CN101412740B

CN101412740B - Hydrate of azithromycin, and preparation and use thereof

Info

Publication number: CN101412740B
Application number: CN2007100535919A
Authority: CN
Inventors: 刘力
Original assignee: Individual
Current assignee: Individual
Priority date: 2007-10-18
Filing date: 2007-10-18
Publication date: 2012-12-19
Anticipated expiration: 2027-10-18
Also published as: CN101412740A

Abstract

The invention relates to an azithromycin hydrate as well as preparation and application thereof. The azithromycin hydrate is C38H72N2O12.A.nH2O, wherein n is between 1.0 and 5.0; and A can be maleic acid, fumaric acid and sulphuric acid. The hydrate has good water solubility and good storage stability, is suitable for treating and preventing infectious diseases of people or animal caused by Gram positive or negative sensitive bacteria.

Description

The hydrate of azithromycin and preparation thereof and purposes

Technical field

The present invention relates to medical technical field, specifically provide the hydrate of azithromycin, be i.e. toxilic acid, fumaric acid, Azithromycin Sulfate salt crystalline hydrate and preparation and purposes.

Background technology

Document has only been reported toxilic acid, fumaric acid Azythromycin [C ₃₈H ₇₂N ₂O ₁₂C ₄H ₄O ₄Molecular weight: 865.08] and Azithromycin Sulfate [C ₃₈H ₇₂N ₂O ₁₂H ₂SO ₄Molecular weight: 847.06] and uses thereof, up to the present, still there is not disclosed bibliographical information Zitromax to have the hydrate [C of salt both at home and abroad ₃₈H ₇₂N ₂O ₁₂AnH ₂O, n=1.0～5.0] be toxilic acid, fumaric acid, Azithromycin Sulfate crystalline hydrate, A can be a kind of in toxilic acid, fumaric acid, the sulfuric acid.

Summary of the invention

Involved in the present invention is Azythromycin (azithromycin) hydrate and the preparation and the purposes of organic acid and inorganic acid salt.The hydrate of azithromycin of the present invention, i.e. the azithromycin hydrate of toxilic acid and fumaric acid, the Azithromycin Sulfate hydrate, its molecular formula is C ₃₈H ₇₂N ₂O ₁₂AnH ₂O, n=1.0～5.0, n can be 1,1.75,2,3,4,4.75,5.0 and between numeral, A can be a kind of in toxilic acid, fumaric acid, the sulfuric acid.

Surprisingly, we are through discovering the hydrate [C of the azithromycin that contains crystal water that we obtain ₃₈H ₇₂N ₂O ₁₂AnH ₂O; N=1.0～5.0, A can be a kind of in toxilic acid, fumaric acid, the sulfuric acid] existence that can be stable, the toxilic acid, fumaric acid, the Azithromycin Sulfate that contain crystal water are different from the characteristic that Azythromycin is insoluble in water; Anhydrous toxilic acid, fumaric acid Azythromycin have the characteristic that more is prone to the moisture absorption; The toxilic acid, fumaric acid, the Azithromycin Sulfate that contain crystal water are all soluble in water, have good room temperature storage stability, are convenient to prepare the preparation that is prone to directly dissolving and absorbs; Be convenient to store and transportation, can conveniently be used for the preparation of pharmaceutical prepn.Thermal analysis test (TG-DTA or TG-DTG) collection of illustrative plates can find out that weightless platform has corresponding endotherm(ic)peak; Match with karl Fischer method mensuration moisture result and hot analytical results, thermogram spectrum TG-DTG collection of illustrative plates is obviously found out 1 hydrate C of the hydrate of toxilic acid Azythromycin ₃₈H ₇₂N ₂O ₁₂C ₄H ₄O ₄H ₂O, fumaric acid Azythromycin 1 hydrate C ₃₈H ₇₂N ₂O ₁₂C ₄H ₄O ₄H ₂O, toxilic acid Azythromycin 2 hydrate C ₃₈H ₇₂N ₂O ₁₂C ₄H ₄O ₄2H ₂O, fumaric acid Azythromycin 2 hydrates, fumaric acid Azythromycin 5 hydrate C ₃₈H ₇₂N ₂O ₁₂C ₄H ₄O ₄5H ₂O, Azithromycin Sulfate 1 hydrate etc., the hydrate that X powder diffraction test discovery contains the azithromycin of crystal water is not amorphous.

The hydrate of Azythromycin organic acid salt of the present invention is that the azithromycin hydrate and the Azithromycin Sulfate hydrate of toxilic acid and fumaric acid is off-white powder, can stable storage.Above-mentioned sample is required to carry out wettability test according to the CP2005 version, or be sealed in the cillin bottle, under 40 ℃, carry out accelerated stability test, with HPLC method (C ₁₈Reversed-phase column, (regulating pH to 7.0 with triethylamine)-acetonitrile (70: 30) is a moving phase to the potassium dihydrogen phosphate of 0.1M, and the detection wavelength is 210nm, and flow velocity is 1.0ml/min, the changing conditions of detection level and related substance.Unexpectedly find; The azithromycin hydrate of toxilic acid of the present invention and fumaric acid, Azithromycin Sulfate crystalline hydrate content and related substance do not have considerable change; Toxilic acid, fumaric acid, vitriolic Azythromycin anhydride accelerated test 6 months were compared with 0 month; Related substance increases azithromycin hydrate and the Azithromycin Sulfate crystalline hydrate of multiple far above toxilic acid and fumaric acid, explains that the azithromycin hydrate of toxilic acid and fumaric acid and Azithromycin Sulfate crystalline hydrate have good storage stability.The result sees table 1～table 5.

