CN112618496A - Preparation method of azithromycin freeze-dried powder injection for injection - Google Patents
Preparation method of azithromycin freeze-dried powder injection for injection Download PDFInfo
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- CN112618496A CN112618496A CN202011637084.1A CN202011637084A CN112618496A CN 112618496 A CN112618496 A CN 112618496A CN 202011637084 A CN202011637084 A CN 202011637084A CN 112618496 A CN112618496 A CN 112618496A
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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 116
- 229960004099 azithromycin Drugs 0.000 title claims abstract description 116
- 238000002347 injection Methods 0.000 title claims abstract description 99
- 239000007924 injection Substances 0.000 title claims abstract description 99
- 239000000843 powder Substances 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 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 125
- 239000000243 solution Substances 0.000 claims abstract description 62
- 239000007788 liquid Substances 0.000 claims abstract description 53
- 239000003814 drug Substances 0.000 claims abstract description 48
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 39
- 229960004543 anhydrous citric acid Drugs 0.000 claims abstract description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000004108 freeze drying Methods 0.000 claims abstract description 29
- 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 24
- 238000001914 filtration Methods 0.000 claims abstract description 23
- 238000005303 weighing Methods 0.000 claims abstract description 23
- 229960004106 citric acid Drugs 0.000 claims abstract description 21
- 239000011259 mixed solution Substances 0.000 claims abstract description 20
- 238000011049 filling Methods 0.000 claims abstract description 17
- 230000001954 sterilising effect Effects 0.000 claims abstract description 10
- 238000003825 pressing Methods 0.000 claims abstract description 3
- 238000003756 stirring Methods 0.000 claims description 36
- 238000001035 drying Methods 0.000 claims description 20
- 238000010438 heat treatment Methods 0.000 claims description 20
- 239000008215 water for injection Substances 0.000 claims description 12
- 238000003860 storage Methods 0.000 claims description 11
- 238000007710 freezing Methods 0.000 claims description 10
- 230000008014 freezing Effects 0.000 claims description 10
- 238000004659 sterilization and disinfection Methods 0.000 claims description 9
- 238000000859 sublimation Methods 0.000 claims description 9
- 230000008022 sublimation Effects 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 238000007689 inspection Methods 0.000 claims description 5
- 238000003760 magnetic stirring Methods 0.000 claims description 5
- 239000012528 membrane Substances 0.000 claims description 5
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- 238000005516 engineering process Methods 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
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Abstract
The invention provides a preparation method of azithromycin freeze-dried powder injection for injection, which comprises the following steps: (1) weighing 20% of injection water according to the prescription amount, adding sodium hydroxide for dissolving, and adding 73.0-73.5% of anhydrous citric acid according to the prescription amount to obtain a sodium hydroxide-citric acid mixed solution; (2) weighing 70% of injection water according to the prescription amount, and adding 24.5-25.0% of anhydrous citric acid according to the prescription amount to obtain a citric acid solution; (3) preparing a pH regulator; (4) weighing azithromycin, adding a citric acid solution, and then adding a sodium hydroxide-citric acid mixed solution; (5) adjusting the pH value to obtain a solution of azithromycin before freeze-drying; (6) sterilizing and filtering; (7) filling and half-pressing; (8) freeze-drying to obtain azithromycin freeze-dried powder injection for injection; the invention improves the stability of intermediate liquid medicine for dissolving azithromycin by optimizing the azithromycin liquid preparation process, so that the obtained azithromycin freeze-dried powder injection for injection has better product stability and redissolution property.
Description
Technical Field
The invention relates to the technical field of medicine processing technology, in particular to a preparation method of azithromycin freeze-dried powder injection 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.
