CN110859812A - Freeze drying method and application thereof - Google Patents
Freeze drying method and application thereof Download PDFInfo
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- CN110859812A CN110859812A CN201911242873.2A CN201911242873A CN110859812A CN 110859812 A CN110859812 A CN 110859812A CN 201911242873 A CN201911242873 A CN 201911242873A CN 110859812 A CN110859812 A CN 110859812A
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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
- 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
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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
- A61K47/02—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
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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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
- A61K9/0012—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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
The invention relates to a freeze drying method and application thereof, comprising the following steps: taking a sterile azithromycin aqueous solution, freezing, vacuumizing, drying for the first time, and performing resolution drying to obtain the azithromycin oral liquid; wherein the sterile azithromycin aqueous solution contains azithromycin, anhydrous citric acid, sodium hydroxide and water. The invention prepares qualified azithromycin for injection by controlling each link of freeze drying, can greatly reduce energy consumption and is suitable for industrial production.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a freeze-drying method and application thereof.
Background
Azithromycin is the first species of 15-membered ring macrolides, the nitrogen vinegar. The mechanism of action is the same as that of erythromycin, and it binds mainly to the 50S subunit of bacterial ribosomes, inhibiting RNA-dependent protein synthesis. The product has good antibacterial effect on Streptococcus mutans, Streptococcus pneumoniae and Bacillus influenzae, and also has antibacterial effect on Staphylococcus. Azithromycin has slightly poorer antibacterial effect on gram-positive cocci such as staphylococcus and streptococcus than erythromycin, has 48 times and 24 times stronger antibacterial effect on influenza bacillus and catamoraxella than the erythromycin, and also has antibacterial effect on a few escherichia coli, salmonella and shigella. The azithromycin has good antimicrobial effect on anaerobic bacteria such as streptococcus, mycoplasma pneumoniae, chlamydia trachomatis and the like.
Azithromycin is determined in the clinical achievement of China, thereby playing an important role in whole-body anti-infection medicines and becoming a leading variety in large-ring vinegar antibiotics at present. In the production process of the pharmaceutical preparation, azithromycin for injection is prepared into freeze-dried powder injection. The existing azithromycin for injection has the problems of low yield, large fluctuation of the content of the obtained product and the like in the vacuum freeze drying process, and does not meet the national quality standard, so that the reasonable design is carried out on the freeze drying process of the medicine, and the method has very important significance for obtaining the medicine with stable quality and safe use.
Disclosure of Invention
Aiming at the defects and shortcomings in the prior art, the invention provides a freeze-drying method (of azithromycin for injection) and application thereof.
One of the objects of the present invention is to provide a freeze-drying method, comprising the steps of: taking a sterile azithromycin aqueous solution, freezing, vacuumizing, drying for the first time, and performing resolution drying to obtain the azithromycin oral liquid; wherein the sterile azithromycin aqueous solution contains azithromycin, anhydrous citric acid, sodium hydroxide and water.
According to some preferred embodiments of the invention, the freezing comprises a first freezing, a second freezing, a third freezing and a fourth freezing.
According to some preferred embodiments of the invention, the freezing process parameters are: the first freezing temperature is 0-5 ℃, and the freezing time is 30-60 min; the second freezing temperature is-30 to-45 ℃, and the freezing time is 0min to 30 min; the third freezing temperature is-10 to-20 ℃, and the freezing time is 60 to 120 min; the fourth freezing temperature is-30 to-45 ℃, and the freezing time is 120 to 240 min. According to the invention, by adopting specific freezing process parameters, the grain size of the crystal can be increased, and the subsequent drying time can be shortened.
According to some preferred embodiments of the present invention, the primary drying includes a first primary drying and a second primary drying.
According to some preferred embodiments of the present invention, the first drying temperature is-15 ℃ to-25 ℃, and the drying time is 2h to 3 h; the temperature of the second primary drying is-10 ℃ to-20 ℃, and the drying time is 4h to 6 h.