Table 1. toxilic acid Azythromycin 1 hydrate accelerated stability test result

Table 2. fumaric acid Azythromycin 1 hydrate accelerated stability test result

Table 3. fumaric acid Azythromycin 5 hydrate accelerated stability test results

The anhydride of table 4. azithromycin and hydrate accelerated stability test result

The anhydride of table 5. azithromycin and hydrate high humidity test-results (75%40 ℃ of RH)

The hydrate preparation method of Azythromycin hydrochlorate is:

Method A. with rudimentary (C3-C6) ketone, is a solvent like one or more of acetone, rudimentary (C2-C6) ester, water or low mass molecule alcohol C1-C5 such as methyl alcohol, ethanol, Virahol in reaction vessel, adds Azythromycin; Stir between 0-55 ℃, dissolving adds organic acid such as toxilic acid or fumaric acid, perhaps sulphuric acid soln; Stir, reaction is finished, slowly add rudimentary (C3-C6) ketone; Like acetone, chloroform or low mass molecule alcohol such as methyl alcohol, ethanol, Virahol, rudimentary (C2-C6) ether, rudimentary (C2-C6) ester; Like one or more of ethyl acetate, formic acid second fat, cooling treats that solid separates out; Filter, solids is with organic solvent low mass molecule alcohol C1-C5 such as methyl alcohol, ethanol, Virahol, rudimentary (C3-C6) ketone, like one or more rinses in acetone, rudimentary (C2-C6) ether such as ether, the chloroform; Drain the dry hydrate that gets the azithromycin hydrate organic acid salt, perhaps Azithromycin Sulfate hydrate;

Perhaps method B adds organic acid such as toxilic acid or fumaric acid or its aqueous solution in reaction vessel, and perhaps sulphuric acid soln adds Azythromycin; Stir between 0-55 ℃, make dissolving, reaction is finished, slowly add rudimentary (C3-C6) ketone; Like acetone, chloroform, rudimentary (C2-C6) ester is like one or more of ethyl acetate, formic acid second fat or low mass molecule alcohol C1-C5 such as methyl alcohol, ethanol, Virahol; Cooling treats that solid separates out, and filters; Solids is with organic solvent low mass molecule alcohol C1-C5 such as methyl alcohol, absolute ethyl alcohol, Virahol, rudimentary (C3-C6) ketone, like acetone, rudimentary (C2-C6) ether, rudimentary (C2-C6) ester, like one or more rinses in ethyl acetate, formic acid second fat, the chloroform; Drain dry organic acid such as toxilic acid, fumaric acid azithromycin hydrate, perhaps Azithromycin Sulfate hydrate;

Perhaps method C. is with toxilic acid or fumaric acid, and perhaps Azithromycin Sulfate hydrate and Azythromycin or azithromycin dihydrate drop in the reaction flask in molar ratio, add water; Between controlled temperature 0-50 ℃, reaction 0.5-6h, question response finishes; It is freezing to-60～-40 ℃; Vacuum lyophilization, the hydrate of Azythromycin organic acid salt, perhaps Azithromycin Sulfate hydrate.

With of the ethanolic soln neutralization of gained sample with sodium hydrogen carbonate solution or ammoniacal liquor or ammoniacal liquor; Sedimentation and filtration; Washing, one or more recrystallizations in water, methyl alcohol, ethanol or the acetone, data such as fusing point, specific rotatory power, IR, MS or collection of illustrative plates are all consistent with the raw material azithromycin dihydrate.

Under vacuum condition, between 50-105 ℃, Vanadium Pentoxide in FLAKES is a siccative with the azithromycin hydrate of toxilic acid and fumaric acid, and vacuum-drying is more than 6 hours, the Azythromycin anhydride of toxilic acid or fumaric acid acid, perhaps Azithromycin Sulfate hydrate.

The azithromycin hydrate of toxilic acid of the present invention or fumaric acid; Perhaps the Azithromycin Sulfate hydrate is used to prepare injection freeze-dried powder, or aseptic subpackaged powder injection or great transfusion preparation, or little water needle injection, through the enterally administering preparation, comprises tablet; Capsule; Granule is through the ointment and the gel of percutaneous drug delivery, the suppository of effervescent tablet, vaginal jellies and transvaginal or rectal administration.

Be used to prepare tablet through the enterally administering preparation; Capsule; Granule wherein can contain pharmaceutically acceptable weighting agent, like in starch, modified starch, lactose, Microcrystalline Cellulose, Schardinger dextrins, sorbyl alcohol, N.F,USP MANNITOL, calcium phosphate, the amino acid etc. one or more; Pharmaceutically acceptable disintegrating agent is like in starch, modified starch, Microcrystalline Cellulose, sodium starch glycolate, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, the tensio-active agent one or more; Pharmaceutically acceptable wetting agent and tackiness agent are like in gelling starch, methylcellulose gum, Xylo-Mucine, TKK 021, Vinylpyrrolidone polymer, Lalgine and the salt thereof one or more; Pharmaceutically acceptable lubricant and glidant are like in Triple Pressed Stearic Acid, Magnesium Stearate, Macrogol 4000-6000, talcum powder, micropowder silica gel, the Stepanol MG etc. one or more; Pharmaceutically acceptable sweeting agent and essence are like in ASPARTAME POWDER BP/USP, Sodium Cyclamate, soluble saccharin, TGS, the food flavour etc. one or more.

Solid preparation of the present invention is different from the characteristic that the Azythromycin difficulty is dissolved in water; Cause the dissulution of its solid preparation to receive the big characteristics of preparation technogenic influence; The azithromycin hydrate of toxilic acid or fumaric acid or Azithromycin Sulfate hydrate are prone to be dissolved in water, so the solid preparation of its preparation has good dissolving out capability, make it be absorbed the entering blood circulation easily; Improve bioavailability, and help bringing into play fast its anti-microbial effect.

Suppository of the present invention and gelifying agent are different from Azithromycin suppository or ointment, because the Azythromycin difficulty is dissolved in water, need add the auxiliary material of oil soluble generally speaking; Be easy to pollute, and difficult the cleaning, toxilic acid or fumaric acid or vitriolic azithromycin hydrate are prone to be dissolved in water; So the suppository of its preparation and gelifying agent have good release performance, make it be absorbed the entering blood circulation easily, improve bioavailability; And help bringing into play fast its anti-microbial effect; And need not to add the auxiliary material of oil soluble, be difficult for polluting, be prone to clean.