Azithromycin is usually prepared into freeze-dried powder injection by using a freeze-drying technology so as to achieve the aims of accurate dosage, good storage and transportation, however, in the preparation process of the prior azithromycin freeze-dried powder injection for injection, the problems of low stability, poor uniformity, reduced stability and redissolution property of the later freeze-dried powder injection and the like easily occur due to low solubility and poor stability of the azithromycin freeze-dried powder injection, therefore, how to improve the stability and the uniformity of the preparation of the intermediate liquid medicine in which the azithromycin is dissolved and reduce the influence of the freeze-drying process is an urgent problem to be solved for realizing the preparation of the good azithromycin freeze-dried powder injection, and the preparation process of the novel azithromycin freeze-dried powder injection for injection, which effectively improves the solubility and the product stability of the azithromycin, is found, so that the preparation process has important significance for better exerting the therapeutic effect of the azithromycin and providing more ideal therapeutic drugs for clinic.
Disclosure of Invention
In view of the above, the invention provides a preparation method of azithromycin freeze-dried powder injection for injection,
the technical scheme of the invention is realized as follows:
the invention provides a preparation method of azithromycin freeze-dried powder injection for injection, which comprises the following steps:
step 1: preparing a sodium hydroxide-citric acid mixed solution: weighing 20% of injection water according to the prescription amount, adding sodium hydroxide at room temperature, stirring and dissolving, cooling to 8-16 ℃, adding 73.0-73.5% of anhydrous citric acid according to the prescription amount, stirring and dissolving, and recovering the temperature to room temperature; obtaining a sodium hydroxide-citric acid mixed solution;
step 2: preparing a citric acid solution: weighing 70% of injection water according to the prescription amount, adding 24.5-25.0% of anhydrous citric acid according to the prescription amount at room temperature, and stirring until the solution is clear;
and step 3: preparing a pH regulator: weighing the balance of anhydrous citric acid, dissolving the anhydrous citric acid in 5% of injection water according to the prescription amount, and uniformly mixing;
and 4, step 4: dissolving the raw material medicines: weighing azithromycin with a prescription amount, firstly slowly adding the azithromycin into a citric acid solution, and stirring until the solution is completely clarified; slowly adding a sodium hydroxide-citric acid mixed solution, and stirring until the solution is completely clear to obtain a primary liquid of the liquid medicine;
and 5: adjusting the pH value: measuring the pH of the initial liquid medicine liquid, adjusting the pH of the liquid medicine to 6.60 +/-0.10 by using the pH regulator in the step 3, and supplementing the remaining water for injection to full dose to obtain a solution of azithromycin before freeze-drying;
step 6: and (3) degerming and filtering: the solution before azithromycin freeze-drying is subjected to sterilization filtration through a 0.22-0.23 mu m filter membrane;
and 7: filling and semi-pressing the solution after degerming and filtering;
and 8: and (3) freeze drying: sequentially pre-freezing, sublimation drying and analysis drying the liquid medicine obtained in the step 7 to obtain a freeze-dried powder medicine;
and step 9: and performing full tamponade, capping and inspection to obtain the azithromycin freeze-dried powder injection for injection.
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), (5548-5991). The stability and the uniformity 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.
Further explaining, in the step 1 and the step 2, the room temperature is 25.5-26.5 ℃; the stirring speed is 600-800 rmp/min. The stability of the citric acid solution with low concentration and the sodium hydroxide-citric acid solution with high concentration is favorably improved.
Further explaining, in the step 4, when the azithromycin is mixed with the citric acid solution, the stirring temperature is 20-30 ℃, and the stirring speed is 280-300 rmp/min. The low-temperature premixing effect of the azithromycin and the low-concentration citric acid solution is favorable for promoting the dispersibility of the azithromycin in the low-concentration salt forming agent.
Further explaining, in the step 4, when the sodium hydroxide-citric acid mixed solution is added and mixed, magnetic stirring is adopted, the stirring temperature is 25-26 ℃, and the magnetic stirring speed is as follows: 320 to 420 rmp/min. The azithromycin premixed liquid and the high-concentration sodium hydroxide-citric acid solution are magnetically stirred and mixed, so that the solubility of the azithromycin is favorably improved, the dissolution rate is accelerated, the homogeneity of intermediate liquid medicine dissolved by the azithromycin is high, the stability of powder injection of a freeze-drying process is improved, and the magnetic stirring speed is preferably 350 rmp/min.
