises: under normal temperature to solvent reflux temperature, by the acid of Antofloxacin hydrochlorid and 1-3 equivalent, in suitable solvent after abundant stirring reaction, filter, then in suitable solvent recrystallization various salt.In more detail, the preparation method of the salt of Antofloxacin hydrochlorid of the present invention is included in normal temperature under solvent reflux temperature, is dissolved in by Antofloxacin hydrochlorid in organic solvent, the acid being dissolved in same solvent is added dropwise under stirring, stirring reaction 1-2 hour, filter generate solid, then in suitable solvent recrystallization.
Wherein, described suitable solvent is methylene dichloride, tetrahydrofuran (THF), acetonitrile or anhydrous methanol, or aforementioned solvents mixed solvent in any proportion.
Described acid is mineral acid (except hydrochloric acid) or organic acid.Organic acid for example there are Phenylsulfonic acid, tosic acid, oxysuccinic acid, fumaric acid, methylsulfonic acid, Citric Acid, maleate.Mineral acid for example there are sulfuric acid, phosphoric acid, nitric acid.
Reaction feed ratio is Antofloxacin hydrochlorid: acid: solvent=1:1.0-3.0:50-100 parts by weight.
Reaction and recrystallization temperature can select room temperature to arrive the applicable temperature of solvent refluxing.
This preparation method is simple, and product yield is high, almost pollution-free, is applicable to large-scale commercial production.
Particularly, be surprised to find the mesylate of Antofloxacin hydrochlorid, very well water-soluble, the solubleness in water reaches 143.2mg/ml, outside being all beyond one's expectations.
Next is that malate and the solubleness of vitriol in water reach 34.8mg/ml, 40.2mg/ml respectively, also apparently higher than the solubleness 30.49mg/ml of Antofloxacin hydrochlorid hydrochloride in water gone on the market.Other water-soluble is in table 1.
Present invention also offers a kind of pharmaceutical composition, it contains one, particularly its mesylate in the salt of the shown Antofloxacin hydrochlorid of above-mentioned formula (I) for the treatment of significant quantity, and pharmaceutically acceptable auxiliary material.Described pharmaceutical composition can make the various preparations can injecting application.Described auxiliary material can be pure water, physiological saline, D/W or other contain and be conducive to improving the ancillary component of pharmaceutical composition pharmaceutical properties or the aqueous solution of nutritive substance.
Optimal composition is configured to injection liquid preparation, and as required, often propping up the salt that injection can contain 30-1000 milligram Antofloxacin hydrochlorid, is 50-600 milligram more specifically.
Certainly, above-mentioned salt, as Antofloxacin hydrochlorid mesylate also can make solid preparation according to a conventional method, oral administration.
Present invention also offers the salt of above-mentioned Antofloxacin hydrochlorid, particularly its mesylate, or its composition, the purposes in the medicine of disease is contaminated in preparation treatment or prevention human or animal bacterium perception.
Embodiment
Below in conjunction with embodiment, the present invention is further elaborated.But should be appreciated that, these embodiments are in order to demonstrate the invention, are never any limitation of the invention.
In all embodiments,
1h-NMR Varian Mercury300 nuclear magnetic resonance analyser record, chemical shift represents with δ (ppm), and coupling constant represents with Hz.Other abbreviation implication is as follows, and s is unimodal; D, bimodal; T, triplet; Q, quartet; Dd, two dually meet; M, multiplet; J, coupling constant; DMSO, dimethyl sulfoxide (DMSO); HPLC, high performance liquid chromatography; EDETATE SODIUM, disodium ethylene diamine tetraacetate.