The preparation of the suppository of toxilic acid, fumaric acid or vitriolic azithromycin hydrate: toxilic acid and fumaric acid or Azithromycin Sulfate hydrate 1-50%, suppository base 50-99% form, and matrix can be one or more in ethanol, glycerine, glycogelatin, Macrogol 200-8000, Prist, semi-synthetic hard fatty acids fat, carbomer serial (931,934,940,974, AA-1,1342 etc.), the polysorbate60-80.The preparation method: main ingredient is mixed with matrix, heating in water bath, stir, wait to melt, be stirred in the mould of suppository that even, rapid impouring scribbled lubricant, to overflowing the bolt mould a little, treat to scabble after cold, molding promptly gets.

The ointment of toxilic acid, fumaric acid or Azithromycin Sulfate hydrate and preparing gel (comprising that gel for eye use, eye are used in body gel, vaginal jellies, common external-use gel): toxilic acid and fumaric acid or Azithromycin Sulfate hydrate are (in Azythromycin; Feed intake) with 50-99% matrix mixing, matrix can be one or more in ethanol, glycerine, trolamine, glycogelatin, Macrogol 200-8000, Prist, Vinylpyrrolidone polymer, semi-synthetic hard fatty acids fat, water-soluble mono-glycerides, carbomer series (931,934,940,974, AA-1,1342 etc.), the polysorbate60-80.Can contain pharmaceutically receivable sanitas and stablizer in the suppository; Can respectively carbomer be used water-dispersion during preparation; Add glycerine, Macrogol 200-8000, heating in water bath, mix, add the azithromycin hydrate, stirring of toxilic acid, the fumaric acid of recipe quantity, with about pharmaceutically acceptable mineral alkali or organic bases adjusting pH=3.0-7.0; Add water to full dose, be stirred to even, packing, promptly get.

The preparation method of freeze-dried powder is: get toxilic acid or fumaric acid or Azithromycin Sulfate hydrate (by Azythromycin), add pharmaceutically acceptable frozen-dried supporting agent or auxiliary shape agent, add injection and blunge and make dissolving, pharmaceutically acceptable acid-alkali accommodation pH is 5.5-7.5; Preferred pH is 6.2-7.0, adds activated carbon 0.005-0.5% (W/V) and stirs 15-45min, filters; Moisturizing, sterile filtration is by 75-500mg/ bottle (in main ingredient) packing; Lyophilize, tamponade gets finished product.

Toxilic acid of the present invention or fumaric acid or vitriolic azithromycin hydrate prepare injection freeze-dried powder, aseptic subpackaged powder injection, and (75～500mg) are dissolved in 10～15ml water the preparation of a unitary dose, and its pH value is between 5.5～7.5.

Toxilic acid or fumaric acid or Azithromycin Sulfate hydrate are used to prepare great transfusion preparation: toxilic acid or fumaric acid or vitriolic azithromycin hydrate add injection water and pharmaceutically acceptable additives; For example pharmaceutically acceptable pH regulator agent, pharmaceutically acceptable oxidation inhibitor and stablizer, pharmaceutically acceptable etc. opened regulator; The large vol sterile solution for injection is processed in filtration, degerming; Its pH value is between 5.5～7.5, and preferred pH is 6.2-7.0.

The injection with small volume of toxilic acid or fumaric acid or vitriolic azithromycin hydrate and preparation technology thereof: the hydrate of azithromycin adds injection water and pharmaceutically acceptable additives; For example: pharmaceutically acceptable pH regulator agent, pharmaceutically acceptable oxidation inhibitor, rare gas element; The sterilization injection with small volume is processed in filtration, degerming; Its pH value is between 5.5～7.5, and preferred pH is 6.2-7.0.

Its pharmaceutically acceptable pH regulator agent can be pharmaceutically acceptable mineral acid or organic acid, mineral alkali or organic bases; Also can be generalized Lewis acid or alkali; Can contain one or several; Can be hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, Hydrogen bromide, propionic acid, acetic acid and acetate, like sodium-acetate etc.; Lactic acid and lactic acid pharmaceutical salts, like Sodium.alpha.-hydroxypropionate etc., Citric Acid, Citric Acid pharmaceutical salts, like Citric Acid trisodium etc., yellow soda ash, sodium hydrogencarbonate, saleratus, sodium hydroxide, Pottasium Hydroxide, phosphoric acid salt, Sodium phosphate, dibasic, SODIUM PHOSPHATE, MONOBASIC, potassium primary phosphate, Secondary ammonium phosphate, potassium hydrogenphosphate, succsinic acid and salt, tartrate and pharmaceutical salts thereof, like sodium hydrotartrate, DL-tartrate, Seignette salt etc., borax, boric acid, Succinic Acid, caproic acid, hexanodioic acid, FUMARIC ACID TECH GRADE, maleic acid, volatile salt, Hypophosporous Acid, 50, sodium-metaphosphate, Potassium polymetaphosphate, potassium metaphosphate; Trihydroxy-aminomethane, trolamine, diethylolamine, thanomin, Yi Bingchunan, HSDB 338,2-amino-2-(methylol) 1; Ammediol amine, 1; 2-hexanediamine, N-methyl grape amine, Diisopropylamine and their salt; Multi-hydroxy carboxy acid and pharmaceutical salts; Like glucuronic acid, glucono-, LBA, lactobionic acid, galacturonic acid, oxysuccinic acid, threonic acid, glucoheptonic acid; Nicotinic acid, glycyrrhetate, phenylformic acid and salt, Sodium Benzoate, methylsulfonic acid, Phenylsulfonic acid, tosic acid, R-Glyceric acid, glycocoll, Methionin, l-arginine, methionine(Met) wait in amino acid and the amino acid salts etc. one or several.

