CN110151706A - The preparation method of azithromycin injection - Google Patents
The preparation method of azithromycin injection Download PDFInfo
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- CN110151706A CN110151706A CN201910384892.2A CN201910384892A CN110151706A CN 110151706 A CN110151706 A CN 110151706A CN 201910384892 A CN201910384892 A CN 201910384892A CN 110151706 A CN110151706 A CN 110151706A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Abstract
The present invention relates to a kind of preparation method of azithromycin injection, include the following steps: to weigh a certain amount of azithromycin drug, appropriate water for injection is added, and stirring to suspension shape is then added citric acid and stirs to solution and clarifies；It is slowly added to citric acid-sodium hydroxide mixed solution, stirring mixes solution uniformly；It is slowly added to sodium hydroxide solution and adjusts solution ph；Water for injection is added by solution constant volume；By solution through filter membrane aseptic filtration, stoste is obtained；It dispenses wait be lyophilized；Freeze-drying.The present invention is that auxiliary material is prepared for azithromycin soluble-salt using azithromycin as raw material, citric acid and sodium hydroxide, entire preparing process pH value is in neutrality, without heat release, it can significantly reduce the degradation impurity that process for preparation is generated due to high temperature and peracid, and avoid a large amount of White Flocculus and generate.
Description
Technical field
The present invention relates to compounding medicine fields, and in particular to a kind of preparation method of azithromycin injection.
Background technique
Azithromycin is the derivative of macrolide antibiotics erythromycin, to respiratory tract infection, urethral infection, skin
The infection of infection, soft tissue infection and other positions of human body is effective.Compared with erythromycin, azithromycin antimicrobial spectrum is wider,
Bioavilability is high, and long half time, administration number of times is few, and gastrointestinal irritation is smaller.
Azithromycin is first preparation of novel azalides antibiotics, mechanism of action and macrolides medicine
Object is identical as erythromycin, can penetrate into that sensitive bacterial is intracellular, and reversibly in conjunction with the 50S subunit of bacterial ribosome,
The displacement of blocking peptide, to prevent the synthesis of bacterial peptide, interference is synthesized dependent on the albumen of RNA.Meanwhile azithromycin is red
The position 9a in 14 ring structure of mycin introduces the nitrogen-atoms of a methylation, forms 15 ring azalides, and the change in structure makes
Azithromycin has the antibacterial activity of unique pharmacokinetic characteristics and wide spectrum.
Currently, azithromycin has become the surging kind in Macrocyclolactone lactone kind medicine in the market.But due to azithromycin
It is almost insoluble in water, therefore the water soluble preparation for developing the medicine has certain difficulty.Clinically there are tablet, particle at present
A variety of dosage forms such as agent, capsule and injection preparation.Wherein Injectable azithromycin freeze-dried powder is since rapid-action, bioavilability is high
The advantages that, it is deep to be welcome by clinic.The solubility of azithromycin is low, stability is poor (not acidproof, high temperature), it is difficult to be directly prepared into injection
Use preparation.Salt is generated currently, usually reacting by sour (such as citric acid, the cosolvents such as acetic acid) with azithromycin to solve its dissolution
Degree problem.Since azithromycin is unstable under acidic condition, therefore pH adjusting agent (such as hydroxide is added in subsequent formulation step
The alkali such as sodium, sodium bicarbonate) make solution finally at neutrallty condition (pH6.0-7.5) that is relatively stable and being easy to store.Match in the past
In method processed, cosolvent and pH adjusting agent are to be added at one time respectively, easily cause azithromycin intermediate in configuration process molten
The peracid of liquid and alkali is crossed, the degradable generation degradation impurity of azithromycin under acid condition.Easily go out during pH adjusting agent is added
There are a large amount of less soluble White Flocculus and generates a large amount of heat in existing partial over-alkali, and this also increases preparing process
The amount of difficulty and impurity.
Summary of the invention
The purpose of the present invention is to provide a kind of preparation methods of azithromycin injection, in the prior art to solve
Azithromycin injection prepares difficult problem.