According to some preferred embodiments of the invention, the desorption drying comprises a first desorption drying and a second desorption drying.
According to some preferred embodiments of the invention, the first desorption drying temperature is 20-30 ℃, and the drying time is 1-3 h; the second time of analysis drying temperature is 30-40 ℃, and the drying time is 3-5 h.
According to some preferred embodiments of the invention, the freezing process parameters are: the first freezing temperature is 0 ℃, and the freezing time is 30 min; the second freezing temperature is-35 ℃, and the freezing time is 15 min; the third freezing temperature is-18 ℃, and the freezing time is 120 min; the fourth freezing temperature is-45 ℃, and the freezing time is 120 min; the primary drying process parameters are as follows: the first drying temperature is-20 ℃, and the drying time is 2 hours; the second time of drying is carried out at the temperature of minus 15 ℃ for 6 hours; the parameters of the analytic drying process are as follows: the first analysis drying temperature is 20 ℃, and the drying time is 2 h; the second analysis drying temperature is 40 ℃, and the drying time is 5 h.
According to some preferred embodiments of the invention, the freezing process parameters are: the first freezing temperature is 5 ℃, and the freezing time is 45 min; the second freezing temperature is-30 ℃, and the freezing time is 0 min; the third freezing temperature is-20 ℃, and the freezing time is 60 min; the fourth freezing temperature is-35 ℃, and the freezing time is 180 min; the primary drying process parameters are as follows: the first drying temperature is-18 ℃, and the drying time is 3 hours; the temperature of the second primary drying is-10 ℃, and the drying time is 5 hours; the parameters of the analytic drying process are as follows: the first analysis drying temperature is 30 ℃, and the drying time is 3 h; the second time of analysis drying temperature is 40 ℃, and the drying time is 3 h.
According to some preferred embodiments of the invention, the freezing process parameters are: the first freezing temperature is 5 ℃, and the freezing time is 30 min; the second freezing temperature is-45 ℃, and the freezing time is 0 min; the third freezing temperature is-10 ℃, and the freezing time is 120 min; the fourth freezing temperature is-35 ℃, and the freezing time is 180 min; the primary drying process parameters are as follows: the first drying temperature is-18 ℃, and the drying time is 2 hours; the temperature of the second primary drying is-10 ℃, and the drying time is 6 hours; the parameters of the analytic drying process are as follows: the first analysis drying temperature is 30 ℃, and the drying time is 2 hours; the second analysis drying temperature is 40 ℃, and the drying time is 5 h.
According to some preferred embodiments of the invention, the freezing process parameters are: the first freezing temperature is 5 ℃, and the freezing time is 30 min; the second freezing temperature is-40 ℃, and the freezing time is 30 min; the third freezing temperature is-15 ℃, and the freezing time is 120 min; the fourth freezing temperature is-40 ℃, and the freezing time is 180 min; the primary drying process parameters are as follows: the first drying temperature is-20 ℃, and the drying time is 2 hours; the temperature of the second primary drying is-10 ℃, and the drying time is 6 hours; the parameters of the analytic drying process are as follows: the first analysis drying temperature is 20 ℃, and the drying time is 2 h; the second analysis drying temperature is 40 ℃, and the drying time is 5 h.
According to some preferred embodiments of the present invention, the sterile azithromycin aqueous solution is composed of azithromycin, anhydrous citric acid, sodium hydroxide and water, preferably water for injection, preferably, the azithromycin accounts for 40 to 50 percent by mass, the anhydrous citric acid accounts for 30 to 40 percent by mass, and the sodium hydroxide is used in an amount of: the pH value of the sterile azithromycin aqueous solution reaches 5.5-7.5, and the balance is water for injection.
