CN112870171B - Freeze-drying method of azithromycin for injection - Google Patents
Freeze-drying method of azithromycin for injection Download PDFInfo
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- CN112870171B CN112870171B CN202011633287.3A CN202011633287A CN112870171B CN 112870171 B CN112870171 B CN 112870171B CN 202011633287 A CN202011633287 A CN 202011633287A CN 112870171 B CN112870171 B CN 112870171B
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- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 title claims abstract description 76
- 229960004099 azithromycin Drugs 0.000 title claims abstract description 76
- 238000004108 freeze drying Methods 0.000 title claims abstract description 62
- 238000002347 injection Methods 0.000 title claims abstract description 59
- 239000007924 injection Substances 0.000 title claims abstract description 59
- 238000000034 method Methods 0.000 title claims abstract description 36
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 102
- 239000000243 solution Substances 0.000 claims abstract description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 42
- 238000010438 heat treatment Methods 0.000 claims abstract description 29
- 238000001035 drying Methods 0.000 claims abstract description 26
- 239000000843 powder Substances 0.000 claims abstract description 24
- 238000007710 freezing Methods 0.000 claims abstract description 16
- IGHGOYDCVRUTSU-UHFFFAOYSA-M sodium;2-hydroxypropane-1,2,3-tricarboxylic acid;hydroxide Chemical compound [OH-].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O IGHGOYDCVRUTSU-UHFFFAOYSA-M 0.000 claims abstract description 13
- 239000007788 liquid Substances 0.000 claims abstract description 11
- 239000011259 mixed solution Substances 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 10
- 238000005507 spraying Methods 0.000 claims abstract description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- 229960004543 anhydrous citric acid Drugs 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 20
- 229960004106 citric acid Drugs 0.000 claims description 19
- 230000008014 freezing Effects 0.000 claims description 15
- 238000000859 sublimation Methods 0.000 claims description 15
- 230000008022 sublimation Effects 0.000 claims description 15
- 238000011049 filling Methods 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 9
- 230000001954 sterilising effect Effects 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 6
- 239000012528 membrane Substances 0.000 claims description 5
- 230000001502 supplementing effect Effects 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 4
- 238000004659 sterilization and disinfection Methods 0.000 claims description 4
- 238000003825 pressing Methods 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 11
- 239000002245 particle Substances 0.000 abstract description 6
- 239000008215 water for injection Substances 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 10
- 230000009471 action Effects 0.000 description 5
- 239000002274 desiccant Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000002349 favourable effect Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000005056 compaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000012792 lyophilization process Methods 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000002229 urogenital system Anatomy 0.000 description 1
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- 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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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F26—DRYING
- F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
- F26B5/00—Drying solid materials or objects by processes not involving the application of heat
- F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
- F26B5/06—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract
The invention provides a freeze-drying method of azithromycin for injection, (1) azithromycin is sequentially mixed with citric acid solution and citric acid-sodium hydroxide mixed solution, stirred, clarified and adjusted in pH value to obtain azithromycin solution before freeze-drying; (2) Pre-freezing after low-temperature water spraying outside the filled liquid medicine; (3) Heating the vacuum degree of 18-22 Pa from minus 45 ℃ to minus 10 ℃ within 110-130 min, keeping the vacuum degree, raising the vacuum degree to 28-30 Pa, keeping the vacuum degree, restoring the vacuum degree to 20-25 Pa, and continuing to keep the vacuum degree; then gradually raising the temperature from-10 ℃ to 0 ℃ within 50-70 min, and keeping the temperature; (4) Resolving and drying to obtain the azithromycin freeze-dried powder injection for injection. The invention combines the high-stability azithromycin solution before freeze-drying with a new freeze-drying process curve, and has the characteristics of high freeze-drying powder forming speed, more uniform powder particles, thorough drying and low rejection rate.
Description
Technical Field
The invention relates to the technical field of medical processing technology, in particular to a freeze-drying method of azithromycin for injection.