The present invention provides a kind of preparation methods of azithromycin injection, include the following steps:
(1) weighing and sample: weighing a certain amount of azithromycin drug, and appropriate water for injection, stirring to suspension is added
Shape is then added citric acid and stirs to solution and clarifies；
(2) it is slowly added to citric acid-sodium hydroxide mixed solution, stirring mixes solution uniformly；
(3) it pH value accurate adjustment: is slowly added to sodium hydroxide solution and adjusts solution ph；
(4) water for injection constant volume: is added by solution constant volume；
(5) degerming: by solution by membrane filtration and degerming, stoste is obtained；
(6) dispense: precision measures stoste, and the half lid rubber plug, wait be lyophilized into borosilicate control cillin bottle is added；
(7) it is lyophilized:
Pre-freeze: dropping to -45 DEG C of maintenance 170min for temperature, and equipment is then adjusted to keeping warm mode and keeps 100min；
Low-temperature distillation: rising to -7 DEG C of maintenance 180min for temperature, temperature is risen to -5 DEG C of maintenance 180min, by temperature
- 3 DEG C of maintenance 170min are risen to, temperature is risen into 0 DEG C of maintenance 170min, temperature is risen into 10 DEG C of maintenance 60min, it will be warm
Degree rises to 20 DEG C of maintenance 60min；
Re-dry: temperature is risen into 45 DEG C of maintenance 360min, obtains azithromycin injection.Further, the step
Suddenly in (5), the aperture of filter membrane is 0.22 μm.
Further, during the low-temperature distillation, vacuum degree 180mtor.
Further, in step (1)-(6), solution temperature is controlled at 30 DEG C or less.
Further, the molar ratio of citric acid and azithromycin is 1:1 in the step (1).
Further, the volume of water for injection is 40% of overall solution volume after constant volume in the step (1).
Further, the concentration of sodium hydroxide solution is 20% in the step (2), and volume is overall solution volume after constant volume
17%.
Further, the concentration of sodium hydroxide solution is 1% in the step (3).
Beneficial effect using aforementioned present invention technical solution is:
The present invention is that auxiliary material is prepared for azithromycin soluble-salt using azithromycin as raw material, citric acid and sodium hydroxide,
Citric acid-sodium hydroxide mixed solution that the present invention will be added in azithromycin-citric acid soln of step (1) and step (2)
PH value control within the scope of 5.0-7.0, entire preparing process pH value is in neutrality, without heat release, can significantly reduce process for preparation
It due to the degradation impurity that high temperature and peracid generate, and avoids a large amount of White Flocculus and generates, compared with being simply mixed, prepare work
The risk of skill has and reduces by a relatively large margin, and product quality is more stable, and impurity content significantly reduces.
Specific embodiment
It in order to make the object, technical scheme and advantages of the embodiment of the invention clearer, below will be in the embodiment of the present invention
Technical solution be clearly and completely described, it is clear that described embodiments are some of the embodiments of the present invention, rather than
Whole embodiments.
Embodiment 1
A kind of preparation method of azithromycin injection, includes the following steps:
(1) azithromycin drug 50g is weighed, is placed in stainless steel cup, the water for injection 170ml of room temperature is added, is stirred
To suspension shape, citric acid 15g is then added and stirs to solution and clarifies；
(2) citric acid 25g is weighed, being slowly poured into concentration is that citric acid-hydroxide is made in 20% sodium hydroxide solution 90ml
Citric acid-sodium hydroxide mixed solution is slowly added in step (1) acquired solution by sodium mixed solution, and stirring keeps solution uniform
Mixing,；
(3) it is slowly added to the sodium hydroxide solution that concentration is 1% and adjusts solution ph to 6.7 ± 0.2；
(4) solution of step (3) is transferred in 500ml volumetric flask, and rinse stainless steel cup, rinse liquid is transferred to appearance
In measuring bottle, and with the water for injection constant volume of room temperature；
(5) membrane filtration by solution by 0.22 μm and degerming, obtain stoste；
(6) accurate to measure stoste 5ml (specification: 0.5g) and 2.5ml (specification: 0.25g), and be added to borosilicate control XiLin
In bottle, half lid rubber plug, wait be lyophilized；
(7) it is lyophilized:
Pre-freeze: dropping to -45 DEG C of maintenance 170min for temperature, and equipment is then adjusted to keeping warm mode and keeps 100min；
Low-temperature distillation: rising to -7 DEG C of maintenance 180min for temperature, temperature is risen to -5 DEG C of maintenance 180min, by temperature
- 3 DEG C of maintenance 170min are risen to, temperature is risen into 0 DEG C of maintenance 170min, temperature is risen into 10 DEG C of maintenance 60min, it will be warm
Degree rises to 20 DEG C of maintenance 60min；
Re-dry: temperature is risen into 45 DEG C of maintenance 360min, obtains azithromycin injection.