Further, in step 6, the pressure for sterilization and filtration is 0.30 to 0.40 MPa. The filtering pressure is controlled, and the loss of effective components is reduced.
Further explaining, in the step 7, the filling temperature is 18-26 ℃, and the filling relative humidity is 45-65%. The penicillin bottle and the rubber plug after dry heat sterilization are adopted for filling and half-tamponade at certain temperature and humidity, so that the stability of the solution before freeze-drying is ensured.
Further explaining, in step 8, the pre-freezing is as follows: pre-freezing at-45 deg.C within 60min, and maintaining for 180 min;
the sublimation drying comprises the following steps: heating from-45 deg.C to-10 deg.C within 120min under 20Pa vacuum degree, maintaining for 1920min, gradually heating from-10 deg.C to 0 deg.C within 60min, and maintaining for 60 min;
the analysis and drying are as follows: heating from 0 deg.C to 10 deg.C within 60min under vacuum degree of 5Pa, maintaining for 60min, and heating from 10 deg.C to 40 deg.C within 60min, and maintaining for 480 min. The combination of prefreezing, sublimation drying and analysis drying is adopted, the drying temperature, time and change rate of each stage are controlled, the drying uniformity of the product is improved, the effective content of the azithromycin is favorably ensured, and the stability and redissolution property of the azithromycin freeze-dried powder are maintained.
Further, the storage time of the azithromycin solution obtained in the step 5 before freeze-drying is less than 6 hours before aseptic filtration, and the storage time of the filled and half-tamponade liquid medicine obtained in the step 7 before freeze-drying is less than 8 hours.
Compared with the prior art, the invention has the beneficial effects that: the preparation method of the azithromycin freeze-dried powder injection for injection provided by the invention optimizes the azithromycin liquid preparation process, adopts the combination of the citric acid solution with low concentration and the sodium hydroxide-citric acid solution with high concentration, the azithromycin is dissolved step by step, and simultaneously, the citric acid solution with micro concentration is used as a pH regulator, thereby being beneficial to improving the solubility of the azithromycin and shortening the dissolving time of the azithromycin, but also obviously improves the uniformity and stability of the solution before the azithromycin is lyophilized, does not need to add any excipient, only needs to carry out one-step sterilization filtration treatment, effectively reduces the introduction of impurities, ensures the stability of intermediate liquid medicine dissolved by the azithromycin, finally combines pre-freezing, sublimation drying and desorption drying, and the rejection rate is reduced, so that the prepared azithromycin freeze-dried powder injection for injection has better product stability and redissolution property.
Drawings
Figure 1 is a freeze-drying curve diagram of the azithromycin freeze-dried powder injection for injection.
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.
Embodiment 1-a method for preparing azithromycin freeze-dried powder for injection, comprising the following steps:
step 1: preparing a sodium hydroxide-citric acid mixed solution: weighing 20% of injection water according to the prescription amount, adding sodium hydroxide 600rmp/min at 25.5 ℃, stirring and dissolving, then cooling to 8 ℃, adding anhydrous citric acid according to 73% of the prescription amount, stirring and dissolving at 600rmp/min, and recovering the temperature to 25.5 ℃; obtaining a sodium hydroxide-citric acid mixed solution;
step 2: preparing a citric acid solution: weighing 70% of injection water according to the prescription amount, adding 25% of anhydrous citric acid according to the prescription amount at 25.5 ℃ and room temperature, and stirring at 600rmp/min until the solution is clear;
and step 3: preparing a pH regulator: weighing the balance of anhydrous citric acid, dissolving the anhydrous citric acid in 5% of injection water according to the prescription amount, and uniformly mixing;
and 4, step 4: dissolving the raw material medicines: weighing azithromycin with a prescription dose, firstly slowly adding the azithromycin into a citric acid solution, stirring at 20 ℃ at 280rmp/min until the solution is completely clarified; slowly adding sodium hydroxide-citric acid mixed solution, magnetically stirring at 25 deg.C and 320rmp/min until completely clarified to obtain primary liquid of the medicinal liquid;