Background
Azithromycin (Azithromycin) is a second generation macrolide semisynthetic broad-spectrum antibiotic, is a derivative of cycloazaerythromycin, has the characteristics of wide antibacterial spectrum, stability to acid, wide in-vivo distribution, short treatment course, low toxicity, good tolerance and the like, can be applied to various crowds, particularly children and the old, is applied to treatment of diseases such as infection of upper and lower respiratory tracts, skin soft tissues and urogenital systems caused by sensitive bacteria, and has obvious curative effect. The azithromycin freeze-dried preparation for injection is well received by clinic because of the advantages of quick effect and high bioavailability.
However, in the existing process of drying the azithromycin intermediate solution by adopting a freeze-drying process, on one hand, the process is limited by low solubility and poor stability of the azithromycin; on the other hand, when the freeze drying is carried out under the control of the freezing conditions at different stages, bottle breaking, incomplete drying, increase of rejection rate and low freeze-dried powder forming speed are easy to occur, so that the obtained azithromycin freeze-dried preparation has the defects of large water content difference, poor uniformity of formed powder, reduced re-solubility, poor stability and the like. Therefore, the freeze-drying method of the injection azithromycin with the advantages of rapid dry powder forming, uniform powder particles and low rejection rate is provided, so that the injection azithromycin freeze-drying agent with stable quality, good redissolution property and low loss rate is efficiently prepared, and better clinical popularization of the injection azithromycin freeze-drying agent is favorably realized.
Disclosure of Invention
In view of the above, the invention provides a freeze-drying method of azithromycin for injection.
The technical scheme of the invention is realized as follows:
the invention provides a freeze-drying method of azithromycin for injection, which comprises the following steps:
step 1: preparing an azithromycin solution before freeze-drying: sequentially mixing azithromycin with a citric acid solution with the prescription amount of 24.5-25.0% and a citric acid-sodium hydroxide mixed solution with the prescription amount of 73.0-73.5%, stirring until the mixture is clear, adjusting the pH to 6.60 +/-0.10 by using the rest citric acid solution with the prescription amount as a pH regulator, and supplementing water for injection to obtain a solution before azithromycin freeze-drying;
step 2: pre-freezing: carrying out sterilization filtration, filling and half-tamponade on the solution before azithromycin freeze-drying, adopting low-temperature water spraying at 1-5 ℃ for 20-30 min outside the filled liquid medicine, taking out, and pre-freezing at-40 to-50 ℃ for 60-120 min;
and step 3: sublimation drying: under the vacuum degree of 18-22 Pa, heating from minus 45 ℃ to minus 10 ℃ within 110-130 min, keeping the temperature for 700-740 min, increasing the vacuum degree to 28-30 Pa, keeping the temperature for 100-140 min, recovering the vacuum degree to 20-25 Pa, and keeping the temperature for 120-150 min; then gradually raising the temperature from-10 ℃ to 0 ℃ within 50-70 min, and keeping the temperature for 50-70 min;
and 4, step 4: and (3) resolving and drying: heating from 0 ℃ to 15 ℃ within 50-70 min under the vacuum degree of 4-6 Pa, keeping the temperature for 50-70 min, heating from 15 ℃ to 40 ℃ within 35-45 min, and keeping the temperature for 460-500 min to obtain the azithromycin freeze-dried powder injection for injection.
Further explaining, in the step 2, the filled liquid medicine is taken out after being sprayed with 3 ℃ low-temperature water for 25min, and is pre-frozen for 90min in a refrigerator at the temperature of minus 45 ℃. The freezing compaction is ensured, the bottle breaking phenomenon of pre-freezing is reduced, and the stability of the liquid medicine is ensured.