Embodiment
The preparation of embodiment 1. Antofloxacin hydrochlorid benzene sulfonate
By Antofloxacin hydrochlorid [reference ZL97106728.7 synthesizes] (20 grams, 0.0531 mole) be dissolved in methylene dichloride (100 milliliters) and methyl alcohol (200 milliliters) mixing solutions, stir the Phenylsulfonic acid (12.6 grams that lower dropping is dissolved in methyl alcohol (3 milliliters), 0.0797 mole) solution, stirring at room temperature 2 hours, filtering precipitate, by throw out and ethanol: water=2:1(250 milliliter) mix, after reflux (1 hour) is dissolved, stop stirring, room temperature places lower crystallization (8 hours), crystallize out, filter, 60 DEG C of heating, vacuum dryings (2 hours), obtain 24.0 grams of Antofloxacin hydrochlorid benzene sulfonates, yield 86%.Fusing point: 246-247 DEG C.
HPLC purity: 99.34%.Analytical procedure and condition: chromatographic column: Diamonsil C18 (4.6mm × 250mm, 5 μm); Moving phase: 0.05mol/L potassium primary phosphate (containing 0.005mol/L sodium hexanesulfonate, 0.007%EDTA disodium, pH=2.5 ± 0.1): acetonitrile (84: 16); Flow velocity: 1ml/min; Determined wavelength: 297nm; Column temperature: 30 DEG C.
MS m/e=377.1(M
+)。
1H NMR(300MHz,DMSO-d
6):δ1.39(d,J=6.7Hz,3H)，2.79(s,3H)，3.20(s,3H),3.20(s,4H),3.48(t,J=4.9Hz,4H),4.14(dd,J=11.4,2.3Hz,1H),4.39(m,1H),4.8(m,1H),6.96(s,2H),7.31(m,2H),7.60(dd,J=7.0,2.6Hz,1H),8.78(s,1H)。
Embodiment 2.
The preparation of Antofloxacin hydrochlorid tosilate:
By Antofloxacin hydrochlorid (20 grams, 0.0531 mole) be dissolved in methylene dichloride (100 milliliters) and methyl alcohol (200 milliliters) mixing solutions, stir the tosic acid (13.7 grams that lower dropping is dissolved in methyl alcohol (2 milliliters), 0.0797 mole) solution, stirring at room temperature 2 hours, filtering precipitate, by throw out and ethanol: water=2:1(250 milliliter) mix, after reflux (1 hour) is dissolved, stop stirring, room temperature places lower crystallization (8 hours), crystallize out, filter, 60 DEG C of heating, vacuum dryings (2 hours), obtain 25.33 grams of Antofloxacin hydrochlorid tosilate, yield 87.2%.Fusing point: 228-230 DEG C.
HPLC purity: 99.54%, analytical procedure: chromatographic column: Diamonsil C18 (4.6mm × 250mm, 5 μm); Moving phase: 0.05mol/L potassium primary phosphate (containing 0.005mol/L sodium hexanesulfonate, 0.007%EDTA disodium, pH=2.5 ± 0.1): acetonitrile (84: 16); Flow velocity: 1ml/min; Determined wavelength: 297nm; Column temperature: 30 DEG C; Fusing point:
228-230℃。
MS m/e=377.2(M
+)。
1H NMR(300MHz,DMSO-d
6):δ1.39(d,J=6.6Hz,3H),2.28(s,3H),2.89(d,J=4.2Hz,3H),3.65-3.35(m,8H),4.14(dd,J=11.2,1.6Hz,1H),4.40(dd,J=11.2,1.6Hz,1H),4.80(q,J=7.0Hz,1H),7.11(d,J=7.9Hz,2H),7.48(m,2H),8.79(s,1H),9.60(s,1H)。
Embodiment 3.
The preparation of Antofloxacin hydrochlorid malate:
By Antofloxacin hydrochlorid (20 grams, 0.0531 mole) be dissolved in methylene dichloride (100 milliliters) and methyl alcohol (200 milliliters) mixing solutions, stir the oxysuccinic acid (10.7 grams that lower dropping is dissolved in methyl alcohol (2 milliliters), 0.0797 mole) solution, stirring at room temperature 2 hours, filtering precipitate, by throw out and ethanol: water=2:1(250 milliliter) mix, after reflux (1 hour) is dissolved, stop stirring, room temperature places lower crystallization (8 hours), crystallize out, filter, 60 DEG C of heating, vacuum dryings (2 hours), obtain 6.4 grams of Antofloxacin hydrochlorid malates, yield 24.3%.Fusing point: 252-254 DEG C.