and 5: adjusting the pH value: measuring the pH of the initial liquid medicine liquid, adjusting the pH of the liquid medicine to 6.60 by adopting the pH regulator in the step 3, and supplementing the remaining water for injection to full dose 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: 500:394:190: 5548;
step 6: and (3) degerming and filtering: the solution before azithromycin freeze-drying is sterilized and filtered by a 0.22 mu m filter membrane, and the pressure of sterilization and filtration is 0.30 Mpa;
and 7: filling and semi-tamponading the solution after degerming and filtering, wherein the filling temperature is 18 ℃, and the filling relative humidity is 45%;
and 8: and (3) freeze drying: sequentially pre-freezing the liquid medicine in the step 7 after the temperature is reduced to-45 ℃ within 60min, and keeping the temperature for 180 min; and then carrying out sublimation drying: heating from-45 deg.C to-10 deg.C within 120min under 20Pa vacuum degree, maintaining for 1920min, gradually heating from-10 deg.C to 0 deg.C within 60min, and maintaining for 60 min; and then carrying out analysis and drying: heating from 0 deg.C to 10 deg.C within 60min under vacuum degree of 5Pa, maintaining for 60min, heating from 10 deg.C to 40 deg.C within 60min, and maintaining for 480 min; obtaining a freeze-dried powder medicine;
and step 9: and performing full tamponade, capping and inspection to obtain the azithromycin freeze-dried powder injection for injection.
Embodiment 2-a method for preparing azithromycin freeze-dried powder for injection, comprising the following steps:
step 1: preparing a sodium hydroxide-citric acid mixed solution: weighing 20% of injection water according to the prescription amount, adding sodium hydroxide 800rmp/min at the room temperature of 26.5 ℃, stirring and dissolving, then cooling to 16 ℃, adding anhydrous citric acid according to the prescription amount of 73.5%, stirring and dissolving at 800rmp/min, and recovering the temperature to the room temperature of 26.5 ℃; obtaining a sodium hydroxide-citric acid mixed solution;
step 2: preparing a citric acid solution: weighing 70% of injection water according to the prescription amount, adding 24.5% of anhydrous citric acid according to the prescription amount at the room temperature of 26.5 ℃, and stirring at 800rmp/min until the solution is clear;
and step 3: preparing a pH regulator: weighing the balance of anhydrous citric acid, dissolving the anhydrous citric acid in 5% of injection water according to the prescription amount, and uniformly mixing;
and 4, step 4: dissolving the raw material medicines: weighing azithromycin with a prescription dose, firstly slowly adding the azithromycin into a citric acid solution, stirring at 30 ℃ at 300rmp/min until the solution is completely clarified; slowly adding sodium hydroxide-citric acid mixed solution, magnetically stirring at 26 deg.C and 420rmp/min to completely clarify to obtain primary liquid medicine;
and 5: adjusting the pH value: measuring the pH of the initial liquid medicine liquid, adjusting the pH of the liquid medicine to 6.60 by adopting the pH regulator in the step 3, and supplementing the remaining water for injection to full dose 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: 540:426:190: 5548;
step 6: and (3) degerming and filtering: the solution before azithromycin freeze-drying is sterilized and filtered by a 0.23-micron filter membrane, and the pressure of sterilization and filtration is 0.40 Mpa;
and 7: filling and semi-tamponading the solution after degerming and filtering, wherein the filling temperature is 26 ℃, and the filling relative humidity is 65%;
and 8: and (3) freeze drying: sequentially pre-freezing the liquid medicine in the step 7 after the temperature is reduced to-45 ℃ within 60min, and keeping the temperature for 180 min; and then carrying out sublimation drying: heating from-45 deg.C to-10 deg.C within 120min under 20Pa vacuum degree, maintaining for 1920min, gradually heating from-10 deg.C to 0 deg.C within 60min, and maintaining for 60 min; and then carrying out analysis and drying: heating from 0 deg.C to 10 deg.C within 60min under vacuum degree of 5Pa, maintaining for 60min, heating from 10 deg.C to 40 deg.C within 60min, and maintaining for 480 min; obtaining a freeze-dried powder medicine;
and step 9: and performing full tamponade, capping and inspection to obtain the azithromycin freeze-dried powder injection for injection.