Its pharmaceutically acceptable oxidation inhibitor and stablizer can be sulfurous acid, sulphite, hydrosulphite, pyrosulfite, hyposulfite, thiosulphate; Organosulfur compound thiocarbamide, gsh, Sulfactin, Thiovanic acid and salt, sodium sulfoxylate formaldehyde, thioglycerol, thiolactic acid and salt, thio-2 acid and salt, phenol compound; Like gallic acid and salt, Progallin A, Tenox PG, Stabilizer GA 8, lauryl gallate, coffic acid, caffeiate, FLA, ferulate, butylated hydroxytoluene, butyl hydroxy anisol, di-t-butyl Pyrogentisinic Acid, nordihydroguaiaretic acid (NDGA), 2; 5-resorcylic acid, 2,5-resorcylic acid salt, phenol or derivatives thereof, Whitfield's ointment or its salt; Sodium Glutamate, glycocoll, halfcystine, methionine(Met), amino acid with and salt; Glycyrrhetate, glycyrrhetate, enols used, as xitix and ascorbate salt, xitix palm ester, saccharosonic acid and erythorbate, acetone close xitix, a-Viteolin, vitamin PP, tartrate, nitrate salt, phosphoric acid salt, acetic acid pharmaceutical salts, Citrate trianion, EDTA and edta salt, like in EDTA disodium, EDTA four sodium, Calcium Disodium Edetate, CDTA, DTPA, N-two (2-hydroxyethyl) glycocoll, divinyl triamino penta acetate, diethyl triamine base penta acetate etc. one or several.

Its pharmaceutically acceptable isotonic regulator can be one or more in glucose, fructose, Xylitol, sorbyl alcohol, N.F,USP MANNITOL, Nulomoline, SANMALT-S, Expex, sodium-chlor, Repone K, magnesium chloride, calcium chloride, the Sodium.alpha.-hydroxypropionate etc.

Source and the degerming mode of reducing phlegm and internal heat can be the gac that the adds dosing amount 0.005-3% source of reducing phlegm and internal heat, and millipore filtration degerming and pressure sterilizing also can adopt heat sterilization, the source of reducing phlegm and internal heat.In the hyperfiltration process; That ultra-fine filter can be selected for use is flat, rolling, tubular type, tubular fibre formula and circle boxlike etc.; Preferred rolling and tubular fibre formula ultra-fine filter; It is after 50,000 to 300,000 filter membrane is removed most of heat generation material and bacterium that relative molecular mass is held back in employing, adopts the ultra-filtration membrane of holding back relative molecular mass 1000-30000 to remove the residue thermal source again, the ultra-filtration membrane of preferred relative molecular mass 1000-10000.

The hydrate anti-microbial activity of azithromycin carries out microbial culture and mensuration according to the pharmacological experiment method, and its result is like table 6,7, shown in 8:

Table 6 toxilic acid Azythromycin 1 hydrate anti-microbial activity MIC (mg/L)

Table 7 fumaric acid Azythromycin 5 hydrate anti-microbial activity MIC (mg/L)

Table 8 Azithromycin Sulfate 1 hydrate anti-microbial activity MIC (mg/L)

The clinical application of target compound of the present invention

Because toxilic acid of the present invention or fumaric acid or vitriolic azithromycin hydrate are the Macrolide antimicrobial drug; The tool broad-spectrum antibacterial action; Be applicable to Gram-positive or negative bacteria sensitive organism; The infection that comprises the human or animal due to streptococcus aureus, streptococcus pyogenes, streptococcus pneumoniae, Hemolytic streptococcus, CPN, trachoma mycoplasma, hemophilus influenzae, legionella pneumophilia, the catarrh mora bacterium etc. comprises treatment and preventions such as respiratory tract, urinary system infection, gonorrhoea, prostatitis, intestinal tract infections, liver and gall infection, skin soft-tissue infection, ocular infection.

Its consumption usage: generally speaking, get preparation 125～500mg of the present invention (in Azythromycin) in 50～500 milliliters of 0.9% sodium-chlor transfusion or 5% glucose, do intravenous drip, every day 1 time, 3～7 is a course of treatment.

Oral administration consumption usage (in Azythromycin): adult's consumption: 1. sexually transmitted disease (STD) due to chlamydia trachomatis or the responsive NEISSERIA GONORRHOEAE needs these article of single oral 1.0g.2. to the treatment of other infection: the 1st day, the 0.5g clothes that pause, the 2nd～5 day, 0.25g on the one clothes that pause; Or 0.5g on the one clothes that pause, serve on 3.Children's's consumption: 1. treatment otitis media, pneumonia, the 1st, by the body weight 10mg/kg clothes (daily maximum is no more than 0.5g) that pause, the 2nd～5, every day was by the body weight 5mg/kg clothes (daily maximum is no more than 0.25g) that pause; Treatment children's pharyngitis, tonsillitis, one by the body weight 12mg/kg clothes (daily maximum is no more than 0.5g) that pause, logotype 5 days.

Suppository administration consumption usage (in Azythromycin): female adult once a day, one on the rectal suppository of single administration 0.125-0.75g or vagina bolt, adult the male sex once a day, one of the rectal suppository of single administration 0.125-0.75g; Children reduce by half.

Description of drawings

Fig. 1 is the thermogram spectrum of rich next sour Azythromycin 1 hydrate.

Fig. 2 is the thermogram spectrum of toxilic acid Azythromycin 1 hydrate.

Fig. 3 is the thermogram spectrum of fumaric acid Azythromycin 5 hydrates.

Fig. 4 is the thermogram spectrum of fumaric acid Azythromycin 2 hydrates.

Test condition: heat-up rate 10K/min, N ₂Protection, TR is about 30-450 ℃.

