CN106188177A - The preparation method of a kind of azithromycin compound and pharmaceutical preparation thereof - Google Patents

The preparation method of a kind of azithromycin compound and pharmaceutical preparation thereof Download PDF

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Publication number
CN106188177A
CN106188177A CN201610552540.XA CN201610552540A CN106188177A CN 106188177 A CN106188177 A CN 106188177A CN 201610552540 A CN201610552540 A CN 201610552540A CN 106188177 A CN106188177 A CN 106188177A
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China
Prior art keywords
azithromycin
preparation
compound
hour
water
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Pending
Application number
CN201610552540.XA
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Chinese (zh)
Inventor
吕旭幸
王丽云
叶江
冯超敏
周亚健
戴兴祥
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Zhejiang Yatai Pharmaceutical Co Ltd
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Zhejiang Yatai Pharmaceutical Co Ltd
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Priority to CN201610552540.XA priority Critical patent/CN106188177A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Dermatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention belongs to medical compounds field, relate to a kind of azithromycin chemical entities, a kind of azithromycin crystalline forms, preparation method and pharmaceutical preparation thereof.Azithromycin compound is crystal, uses X diffraction powder diffraction, its collection of illustrative plates the angle of diffraction 2 θ be 4.021 °, 6.095 °, 6.553 °, 6.719 °, have stronger characteristic peak at 12.02 °.Azithromycin chemical entities of the present invention still dissolves in alkalescence system when preparing lyophilized injectable powder, and the injection azithromycin product stability of preparation is good, has related substance to increase few, and alkalescence injection is little to vascular stimulation in use.