Further explaining, in the step 3, the sublimation drying is carried out, the temperature is increased from minus 45 ℃ to minus 10 ℃ within 120min under the vacuum degree of 20Pa, the vacuum degree is increased to 29Pa after the temperature is maintained for 720min, the vacuum degree is recovered to 20Pa after the temperature is maintained for 120min, and the temperature is continuously maintained for 120min; then gradually heating from-10 deg.C to 0 deg.C within 60min, and maintaining for 60min.
After certain sublimation drying, through increasing vacuum and regulating and controlling different rate of rise, be favorable to having increased convection action and transmission in the bottle, increase the conduction heat conduction at liquid medicine middle part, improve sublimation rate and stability, reduce the rejection rate to and effectively avoided broken bottle phenomenon.
Further, in step 4, the desorption drying: heating from 0 deg.C to 15 deg.C within 60min under vacuum degree of 5Pa, maintaining for 60min, and heating from 15 deg.C to 40 deg.C within 40min, and maintaining for 480min.
Further explaining, in the step 2, a 0.22-0.23 mu m filter membrane is adopted for sterilization and filtration, the filtration pressure is 0.30-0.40 Mpa, the filling temperature is 18-26 ℃, and the filling relative humidity is 45-65%. And filling and semi-tamponade are carried out at certain temperature and humidity, so that the stability of the solution before freeze drying is ensured.
Further explaining, in step 1: the citric acid-sodium hydroxide mixed solution is prepared by adding sodium hydroxide 700rmp/min into 20% of injection water at the room temperature of 26 ℃, stirring and dissolving, then cooling to 8-16 ℃, adding anhydrous citric acid 73.0-73.5% of the prescription amount, stirring and dissolving at 700rmp/min, and recovering to the room temperature of 26 ℃. The combination of the low-concentration citric acid solution and the high-concentration sodium hydroxide-citric acid solution is adopted to dissolve the azithromycin step by step, so that the uniformity and the stability of the solution before the azithromycin is lyophilized are improved, and the reduction of the rejection rate in the lyophilization process is facilitated.
Further, in step 1, the citric acid solution is prepared by adding anhydrous citric acid 24.5-25.0% at room temperature of 26 ℃ in a prescription amount of 70% of water for injection, and stirring until the solution is clear. The pH regulator is prepared by dissolving the rest of anhydrous citric acid in 5 percent of injection water according to the prescription amount and uniformly mixing.
Further explaining, the prescription amount ratio of the azithromycin, the anhydrous citric acid, the sodium hydroxide and the water for injection is as follows: (500-540), (394-426), (190-205) and (5548-5991). The stability and the homogeneity of intermediate liquid medicine dissolved by the azithromycin are ensured by regulating and controlling the prescription amounts of the azithromycin, the anhydrous citric acid, the sodium hydroxide and the water for injection.
Compared with the prior art, the invention has the beneficial effects that: the freeze-drying process curve of the combination of low-temperature water spraying treatment, prefreezing, sublimation drying and analysis drying is adopted to realize the freeze-drying of the azithromycin on the basis of preparing the solution before the azithromycin is freeze-dried by utilizing the combination of low-concentration citric acid solution and high-concentration sodium hydroxide-citric acid solution and ensuring the stability of the solution, wherein the low-temperature water spraying treatment is favorable for reducing the temperature difference between each part of a bottle body and the inside of liquid medicine, improving the dissolving stability of the azithromycin in the prefreezing process and promoting the rapid stability of the prefreezing treatment, and the temperature and the vacuum degree of the sublimation drying are combined and regulated in a segmented way during the sublimation drying, the sublimation action of the sublimation drying under the action of front-end low vacuum micro-convection and the strong convection action of rear-section high vacuum is utilized, and different heating rates are combined, so as to be favorable for promoting the conduction heat conduction action in the middle part of the liquid medicine, accelerating the sublimation rate and the stability and reducing the rejection rate, and after the vacuum degree is continuously reduced and heated to 0-15 ℃, the drying stage is basically completed, the heating rate is increased again, thereby fully accelerating the rapid forming of the freeze-dried powder and the freeze-dried powder is more uniform. The invention combines the high-stability azithromycin solution before freeze-drying with a new freeze-drying process curve, thereby not only effectively reducing the bottle breaking phenomenon in the freeze-drying process, but also having the advantages of high freeze-drying powder forming speed, more uniform powder particles, thorough drying and low rejection rate, and having important function for efficiently preparing the azithromycin freeze-drying agent for injection with stable quality, good redissolution property and low loss rate and realizing better clinical popularization.