According to some preferred embodiments of the present invention, the first freezing temperature is adjusted to the second freezing temperature at 1.5 ℃/min to 2.0 ℃/min, the third freezing temperature is adjusted to 0.25 ℃/min, and the fourth freezing temperature is adjusted to 0.25 ℃/min; adjusting the temperature to the first drying at 0.15-0.2 ℃/min; adjusting the temperature to the second time drying at 0.5-1.0 ℃/min; adjusting the temperature to the first analysis and drying at 0.6 ℃/min; adjusting the temperature to the second time of analysis and drying at 1.0 ℃/min.
According to some preferred embodiments of the present invention, the vacuum degree in the vacuum pumping is controlled to be 0.10 to 0.20 MPa.
The invention also provides application of the freeze-drying method in freeze-drying of azithromycin for injection, preferably in azithromycin freeze-dried powder injection.
The invention has the beneficial effects that: the prescription composition selected by the invention is consistent with the original ground product, and has advantages in consistency evaluation. The invention avoids the phenomena of low product yield, large fluctuation of the content of the obtained product and bottom atrophy of the product by reasonably designing the freeze drying process of the medicine. The qualification rate of each index of the azithromycin freeze-dried powder injection is improved, and the yield of the product is finally improved. The azithromycin powder injection for injection prepared by the method provided by the invention has high yield and stable quality, meets the national quality standard, and is suitable for industrial production of products. The freeze drying method provided by the invention can effectively improve the yield of azithromycin for injection and ensure the product quality stability and accord with the national medicine quality standard by adjusting the technological parameters of freezing, primary drying and resolution drying, and is suitable for industrial production.
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention. The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications.
In the present invention, the instruments and the like used are conventional products which are purchased from regular vendors, not indicated by manufacturers. The raw materials used in the invention can be conveniently bought in domestic product markets. In the present invention, the vacuum freeze dryer is available from Shanghai Toulong science and technology, Inc. with a model of LYO-0.5.
Example 1
The embodiment provides a method for freeze-drying azithromycin for injection, which comprises the following steps:
accurately weighing anhydrous citric acid to be dissolved in water for injection, adding azithromycin, stirring to dissolve, adjusting the pH value to 6.5 by using sodium hydroxide, and adding water for injection until the concentration of the azithromycin is 0.1 g/ml. And subpackaging the azithromycin aqueous solution into glass bottles with 5.0ml per bottle.
The azithromycin aqueous solution is frozen and dried to prepare the powder injection according to the following steps:
a) pushing a glass bottle filled with sterile azithromycin aqueous solution into a vacuum freeze dryer;
b) and (3) freezing: refrigerating the oil temperature of a front box (heat conducting oil) of the vacuum freezer to 0 ℃ for 30 min; then cooling to-35 ℃ at the speed of 1.5 ℃/min, and lasting for 15 min; then heating to-18 ℃ at the speed of 0.25 ℃/min, and lasting for 120 min; then cooling to-45 deg.C at a rate of 0.25 deg.C/min for 120 min.
c) And vacuumizing: and starting vacuumizing, and stopping vacuumizing after the vacuum degree reaches 0.20 MPa.
d) Primary drying: heating to-20 deg.C at a speed of 0.15 deg.C/min for 2 times; then the temperature is raised to-15 ℃ at the speed of 1 ℃/min, and the duration is 6 h.
e) And (3) analysis and drying: heating to 20 ℃ at the speed of 0.6 ℃/min, and keeping the temperature for 2 hours; then the temperature is raised to 40 ℃ at the speed of 1 ℃/min for 5 h.
f) And (5) plugging and discharging the container to obtain the product.
The results of the quality evaluation of azithromycin prepared by the freeze-drying method provided in this example are shown in table 1.
Example 2
The embodiment provides a method for freeze-drying azithromycin for injection, which comprises the following steps:
accurately weighing anhydrous citric acid to be dissolved in water for injection, adding azithromycin, stirring to dissolve, adjusting the pH value to 6.5 by using sodium hydroxide, and adding water for injection until the concentration of the azithromycin is 0.1 g/ml. And subpackaging the azithromycin aqueous solution into glass bottles with 5.0ml per bottle.