Embodiment

Embodiment 1 with fumaric acid 5g and azithromycin dihydrate in molar ratio example (1: 1) drop in the reaction flask, add water, heating is stirred, between the controlled temperature 2-40 ℃; Reaction 10-90min, question response finishes, and it is freezing to-50 ℃, keeps 0.5-6 hour; Reduce condenser temperature to-55 ℃, vacuumize, make temperature rise to about-20 ℃ gradually through shelf after, keeping about 24 hours about-20 ℃; Continue heating medicine is warming up to about 28 ℃, kept 6 hours, get the off-white color crystalline powder, yield 99%; Sample is soluble in water, HPLC: the sample main peak is consistent with the RT of Azythromycin reference substance main peak, fusing point: 149.5-153.5 ℃; (not proofreading and correct), it is 2.23% that the Ka Shi method is measured moisture, this and sample contain result's (theoretical value 2.04%) of 1 crystal water in limit of error.TG-DTG:60～130 ℃ weightlessness is about 2.50%, and this and sample contain the result of 1 crystal water in limit of error, and TG-DTG has tangible endotherm(ic)peak before being illustrated in 130 ℃, contains crystal water (seeing accompanying drawing 1) in the interpret sample.With of the ethanolic soln neutralization of gained sample with sodium hydrogencarbonate or ammoniacal liquor or organic amine, sedimentation and filtration, washing, the aqueous ethanolic solution recrystallization, fusing point, specific rotatory power, IR, MS etc. are all consistent with the raw material Azythromycin.

Ultimate analysis measured value: C57.17, H8.99, N3.11

Theoretical value: C57.12, H8.90, N3.17

Under vacuum condition, between 80-105 ℃, Vanadium Pentoxide in FLAKES is a siccative with the hydrate of above-mentioned azithromycin, and vacuum-drying is more than 6 hours, fumaric acid Azythromycin anhydride.

Embodiment 2 adds ethanol and makes the Azythromycin dissolving in three-necked flask, adds equimolar fumaric acid under 15～55 ℃ of stirrings, makes dissolving; Continue reaction 2 hours, after reaction finishes, slowly add 2-15 formic acid second fat and Virahol (5～1: 1), cool off doubly; Treat that solid separates out, filter that solids is drained with the rinse of formic acid second fat; Dry about 50 ℃, get off-white powder, soluble in water, HPLC: the sample main peak is consistent with the RT of Azythromycin reference substance main peak.Fusing point: 138.5-142.6 ℃,, do not proofread and correct; Moisture (Ka Shi method): 4.09%, about 3.52% (the seeing accompanying drawing 4) of TG-DTG:50～120 ℃ weightlessness, this and sample contain result's (theoretical value 4.0%) of 2 crystal water in limit of error.TG-DTG has tangible endotherm(ic)peak before being illustrated in 130 ℃, contains crystal water in the interpret sample.With of the ethanolic soln neutralization of gained sample with sodium hydrogencarbonate or ammoniacal liquor or organic amine, sedimentation and filtration, washing, the aqueous ethanolic solution recrystallization, specific rotatory power, IR, MS etc. are all consistent with the raw material Azythromycin.

Ultimate analysis measured value: C55.82, H9.06, N3.04

Theoretical value: C55.98, H8.95, N3.11

Embodiment 3 with toxilic acid 10g and azithromycin dihydrate in molar ratio example (1: 1) drop in the reaction flask, add water, heating is stirred, between the controlled temperature 2-40 ℃; Reaction 10-90min, question response finishes, and it is freezing to-50 ℃, keeps 0.5-6 hour; Reduce condenser temperature to-55 ℃, vacuumize, make temperature rise to about-25 ℃ gradually through shelf after, keeping about 24 hours about-25 ℃; Continue heating medicine is warming up to about 40 ℃, kept 8 hours, get the off-white color crystalline powder; Yield 99%, sample is soluble in water, HPLC: the sample main peak is consistent with the RT of Azythromycin reference substance main peak.Fusing point: 141.2-145.2 ℃ (not proofreading and correct); It is 2.16% that the Ka Shi method is measured moisture, and this and sample contain result's (theoretical value 2.04%) of 1 crystal water in limit of error.TG-DTG: weightless about 2.42% between the platform, the result that this and sample contain 1 crystal water matches, and TG-DTG is illustrated between the weightless zone between the platform has tangible endotherm(ic)peak, contains crystal water (seeing accompanying drawing 2) in the interpret sample.With of the ethanolic soln neutralization of gained sample with sodium hydrogencarbonate or ammoniacal liquor or organic amine, sedimentation and filtration, washing, the aqueous ethanolic solution recrystallization, fusing point, specific rotatory power, IR, MS etc. are all consistent with the raw material Azythromycin.

Ultimate analysis measured value: C57.06, H8.96, N3.13

Theoretical value: C57.12, H8.90, N3.17

Under vacuum condition, between 90-105 ℃, Vanadium Pentoxide in FLAKES is a siccative with the hydrate of this azithromycin, and vacuum-drying is more than 6 hours, toxilic acid Azythromycin anhydride.

Embodiment 4 drops into fumaric acid and Azythromycin (30g) in the reaction flask by example (1: 1) in molar ratio, adds water, heating; Stir, between the controlled temperature 2-40 ℃, reaction 10-90min, question response finishes; It is freezing to-50 ℃, the mixed solvent crystallization of solid water that obtains and organic solvent Virahol, chloroform, formic acid second fat, suction filtration; Use the chloroform rinse, drain, 50 ℃ of dryings; Get the off-white color crystalline powder, soluble in water, HPLC: the sample main peak is consistent with the RT of Azythromycin reference substance main peak.Fusing point: 103.1-107.2 ℃, 153-157 ℃ of decomposition (not proofreading and correct), it is 9.52% that the Ka Shi method is measured moisture, this and sample contain result's (theoretical value 9.43%) of 5 crystal water in limit of error.Weightless about 8.97% between ℃ platform of TG-DTA:50～140, the result that this and sample contain 5 crystal water matches, and TG-DTA is illustrated between the weightless zone between the platform has tangible endotherm(ic)peak, contains crystal water (seeing accompanying drawing 3) in the interpret sample.With of the ethanolic soln neutralization of gained sample with sodium hydrogencarbonate or ammoniacal liquor or organic amine, sedimentation and filtration, washing, the aqueous ethanolic solution recrystallization, specific rotatory power, IR, MS etc. are all consistent with the raw material Azythromycin.

