CN117815189A - Preparation method for industrially preparing amifostine freeze-dried preparation - Google Patents
Preparation method for industrially preparing amifostine freeze-dried preparation Download PDFInfo
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- CN117815189A CN117815189A CN202211193414.1A CN202211193414A CN117815189A CN 117815189 A CN117815189 A CN 117815189A CN 202211193414 A CN202211193414 A CN 202211193414A CN 117815189 A CN117815189 A CN 117815189A
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- JKOQGQFVAUAYPM-UHFFFAOYSA-N amifostine Chemical compound NCCCNCCSP(O)(O)=O JKOQGQFVAUAYPM-UHFFFAOYSA-N 0.000 title claims abstract description 66
- 229960001097 amifostine Drugs 0.000 title claims abstract description 64
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 34
- 238000000034 method Methods 0.000 claims abstract description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000004108 freeze drying Methods 0.000 claims abstract description 19
- 238000001816 cooling Methods 0.000 claims abstract description 10
- 238000001914 filtration Methods 0.000 claims abstract description 10
- 239000000047 product Substances 0.000 claims abstract description 4
- 239000000706 filtrate Substances 0.000 claims abstract description 3
- 238000002156 mixing Methods 0.000 claims abstract description 3
- 238000007710 freezing Methods 0.000 claims description 13
- 238000001291 vacuum drying Methods 0.000 claims description 9
- 239000012982 microporous membrane Substances 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 abstract description 26
- 238000002347 injection Methods 0.000 abstract description 26
- 239000000843 powder Substances 0.000 abstract description 12
- 239000002904 solvent Substances 0.000 abstract description 4
- 230000003749 cleanliness Effects 0.000 abstract description 3
- 239000013078 crystal Substances 0.000 abstract description 2
- 238000002425 crystallisation Methods 0.000 abstract description 2
- 230000008025 crystallization Effects 0.000 abstract description 2
- 230000003321 amplification Effects 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 238000003199 nucleic acid amplification method Methods 0.000 abstract 1
- 229940090044 injection Drugs 0.000 description 22
- 239000000243 solution Substances 0.000 description 22
- 230000008014 freezing Effects 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 238000001035 drying Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000008215 water for injection Substances 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000337 buffer salt Substances 0.000 description 4
- 238000011049 filling Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000008176 lyophilized powder Substances 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 238000000137 annealing Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000009210 therapy by ultrasound Methods 0.000 description 2
- XINQFOMFQFGGCQ-UHFFFAOYSA-L (2-dodecoxy-2-oxoethyl)-[6-[(2-dodecoxy-2-oxoethyl)-dimethylazaniumyl]hexyl]-dimethylazanium;dichloride Chemical compound [Cl-].[Cl-].CCCCCCCCCCCCOC(=O)C[N+](C)(C)CCCCCC[N+](C)(C)CC(=O)OCCCCCCCCCCCC XINQFOMFQFGGCQ-UHFFFAOYSA-L 0.000 description 1
- -1 2- [ (3-aminopropyl) amino ] ethyl Chemical group 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- GHAZCVNUKKZTLG-UHFFFAOYSA-N N-ethyl-succinimide Natural products CCN1C(=O)CCC1=O GHAZCVNUKKZTLG-UHFFFAOYSA-N 0.000 description 1
- HDFGOPSGAURCEO-UHFFFAOYSA-N N-ethylmaleimide Chemical compound CCN1C(=O)C=CC1=O HDFGOPSGAURCEO-UHFFFAOYSA-N 0.000 description 1
- YHPLKWQJMAYFCN-UHFFFAOYSA-N WR-1065 Chemical compound NCCCNCCS YHPLKWQJMAYFCN-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940092936 amifostine injection Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000001120 cytoprotective effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000012931 lyophilized formulation Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- KWKAKUADMBZCLK-UHFFFAOYSA-N methyl heptene Natural products CCCCCCC=C KWKAKUADMBZCLK-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N n-Octanol Natural products CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- QWSZRRAAFHGKCH-UHFFFAOYSA-M sodium;hexane-1-sulfonate Chemical compound [Na+].CCCCCCS([O-])(=O)=O QWSZRRAAFHGKCH-UHFFFAOYSA-M 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a method for industrially preparing amifostine freeze-dried preparation, which comprises the following steps: (1) Dissolving amifostine in water in a C-level clean area, adding ethanol, mixing uniformly, standing at 0-25 ℃ for 0.5-10 h, and filtering; (2) And (3) in the A-level clean area, taking the filtrate obtained in the step (1), standing for 0.5-10 h at the temperature of 0-25 ℃, and freeze-drying to obtain the product. In the invention, water and ethanol are used as solvents of amifostine, in a cleanliness zone meeting the preparation environment requirement of a freeze-drying preparation, the amifostine is kept stand for a specific time at a specific temperature, the seed crystal is sterilized and separated out, and then the amifostine is fully crystallized in the cooling process under a specific freeze-drying condition, so that the problem of the formation of an amplification risk due to insufficient crystallization in the freeze-drying process is solved, and the amifostine powder injection with good batch-to-batch consistency, high stability and qualified quality is obtained, and the amifostine powder injection has practical popularization and application values.
Description
Technical Field
The invention belongs to the field of medicine manufacturing, and particularly relates to a preparation method for industrially preparing amifostine freeze-dried preparation.