Embodiment 3-a method for preparing azithromycin freeze-dried powder for injection, comprising the following steps:
step 1: preparing a sodium hydroxide-citric acid mixed solution: weighing 20% of injection water according to the prescription amount, adding sodium hydroxide 700rmp/min at the room temperature of 26 ℃, stirring and dissolving, then cooling to 12 ℃, adding anhydrous citric acid 73.2% of the prescription amount, stirring and dissolving at 700rmp/min, and recovering the temperature to the room temperature of 26 ℃; obtaining a sodium hydroxide-citric acid mixed solution;
step 2: preparing a citric acid solution: weighing 70% of injection water according to the prescription amount, adding 24.8% of anhydrous citric acid according to the prescription amount at the room temperature of 26 ℃, and stirring at 700rmp/min until the solution is clear;
and step 3: preparing a pH regulator: weighing the balance of anhydrous citric acid, dissolving the anhydrous citric acid in 5% of injection water according to the prescription amount, and uniformly mixing;
and 4, step 4: dissolving the raw material medicines: weighing azithromycin with a prescription dose, firstly slowly adding the azithromycin into a citric acid solution, and stirring at 25 ℃ at 290rmp/min until the solution is completely clarified; slowly adding sodium hydroxide-citric acid mixed solution, magnetically stirring at 25.5 deg.C and 380rmp/min to completely clarify to obtain primary liquid medicine;
and 5: adjusting the pH value: measuring the pH of the initial liquid medicine liquid, adjusting the pH of the liquid medicine to 6.60 by adopting the pH regulator in the step 3, and supplementing the remaining water for injection to full dose 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: 520:410:197.5: 5769.5;
step 6: and (3) degerming and filtering: the solution before azithromycin freeze-drying is sterilized and filtered by a 0.22 mu m filter membrane, and the pressure of sterilization and filtration is 0.35 Mpa;
and 7: filling and semi-tamponading the solution after degerming and filtering, wherein the filling temperature is 22 ℃, and the filling relative humidity is 55%;
and 8: and (3) freeze drying: sequentially pre-freezing the liquid medicine in the step 7 after the temperature is reduced to-45 ℃ within 60min, and keeping the temperature for 180 min; and then carrying out sublimation drying: heating from-45 deg.C to-10 deg.C within 120min under 20Pa vacuum degree, maintaining for 1920min, gradually heating from-10 deg.C to 0 deg.C within 60min, and maintaining for 60 min; and then carrying out analysis and drying: heating from 0 deg.C to 10 deg.C within 60min under vacuum degree of 5Pa, maintaining for 60min, heating from 10 deg.C to 40 deg.C within 60min, and maintaining for 480 min; obtaining a freeze-dried powder medicine;
and step 9: and performing full tamponade, capping and inspection to obtain the azithromycin freeze-dried powder injection for injection.
Wherein the storage time of the azithromycin solution before freeze-drying in the embodiments 1-3 before degerming and filtering is 4 hours, and the storage time of the filled and half-pressed liquid medicine before freeze-drying is 6 hours.
Comparative example 1-preparation method of azithromycin freeze-dried powder for injection according to example 3, the difference is that: step 1-4, sequentially adding 98% of anhydrous citric acid 700rmp/min in the prescription amount to 90% of injection water in the prescription amount at the room temperature of 26 ℃, stirring and dissolving, adding azithromycin in the prescription amount, magnetically stirring and dissolving at 380rmp/min until the mixture is clear, adding sodium hydroxide, and stirring and mixing at 700rmp/min to obtain a liquid medicine initial solution; the rest is the same as in example 3.