Detailed Description
In order to better understand the technical content of the invention, specific examples are provided below to further illustrate the invention.
The experimental methods used in the examples of the present invention are all conventional methods unless otherwise specified.
The materials, reagents and the like used in the examples of the present invention can be obtained commercially without specific description.
Example 1-a method for freeze-drying azithromycin for injection, comprising the steps of:
step 1: preparing a solution of azithromycin before freeze-drying: sequentially mixing azithromycin with 25% of citric acid solution and 73% of citric acid-sodium hydroxide mixed solution, stirring until the mixture is clear, adjusting the pH to 6.60 by using the rest of citric acid solution as a pH regulator, and supplementing the rest of water for injection to obtain a solution of azithromycin before freeze-drying;
wherein the prescription amount ratio of the azithromycin, the anhydrous citric acid, the sodium hydroxide and the water for injection is as follows: 500;
the citric acid-sodium hydroxide mixed solution is prepared by adding sodium hydroxide 700rmp/min into 20 percent of injection water at the room temperature of 26 ℃, stirring and dissolving, then cooling to 8 ℃, adding 73.0 percent of anhydrous citric acid, stirring and dissolving at 700rmp/min, and recovering to the room temperature of 26 ℃. The citric acid solution is prepared by adding 70 percent of water for injection according to the prescription amount, 25.0 percent of anhydrous citric acid according to the prescription amount at the room temperature of 26 ℃, and stirring until the solution is clear. The pH regulator is prepared by dissolving the rest anhydrous citric acid in 5 percent of injection water according to the prescription amount, and uniformly mixing;
step 2: pre-freezing: sterilizing and filtering the solution before freeze-drying with 0.22 μm filter membrane at 0.30Mpa, bottling at 18 deg.C and relative humidity of 45%, spraying with 1 deg.C low-temperature water for 20min, and pre-freezing at-40 deg.C for 60min;
and step 3: sublimation drying: heating from-45 deg.C to-10 deg.C within 110min under 18Pa vacuum degree, maintaining for 700min, increasing vacuum degree to 28Pa, maintaining for 100min, recovering vacuum degree to 20Pa, and maintaining for 120min; gradually heating from-10 deg.C to 0 deg.C within 50min, and maintaining for 50min;
and 4, step 4: and (3) resolving and drying: heating from 0 ℃ to 15 ℃ within 50min under the vacuum degree of 4Pa, keeping for 50min, heating from 15 ℃ to 40 ℃ within 35min, and keeping for 460min to obtain the azithromycin freeze-dried powder injection for injection.
