CN100427499C - Soluble salt of azithromycin and its preparation process - Google Patents
Soluble salt of azithromycin and its preparation process Download PDFInfo
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- CN100427499C CN100427499C CNB2005100455972A CN200510045597A CN100427499C CN 100427499 C CN100427499 C CN 100427499C CN B2005100455972 A CNB2005100455972 A CN B2005100455972A CN 200510045597 A CN200510045597 A CN 200510045597A CN 100427499 C CN100427499 C CN 100427499C
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Abstract
The present invention relates to a novel azithromycin soluble salt compound-azithromycin fumarate, which has a chemical name of 9-deoxidizing-9 alpha-aza-9 alpha-methyl-9 alpha-erythromycin A fumarate. A molecular formula is C42H76N2O16, and molecular weight is 865.05. A structural formula is shown in the right, and the present invention is arranged in a crystallization form or a non-crystallization mode or a mixture mode of the crystallization mode and the non-crystallization mode. Compared with azithromycin and other salts, the bioavailability of a human body by oral administration is increased from 37% to 48%, and the moisture absorption, water solubility, ester solubility, stability, etc. are all largely improved. The present invention has a preparation method that the azithromycin and the fumarate are used for reaction in solvent, and then, solid product is separated through dryness or crystallization.
Description
Technical field:
The invention belongs to field of medicaments, relate to a kind of soluble salt compound of new Azythromycin and the preparation method of this compound.
Background technology:
Azythromycin is the derivative of Erythromycin A, it is a kind of semisynthetic novel macrolide antibiotics, its structure is similar to erythromycin, but its antimicrobial spectrum is wider than erythromycin, anti-microbial activity is stronger, bioavailability is higher, and chemical property is also more stable, and particularly the stability to acid is higher than erythromycin.Its chemical name is 9-deoxidation-9 α-azepine-9 Alpha-Methyl-9 α-Erythromycin A.
Azythromycin is that Yugoslavia develops the earliest, nineteen eighty-two U.S. Pat 4328334 anti-microbial activity and the preparation technology of Azythromycin and derivative thereof disclosed, Pfizer Inc. was changeed in the listing back in 1989.
According to relevant bibliographical information, during the azithromycin oral administration, bioavailability not high (37%), just cause bigger waste so clinically, but drug administration by injection or topical are relatively more difficult again, because the solubleness of Azythromycin in water very little (almost insoluble in water) can not directly be made solution and use.U.S. Pat 4474768 disclosed part inorganic acid salt and organic acid Salt And Preparation Methods such as Azythromycin hydrochloride in 1984, was used for parenteral administration.U.S. FDA has been ratified Pfizer's Azythromycin hydrochloride injection listing in 1997, this medicine can be used for respiratory tract infection and gynecology pelvic inflammatory disease.The pharmacokinetic of intravenous administration confirms that Max is 3.2mg/L for 500mg/ time, and Auc is respectively 8 times of oral administration.After this Chinese patent CN1096468 etc. also discloses the organic acid salt of several Azythromycins, as Citrate trianion, glutaminate and preparation method thereof.The organic acid salt of disclosed these Azythromycins of prior art has improved the water-soluble of Azythromycin, but its crystallization has water absorbability, is difficult to carry out industrial production.
Summary of the invention:
In order further to overcome the water absorbability of azithromycin, increase its stability, improve the bioavailability of Azythromycin, the inventor has developed a kind of soluble salt compound-Azythromycin fumarate of new Azythromycin, and has developed the preparation method who is applicable to medicine industry production.
The soluble salt compound of a kind of new Azythromycin of the present invention is the Azythromycin fumarate, and its chemical name is 9-deoxidation-9 α-azepine-9 Alpha-Methyl-9 α-Erythromycin A fumarate.
Its molecular formula is C
42H
76N
2O
16Molecular weight 865.05
Structural formula is:
Azythromycin fumarate of the present invention provides with the mixture of crystallized form or noncrystalline form or crystallized form and noncrystalline form, and when crystallized form existed above a kind of polymorphic form, each polymorphic form formed another aspect of the present invention.