HPLC purity: 99.35%, analytical procedure: chromatographic column: Diamonsil C18 (4.6mm × 250mm, 5 μm); Moving phase: 0.05mol/L potassium primary phosphate (containing 0.005mol/L sodium hexanesulfonate, 0.007%EDTA disodium, pH=2.5 ± 0.1): acetonitrile (84: 16); Flow velocity: 1ml/min; Determined wavelength: 297nm; Column temperature: 30 DEG C.
MS m/e=377.1(M
+)。
1H NMR(300MHz,D
2O):δ1.45(d,J=6.6Hz,3H),2.61(dd,1H),2.72(dd,1H),2.98(s,3H),3.27(t,J=11.5Hz,2H),3.47-3.6(m,6H),4.15(d,J=11.3Hz,1H),4.31(m,1H),4.37(dd,J=8.2,4.3Hz,1H),4.49(d,J=7.1Hz,1H),8.28(s,1H)。
Embodiment 4.
The preparation of Antofloxacin hydrochlorid vitriol:
By Antofloxacin hydrochlorid (20 grams, 0.0531 mole) be dissolved in methylene dichloride (100 milliliters) and methyl alcohol (200 milliliters) mixing solutions, stir (4.24 milliliters, the sulfuric acid that lower dropping is dissolved in methyl alcohol (2 milliliters), 0.0797 mole) solution, stirring at room temperature 2 hours, filtering precipitate, by throw out and ethanol: water=2:1(250 milliliter) mix, after reflux (1 hour) is dissolved, stop stirring, room temperature places lower crystallization (8 hours), crystallize out, filters, 60 DEG C of heating, vacuum dryings (2 hours), obtain 24.2 grams of Antofloxacin hydrochlorid vitriol, yield 95%.Fusing point: 285-287 DEG C.
HPLC purity: 99.59%, analytical procedure: chromatographic column: Diamonsil C18 (4.6mm × 250mm, 5 μm); Moving phase: 0.05mol/L potassium primary phosphate (containing 0.005mol/L sodium hexanesulfonate, 0.007%EDTA disodium, pH=2.5 ± 0.1): acetonitrile (84: 16); Flow velocity: 1ml/min; Determined wavelength: 297nm; Column temperature: 30 DEG C.
MS m/e=377.2(M
+)。
1H NMR(300MHZ,D
2O):δ1.46(d,J=7.1Hz,3H),2.99(S,3H),3.29(d,J=12.4Hz,2H),3.58(d,J=14.9Hz,6H),4.18(d,J=11.8,1H),4.41-4.28(m,1H),4.51(s,1H),8.3(m,1H)。
Embodiment 5.
The phosphatic preparation of Antofloxacin hydrochlorid:
By Antofloxacin hydrochlorid (20 grams, 0.0531 mole) be dissolved in methylene dichloride (100 milliliters) and methyl alcohol (200 milliliters) mixing solutions, stir 85% phosphoric acid (5.88 milliliters that lower dropping is dissolved in methyl alcohol (2 milliliters), 0.0797 mole) solution, stirring at room temperature 2 hours, filtering precipitate, by throw out and ethanol: water=2:1(250 milliliter) mix, after reflux (1 hour) is dissolved, stop stirring, room temperature places lower crystallization (8 hours), crystallize out, filter, 60 DEG C of heating, vacuum dryings (2 hours), obtain 24.0 grams of Antofloxacin hydrochlorid phosphoric acid salt, yield 92%.Fusing point: 285-287 DEG C.
HPLC purity: 99.81%, analytical procedure: chromatographic column: Diamonsil C18 (4.6mm × 250mm, 5 μm); Moving phase: 0.05mol/L potassium primary phosphate (containing 0.005mol/L sodium hexanesulfonate, 0.007%EDTA disodium, pH=2.5 ± 0.1): acetonitrile (84: 16); Flow velocity: 1ml/min; Determined wavelength: 297nm; Column temperature: 30 DEG C.