Embodiment 2
A kind of preparation method of azithromycin injection, includes the following steps:
(1) azithromycin drug 50g is weighed, is placed in stainless steel cup, the water for injection 170ml of room temperature is added, is stirred
To suspension shape, citric acid 40g is then added and stirs to solution and clarifies；
(2) 20% sodium hydroxide solution 90ml is slowly added in step (1) acquired solution, it is stirring while adding, make solution
Uniformly mixing,；
(3) it is slowly added to the sodium hydroxide solution that concentration is 2% and adjusts solution ph to 6.6；
(4) solution of step (3) is transferred in 500ml volumetric flask, and rinse stainless steel cup, rinse liquid is transferred to appearance
In measuring bottle, and with the water for injection constant volume of room temperature；
(5) membrane filtration that solution is passed through to 0.22 μm, obtains stoste；
(6) accurate to measure stoste 5ml (specification: 0.5g) and 2.5ml (specification: 0.25g), and be added to middle borosilicate control west
In woods bottle, half lid rubber plug, wait be lyophilized；
(7) it is lyophilized:
Pre-freeze: dropping to -45 DEG C of maintenance 170min for temperature, and equipment is then adjusted to keeping warm mode and keeps 100min；
Low-temperature distillation: rising to -7 DEG C of maintenance 180min for temperature, temperature is risen to -5 DEG C of maintenance 180min, by temperature
- 3 DEG C of maintenance 170min are risen to, temperature is risen into 0 DEG C of maintenance 170min, temperature is risen into 10 DEG C of maintenance 60min, it will be warm
Degree rises to 20 DEG C of maintenance 60min；
Re-dry: temperature is risen into 45 DEG C of maintenance 360min, obtains azithromycin injection.
Wherein, in step (1)-(6), solution temperature is controlled at 30 DEG C or less.
The impurity content of azithromycin prepared by embodiment 1-2 is as follows:
| Classification | Embodiment 1 | Embodiment 2 |
| Impurity J (%) | It is not detected | 0.6 |
| Dopant species | 6 | 9 |
| Total impurities (%) | 0.4 | 1.5 |
It can be seen that impurity content is considerably less than embodiment 2 in azithromycin prepared by embodiment 1, and it is not detected miscellaneous
Matter J, impurity J are the degradation impurity being also easy to produce in peracid and hot environment in azithromycin preparation process；The method of the present invention
Product impurity content is substantially reduced, and substantially reduces the addition time of sodium hydroxide, improves working efficiency.
To sum up, it is solvable using azithromycin as raw material, citric acid and sodium hydroxide to be that auxiliary material is prepared for azithromycin by the present invention
Property salt, the present invention mixes the citric acid-sodium hydroxide being added in azithromycin-citric acid soln of step (1) and step (2)
The pH value of solution controls within the scope of 5.0-7.0, and entire preparing process pH value is in neutrality, without heat release, can significantly reduce preparation
The degradation impurity that process is generated due to high temperature and peracid, and avoid a large amount of White Flocculus and generate, compared with being simply mixed, match
The risk of technique processed has and reduces by a relatively large margin, and product quality is more stable, and impurity content significantly reduces.
Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention., rather than its limitations；To the greatest extent
Pipe present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that: its according to
So be possible to modify the technical solutions described in the foregoing embodiments, or to some or all of the technical features into
Row equivalent replacement；And these are modified or replaceed, various embodiments of the present invention technology that it does not separate the essence of the corresponding technical solution
The range of scheme.