Example 2-a method of freeze-drying azithromycin for injection, comprising the steps of:
step 1: preparing an azithromycin solution before freeze-drying: sequentially mixing azithromycin with a citric acid solution with the prescription amount of 24.5 percent and a citric acid-sodium hydroxide mixed solution with the prescription amount of 73.5 percent, stirring until the mixture is clear, adjusting the pH to 6.60 by adopting the citric acid solution with the rest prescription amount as a pH regulator, and supplementing the pH with the rest of injection water to obtain a solution before azithromycin freeze-drying;
wherein the prescription amount ratio of the azithromycin, the anhydrous citric acid, the sodium hydroxide and the water for injection is as follows: 540;
the citric acid-sodium hydroxide mixed solution is prepared by adding sodium hydroxide 700rmp/min into 20 percent of injection water at the room temperature of 26 ℃, stirring and dissolving, then cooling to 16 ℃, adding 73.5 percent of anhydrous citric acid, stirring and dissolving at 700rmp/min, and recovering to the room temperature of 26 ℃. The citric acid solution is prepared by adding anhydrous citric acid 24.5% in a prescription amount into 70% of water for injection at the room temperature of 26 ℃, and stirring until the solution is clear. The pH regulator is prepared by dissolving the rest of anhydrous citric acid in 5 percent of injection water according to the prescription amount, and uniformly mixing;
step 2: pre-freezing: sterilizing and filtering the solution before freeze-drying with 0.23 μm filter membrane at filtration pressure of 0.40Mpa, filling at filling temperature of 26 deg.C and relative humidity of 65%, spraying with 5 deg.C low-temperature water outside the filled medicinal liquid for 30min, taking out, and pre-freezing at-50 deg.C for 120min;
and step 3: sublimation drying: heating from-45 deg.C to-10 deg.C within 130min under 22Pa vacuum degree, maintaining for 740min, increasing vacuum degree to 30Pa, maintaining for 140min, recovering vacuum degree to 25Pa, and maintaining for 150min; gradually heating from-10 deg.C to 0 deg.C within 70min, and maintaining for 70min;
and 4, step 4: and (3) resolving and drying: heating from 0 ℃ to 15 ℃ within 70min under the vacuum degree of 6Pa, keeping the temperature for 70min, heating from 15 ℃ to 40 ℃ within 45min, and keeping the temperature for 500min to obtain the azithromycin freeze-dried powder injection for injection.
Example 3-a method for freeze-drying azithromycin for injection, comprising the steps of:
step 1: preparing an azithromycin solution before freeze-drying: sequentially mixing azithromycin with a citric acid solution with the prescription amount of 24.8 percent and a citric acid-sodium hydroxide mixed solution with the prescription amount of 73.2 percent, stirring until the mixture is clear, adjusting the pH to 6.60 by adopting the citric acid solution with the rest prescription amount as a pH regulator, and supplementing the pH with the rest of injection water to obtain a solution before azithromycin freeze-drying;
wherein the prescription amount ratio of the azithromycin, the anhydrous citric acid, the sodium hydroxide and the water for injection is as follows: 520;
the citric acid-sodium hydroxide mixed solution is prepared by adding sodium hydroxide 700rmp/min into 20 percent of injection water at the room temperature of 26 ℃, stirring and dissolving, then reducing the temperature to 12 ℃, adding 73.2 percent of anhydrous citric acid, stirring and dissolving at 700rmp/min, and recovering to the room temperature of 26 ℃. The citric acid solution is prepared by adding prescription amount of anhydrous citric acid 24.8% into prescription amount of 70% water for injection at room temperature of 26 ℃, and stirring until the solution is clear. The pH regulator is prepared by dissolving the rest anhydrous citric acid in 5 percent of injection water according to the prescription amount, and uniformly mixing;
step 2: pre-freezing: sterilizing and filtering the solution before freeze-drying with 0.22 μm filter membrane at a pressure of 0.35Mpa, filling at 22 deg.C and a relative humidity of 55%, spraying with 3 deg.C low-temperature water for 25min, taking out, and pre-freezing at-45 deg.C for 90min;
and step 3: sublimation drying: heating from-45 deg.C to-10 deg.C within 120min under 20Pa vacuum degree, maintaining for 720min, increasing vacuum degree to 29Pa, maintaining for 120min, recovering vacuum degree to 20Pa, and maintaining for 120min; then gradually heating from-10 deg.C to 0 deg.C within 60min, and maintaining for 60min;
and 4, step 4: and (3) resolving and drying: heating from 0 ℃ to 15 ℃ within 60min under the vacuum degree of 5Pa, keeping for 60min, heating from 15 ℃ to 40 ℃ within 40min, and keeping for 480min to obtain the azithromycin freeze-dried powder injection for injection.