The Azythromycin fumarate is a kind of white powder, and 6% pH value of water solution is 5.8.The pH value is 5.8.
The Azythromycin fumarate of crystallization provided by the present invention or noncrystalline form has identical or essentially identical infrared spectra.It has one or more following feature IR peak: 3405,2974,2937,1732,1638,1577,1464,1382,1170,1078,1059,1013,901,806,633,574, and 464 ± 4cm
-1
The Azythromycin fumarate of crystallized form provided by the present invention has one or more following feature XRD peak: 4.2,6.9,8.4,9.9,11.3,12.3,14.5,15.6,17.4,17.9,18.9,21.4,23.0,23.6,24.8,25.9,27.7,29.4,31.3,39.9 ± 0.2 ° of 2 θ.
The Azythromycin fumarate of crystallization provided by the present invention and noncrystalline form can be processed as oral tablet separately or with the other medicines combination, also can be processed as capsule, granule, syrup, oral liquid, aqueous injection, powder injection, infusion solution etc.
The Azythromycin fumarate that crystallization provided by the present invention or noncrystalline form should be arranged is whole indications that the various preparations of raw material processing all can be used for Azythromycin.
Fumaric acid is excipient substance and the foodstuff additive of using always, It is generally accepted it is safe.Its formal name used at school is a FUMARIC ACID TECH GRADE, have two acidic-groups, can react its branch of salify at 1: 1 with Azythromycin, the son amount is 116,1 molecule only increases weight 116 behind the salify, less than lactic acid salt (180), Lactobionate (716), aspartic acid (266) and glutaminate (294) help improving content of effective in the product medicine.The Azythromycin fumarate is compared with other Azythromycin soluble salts, and its pH value of water solution is preferably, and is little to blood vessel irritation near the pH value of blood of human body, also can guarantee the stability of Azythromycin simultaneously.
The Azythromycin fumarate is compared oral human bioavailability and is brought up to 48% by 37% with Azythromycin, improved 30%, and the also corresponding raising of human plasma drug level helps improving the curative effect of Azythromycin.
The Azythromycin fumarate has changed the water/oil content distribution coefficient of original medicine, has improved ester dissolubility and water miscible dual capability.
The easier stomach and intestine shielding harness that penetrates of Azythromycin fumarate, and then improve absorption, improve blood plasma Chinese traditional medicine concentration, also improved curative effect thereupon; In addition, because the Azythromycin absorption site is in the small intestine part, and Azythromycin is insoluble under alkaline environment, and the Azythromycin fumarate can dissolve at this position, can effectively discharge, absorb, thereby has improved drug effect.
The increase of Azythromycin fumarate Plasma Concentration can enlarge the scope of sensitive organism; Reduced the resistance of Azythromycin.
Compare with other salt, the water absorbability of Azythromycin fumarate is greatly improved.
Water absorbability compares:
| Water-soluble salt | RH75% placed 1 day | RH75% placed 3 days |
| The azithromycin fumarate | Weightening finish 2.5% | Weightening finish 5.1% |
| The azithromycin lactic acid salt | Major part is dissolved | Off-bottom |
| The azithromycin Citrate trianion | Major part is dissolved | Off-bottom |
Stability experiment:
Respectively to the azithromycin fumarate illumination (4500LX) 10 days, high temperature (40,60,80 ℃) high humidity (RH75,92.5%) 10 days, room temperature were placed 10 days.Except under high temperature, super-humid conditions, moisture absorption, outward appearance slightly change, and investigating 10 days degraded products down for 80 ℃ slightly increases, and does not all have considerable change under other conditions.