Description

The preparation method of a kind of azithromycin compound and pharmaceutical preparation thereof
Technical field
The invention belongs to the technical field of medical compounds, be specifically related to the preparation method of a kind of azithromycin compound And pharmaceutical preparation.
Background technology
Azithromycin (9-deoxidation-9a-azepine-9a-methyl-9a-Erythromycin A), its structural formula is:
Molecular formula: C38H72N2O12
Molecular weight: 748.0
Azithromycin, as second filial generation erythromycin product, is first semisynthetic fifteen-membered ring Macrolide antibiosis Element, compared with erythromycin, azithromycin remains the advantage of erythromycin, and antimicrobial spectrum expands further.And have and partly decline The advantages such as phase length, administration number of times are few, the course for the treatment of is shorter, adverse reaction rate is low.It is pushed away by U.S. FDA infection Advisory Board Recommend the medicine for infecting for the respiratory tract caused by sensitive bacterial, genitourinary system, skin and soft tissue etc., spreading through sex intercourse Today that disease incidence is the highest, also imply that more wide market prospect.
Current azithromycin is mainly crystallize in the mixed solution of acetone and water and prepares, and causes using general Archie Mycin needs to add acid (generally citric acid) hydrotropy of more amount when preparing lyophilized injectable powder and dissolving, and is finally made into faintly acid System, and azithromycin is in acid system, easily degrades, and makes the injection azithromycin quality stability prepared poor, the later stage has Related substance is big, bigger to vascular stimulation time in injected into blood vessel, it is impossible to meet the pharmaceuticals industry requirement to injection azithromycin. Therefore, find a kind of suitably azithromycin chemical entities still can dissolve in alkalescence system, prepare lyophilized injectable powder and show Obtain particularly important.
Summary of the invention
For solving the above-mentioned technical problem of prior art, it is an object of the invention to provide a kind of azithromycin compound real The body i.e. preparation method of azithromycin crystalline forms and pharmaceutical preparation, azithromycin chemical entities of the present invention is preparing lyophilized injectable powder Time alkalescence system in still solubilized, the injection azithromycin product stability of preparation is good, has related substance to increase few, and alkalescence is noted Penetrate agent little to vascular stimulation in use.
For reaching above-mentioned purpose, the present invention is achieved by the following technical solutions:
A kind of azithromycin compound, has a following structural formula:
Described azithromycin compound is crystal, uses X-diffraction powder diffraction, described azithromycin compound Collection of illustrative plates be to have stronger characteristic peak at 4.021 °, 6.095 °, 6.553 °, 6.719 ° or 12.02 ° at the angle of diffraction 2 θ.
The preparation method of a kind of azithromycin compound, comprises the steps: to add azithromycin crude product and good solvent Reaction bulb, stirs intensification uniform temperature, after being completely dissolved, stops heating, purified water instills reactant liquor, after dropping, in Stir certain time under uniform temperature, filter, wash by purified water, be filtered dry, be dried to obtain azithromycin crystal.
Described good solvent is isopropanol or normal propyl alcohol.
Described crude product weight: good solvent volume is 1:2-1:10.
Described good solvent volume: purified water volume is 1:1-1:8.
Described rate of addition increases with azithromycin crude product inventory equal proportion.
Employing is dripped growing the grain 10-60 minute after crystallize, continues dropping water, and continuing rate of addition is 30-100ml/ hour.
A kind of pharmaceutical preparation, described pharmaceutical preparation includes active constituents of medicine and pharmaceutic adjuvant, and described pharmaceutically active becomes Be divided into the azithromycin compound described in claim 1, described excipient substance be on pharmaceutics acceptable diluent and Excipient.
Described pharmaceutical preparation is lyophilized injectable powder, described lyophilized injectable powder by weight, including following component:
Described pharmaceutical preparation prepares as follows:
A, measuring citric acid by prescription, appropriate water for injection dissolves standby；Sodium hydroxide, appropriate injection is measured by prescription Water dissolution is standby；
B, the water for injection taking certain recipe quantity are placed in aseptic material-compound tank, then take azithromycin and be configured to azithromycin and mix Suspension is standby, is added to Azithromycin mix suspension liquid by citric acid soln, is stirred to dissolve, adds sodium hydroxide solution, adjusts Joint pH value is to 7～8, and completion water for injection；
C, addition medicinal carbon, stirring and adsorbing certain time, through filter element filtering, then through barrel type filtering；
Putting into freeze drying box after d, fill, freeze drying box first keeps 0.5-1 hour at-12 DEG C to-10 DEG C, then at-31 DEG C to 30 DEG C keep 0.5-1 hour, then-40 DEG C to-35 DEG C holdings 1-1.5 hour；Product gradually heats up, and keeps 7-9 at 5 DEG C-6 DEG C Hour, keep 8-9 hour at 12 DEG C-15 DEG C, keep 5-6 hour at 45 DEG C-50 DEG C.
Beneficial effects of the present invention is as follows:
The azithromycin polymorph of the present invention still dissolves in alkalescence system when preparing lyophilized injectable powder, the note of preparation Penetrating azithromycin product stability good, have related substance to increase few, alkalescence injection is little to vascular stimulation in use, can be fine Solution currently available technology in deficiency and problem, there is significant beneficial effect.
Accompanying drawing explanation
Fig. 1 is the x-ray diffraction pattern of the azithromycin polymorph in the present invention.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is further illustrated, but protection scope of the present invention is not limited to This.
Embodiment 1
Azithromycin crude product 50g and isopropanol 310ml is added reaction bulb, stirs intensification 45 ± 2 DEG C, after being completely dissolved, Stop heating, purified water 620ml is instilled reactant liquor, rate of addition 70ml/ hour, after dropping, stirs at 20 ± 2 DEG C 3.5 hours, filter, wash by purified water, be filtered dry, be dried to obtain azithromycin crystal, obtain dry product 43.6g, yield 87.2%.
Embodiment 2
Azithromycin crude product 50g and normal propyl alcohol 180ml is added reaction bulb, stirs intensification 45 ± 2 DEG C, after being completely dissolved, Stop heating, purified water 360ml is instilled reactant liquor, rate of addition 70ml/ hour, after dropping, stirs at 20 ± 2 DEG C 3.5 hours, filter, wash by purified water, be filtered dry, be dried to obtain azithromycin crystal, obtain dry product 46.2g, refined yield 92.4%.
Embodiment 3
By 0.5g specification, in terms of 1000:
Step a: measure citric acid by prescription, appropriate water for injection dissolves standby；Measure sodium hydroxide by prescription, note in right amount Penetrate with water dissolution standby；
Step b: the water for injection taking about 2/3 recipe quantity is placed in aseptic material-compound tank, then take azithromycin and be configured to Archie Mycin suspension is standby.Citric acid soln is added to Azithromycin mix suspension liquid, is stirred to dissolve.Add sodium hydroxide molten Liquid, regulation pH value is to 7.25～7.75, and completion water for injection；
Step c: adding medicinal carbon (unit: W/V, 0.06%), stirring and adsorbing 20 minutes, through 0.45um filter element mistake Filter, then through 0.22 μm barrel type filtering；
Step d: put into freeze drying box after fill, freeze drying box first keeps 1 hour at-10 DEG C, then-30 DEG C of holdings 1 hour, so After-35 DEG C keep 1.5 hours.Product gradually heats up, and keeps 9 hours at 5 DEG C, keeps 8 hours at 15 DEG C, keeps at 45 DEG C 6 hours.
In order to verify injection azithromycin product stability prepared by the azithromycin chemical entities of the present invention further Good, there is related substance to increase few, the present invention has carried out long-time stability experiment to it.
Put temperature 25 DEG C ± 2 DEG C, in the climatic chamber of relative humidity 60% ± 10% place 36 months, in place 3,6, 9, respectively taking a sample 12,18,24,36 the end of month, investigate indices, current long-term stable experiment has completed 18 Month, the results are shown in Table 1.
Table 1: long term test data
Shown by the long-term test results of upper table 1: the azithromycin of the present invention 25 DEG C, place 18 under the conditions of RH60% Month, there is related substance to be increased slightly, content slightly reduces, and remaining indices is showed no significant change, and this test is still being carried out In.
In sum, azithromycin chemical entities of the present invention is the most molten in alkalescence system when preparing lyophilized injectable powder Solving, the injection azithromycin product stability of preparation is good, has related substance to increase few, and blood vessel is stung by alkalescence injection in use Swash little.
Above-described embodiment is only used for illustrating the inventive concept of the present invention, rather than the restriction to rights protection of the present invention, All changes utilizing this design that the present invention carries out unsubstantiality, all should fall into protection scope of the present invention.