The azithromycin aqueous solution is frozen and dried to prepare the powder injection according to the following steps:
a) pushing a glass bottle filled with sterile azithromycin aqueous solution into a vacuum freeze dryer;
b) and (3) freezing: refrigerating the oil temperature of a front box (heat conducting oil) of the vacuum freezer to 5 ℃ for 45 min; then cooling to-30 ℃ at the speed of 1.5 ℃/min, and lasting for 0 min; then heating to-20 ℃ at the speed of 0.25 ℃/min, and keeping the time for 60 min; then the temperature is reduced to-35 ℃ at the speed of 0.25 ℃/min, and the duration is 180 min.
c) And vacuumizing: and starting vacuumizing, and when the vacuum degree reaches 0.15MPa, closing the vacuum unit and stopping vacuumizing.
d) Primary drying: heating to-18 ℃ at the speed of 0.15 ℃/min, and keeping the temperature for 3 hours; then the temperature is raised to-10 ℃ at the speed of 1 ℃/min, and the duration is 5 h.
e) And (3) analysis and drying: heating to 30 ℃ at the speed of 0.6 ℃/min, and keeping for 3 h; then the temperature is raised to 40 ℃ at the speed of 1 ℃/min for 3 h.
f) And (5) plugging and discharging the container to obtain the product.
The results of the quality evaluation of azithromycin prepared by the freeze-drying method provided in this example are shown in table 1.
Example 3
The embodiment provides a method for freeze-drying azithromycin for injection, which comprises the following steps:
accurately weighing anhydrous citric acid to be dissolved in water for injection, adding azithromycin, stirring to dissolve, adjusting the pH value to 6.5 by using sodium hydroxide, and adding water for injection until the concentration of the azithromycin is 0.1 g/ml. And subpackaging the azithromycin aqueous solution into glass bottles with 5.0ml per bottle.
The azithromycin aqueous solution is frozen and dried to prepare the powder injection according to the following steps:
a) pushing a glass bottle filled with sterile azithromycin aqueous solution into a vacuum freeze dryer;
b) and (3) freezing: refrigerating the oil temperature of a front box (heat conducting oil) of the vacuum freezer to 5 ℃ for 30 min; then cooling to-45 deg.C at a speed of 2.0 deg.C/min for 0 min; then heating to-10 ℃ at the speed of 0.25 ℃/min, and lasting for 120 min; then the temperature is reduced to-35 ℃ at the speed of 0.25 ℃/min, and the duration is 180 min.
c) And vacuumizing: and starting vacuumizing, and stopping vacuumizing after the vacuum degree reaches 0.10 MPa.
d) Primary drying: heating to-18 ℃ at the speed of 0.2 ℃/min, and keeping the temperature for 2 hours; then the temperature is raised to-10 ℃ at the speed of 0.5 ℃/min, and the duration is 6 h.
e) And (3) analysis and drying: heating to 30 ℃ at the speed of 0.6 ℃/min, and keeping the temperature for 2 hours; then the temperature is raised to 40 ℃ at the speed of 1 ℃/min for 5 h.
f) And (5) plugging and discharging the container to obtain the product.
The results of the quality evaluation of azithromycin prepared by the freeze-drying method provided in this example are shown in table 1.
Example 4
The embodiment provides a method for freeze-drying azithromycin for injection, which comprises the following steps:
accurately weighing anhydrous citric acid to be dissolved in water for injection, adding azithromycin, stirring to dissolve, adjusting the pH value to 6.5 by using sodium hydroxide, and adding water for injection until the concentration of the azithromycin is 0.1 g/ml. And subpackaging the azithromycin aqueous solution into glass bottles with 5.0ml per bottle.