Pharmacodynamic study:
Respectively the azithromycin fumarate has been carried out antibacterial experiment in external, the body.The result shows, the azithromycin fumarate has tangible anti-microbial effect external to streptococcus pneumoniae, A group streptococcus, B suis, and streptococcus aureus, staphylococcus epidermidis, faecalis, intestinal bacteria, Cray uncle pneumobacillus, enteroaerogen are had certain anti-microbial effect.The streptococcus aureus of abdominal injection 100% minimum lethal dose and beta hemolytic streptococcus infecting mouse are irritated the stomach treatment with azithromycin fumarate, azithromycin and erythromycin respectively.The result, the azithromycin fumarate is respectively 33.38mg/kg and 18.25mg/kg to the ED50 of streptococcus aureus and beta hemolytic streptococcus, azithromycin is respectively 58.22mg/kg and 17.81mg/kg, and erythromycin is respectively 116.92mg/kg and 47.51mg/kg.
The human bioavailability experiment:
The design of three cross-over experiments is adopted in test, and 12 healthy volunteers are divided into first, second, the third three groups at random, and (500mg) reference preparation azithromycin capsule of oral same dose is subjected to test preparation azithromycin fumarate capsule and azithromycin fumarate sheet.It is 130.19% that the result is subjected to the average relative bioavailability of test preparation azithromycin fumarate.
The preparation method of Azythromycin fumarate of the present invention is as follows:
Azythromycin fumarate of the present invention can make by reacting in solution by stoichiometric Azythromycin and fumaric acid.Its operation steps is: the dissolving Azythromycin makes Azythromycin solution in solvent; The fumaric acid of solid or solution form is added in the Azythromycin solution, and reaction under agitation generates the Azythromycin fumarate; Drying or crystallization then separates preparation Azythromycin fumarate product.
The mol ratio of Azythromycin and fumaric acid is 1: 1～1.2
Temperature of reaction is generally 39-80 ℃
Required Azythromycin can be provided by the method preparation of patent and the disclosed prior art of document.In preparation process, can not need to use pure form Azythromycin as starting material.
Azythromycin is soluble in solvent commonly used, for example the solvent of aromatic hydrocarbon type: benzene,toluene,xylene; Alcohol: C
1-8Alkanol, it can be a straight or branched; Ester: C
1-5Alkanoates; Ketone: two C
1-5Alkyl ketone; Acid amides: C
1-5Ethanamide and methane amide that alkyl replaces; Heterocyclic amine: pyridine; Halohydrocarbon: fluorine and/or chlorine C
1-10Alkane; Nitrile: C
1-10Alkyl nitrile; Ether: two C
1-5Alkyl oxide and cyclic ethers; Sherwood oil.
Following solvent is particularly useful for the dissolving of Azythromycin: toluene, methyl alcohol, ethanol, Virahol, ethyl acetate, acetone, butanone, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, N, N-diethylformamide, N, N-diethyl acetamide, methylene dichloride, chloroform, tetracol phenixin, ether, propyl ether, isopropyl ether, tetrahydrofuran (THF), acetonitrile and sherwood oil.Suitable mixed solvent also can use, as the miscellany of above-mentioned solvent.
Fumaric acid is that industry is available, and it can directly use as pure solid, also can be dissolved in the solvent and using.The employed solvent of employed solvent and Azythromycin is basic identical.
In the preparation method of Azythromycin fumarate of the present invention, the concentration of Azythromycin in solvent can be controlled in 5-80% (weight/volume), preferred 10-50% (weight/volume), especially 10-40% (weight/volume).Fashionable when adding with the solution form, the concentration of fumaric acid is the 0.1-7 mole in the acid starting material, more preferably the 1-5 mole.The acid of high or low concentration can join respectively in the alkali of low or high density, and the mode effect of selecting the acid solution of high density to join in the alkaline solution of lower concentration is more satisfactory.According to employed solvent, the suitable concentration of formed Azythromycin fumarate is 2-50% (weight/volume), is preferably 5-30% (weight/volume).Above-mentioned concentration of reactants scope help crystallized form the Azythromycin fumarate formation with separate.