Claims (10)

1. an azithromycin compound, has a following structural formula:
It is characterized in that: described azithromycin compound is crystal, use X-diffraction powder diffraction, described azithromycin The collection of illustrative plates of compound is to have stronger characteristic peak at 4.021 °, 6.095 °, 6.553 °, 6.719 ° or 12.02 ° at the angle of diffraction 2 θ.
2. the preparation method of an azithromycin compound, it is characterised in that comprise the steps: azithromycin crude product and good Solvent adds reaction bulb, stirs intensification uniform temperature, after being completely dissolved, stops heating, purified water is instilled reactant liquor, drips Bi Hou, stirs certain time under uniform temperature, filters, and washs by purified water, is filtered dry, and is dried to obtain azithromycin crystal.
3. the preparation method of azithromycin compound as claimed in claim 2, it is characterised in that: described good solvent is isopropanol Or normal propyl alcohol.
4. the preparation method of azithromycin compound as claimed in claim 2, it is characterised in that: described crude product weight: good molten Agent volume is 1:2-1:10.
5. the preparation method of azithromycin compound as claimed in claim 2, it is characterised in that: described good solvent volume: pure Change water volume is 1:1-1:8.
6. the preparation method of azithromycin compound as claimed in claim 2, it is characterised in that: described rate of addition is with Zitromax Element crude product inventory equal proportion increases.
7. the preparation method of azithromycin compound as claimed in claim 2, it is characterised in that: use growing the grain after the crystallize that drips 10-60 minute, continuing dropping water, continuing rate of addition is 30-100ml/ hour.
8. a pharmaceutical preparation, it is characterised in that: described pharmaceutical preparation includes active constituents of medicine and pharmaceutic adjuvant, described medicine Thing active component is the azithromycin compound described in claim 1, and described excipient substance is acceptable on pharmaceutics Diluent and excipient.
9. the pharmaceutical preparation as described in right 8, it is characterised in that: described pharmaceutical preparation is lyophilized injectable powder, described lyophilizing Injectable powder by weight, including following component:
10. pharmaceutical preparation as claimed in claim 8 or 9, it is characterised in that described pharmaceutical preparation prepares as follows:
A, measuring citric acid by prescription, appropriate water for injection dissolves standby；Measuring sodium hydroxide by prescription, appropriate injection is water-soluble Solve standby；
B, the water for injection taking certain recipe quantity are placed in aseptic material-compound tank, then take azithromycin and be configured to Azithromycin mix suspension liquid Standby, citric acid soln is added to Azithromycin mix suspension liquid, is stirred to dissolve, add sodium hydroxide solution, regulate PH Value is to 7～8, and completion water for injection；
C, addition medicinal carbon, stirring and adsorbing certain time, through filter element filtering, then through barrel type filtering；
Putting into freeze drying box after d, fill, freeze drying box first keeps 0.5-1 hour at-12 DEG C to-10 DEG C, then-31 DEG C to 30 DEG C of guarantors Hold 0.5-1 hour, then keep 1-1.5 hour at-40 DEG C to-35 DEG C；Product gradually heats up, and keeps 7-9 little at 5 DEG C-6 DEG C Time, keep 8-9 hour at 12 DEG C-15 DEG C, keep 5-6 hour at 45 DEG C-50 DEG C.
CN201610552540.XA 2016-07-12 2016-07-12 The preparation method of a kind of azithromycin compound and pharmaceutical preparation thereof Pending CN106188177A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110859812A (en) * 2019-12-06 2020-03-06 北京悦康科创医药科技股份有限公司 Freeze drying method and application thereof