The azithromycin aqueous solution is frozen and dried to prepare the powder injection according to the following steps:
a) pushing a glass bottle filled with sterile azithromycin aqueous solution into a vacuum freeze dryer;
b) and (3) freezing: refrigerating the oil temperature of a front box (heat conducting oil) of the vacuum freezer to 5 ℃ for 30 min; then cooling to-40 ℃ at the speed of 1.5 ℃/min, and lasting for 30 min; then heating to-15 ℃ at the speed of 0.25 ℃/min, and keeping the temperature for 120 min; then the temperature is reduced to-40 ℃ at the speed of 0.25 ℃/min, and the duration is 180 min.
c) And vacuumizing: and starting vacuumizing, and stopping vacuumizing after the vacuum degree reaches 0.20 MPa.
d) Primary drying: heating to-20 ℃ at the speed of 0.15 ℃/min, and keeping the temperature for 2 hours; then the temperature is raised to-10 ℃ at the speed of 1 ℃/min, and the duration is 6 h.
e) And (3) analysis and drying: heating to 20 ℃ at the speed of 0.6 ℃/min, and keeping the temperature for 2 hours; then the temperature is raised to 40 ℃ at the speed of 1 ℃/min for 5 h.
f) And (5) plugging and discharging the container to obtain the product.
The results of the quality evaluation of azithromycin prepared by the freeze-drying method provided in this example are shown in table 1.
And respectively counting the appearance of the azithromycin freeze-dried powder injection for injection prepared in the embodiments 1 to 4 and various indexes of the obtained product. The quality indexes of the azithromycin freeze-dried powder injection for injection are evaluated according to the legal quality standard (the second azithromycin injection in the 'Chinese pharmacopoeia' 2015 edition).
TABLE 1 summary of quality evaluations
According to the test results in table 1, the samples in examples 1 to 4 are all qualified samples, which indicates that the reasonable design of the freeze drying process of the medicine can avoid the phenomena of low product yield, large fluctuation of the obtained product content and bottom atrophy of the product. Thereby improving the qualification rate of each index of the azithromycin freeze-dried powder injection and finally improving the yield of the product.
In conclusion, the azithromycin powder injection for injection prepared by the method provided by the invention has high yield and stable quality, meets the national quality standard, and is suitable for industrial production of products.
Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (10)
1. A method of freeze drying, comprising the steps of: taking a sterile azithromycin aqueous solution, freezing, vacuumizing, drying for the first time, and performing resolution drying to obtain the azithromycin oral liquid; wherein the sterile azithromycin aqueous solution contains azithromycin, anhydrous citric acid, sodium hydroxide and water.
2. The freeze-drying method of claim 1, wherein the freezing includes a first freezing, a second freezing, a third freezing, and a fourth freezing; preferably, the freezing process parameters are as follows: the first freezing temperature is 0-5 ℃, and the freezing time is 30-60 min; the second freezing temperature is-30 to-45 ℃, and the freezing time is 0min to 30 min; the third freezing temperature is-10 to-20 ℃, and the freezing time is 60 to 120 min; the fourth freezing temperature is-30 to-45 ℃, and the freezing time is 120 to 240 min.
3. The freeze-drying method according to claim 1 or 2, wherein the primary drying comprises a first drying and a second drying.
4. The freeze-drying method according to claim 3, wherein the first drying temperature is-15 ℃ to-25 ℃, and the drying time is 2h to 3 h; the temperature of the second primary drying is-10 ℃ to-20 ℃, and the drying time is 4h to 6 h.
5. The freeze-drying method according to any one of claims 1 to 4, wherein the resolution drying includes a first resolution drying and a second resolution drying.
6. The freeze-drying method according to claim 5, wherein the first desorption drying temperature is 20 ℃ to 30 ℃ and the drying time is 1h to 3 h; the second time of analysis drying temperature is 30-40 ℃, and the drying time is 3-5 h.