Comparative example 1-method of freeze-drying azithromycin for injection according to example 3, with the difference that: in the step 1, 90% of injection water in the prescription amount is sequentially added to 98% of anhydrous citric acid in the prescription amount at the room temperature of 26 ℃ for 700rmp/min, stirred and dissolved, then azithromycin in the prescription amount is added, stirred and dissolved until the mixture is clear, sodium hydroxide is added, 700rmp/min is stirred and mixed, the pH is adjusted to 6.60 by taking the rest of citric acid solution in the prescription amount as a pH regulator, the rest of the citric acid solution is supplemented with the rest of injection water, and a solution before azithromycin freeze-drying is obtained, wherein the rest of the solution is the same as that in the embodiment 3.
Comparative example 2-method of freeze-drying azithromycin for injection according to example 3, with the difference that: in the step 2, the filling liquid medicine is not subjected to low-temperature water spraying treatment, and is directly subjected to pre-freezing treatment.
Comparative example 3-method of freeze-drying azithromycin for injection according to example 3, with the difference that: in step 3, under the vacuum degree of 20Pa, the temperature is increased from minus 45 ℃ to minus 10 ℃ within 120min and is kept for 960min, and then the temperature is gradually increased from minus 10 ℃ to 0 ℃ within 60min and is kept for 60min.
Comparative example 4-method of freeze-drying azithromycin for injection according to example 3, with the difference that: in step 4, under the vacuum degree of 5Pa, the temperature is increased from 0 ℃ to 10 ℃ within 60min and is kept for 60min, and then the temperature is increased from 10 ℃ to 40 ℃ within 60min and is kept for 480min.
According to the freeze-drying methods of azithromycin for injection in the above examples 1 to 3 and comparative examples 1 to 4, three batches of azithromycin freeze-dried powder injections for injection are continuously produced, respectively, with the batch numbers: 20200501, 20200502 and 20200503, wherein 1000 azithromycin freeze-dried powder injections for injection are produced in each batch, the rejection rate and the bottle breakage rate are respectively counted, product sampling is carried out, each group of azithromycin freeze-dried powder injections is respectively sampled in the middle and four corners of 3 plate layers, 5 bottles are taken for each point, 75 bottles are taken in total, the determination of the properties, the water content and the pH value is observed, and the results are as follows:
as can be seen from the table above, the azithromycin freeze-dried powder injection for injection prepared in the embodiments 1-3 of the invention has more uniform freeze-dried powder particles and high content, the water content can be below 1.5%, the rejection rate can be below 0.2%, and the bottle breaking phenomenon in the freeze-drying process is effectively reduced.
Compared with the comparative examples 1 to 4, the embodiment 3 shows that in the comparative example 1, the preparation of the solution before azithromycin freeze-drying is changed, the stability is reduced, the content is obviously reduced on the contrary by combining a new freeze-drying process curve subsequently, the freeze-drying forming effect is obviously reduced, and the rejection rate is high, which indicates that the freeze-drying process curve of the invention can effectively ensure the stable forming of freeze-dried powder by combining the solution before azithromycin freeze-drying with high stability, the powder particles are more uniform, and the rejection rate is reduced. In comparative examples 2 to 4, the water content was increased as compared with example 3, the defective rate was relatively high, and in comparative examples 2 and 3, breakage was likely to occur, and in comparative examples 3 and 4, the uniformity of the formed powder particles was low.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and should not be taken as limiting the scope of the present invention, which is intended to cover any modifications, equivalents, improvements, etc. within the spirit and scope of the present invention.