Comparative example 2-preparation method of azithromycin freeze-dried powder for injection according to example 3, the difference is that: in step 1, the addition amount of the anhydrous citric acid is 80%, the addition amount of the anhydrous citric acid in step 2 is 18%, and the rest is the same as that in example 3.
Comparative example 3-preparation method of azithromycin freeze-dried powder for injection according to example 3, the difference is that: in the step 4, azithromycin with the prescription dose is firstly added with a sodium hydroxide-citric acid mixed solution, the mixture is magnetically stirred and dissolved at the temperature of 25.5 ℃ and at the speed of 380rmp/min, then a citric acid solution is added, the mixture is stirred at the temperature of 25 ℃ and at the speed of 290rmp/min until the mixture is completely clarified, and a primary liquid of the liquid medicine is obtained, and the rest is the same as that in the embodiment 3.
1. Product stability and resolubility experiments
The azithromycin freeze-dried powder injection for injection prepared by the preparation methods of the embodiments 1 to 3 and the comparative examples 1 to 3 is subjected to stability experiment and redissolution experiment.
(1) The experimental method comprises the following steps:
the azithromycin freeze-dried powder injection samples of each embodiment and comparative example are respectively placed in a sealed clean container and are respectively placed at the temperature of 6 ℃ for 24 months (the humidity is 75-80%), 3 experiments are repeated, and the stability items of the samples are regularly checked.
And taking the azithromycin freeze-dried powder injection products (25-27 ℃ and humidity of 75-80%) placed under the same condition for 12-24 months in each embodiment and comparative example, respectively injecting 20ml of water for injection into each group of 60 bottles, dissolving at the same vibration frequency of 60 times/min, and counting the time required for the azithromycin freeze-dried powder injection to be completely dissolved until the azithromycin freeze-dried powder injection is clarified.
(2) The experimental results are as follows:
table 1: stability of different Azithromycin freeze-dried powder injection
Table 2: redissolution of different azithromycin freeze-dried powder injection
As can be seen from the above tables 1-2, the azithromycin freeze-dried powder injection for injection prepared in the embodiments 1-3 of the invention has good stability and re-solubility, the content of related substances of the azithromycin freeze-dried powder injection for injection in 24 months under the condition of low-temperature storage meets the specification, and the content of active ingredients is high. Compared with the comparative example, the azithromycin freeze-dried powder injection for injection in the comparative example 1 has obviously reduced stability and re-solubility, the content of related substances is increased after the azithromycin freeze-dried powder injection is stored for 24 months in the comparative examples 1 and 3, and the re-solubility of the azithromycin freeze-dried powder injection after 24 months is obviously reduced.
2. Stability test of intermediate liquid medicine for azithromycin dissolution
The azithromycin solution before lyophilization obtained by the preparation of the above examples 1 to 3 and comparative examples 1 to 3 was subjected to a stability test.
(1) The experimental method comprises the following steps: the azithromycin solution before freeze-drying of each example and each comparative example is equally taken out of a sterilized stainless steel barrel to prepare 50ml of liquid medicine, 50ml of each upper point and 50ml of each lower point are respectively taken out by a disposable syringe at intervals of 3 hours from 0 hour, the total volume is 100ml, the properties, the pH value, the content, related substances and other items of the liquid medicine are detected, and the detection result within 9 hours is compared with 0 hour to determine whether the obvious change is generated or not, so that the liquid medicine conforms to the specification.
(2) The experimental results are as follows:
table 3: stability of intermediate liquid medicine for dissolving azithromycin
As can be seen from the above table 3, the intermediate liquid medicine for dissolving azithromycin prepared by the invention has high uniformity and stability, can still keep clear and colorless after being stored for 9 hours, and has small content change of active ingredients; in contrast, in example 3, compared with comparative examples 1 to 3, in comparative example 3, the pH value was significantly changed and the color of the liquid was changed after the storage for 6 hours, and the content of the related substances was increased after the storage for 9 hours. In comparative examples 2 and 3, the change of the pH value was significant, the color of the liquid was changed, and the content of the effective ingredient was reduced after the storage for 9 hours.