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1234833A2 (en) * 1999-11-26 2002-08-28 Astur-Pharma, S.A. Preparation of crystalline azithromycin dihydrate.
US20060063725A1 (en) * 2004-08-30 2006-03-23 Daniella Gutman Process of preparing a crystalline azithromycin monohydrate
CN1780847A (en) * 2001-05-22 2006-05-31 辉瑞产品公司 Crystal forms of azithromycin
CN101418026A (en) * 2008-10-09 2009-04-29 南京工业大学 Paeoniflorin crystallization process with controllable crystal form and granularity
CN101940555A (en) * 2009-07-10 2011-01-12 华北制药集团制剂有限公司 Method for preparing azithromycin freeze-dried powder injection for injection
CN102552918A (en) * 2012-02-02 2012-07-11 山东齐都药业有限公司 Stabilizer of lyophilized powder injection for azithromycin injection
CN104892697A (en) * 2015-05-05 2015-09-09 黄石世星药业有限责任公司 Azithromycin production technology
CN104910222A (en) * 2015-06-29 2015-09-16 石药集团欧意药业有限公司 Azithromycin new crystal-form compound and preparation method thereof
CN105001283A (en) * 2015-07-09 2015-10-28 北京红太阳药业有限公司 Azithromycin refining method

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1234833A2 (en) * 1999-11-26 2002-08-28 Astur-Pharma, S.A. Preparation of crystalline azithromycin dihydrate.
CN1780847A (en) * 2001-05-22 2006-05-31 辉瑞产品公司 Crystal forms of azithromycin
US20060063725A1 (en) * 2004-08-30 2006-03-23 Daniella Gutman Process of preparing a crystalline azithromycin monohydrate
CN101418026A (en) * 2008-10-09 2009-04-29 南京工业大学 Paeoniflorin crystallization process with controllable crystal form and granularity
CN101940555A (en) * 2009-07-10 2011-01-12 华北制药集团制剂有限公司 Method for preparing azithromycin freeze-dried powder injection for injection
CN102552918A (en) * 2012-02-02 2012-07-11 山东齐都药业有限公司 Stabilizer of lyophilized powder injection for azithromycin injection
CN104892697A (en) * 2015-05-05 2015-09-09 黄石世星药业有限责任公司 Azithromycin production technology
CN104910222A (en) * 2015-06-29 2015-09-16 石药集团欧意药业有限公司 Azithromycin new crystal-form compound and preparation method thereof
CN105001283A (en) * 2015-07-09 2015-10-28 北京红太阳药业有限公司 Azithromycin refining method

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
金勇,等，: "阿奇霉素合成工艺改进", 《精细化工中间体》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110859812A (en) * 2019-12-06 2020-03-06 北京悦康科创医药科技股份有限公司 Freeze drying method and application thereof

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Application publication date: 20161207