Among the preparation method of Azythromycin fumarate of the present invention, solvent can be selected independent solvent or solvent mixture for use, selecting for use of solvent system not only influences the salt-forming reaction situation, and the Crystallization Separation purifying of reaction product Azythromycin fumarate is also had considerable influence.The screening of usual solvents system need be considered following factor:
Selected solvent system has solubleness preferably to Azythromycin and fumaric acid, helps carrying out smoothly of salt-forming reaction; Can form azeotrope with water, help removing small amount of moisture in the system by component distillation; The solubleness of reaction product Azythromycin fumarate in this solvent system has bigger difference with the variation of solvent temperature, in this solvent, the Azythromycin fumarate under comparatively high temps than having bigger solvability under the low temperature, the solubleness of Azythromycin fumarate is higher more than 5 times than the solubleness when room temperature or temperature are lower a little less than solvent boiling point the time, even more ideal more than 10 times, help the Crystallization Separation of Azythromycin fumarate.Proper solvent system comprises aforesaid alkylbenzene, alkyl alcohol, alkyl ketone, alkyl acid esters and alkyl oxide.Independent and mixed solvent system can be used as solvent or secondary solvent.
Before separating the Azythromycin fumarate, can remove water in the reaction system by component distillation, to avoid forming hydrate.
The Azythromycin fumarate can be separated from reaction soln by several different methods, and its product can be the mixture of crystallized form or noncrystalline form or crystallized form and noncrystalline form.
The Azythromycin fumarate product of noncrystalline form can adopt to comprise the solution of precipitation, spraying drying or freeze-drying Azythromycin fumarate from solution of Azythromycin fumarate or the solution of evaporation Azythromycin fumarate are obtained glassy mass or melts.
The Azythromycin fumarate product of crystallized form can obtain by the whole bag of tricks.Comprise that product has in the limited deliquescent solvent direct crystallization or by using anti-solvent method or using ether development preparation Azythromycin fumarate product at it.
A kind of method for preparing the Azythromycin fumarate of crystallized form in the autoreaction solution comprises makes the reaction soln cooling, in solvent, form the supersaturated solution of Azythromycin fumarate, by keeping solution under relative immobilized condition, for example under slowly stirring or make solution static, by the Azythromycin fumarate that is settled out crystallized form in the solution.The crystalline temperature should surpass 0 ℃, preferably precipitates under the condition under 10-25 ℃ the room temperature.The suitable solvent that is used for this method comprises the same alkylbenzene, alkyl ketone, alkyl alcohol, ether, ester or their miscellany.
The another kind of method of the Azythromycin fumarate of preparation crystallized form comprises the solution with the Azythromycin fumarate, makes the solution supersaturation by evaporating solvent or by adding anti-solvent, with precipitated crystal salt from solution.The anti-solvent that is used for present method is a kind of organic solvent, and it is miscible with the solvent that is used for the reaction of Azythromycin and fumaric acid, but Azythromycin fumarate solubleness therein is lower.The solvability of Azythromycin fumarate should be less than 1mg/mL, preferably less than 0.2mg/mL, especially less than 0.1mg/mL in anti-solvent.Anti-solvent comprises ether, as two C
1-5Alkyl oxide is as ether, propyl ether, isopropyl ether, butyl ether; Alkane such as C
5-10Alkane, it can be straight chain, side chain and cyclic; Sherwood oil.
Be applicable to the solvent system of preparation Azythromycin fumarate, also can be by being used for recrystallization with anti-solvent deposition.
The preferred method of preparation Azythromycin fumarate comprises to be made the reaction soln cooling and optionally inoculate crystal seed in solution.In the solvent of this reaction soln, the Azythromycin fumarate under comparatively high temps than having bigger solvability under the low temperature, thereby when solution was cooled to lesser temps, Azythromycin fumarate had wherein surpassed the solubleness under this temperature, and crystallization goes out the Azythromycin fumarate.