The analysis shows that the azithromycin liquid preparation process is optimized, 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, and meanwhile, the micro-concentration citric acid solution is used as a pH regulator, so that the solubility of the azithromycin is favorably improved, the uniformity and the stability of the solution before the azithromycin is freeze-dried are obviously improved, the stability of an intermediate liquid medicine for dissolving the azithromycin is improved, and the azithromycin (C) in the obtained liquid medicine before the azithromycin is freeze-dried is obtained38H72N2O12) The content can be kept between 71.3mg/g and 78.8 mg/g.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (9)
1. A preparation method of azithromycin freeze-dried powder injection for injection is characterized in that: the method comprises the following steps:
step 1: preparing a sodium hydroxide-citric acid mixed solution: weighing 20% of injection water according to the prescription amount, adding sodium hydroxide at room temperature, stirring and dissolving, cooling to 8-16 ℃, adding 73.0-73.5% of anhydrous citric acid according to the prescription amount, stirring and dissolving, and recovering the temperature to room temperature; obtaining a sodium hydroxide-citric acid mixed solution;
step 2: preparing a citric acid solution: weighing 70% of injection water according to the prescription amount, adding 24.5-25.0% of anhydrous citric acid according to the prescription amount at room temperature, and stirring until the solution is clear;
and step 3: preparing a pH regulator: weighing the balance of anhydrous citric acid, dissolving the anhydrous citric acid in 5% of injection water according to the prescription amount, and uniformly mixing;
and 4, step 4: dissolving the raw material medicines: weighing azithromycin with a prescription amount, firstly slowly adding the azithromycin into a citric acid solution, and stirring until the solution is completely clarified; slowly adding a sodium hydroxide-citric acid mixed solution, and stirring until the solution is completely clear to obtain a primary liquid of the liquid medicine;
and 5: adjusting the pH value: measuring the pH of the initial liquid medicine liquid, adjusting the pH of the liquid medicine to 6.60 +/-0.10 by using the pH regulator in the step 3, and supplementing the remaining water for injection to full dose to obtain a solution of azithromycin before freeze-drying;
step 6: and (3) degerming and filtering: the solution before azithromycin freeze-drying is subjected to sterilization filtration through a 0.22-0.23 mu m filter membrane;
and 7: filling and semi-pressing the solution after degerming and filtering;
and 8: and (3) freeze drying: sequentially pre-freezing, sublimation drying and analysis drying the liquid medicine obtained in the step 7 to obtain a freeze-dried powder medicine;
and step 9: and performing full tamponade, capping and inspection to obtain the azithromycin freeze-dried powder injection for injection.
2. The preparation method of the azithromycin freeze-dried powder injection for injection as claimed in claim 1, which is characterized in that: 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), (5548-5991).
3. The preparation method of the azithromycin freeze-dried powder injection for injection as claimed in claim 1, which is characterized in that: in the step 1 and the step 2, the room temperature is 25.5-26.5 ℃; the stirring speed is 600-800 rmp/min.
4. The preparation method of the azithromycin freeze-dried powder injection for injection as claimed in claim 1, which is characterized in that: in the step 4, when the azithromycin is mixed with the citric acid solution, the stirring temperature is 20-30 ℃, and the stirring speed is 280-300 rmp/min.
5. The preparation method of the azithromycin freeze-dried powder injection for injection as claimed in claim 1, which is characterized in that: and 4, adding a sodium hydroxide-citric acid mixed solution, and mixing, wherein magnetic stirring is adopted, the stirring temperature is 25-26 ℃, and the magnetic stirring speed is as follows: 320 to 420 rmp/min.
6. The preparation method of the azithromycin freeze-dried powder injection for injection as claimed in claim 1, which is characterized in that: in the step 6, the pressure for degerming and filtering is 0.30-0.40 Mpa.
7. The preparation method of the azithromycin freeze-dried powder injection for injection as claimed in claim 1, which is characterized in that: in the step 7, the filling temperature is 18-26 ℃, and the filling relative humidity is 45-65%.