Ultimate analysis measured value: C 52.77%, H9.11%, N2.89%.

Theoretical value: C 52.81%, H9.08%, N2.93%.

Embodiment 5 with toxilic acid 5g and azithromycin dihydrate in molar ratio example (1: 1) drop in the reaction flask, add water, heating is stirred, between the controlled temperature 2-40 ℃; Reaction 10-90min, question response finishes, and it is freezing to-50 ℃, keeps 0.5-6 hour; Reduce condenser temperature to-55 ℃, vacuumize, make temperature rise to about-20 ℃ gradually through shelf after, keeping about 24 hours about-20 ℃; Continue heating medicine is warming up to about 25 ℃, kept 6 hours, get the off-white color crystalline powder; Yield 99%, sample is soluble in water, HPLC: the sample main peak is consistent with the RT of Azythromycin reference substance main peak.Fusing point: 153-157 ℃ (not proofreading and correct) decomposes; It is 3.96% that the Ka Shi method is measured moisture, and this and sample contain result's (theoretical value 4.0%) of 2 crystal water in limit of error.TG-DTG: weightless about 3.46% between the platform, the result that this and sample contain 2 crystal water matches, and TG-DTG is illustrated between the weightless zone between the platform has tangible endotherm(ic)peak, contains crystal water in the interpret sample.With of the ethanolic soln neutralization of gained sample with sodium hydrogencarbonate or ammoniacal liquor or organic amine, sedimentation and filtration, washing, the aqueous ethanolic solution recrystallization, fusing point, specific rotatory power, IR, MS etc. are all consistent with the raw material azithromycin dihydrate.

Ultimate analysis measured value: C55.86, H8.88, N3.09

Theoretical value: C55.98, H8.95, N3.11

Embodiment 6 drops into azithromycin dihydrate 5g in the reaction flask, adds water, under ice bath, drips the 1M sulphuric acid soln during example (1: 1) stirs in molar ratio and drops in the reaction flask; Stir, between the controlled temperature 0-40 ℃, reaction 10-90min, question response finishes; It is freezing to-50 ℃, kept 0.5-6 hour, reduce condenser temperature and arrive-55 ℃; Vacuumize, make temperature rise to about-20 ℃ gradually through shelf after, keeping about-20 ℃ about 24 hours; Continue heating medicine is warming up to about 28 ℃, kept 6 hours, get the off-white color crystalline powder; Yield 98%, sample is soluble in water, HPLC: the sample main peak is consistent with the RT of Azythromycin reference substance main peak.It is 2.48% that the Ka Shi method is measured moisture, and this and sample contain result's (theoretical value 2.08%) of 1 crystal water in limit of error.TG-DTG: weightless about 2.56% between the platform, the result that this and sample contain 1 crystal water matches, and TG-DTG is illustrated between the weightless zone between the platform has tangible endotherm(ic)peak, contains crystal water in the interpret sample.With of the ethanolic soln neutralization of gained sample with sodium hydrogencarbonate or ammoniacal liquor or organic amine, sedimentation and filtration, washing, the aqueous ethanolic solution recrystallization, specific rotatory power, IR, MS etc. are all consistent with the raw material Azythromycin.

Ultimate analysis measured value: C52.68, H8.95, N3.16, S3.63

Theoretical value: C52.76, H8.86, N3.24, S3.71

Under vacuum condition, between 90-115 ℃, Vanadium Pentoxide in FLAKES is a siccative with the hydrate of this azithromycin, and vacuum-drying is more than 6 hours, the Azithromycin Sulfate anhydride.

Embodiment 7 gets toxilic acid Azythromycin 1 hydrate 20Kg (by Azythromycin), adds Xylitol 2.0～5kg and adds fresh water for injection 130～320L and stir and make dissolving, and using pharmaceutically acceptable acid or alkali such as 1M SODIUM PHOSPHATE, MONOBASIC and 1M Sodium phosphate, dibasic adjusting pH is 6.0～7.0; Add activated carbon 0.01～0.5% (W/V) and stir 15～45min; Filter, moisturizing to 150～400L is perhaps adopted the ultrafiltration membrance filter of holding back relative molecular mass 1000-8000 with 0.22 micron filtering with microporous membrane; By 125mg/ bottle or 250mg/ bottle or 500mg/ bottle (in Azythromycin) packing; Lyophilize, tamponade gets finished product.

Embodiment 6 gets toxilic acid Azythromycin 2 hydrate 20g (by Azythromycin), with N.F,USP MANNITOL 40g, adds 40-60 ℃ of water for injection 180～450ml stirring and makes dissolving; Using Aspartic Acid acid and the 1M sodium hydrogencarbonate adjusting pH of 1M is 6.2～6.5, adds activated carbon 0.01～0.5% (W/V) and stirs 15～45min, filters; Moisturizing to 220～500ml; Perhaps adopt the ultrafiltration membrance filter of holding back relative molecular mass 1000-8000 with 0.22 micron filtering with microporous membrane, by 125mg/ bottle or 250mg/ bottle or 500mg/ bottle (by Azythromycin) packing, lyophilize; Tamponade gets finished product.

Embodiment 8 gets 2 hydrates or aseptic fumaric acid Azythromycin 5 hydrates or aseptic fumaric acid Azythromycin 1 hydrate or the aseptic Azithromycin Sulfate 1 hydrate 25Kg (by Azythromycin) of aseptic toxilic acid Azythromycin 1 hydrate or aseptic toxilic acid azithromycin hydrate; Press 125mg/ bottle or 250mg/ bottle or 500mg/ bottle (by Azythromycin) packing in aseptic subpackaged technology; Jump a queue, tamponade, roll aluminium lid and get finished product.