Claims (8)
1. a kind of preparation method of azithromycin injection, which comprises the steps of:
(1) weighing and sample: weighing a certain amount of azithromycin drug, and appropriate water for injection is added, and stirs to suspension shape, with
Citric acid is added afterwards and stirs to solution and clarifies；
(2) it is slowly added to citric acid-sodium hydroxide mixed solution, stirring mixes solution uniformly；
(3) it pH value accurate adjustment: is slowly added to sodium hydroxide solution and adjusts solution ph；
(4) water for injection constant volume: is added by solution constant volume；
(5) it filters: solution being passed through into membrane filtration, obtains stoste；
(6) dispense: precision measures stoste, and the half lid rubber plug, wait be lyophilized into middle borosilicate control cillin bottle is added；
(7) it is lyophilized:
Pre-freeze: dropping to -45 DEG C of maintenance 170min for temperature, and equipment is then adjusted to keeping warm mode and keeps 100min；
Low-temperature distillation: rising to -7 DEG C of maintenance 180min for temperature, and temperature is risen to -5 DEG C of maintenance 180min, temperature is risen
To -3 DEG C of maintenance 170min, temperature is risen into 0 DEG C of maintenance 170min, temperature is risen into 10 DEG C of maintenance 60min, it will be in temperature
Rise to 20 DEG C of maintenance 60min；
Re-dry: temperature is risen into 45 DEG C of maintenance 360min, obtains azithromycin injection.
2. the preparation method of azithromycin injection according to claim 1, which is characterized in that in the step (5), filter
The aperture of film is 0.22 μm.
3. the preparation method of azithromycin injection according to claim 1, which is characterized in that the low-temperature distillation process
In, vacuum degree 180mtor.
4. the preparation method of azithromycin injection according to claim 1, which is characterized in that step (1)-(6)
In, solution temperature is controlled at 30 DEG C or less.
5. the preparation method of azithromycin injection according to claim 1, which is characterized in that Chinese holly in the step (1)
The molar ratio of rafter acid and azithromycin is 1:1.
6. the preparation method of azithromycin injection according to claim 1, which is characterized in that note in the step (1)
Penetrate 40% of overall solution volume after being constant volume with the volume of water.
7. the preparation method of azithromycin injection according to claim 1, which is characterized in that hydrogen in the step (2)
The concentration of sodium hydroxide solution is 20%, and volume is 17% of overall solution volume after constant volume.
8. the preparation method of azithromycin injection according to claim 1, which is characterized in that hydrogen in the step (3)
The concentration of sodium hydroxide solution is 1%.
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| CN201910384892.2A CN110151706A (en) | 2019-05-09 | 2019-05-09 | The preparation method of azithromycin injection |
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| CN201910384892.2A CN110151706A (en) | 2019-05-09 | 2019-05-09 | The preparation method of azithromycin injection |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111544399A (en) * | 2020-06-24 | 2020-08-18 | 福州华为医药技术开发有限公司 | Preparation method of azithromycin for injection |
| CN111803455A (en) * | 2020-08-19 | 2020-10-23 | 湖北潜龙药业有限公司 | Preparation method of azithromycin freeze-dried preparation for injection |
| CN112618496A (en) * | 2020-12-31 | 2021-04-09 | 海南葫芦娃药业集团股份有限公司 | Preparation method of azithromycin freeze-dried powder injection for injection |
| CN112870171A (en) * | 2020-12-31 | 2021-06-01 | 海南葫芦娃药业集团股份有限公司 | Freeze-drying method of azithromycin for injection |
| CN113827573A (en) * | 2020-06-24 | 2021-12-24 | 北京济美堂医药研究有限公司 | Preparation method of azithromycin for injection |
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Cited By (5)
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| CN112870171A (en) * | 2020-12-31 | 2021-06-01 | 海南葫芦娃药业集团股份有限公司 | Freeze-drying method of azithromycin for injection |
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Application publication date: 20190823 |