8. The preparation method of the azithromycin freeze-dried powder injection for injection as claimed in claim 1, which is characterized in that: in step 8, the pre-freezing is as follows: pre-freezing at-45 deg.C within 60min, and maintaining for 180 min;
the sublimation drying comprises the following steps: heating from-45 deg.C to-10 deg.C within 120min under 20Pa vacuum degree, maintaining for 1920min, gradually heating from-10 deg.C to 0 deg.C within 60min, and maintaining for 60 min;
the analysis and drying are as follows: heating from 0 deg.C to 10 deg.C within 60min under vacuum degree of 5Pa, maintaining for 60min, and heating from 10 deg.C to 40 deg.C within 60min, and maintaining for 480 min.
9. The preparation method of the azithromycin freeze-dried powder injection for injection as claimed in claim 1, which is characterized in that: the storage time of the azithromycin solution obtained in the step 5 before sterilization and filtration is less than 6 hours, and the storage time of the filled and half-tamponade liquid medicine obtained in the step 7 before freeze drying is less than 8 hours.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113274359A (en) * | 2021-05-08 | 2021-08-20 | 南京海纳医药科技股份有限公司 | Azithromycin freeze-dried powder for injection and production method thereof |
| CN113577033A (en) * | 2021-08-28 | 2021-11-02 | 海南海灵化学制药有限公司 | Preparation process of azithromycin for injection |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002007736A1 (en) * | 2000-07-24 | 2002-01-31 | Cadila Pharmaceuticals Limited | The process for manufacturing of clear liquid pharmaceutical composition of azithromycin |
| US20050209172A1 (en) * | 2004-03-17 | 2005-09-22 | American Pharmaceutical Partners, Inc. | Lyophilized azithromycin formulation |
| 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 |
| CN102743343A (en) * | 2012-05-21 | 2012-10-24 | 江苏奥赛康药业股份有限公司 | Decitabine composition, preparation method thereof, application thereof in medicinal lyophilized preparation, medicinal lyophilized preparation product, and preparation method of medicinal lyophilized preparation product |
| CN103494811A (en) * | 2013-10-09 | 2014-01-08 | 南京绿叶思科药业有限公司 | Sodium glycididazole composition and preparation method thereof |
| CN110151706A (en) * | 2019-05-09 | 2019-08-23 | 苏州朗易生物医药研究有限公司 | The preparation method of azithromycin injection |
| 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 |
-
2020
- 2020-12-31 CN CN202011637084.1A patent/CN112618496A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002007736A1 (en) * | 2000-07-24 | 2002-01-31 | Cadila Pharmaceuticals Limited | The process for manufacturing of clear liquid pharmaceutical composition of azithromycin |
| US20050209172A1 (en) * | 2004-03-17 | 2005-09-22 | American Pharmaceutical Partners, Inc. | Lyophilized azithromycin formulation |
| 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 |
| CN102743343A (en) * | 2012-05-21 | 2012-10-24 | 江苏奥赛康药业股份有限公司 | Decitabine composition, preparation method thereof, application thereof in medicinal lyophilized preparation, medicinal lyophilized preparation product, and preparation method of medicinal lyophilized preparation product |
| CN103494811A (en) * | 2013-10-09 | 2014-01-08 | 南京绿叶思科药业有限公司 | Sodium glycididazole composition and preparation method thereof |
| CN110151706A (en) * | 2019-05-09 | 2019-08-23 | 苏州朗易生物医药研究有限公司 | The preparation method of azithromycin injection |
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| 白荣: "注射用阿奇霉素冻干收率提高的工艺改进", 《海峡药学》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113274359A (en) * | 2021-05-08 | 2021-08-20 | 南京海纳医药科技股份有限公司 | Azithromycin freeze-dried powder for injection and production method thereof |
| CN113577033A (en) * | 2021-08-28 | 2021-11-02 | 海南海灵化学制药有限公司 | Preparation process of azithromycin for injection |
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