Contain by the starting temperature of the solution of crystalline Azythromycin fumarate and can select according to the changes in solubility of reactant in solvent system.Suitable temperature is 40-80 ℃, preferred 45-70 ℃.When solution is cooled to the temperature that causes the metastable zone of crystalline, carry out crystallization at the beginning, can be stably or reduce the temperature of miscellany step by step, with the degree of saturation of protection supersaturated solution, to improve crystallization yield.Rate of cooling is preferably 0.1-5 ℃/minute, especially is 0.1-2 ℃/minute.Outlet temperature when crystallisation process finishes preferably is near or below room temperature, is good at 10-20 ℃ especially.
Method of the present invention does not need low temperature to guarantee crystallisation process, can implement by the method for controlled chilling speed or preferred gradient cooling subsequently as passing through evaporation section or whole solvent or crystallization at high temperature by obtaining in conjunction with two or more above-mentioned crystallization method.
Above-mentionedly be used for the crystalline solvent and method can be used for recrystallization.The most frequently used solvent that is used for recrystallization is aromatic hydrocarbons, alcohol, ester, halohydrocarbon and ketone, also can use the miscellany of solvent.Every kilogram of Azythromycin fumarate of recrystallization uses the solvent of 2-20L in technical scale, preferred 5-10L.
The aforesaid method that is used for preparing the Azythromycin fumarate can carry out at dissimilar reactors, is applicable to that the crystallization of the Azythromycin fumarate of medicine can be in reaction vessel, as carrying out in the agitator tank reactor.Described reactor can be made of lass lining liner or stainless steel, stirring rake and one or more chuck is housed with the temperature in the crystallization control process.In addition, crystallization can be carried out in the discontinuous crystallizer of the custom-designed careful control that keeps crystallization condition.
Embodiment:
Enumerate embodiment below and further explain the present invention, but not limited by these embodiment.
Embodiment 1 joins the 7.49g Azythromycin in the ethanol of 35mL, is heated to 50 ℃, stirs to make the Azythromycin dissolving, and under this temperature, add the fumaric acid of 1.16g, restir is 15 minutes after the stirring and dissolving, solvent removed in vacuo, melts cooling back grind into powder.Obtain the noncrystalline powder 8.62g of Azythromycin fumarate.Yield 99.6%, purity 97.2%.
IR absorption peak (KBr): 3419,2974,2938,1732,1638,1575,1464,1382,1169,1079,1059,1012,958,900,805,667,572,464 ± 4cm
-1
Embodiment 2 joins the 7.49g Azythromycin in the methyl alcohol of 30mL, be heated to 50 ℃, stirring makes the Azythromycin dissolving, and under this temperature, adding the fumaric acid of 1.15g, restir is 25 minutes after the stirring and dissolving, solvent removed in vacuo, resistates produces pressed powder with ether (90mL) development, with its filtration,, dry in vacuum drier with the ether washing.Obtain crystallization of Azythromycin fumarate and noncrystalline powder mixture 8.55g.Yield 98.8%, purity 97.3%
IR absorption peak (KBr): 3405,2973,2937,1731,1638,1579,1464,1382,1284,1169,1080,1058,1012,957,899,806,665,573,464 ± 4cm
-1
Embodiment 3 joins the 10g Azythromycin in the dehydrated alcohol of 35mL, is heated to 50 ℃, stirs to make the Azythromycin dissolving, and under this temperature, add the fumaric acid of 1.05g, restir is 15 minutes after the stirring and dissolving, cools then to filter below 30 ℃, adds the 110mL isopropyl ether in filtrate, stirring is cooled to below-10 ℃, be incubated 10 hours, filter, filter cake washs with isopropyl ether, vacuum-drying obtains Azythromycin fumarate crystallization 8.7g.Yield 75.3%, purity 98.5%
IR absorption peak (KBr): 3362,2973,2936,1731,1585,1469,1383,1284,1170,1078,1060,1001,982,956,901,661,577,463 ± 4cm
-1
The XRD peak: 4.1,6.9,8.4,9.9,11.3,12.3,14.5,15.6,17.4,17.9,18.9,19.4,20.0,21.4,23.0,23.6,24.8,25.9,27.7,28.5,29.4,29.8,31.3,39.9 ± 0.2 ° of 2 θ.