MS m/e=377.2(M
+)。
1H NMR(300MHz,DMSO-d
6):δ1.38(d,J=6.7Hz3H),2.28(s,3H),2.62(m,J=6.0Hz,3H),3.29-3.40(m,4H),4.12(dd,J=11.3,2.3Hz,2H),4.38(m,2H),4.78(m,2H),6.92(s,2H),8.76(s,1H)。
Embodiment 6.
The preparation of Antofloxacin hydrochlorid fumarate:
By Antofloxacin hydrochlorid (20 grams, 0.0531 mole) be dissolved in methylene dichloride (100 milliliters) and methyl alcohol (200 milliliters) mixing solutions, stir the fumaric acid (7.66 grams that lower dropping is dissolved in methyl alcohol (2 milliliters), 0.0797 mole) solution, stirring at room temperature 2 hours, filtering precipitate, by throw out and ethanol: water=2:1(250 milliliter) mix, after reflux (1 hour) is dissolved, stop stirring, room temperature places lower crystallization (8 hours), crystallize out, filters, 60 DEG C of heating, vacuum dryings (2 hours), obtain 24.8 grams of Antofloxacin hydrochlorid fumarates, yield 99%.Fusing point: 271-273 DEG C.
HPLC purity: 98.44%, analytical procedure: chromatographic column: Diamonsil C18 (416mm × 250mm, 5 μm); Moving phase: 0.05mol/L potassium primary phosphate (containing 0.005mol/L sodium hexanesulfonate, 0.007%EDTA disodium, pH=2.5 ± 0.1): acetonitrile (84: 16); Flow velocity: 1ml/min; Determined wavelength: 297nm; Column temperature: 30 DEG C.
MS m/e=377.2(M
+)。
1H NMR(300MHz,DMSO-d
6):δ1.38(d,J=6.7Hz,3H),2.32(s,3H),2.56(t,J=5.1Hz,4H),3.32(q,J=5.7Hz,4H),4.11(dd,J=11.3,2.3Hz,1H),4.39(dd,J=11.3,1.6Hz,1H),4.78(d,J=6.8Hz,1H),6.60(s,1H),6.91(s,2H),8.75(s,1H)。
Embodiment 7.
The preparation of Antofloxacin hydrochlorid mesylate:
By Antofloxacin hydrochlorid (20 grams, 0.0531 mole) be dissolved in methylene dichloride (100 milliliters) and methyl alcohol (200 milliliters) mixing solutions, stir the methylsulfonic acid (7.66 grams that lower dropping is dissolved in methyl alcohol (2 milliliters), 0.0797 mole) solution, stirring at room temperature 3 hours, filtering precipitate, by throw out and ethanol: water=2:1(250 milliliter) mix, after reflux (1 hour) is dissolved, stop stirring, room temperature places lower crystallization (8 hours), crystallize out, filter, 60 DEG C of heating, vacuum dryings (2 hours), obtain 19.84 grams of Antofloxacin hydrochlorid mesylates, yield 79.1%.Fusing point: 269-271 DEG C.
HPLC purity: 99.85%, analytical procedure: chromatographic column: Diamonsil C18 (4.6mm × 250mm, 5 μm); Moving phase: 0.05mol/L potassium primary phosphate (containing 0.005mol/L sodium hexanesulfonate, 0.007%EDTA disodium, pH=2.5 ± 0.1): acetonitrile (84: 16); Flow velocity: 1ml/min; Determined wavelength: 297nm; Column temperature: 30 DEG C.
MS m/e=377.1(M
+)。
1H NMR(300MHz,D
2O):δ1.5(s,3H),2.81(s,3H),3.0(s,3H),3.30(d,2H),3.48-3.66(dd,6H),4.22(d,1H),4.38(d,1H),4.55(m,1H),8.33(s,1H)。
The water-soluble test of embodiment 8
Method: the high performance liquid chromatography shown in " Chinese Pharmacopoeia " 2,010 two annex VD.29 pages.