7. The method according to claim 5 or 6, wherein the freezing process parameters are: the first freezing temperature is 0 ℃, and the freezing time is 30 min; the second freezing temperature is-35 ℃, and the freezing time is 15 min; the third freezing temperature is-18 ℃, and the freezing time is 120 min; the fourth freezing temperature is-45 ℃, and the freezing time is 120 min; the primary drying process parameters are as follows: the first drying temperature is-20 ℃, and the drying time is 2 hours; the second time of drying is carried out at the temperature of minus 15 ℃ for 6 hours; the parameters of the analytic drying process are as follows: the first analysis drying temperature is 20 ℃, and the drying time is 2 h; the second analysis drying temperature is 40 ℃, and the drying time is 5 h; or the like, or, alternatively,
the freezing process parameters are as follows: the first freezing temperature is 5 ℃, and the freezing time is 45 min; the second freezing temperature is-30 ℃, and the freezing time is 0 min; the third freezing temperature is-20 ℃, and the freezing time is 60 min; the fourth freezing temperature is-35 ℃, and the freezing time is 180 min; the primary drying process parameters are as follows: the first drying temperature is-18 ℃, and the drying time is 3 hours; the temperature of the second primary drying is-10 ℃, and the drying time is 5 hours; the parameters of the analytic drying process are as follows: the first analysis drying temperature is 30 ℃, and the drying time is 3 h; the second time of analysis and drying is carried out at the temperature of 40 ℃ for 3 h; or the like, or, alternatively,
the freezing process parameters are as follows: the first freezing temperature is 5 ℃, and the freezing time is 30 min; the second freezing temperature is-45 ℃, and the freezing time is 0 min; the third freezing temperature is-10 ℃, and the freezing time is 120 min; the fourth freezing temperature is-35 ℃, and the freezing time is 180 min; the primary drying process parameters are as follows: the first drying temperature is-18 ℃, and the drying time is 2 hours; the temperature of the second primary drying is-10 ℃, and the drying time is 6 hours; the parameters of the analytic drying process are as follows: the first analysis drying temperature is 30 ℃, and the drying time is 2 hours; the second analysis drying temperature is 40 ℃, and the drying time is 5 h; or the like, or, alternatively,
the freezing process parameters are as follows: the first freezing temperature is 5 ℃, and the freezing time is 30 min; the second freezing temperature is-40 ℃, and the freezing time is 30 min; the third freezing temperature is-15 ℃, and the freezing time is 120 min; the fourth freezing temperature is-40 ℃, and the freezing time is 180 min; the primary drying process parameters are as follows: the first drying temperature is-20 ℃, and the drying time is 2 hours; the temperature of the second primary drying is-10 ℃, and the drying time is 6 hours; the parameters of the analytic drying process are as follows: the first analysis drying temperature is 20 ℃, and the drying time is 2 h; the second analysis drying temperature is 40 ℃, and the drying time is 5 h.
8. The freeze-drying method according to any one of claims 1 to 7, wherein the first freezing temperature is adjusted to the second freezing temperature at 1.5 ℃/min to 2.0 ℃/min, the third freezing temperature is adjusted to 0.25 ℃/min, and the fourth freezing temperature is adjusted to 0.25 ℃/min; adjusting the temperature to the first drying at 0.15-0.2 ℃/min; adjusting the temperature to the second time drying at 0.5-1.0 ℃/min; adjusting the temperature to the first analysis and drying at 0.6 ℃/min; adjusting the temperature to the second time of analysis and drying at 1.0 ℃/min; and/or controlling the vacuum degree to be 0.10-0.20 MPa in the vacuum pumping.
9. The method according to any one of claims 1 to 8, wherein the sterile azithromycin aqueous solution consists of azithromycin, anhydrous citric acid, sodium hydroxide and water, preferably water for injection, preferably wherein the azithromycin is present in a ratio of 40 to 50% by mass, the anhydrous citric acid is present in a ratio of 30 to 40% by mass, and the sodium hydroxide is present in an amount of: the pH value of the sterile azithromycin aqueous solution reaches 5.5-7.5, and the balance is water for injection.
10. Use of the method of freeze-drying according to any one of claims 1-9 for freeze-drying azithromycin for injection, preferably for freeze-dried powder injection of azithromycin.
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