Embodiment 4 joins the 15g Azythromycin in the dehydrated alcohol of 40mL, be heated to 55 ℃, stir and make the Azythromycin dissolving, and under this temperature, add the fumaric acid of 1.65g, restir is 15 minutes after the stirring and dissolving, slowly cool off in 1 hour then and reduce to room temperature, be cooled to again about 0 ℃, be incubated 10 hours, filter, the cold absolute ethanol washing of filter cake, vacuum-drying obtains Azythromycin fumarate crystallization 10.3g.Yield 59.5%, purity 98.9%.
IR absorption peak (KBr): 3392,2974,2938,1724,1583,1470,1383,1284,1171,1078,1061,1014,983,957,902,807,735,661,578,464 ± 4cm
-1
The XRD peak: 4.2,8.4,9.9,11.3,12.3,12.7,14.5,15.6,16.5,17.5,17.9,18.9,20.1,21.0,21.5,23.0,23.6,24.9,25.9,29.8,31.6,33.5,39.6 ± 0.2 ° of 2 θ.
Embodiment 5 joins the 15g Azythromycin in the Virahol of 40mL, be heated to 55 ℃, stir and make the Azythromycin dissolving, and under this temperature, add the fumaric acid of 1.65g, restir is 15 minutes after the stirring and dissolving, slowly cool off in 1 hour then and reduce to room temperature, be cooled to again about 0 ℃, be incubated 10 hours, filter, filter cake washs with cold isopropanol, and vacuum-drying obtains Azythromycin fumarate 11.5g.Yield 66.4%, purity 98.6%.
IR absorption peak (KBr): 3495,3417,2974,2938,1733,1639,1568,1454,1367,1182,1120,1077,1060,1014,984,958,902,805,663,594,570,540,502,464 ± 4cm
-1
The XRD peak: 6.3,8.3,8.9,10.5,12.5,13.0,13.7,15.3,15.9,16.8,18.5,19.4,19.7,20.2,20.6,20.8,22.2,22.8,23.4,24.3,25.6,27.4,30.1,33.9,36.1,38.6 ± 0.2 ° of 2 θ.
Embodiment 6 joins the 25g Azythromycin in the acetone of 80mL, and stirring and dissolving under the room temperature adds the fumaric acid of 2.6g again, and restir is 35 minutes after the stirring and dissolving, filters, and adds the 300mL sherwood oil in filtrate, stirs and is cooled to-5 ℃, is incubated 24 hours.Filter, the cold petroleum ether of filter cake, vacuum-drying obtains Azythromycin fumarate white crystals 19.8g.Yield 68.6%, purity 98.6%.
Results of elemental analyses:
Theoretical value: C58.31%, H8.85%, 3.24%
Measured value: C58.76%, H8.28%, 2.96%
Embodiment 7 joins the 25g Azythromycin in the methyl alcohol of 50mL, is heated to 50 ℃, stirs to make the Azythromycin dissolving, the fumaric acid that adds 2.6g again, restir is 35 minutes after the stirring and dissolving, is cooled to the room temperature after-filtration, in filtrate, add the 200mL ether, stir and be cooled to-5 ℃, be incubated 24 hours.Filter, filter cake washs with cold diethyl ether, and vacuum-drying obtains Azythromycin fumarate white crystals 12.7g.Yield 44%, purity 98.9%.
Results of elemental analyses:
Theoretical value: C58.31%, H8.85%, 3.24%
Measured value: C58.80%, H8.23%, 2.90%
Claims (10)
1. the soluble salt of an Azythromycin is characterized in that it is the Azythromycin fumarate,
Molecular formula is C
42H
76N
2O
16, molecular weight 865.05,
Structural formula is:
2. the soluble salt of a kind of Azythromycin as claimed in claim 1 is characterized in that said Azythromycin fumarate is the mixture of crystallized form or noncrystalline form or crystallized form and noncrystalline form.