(1) the configuration of testing compound saturated solution: get testing compound and be placed in a certain amount of pure water at 20 DEG C, forms supersaturated solution, for subsequent use.
(2) the configuration of testing compound standard solution: get testing compound 40 DEG C of dryings 2 hours.Accurately weighed a certain amount of testing compound is placed in volumetric flask, adds pure water and makes it to dissolve, and be diluted to scale.Certain density testing compound standardized solution is obtained after shaking up.
(3) the peak area of testing compound saturated solution and testing compound standardized solution is measured by HPLC method.
(4) go out solubleness by formulae discovery: C
sample=C
mark× A
sample/ A
mark
C
sample: testing compound saturated solution concentration (mg/ml), C
marktesting compound concentration of standard solution (mg/ml), A
sampletesting compound saturated solution HPLC peak area; A
marktesting compound standardized solution HPLC peak area.
HPLC condition: chromatographic column: Diamonsil C18 (4.6mm × 250mm, 5 μm); Moving phase: 0.05mol/L potassium primary phosphate (containing 0.005mol/L hexane sulphur sodium, 0.007%EDTA disodium, pH=2.5 ± 0.1): acetonitrile (84: 16); Flow velocity: 1ml/min; Determined wavelength: 297nm; Column temperature: 30 DEG C.
Measurement result is in table 1.
Table 1 the compounds of this invention water solubility
As can be seen from Table 1, embodiment 7 gained compound (Antofloxacin hydrochlorid mesylate) is water-soluble improves 275 times than Antofloxacin hydrochlorid, improves nearly 5 times, can meet the requirement of water soluble preparation completely than antofloxacin hydrochloride.
Embodiment 9 stability test
Accurately weighed Antofloxacin hydrochlorid mesylate 1.0g, is placed in the volumetric flask of 10ml, and add pure water and dissolve, be diluted to scale, concentration is 100mg/ml.After fully shaking up, be positioned over room temperature 15-20 DEG C, in the environment of humidity 30-45%, by following " HPLC condition ", sample measured.HPLC condition: chromatographic column: DiamonsilC18 (4.6mm × 250mm, 5 μm); Moving phase: 0.05mol/L potassium primary phosphate (containing 0.005mol/L hexane sulphur sodium, 0.007%EDTA disodium, pH=2.5 ± 0.1): acetonitrile (84: 16); Flow velocity: 1ml/min; Determined wavelength: 297nm; Column temperature: 30 DEG C.The results are shown in Table 2.
Table 2 the compounds of this invention aqueous stability
As seen from table, the compounds of this invention has good aqueous stability, is suitable for preparing water fluid preparation.
Prepared by embodiment 10 composition
Embodiment 7 gained compound (methylsulfonic acid Antofloxacin hydrochlorid) 200.0 grams
The D/W of 5.0% 2.0 liters
Packing 2000.0
Take embodiment 7 gained compound 200.0 grams, be dissolved in the D/W of 1.7 liter 5.0% under stirring at room temperature, and then continue to add, make liquor capacity reach 2.0 liters, be made into the solution of 100mg/mL, through the appropriate charcoal process of activity, filter, then filling one-tenth 2000.0 preparation unit.High-temperature sterilization process can be taked on demand.
As required, aforesaid liquid preparation available hydrogen sodium oxide or salt acid for adjusting pH value.
The D/W of above-mentioned 5.0% can use the D/W of different concns, or the injection physiological saline of injection pure water or different concns substitutes.
Prepared by embodiment 11 composition
Embodiment 7 gained compound (methylsulfonic acid Antofloxacin hydrochlorid) 400.0 grams
Injection pure water 4.0 liters
Packing 4000.0
Take embodiment 7 gained compound 400.0 grams, be dissolved in 3.5 liters of injection pure water under stirring at room temperature, and then continue to add, make liquor capacity reach 4.0 liters, be made into the solution of 100mg/mL, through the appropriate charcoal process of activity, filter, then filling one-tenth 4000.0 preparation unit.High-temperature sterilization process can be taked on demand.