Embodiment 9 toxilic acid Azythromycins, 1 hydrates (in Azythromycin) 25.0g adds cysteine hydrochloride 0.8g, EDTA disodium 0.1g; Add injection and blunge and make dissolving, it is 6.5～7.0 that 2M lactic acid is regulated pH with Sodium.alpha.-hydroxypropionate, adds activated carbon 0.01% (W/V) stirring 15～45min; Filter, moisturizing is perhaps adopted twice filtration of ultra-filtration membrane of holding back relative molecular mass 1000-8000 to 250ml with 0.22 micron filtering with microporous membrane; Press the packing of 5ml/ bottle, sterilize finished product.

Embodiment 10 toxilic acid Azythromycins 1 hydrate high-capacity injection takes by weighing glucose 50g and adds in the water for injection, stirs to make dissolving fully, adds the gac of dosing amount 0.05%, heat about 10-30 minute, put cold, through the excellent filtering decarbonization of sand filtration; After dissolving fully with fresh water for injection toxilic acid Azythromycin 2 hydrates (in Azythromycin) 10.0g, mix, add hydrochloric acid L-halfcystine 1g with above-mentioned filtrating; EDTA disodium 0.2g regulates the pH value in the scope of 6.5-7.0 with 1M lactic acid and sodium lactate solution, adds the injection water to 5000ml; The gac that adds dosing amount 0.01% stirred filtering decarbonization about 10-30 minute; Perhaps adopt the ultrafiltration membrance filter of holding back relative molecular mass 1000-8000 through the smart filter of 0.22um millipore filtration again,, chemically examine through work in-process; After treating that its content, pH value and clarity are qualified, embedding is in the vial of 50ml or 100ml or 250ml, through pressure sterilizing; Finished product inspection, packing promptly gets.

Embodiment 11 fumaric acid Azythromycins, 1 hydrate tablets (the 250mg/ sheet is in Azythromycin)

Prescription: fumaric acid Azythromycin 1 hydrate 250g (in Azythromycin)

Microcrystalline Cellulose 200g

Sodium starch glycolate 20g

ASPARTAME POWDER BP/USP 2g

Vinylpyrrolidone polymer 10% is an amount of

Micropowder silica gel 1g

Magnesium Stearate 2g

Fumaric acid Azythromycin 1 hydrate, Microcrystalline Cellulose, sodium starch glycolate, ASPARTAME POWDER BP/USP are crossed 100 mesh sieves, and the Vinylpyrrolidone polymer with 10% is made softwood in right amount, crosses the 18-24 mesh sieve and granulates; Dry; After crossing the whole grain of 14-20 mesh sieve, add micropowder silica gel, Magnesium Stearate mixing, compressing tablet.

Embodiment 12 fumaric acid Azythromycins, 1 hydrate capsules (the 125mg/ grain is in Azythromycin)

Prescription: fumaric acid Azythromycin 1 hydrate 125g (in Azythromycin)

Microcrystalline Cellulose 100g

Lactose 20g

Gelling starch 10% is an amount of

Magnesium Stearate 2g

Fumaric acid Azythromycin 1 hydrate, Microcrystalline Cellulose, lactose are crossed 100 mesh sieves, and the gelling starch with 10% is made softwood in right amount, cross the 18-24 mesh sieve and granulate, drying, cross the whole grain of 14-20 mesh sieve after, add Magnesium Stearate and mix the can capsule.

The granule of embodiment 13 fumaric acid Azythromycins 5 hydrates (the 125mg/ bag is in Azythromycin)

Prescription: fumaric acid Azythromycin 1 hydrate 125g (in Azythromycin)

N.F,USP MANNITOL 100g

Lactose 20g

Sodium Cyclamate 2g

Solid food flavour 1g

Vinylpyrrolidone polymer 8% is an amount of

Fumaric acid Azythromycin 1 hydrate, N.F,USP MANNITOL, lactose, Sodium Cyclamate, food flavour are crossed 100 mesh sieves, and the Vinylpyrrolidone polymer with 8% is made softwood in right amount, crosses the 18-24 mesh sieve and granulates, and is dry below 60 ℃, cross the whole grain of 14-20 mesh sieve after, divide packing.

The suppository of embodiment 14 toxilic acid azithromycin hydrates (the 250mg/ grain is in Azythromycin)

Prescription: toxilic acid Azythromycin 2 hydrate 25g (in Azythromycin, 100 feed intake)

Macrogol 4000 200g

Glycerine 5ml

Prist 70g

Tween 80 1ml

Toxilic acid Azythromycin 2 hydrates, glycerine, Macrogol 4000, Prist, tween 80 are mixed; Heating in water bath, stir, wait to melt, be stirred in the mould of suppository that even, rapid impouring scribbled lubricant, to overflowing the bolt mould a little; Treat to scabble after cold, molding promptly gets.

The gel of embodiment 15 Azithromycin Sulfate hydrates

Prescription: Azithromycin Sulfate 1 hydrate 25g (, feeding intake) in Azythromycin

Ucar 35 10g

Trolamine 2g

Glycerine 10ml

Carbomer 934 20g

Carbomer 1342 5g

Hydrochloric acid 1M or sodium hydroxide 1M are an amount of

Water is to 1000g

To respectively carbomer 934 and carbomer 1342 be used water-dispersion; Add glycerine, Ucar 35, trolamine, mix, add Azithromycin Sulfate 1 hydrate, heating in water bath, stirring, hydrochloric acid 1M or sodium hydroxide 1M and regulate between the pH value 3-7, be stirred to even; Vacuum outgas promptly gets.

Embodiment 16 toxilic acid azithromycin hydrate eye drops

Prescription: toxilic acid Azythromycin 1 hydrate 3g (, feeding intake) in Azythromycin

Borax 0.6g

Boric acid 0.5g

Hyaluronic acid sodium 1g

Zonon D 0.1g

Sodium-chlor 8.5g

Ethyl p-hydroxybenzoate 0.3g

Hydrochloric acid (1M) is an amount of

Water is to 1000ml

To respectively toxilic acid Azythromycin 1 hydrate and Zonon D be added proper amount of water for injection, heating for dissolving, subsequent use; Borax, boric acid, sodium-chlor, hyaluronic acid sodium, ethyl p-hydroxybenzoate add proper amount of water for injection, and heating for dissolving is subsequent use; Above-mentioned two kinds of solution merging is added the injection water, and hydrochloric acid is regulated pH value in right amount between the 5-6.5, is stirred to even, sterile filtration, places container, measures the pH and the content of midbody, sealing, and sterilization, sterile filling is in the eye drop bottle of cleaning, and tight the envelope promptly gets.