3.. the soluble salt of a kind of Azythromycin as claimed in claim 2 is characterized in that the crystallized form of said Azythromycin fumarate or noncrystalline form have identical or essentially identical infrared spectra, it has following feature IR peak: 3405,2974,2937,1732,1638,1577,1464,1382,1170,1078,1059,1013,901,806,633,574,464 ± 4cm
-1
The Azythromycin fumarate of said crystallized form has following X diffraction peak 2 θ: 4.2,6.9,8.4,9.9,11.3,12.3,14.5,15.6,17.4,17.9,18.9,21.4,23.0,23.6,24.8,25.9, and 27.7,29.4,31.3,39.9 ± 0.2 °.
4. the preparation method of the soluble salt of a kind of Azythromycin as claimed in claim 1, it is characterized in that said Azythromycin fumarate is reacted in solution by Azythromycin and fumaric acid makes, and its operation steps is: the dissolving Azythromycin makes Azythromycin solution in solvent; The fumaric acid of solid or solution form is added in the Azythromycin solution, and reaction under agitation generates the Azythromycin fumarate; Drying or crystallization make Azythromycin fumarate product then.
5. the preparation method of the soluble salt of a kind of Azythromycin as claimed in claim 4 is characterized in that the mol ratio of Azythromycin and fumaric acid is 1: 1～1.2 in the said preparation Azythromycin fumarate reaction; Temperature of reaction is 39-80 ℃.
6. the preparation method of the soluble salt of a kind of Azythromycin as claimed in claim 4 is characterized in that said drying prepares the method for Azythromycin fumarate product for the solution of Azythromycin fumarate precipitation, spraying drying or freeze-drying Azythromycin fumarate from solution or the solution of evaporation Azythromycin fumarate are obtained glassy mass or melts Azythromycin fumarate product.
7. the preparation method of the soluble salt of a kind of Azythromycin as claimed in claim 4, it is characterized in that said crystallization prepares the method for Azythromycin fumarate product for making the reaction soln cooling, in solvent, form the supersaturated solution of Azythromycin fumarate, under slowly stirring or make under the solution immobilized condition, by the Azythromycin fumarate of precipitated crystal form in the solution.
8. the preparation method of the soluble salt of a kind of Azythromycin as claimed in claim 4, it is characterized in that the method that said crystallization prepares Azythromycin fumarate product is the solution with the Azythromycin fumarate, make the solution supersaturation by evaporating solvent, with precipitation Azythromycin fumarate crystallization from solution.
9. the preparation method of the soluble salt of a kind of Azythromycin as claimed in claim 4, it is characterized in that the method that said crystallization prepares Azythromycin fumarate product is the solution with the Azythromycin fumarate, make the solution supersaturation by adding anti-solvent, with precipitation Azythromycin fumarate crystallization from solution.
10. the preparation method of the soluble salt of a kind of Azythromycin as claimed in claim 4 is characterized in that before drying or crystalline azithromycin fumarate, removed water in the reaction system by component distillation.
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| US4963531A (en) * | 1987-09-10 | 1990-10-16 | Pfizer Inc. | Azithromycin and derivatives as antiprotozoal agents |
| CN1112566A (en) * | 1994-04-15 | 1995-11-29 | 普利瓦药物，化学，食品，化妆品工业公司 | Process for the preparation of azithromycin dihydrochloride |
| CN1123279A (en) * | 1995-06-15 | 1996-05-29 | 沈家祥 | Azithmycin water-soluble salt, injection thereof and their usage |
| CN1344541A (en) * | 2001-08-04 | 2002-04-17 | 安徽省新药研究院 | Water soluble Azithromycin salt and its eye drop |
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