As required, aforesaid liquid preparation available hydrogen sodium oxide or salt acid for adjusting pH value.
Above-mentioned injection pure water can use the D/W of different concns, or the injection physiological saline of different concns substitutes.
As required, the compounds of this invention also can according to a conventional method, and with water for injection, desired concn made by different glucose and different concns physiological saline, the liquid preparation of required unit volume.
In addition, embodiment 7 gained compound (methylsulfonic acid Antofloxacin hydrochlorid) also can make tablet or capsule according to a conventional method.
Claims (9)
1. the salt of Antofloxacin hydrochlorid shown in formula I, comprises the benzene sulfonate of Antofloxacin hydrochlorid, tosilate, malate, vitriol, phosphoric acid salt, nitrate, fumarate, mesylate, citrate or maleate
2. prepare the method for the salt of Antofloxacin hydrochlorid described in claim 1 for one kind, described method comprises: under normal temperature to solvent refluxing, by the acid of Antofloxacin hydrochlorid and 1-3 equivalent, in a solvent fully after stirring reaction, filter, then in solvent recrystallization corresponding salt.
3. method according to claim 2, wherein, described solvent is methylene dichloride, tetrahydrofuran (THF), acetonitrile or anhydrous methanol, or aforementioned solvents mixed solvent in any proportion; Described acid is Phenylsulfonic acid, tosic acid, oxysuccinic acid, fumaric acid, methylsulfonic acid, Citric Acid, toxilic acid, sulfuric acid, phosphoric acid or nitric acid; Reaction feed ratio is Antofloxacin hydrochlorid: acid: solvent=1:1.0-3.0:50-100 parts by weight.
4. a pharmaceutical composition, what it contained treatment significant quantity is selected from one in the salt of Antofloxacin hydrochlorid according to claim 1 and pharmaceutically acceptable auxiliary material.
5. a pharmaceutical composition, it contains the mesylate of the Antofloxacin hydrochlorid for the treatment of significant quantity and pharmaceutically acceptable auxiliary material.
6. the purposes of salt in preparation antibacterials of Antofloxacin hydrochlorid according to claim 1.
7. an injection for the salt of Antofloxacin hydrochlorid, wherein, the injection of the salt of Antofloxacin hydrochlorid described in per unit preparation comprises 30-1000mg and is selected from the salt of Antofloxacin hydrochlorid according to claim 1 and pharmaceutically acceptable auxiliary material.
8. the injection of the salt of Antofloxacin hydrochlorid according to claim 7, wherein, the injection of the salt of Antofloxacin hydrochlorid described in per unit preparation comprises the mesylate of the Antofloxacin hydrochlorid of 50-600mg and pharmaceutically acceptable auxiliary material.
9. the injection of the salt of the Antofloxacin hydrochlorid according to claim 7 or 8, wherein, described pharmaceutically acceptable auxiliary material be injection pure water, physiological saline, D/W or other contain and be conducive to improving the ancillary component of pharmaceutical composition pharmaceutical properties or the aqueous solution of nutritive substance.
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Cited By (2)
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| CN106109407A (en) * | 2016-08-25 | 2016-11-16 | 安徽环球药业股份有限公司 | The compound method of antofloxacin hydrochloride sodium chloride injection |
| CN112390754A (en) * | 2020-11-17 | 2021-02-23 | 华南农业大学 | Enrofloxacin salt hydrate and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106109407A (en) * | 2016-08-25 | 2016-11-16 | 安徽环球药业股份有限公司 | The compound method of antofloxacin hydrochloride sodium chloride injection |
| CN112390754A (en) * | 2020-11-17 | 2021-02-23 | 华南农业大学 | Enrofloxacin salt hydrate and preparation method and application thereof |
| CN112390754B (en) * | 2020-11-17 | 2022-12-09 | 华南农业大学 | Enrofloxacin salt hydrate and preparation method and application thereof |
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