Embodiment 17 toxilic acid azithromycin hydrate gel for eye use

Prescription: toxilic acid Azythromycin 1 hydrate 5g (, feeding intake) in Azythromycin

Borax 0.5g

Boric acid 0.5g

Zonon D 0.1g

Carbopol 941 5g

Ethyl p-hydroxybenzoate 0.3g

Hydrochloric acid 1M or sodium hydroxide 1M are an amount of

Water is to 1000g

To respectively Carbopol 941 be used water-dispersion, respectively toxilic acid Azythromycin 1 hydrate and Zonon D added proper amount of water for injection, heating for dissolving, subsequent use; Borax, boric acid, ethyl p-hydroxybenzoate add proper amount of water for injection, and heating for dissolving is subsequent use; Above-mentioned two kinds of solution are merged, filter, add the injection water to configuration amount, hydrochloric acid 1M or sodium hydroxide 1M regulate pH value in right amount between the 5.5-6.1, be stirred to even, place container, vacuum outgas, sterilization, can are in the eye drop bottle of cleaning, tight envelope promptly gets.

The present invention is not limited to the foregoing description.

Claims

1. the hydrate of azithromycin, it is characterized in that: the hydrate of azithromycin is C ₃₈H ₇₂N ₂O ₁₂AnH ₂O, n=1.0,2,5.0, when A is toxilic acid, n=1.0,2; When A is fumaric acid, n=1.0,2,5.0, the thermogram spectrum of the hydrate of azithromycin, promptly the weightless platform correspondence of TG-DTA or TG-DTG collection of illustrative plates has the characteristic endotherm(ic)peak.

2. the hydrate of azithromycin according to claim 1, it is characterized in that: the hydrate of azithromycin is toxilic acid Azythromycin 1 hydrate C ₃₈H ₇₂N ₂O ₁₂C ₄H ₄O ₄H ₂O.

3. the hydrate of azithromycin according to claim 1, it is characterized in that: the hydrate of Azythromycin organic acid salt is that fumaric acid Azythromycin 1 hydrate is C ₃₈H ₇₂N ₂O ₁₂C ₄H ₄O ₄H ₂O.

4. the hydrate of azithromycin according to claim 1, it is characterized in that: the hydrate of azithromycin is that fumaric acid Azythromycin 2 hydrates are C ₃₈H ₇₂N ₂O ₁₂C ₄H ₄O ₄2H ₂O.

5. the hydrate of azithromycin according to claim 1, it is characterized in that: the hydrate of azithromycin is that fumaric acid Azythromycin 5 hydrates are C ₃₈H ₇₂N ₂O ₁₂C ₄H ₄O ₄5H ₂O.

6. the hydrate of azithromycin according to claim 1, it is characterized in that: the hydrate of azithromycin is that toxilic acid Azythromycin 2 hydrates are C ₃₈H ₇₂N ₂O ₁₂C ₄H ₄O ₄2H ₂O.

7. the hydrate of azithromycin according to claim 1, it is characterized in that: its preparation method is selected from:

Method A. is a solvent with one or more of acetone, water or methyl alcohol, ethanol, Virahol in reaction vessel, adds Azythromycin, stirs between 0-55 ℃; Dissolving adds toxilic acid or fumaric acid, and perhaps solution stirs; Reaction is finished, slowly add acetone, chloroform or methyl alcohol, ethanol, Virahol, one or more of N-BUTYL ACETATE, ETHYLE ACETATE, ethyl formate, cooling; Treat that solid separates out, filter that solids is with methyl alcohol, ethanol, Virahol, acetone, ether, N-BUTYL ACETATE, ETHYLE ACETATE, ethyl formate; Or one or more rinses in the chloroform, drain dry toxilic acid or the fumaric acid azithromycin hydrate of getting;

Perhaps method B adds the aqueous solution of toxilic acid or fumaric acid in reaction vessel, adds Azythromycin; Stir between 0-55 ℃, make dissolving, reaction is finished; Slowly add one or more of acetone, chloroform, N-BUTYL ACETATE, N-BUTYL ACETATE, ETHYLE ACETATE, ethyl formate, methyl alcohol, ethanol, Virahol, cooling treats that solid separates out; Filter, solids is with methyl alcohol, absolute ethyl alcohol, Virahol, acetone, N-BUTYL ACETATE, ETHYLE ACETATE, ethyl formate, or one or more rinses in the chloroform; Drain dry toxilic acid or the fumaric acid azithromycin hydrate of getting;

Perhaps method C. drops into toxilic acid or fumaric acid and Azythromycin in the reaction flask in molar ratio, adds water, between controlled temperature 0-50 ℃; Reaction 0.5-6h, question response finishes, and it is freezing to-60～-40 ℃; Vacuum lyophilization gets toxilic acid or fumaric acid azithromycin hydrate.

8. the purposes of the hydrate of azithromycin according to claim 1 is characterized in that: be used to prepare the injection freeze-dried powder, or aseptic subpackaged powder injection or great transfusion preparation, or little water needle injection, tablet, capsule, granule, through the ointment of percutaneous drug delivery and the suppository of gel and transvaginal or rectal administration.

9. the purposes of the hydrate of azithromycin according to claim 1; It is characterized in that: be applicable to the infection of preparation, be selected from the application in the medicine of respiratory tract, urinary system infection, intestinal tract infections, liver and gall infection, skin soft-tissue infection, ocular infection treatment and prevention the human or animal due to Gram-positive or negative bacteria sensitive organism, CPN, the trachoma mycoplasma.