Claims (5)
1. A freeze-drying method of azithromycin for injection is characterized in that: the method comprises the following steps:
step 1: preparing an azithromycin solution before freeze-drying: sequentially mixing azithromycin with a citric acid solution with the prescription amount of 24.5-25.0% and a citric acid-sodium hydroxide mixed solution with the prescription amount of 73.0-73.5%, stirring until the mixture is clear, adjusting the pH to 6.60 +/-0.10 by using the residual citric acid solution with the prescription amount as a pH regulator, and supplementing the pH with injection water to obtain a solution before azithromycin freeze-drying, wherein the prescription amount ratio of the azithromycin, the anhydrous citric acid, the sodium hydroxide and the injection water is as follows: (500 to 540): (394 to 426): (190 to 205): (5548 to 5991), the citric acid solution is prepared by adding anhydrous citric acid 24.5 to 25.0 percent of the prescription amount into injection water with the prescription amount of 70 percent at the room temperature of 26 ℃, stirring until the solution is clear, the citric acid-sodium hydroxide mixed solution is prepared by adding sodium hydroxide 700rmp/min into the injection water with the prescription amount of 20 percent at the room temperature of 26 ℃, stirring and dissolving, then cooling to 8 to 16 ℃, adding anhydrous citric acid with the prescription amount of 73.0 to 73.5 percent, stirring and dissolving at 700rmp/min, and recovering to the room temperature of 26 ℃;
and 2, step: pre-freezing: carrying out sterilization filtration, filling and half-pressing on the solution before azithromycin freeze-drying, adopting low-temperature water spraying at 1-5 ℃ for 20-30min outside the filled liquid medicine, taking out, and pre-freezing for 60-120min at-40-50 ℃;
and step 3: sublimation drying: heating to-10 ℃ from-45 ℃ in vacuum of 18 to 22Pa in vacuum of 110 to 130min, keeping the temperature for 700 to 740min, then heating to 28 to 30Pa in vacuum of 100 to 140min, restoring the vacuum of 20 to 25Pa, and keeping the temperature for 120 to 150min; gradually heating from-10 ℃ to 0 ℃ within 50 to 70min, and keeping for 50 to 70min;
and 4, step 4: and (3) resolving and drying: heating from 0 ℃ to 15 ℃ in a vacuum degree of 4 to 6Pa in 50 to 70min, keeping the temperature for 50 to 70min, heating from 15 ℃ to 40 ℃ in a vacuum degree of 35 to 45min, and keeping the temperature for 460 to 500min to obtain the azithromycin freeze-dried powder injection for injection.
2. The freeze-drying method of azithromycin for injection as claimed in claim 1, wherein the freeze-drying method comprises the following steps: in step 2, spraying low temperature water at 3 deg.C for 25min, taking out, and pre-freezing in a freezer at-45 deg.C for 90min.
3. The freeze-drying method of azithromycin for injection as claimed in claim 1, wherein the freeze-drying method comprises the following steps: in the step 3, the sublimation drying is carried out, the temperature is increased from minus 45 ℃ to minus 10 ℃ within 120min under the vacuum degree of 20Pa, the vacuum degree is increased to 29Pa after the temperature is maintained for 720min, the vacuum degree is recovered to 20Pa after the temperature is maintained for 120min, and the temperature is continuously maintained for 120min; then gradually heating from-10 deg.C to 0 deg.C within 60min, and maintaining for 60min.
4. The freeze-drying method of azithromycin for injection as claimed in claim 1, wherein the freeze-drying method comprises the following steps: in step 4, the analysis and drying: heating from 0 deg.C to 15 deg.C within 60min under vacuum degree of 5Pa, maintaining for 60min, and heating from 15 deg.C to 40 deg.C within 40min, and maintaining for 480min.
5. The freeze-drying method of azithromycin for injection as claimed in claim 1, wherein the freeze-drying method comprises the following steps: in the step 2, a filter membrane of 0.22 to 0.23 mu m is adopted for sterilization and filtration, the filtration pressure is 0.30 to 0.40Mpa, the filling temperature is 18 to 26 ℃, and the filling relative humidity is 45 to 65 percent.
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