Background
Amifostine (Amifostine), the name An Linting, is 2- [ (3-aminopropyl) amino ] ethyl thio-dihydrogen phosphate, is a small molecular compound containing a phosphate group, is a normal cytoprotective agent, and is used for preventing adverse reactions of chemotherapy.
The type of the amifostine preparation sold in the market at present is only freeze-dried powder injection for injection, so that more research reports on technological improvement of the freeze-dried powder injection for amifostine injection are provided. For example: patent ZL00119038.5 discloses that amifostine is frozen and crystallized by adjusting the pH under aseptic conditions, and the maximum implementation batch of amifostine is only 100g because freeze-drying is not needed and sieving and split charging are needed; patent ZL200410037763.X discloses that the solution of amifostine in acetone and water is freeze-dried and crystallized to form amifostine, and the freeze-drying process needs annealing due to the use of acetone solvent, and the temperature range is wide, the time is long, and the maximum implementation batch is only 250g; patent ZL200810146538.8 discloses that the mixed solution of ethanol and acetone mixed solvent and water of amifostine is freeze-dried and crystallized to obtain amifostine, and long-time low-temperature drying is needed in the freeze-drying process due to the use of the ethanol and acetone mixed solvent, so that the maximum implementation batch is only 120g; although patent ZL93117436.8 discloses water and ethanol as solvents for amifostine, the freeze-drying process requires annealing, the temperature range is wide, the freeze-drying time is longer than 50 hours, and the maximum implementation batch is only 438.3g.
The preparation method of the amifostine freeze-dried preparation disclosed in the patent ZL93117436.8 does not involve acetone, has few raw materials and simple process, tries to realize the large-scale production of the amifostine freeze-dried preparation in a cleanliness grade environment conforming to the powder injection, finds that the amifostine freeze-dried preparation cannot be prepared into freeze-dried powder injection which meets the quality requirements and has good consistency among batches, and solves the problem that the existing industrial mass production of the amifostine freeze-dried preparation is difficult.
Disclosure of Invention
In order to solve the problems, the invention provides a method for industrially preparing a amifostine freeze-dried preparation, which comprises the following steps:
(1) Dissolving amifostine in water in a C-level clean area, adding ethanol, mixing uniformly, standing at 0-25 ℃ for 0.5-10 h, and filtering;
(2) And (3) in the A-level clean area, taking the filtrate obtained in the step (1), standing for 0.5-10 h at the temperature of 0-25 ℃, and freeze-drying to obtain the product.
Further, the temperature of the dissolution in step (1) is > 30 ℃.
Further, the filtration in step (1) is filtration with a 0.22 μm microporous filter membrane.
Further, the freeze-drying in the step (2) is to firstly cool to-18 to-48 ℃ at 1-15 min/DEG C, pre-freeze for 1-10 h, and then vacuum-dry to the pressure test of 0.05-2 pa/m at the temperature of-30-0 ℃ at the vacuum degree of more than 0.2mbar 2 /120s。
Further, the freeze-drying in the step (2) is to firstly cool to-20 to-30 ℃ at 3-10 min/DEG C, pre-freeze for 2-4 h, and then vacuum-dry at the temperature of-30 to 0 ℃ until the pressure is 0.05 to 2pa/m under the vacuum degree of more than 0.2mbar 2 /120s。
Further, the freeze-drying in the step (2) is to firstly cool to-25 ℃ for 3-10 min/DEG C, pre-freeze for 2-4 h, and then vacuum-dry at the temperature of-20-0 ℃ to the pressure of 0.05-2 pa/m under the vacuum degree of more than 0.2mbar 2 /120s。
Further, the standing temperature is 5-20 ℃ and the time is 1-2 h.
Further, the mass volume ratio of the amifostine to the water to the ethanol is 80-200 mg: 0.78-0.9 ml:0.1 to 0.25ml.
Still further, the mass to volume ratio of amifostine, water and ethanol is 125mg: 0.8-0.9 ml:0.1 to 0.2ml.
Still further, the mass to volume ratio of amifostine, water and ethanol is 125mg:0.85ml:0.15ml.
According to the preparation method of the amifostine freeze-dried preparation, water and ethanol are used as solvents of the amifostine, the amifostine is kept stand for a specific time at a specific temperature in a cleanliness zone meeting the preparation environment requirements of the freeze-dried preparation, the seed crystal is sterilized and separated out, and then the amifostine is fully crystallized in a cooling process under a specific freeze-drying condition, so that the amifostine powder injection with good batch consistency, high stability and qualified quality can be obtained, and the kilogram-level mass production can be achieved, so that the problems that the existing amifostine powder injection is insufficient in crystallization and long in time and cannot be industrially produced in a large scale are solved, and the preparation method has practical popularization and application values.
The above-described aspects of the present invention will be described in further detail with reference to the following embodiments. It should not be construed that the scope of the above subject matter of the present invention is limited to the following examples. All techniques implemented based on the above description of the invention are within the scope of the invention.
Detailed Description
EXAMPLE 1 preparation of the amifostine lyophilized powder of the invention
1) In the C-level clean zone, 10kg of amifostine trihydrate is added with 40L of water for injection, after stirring and dissolving at 35 ℃, 12L of ethanol is added under the stirring state, and the water for injection is added to be constant in volume to 80L; cooling the solution to 15 ℃ and maintaining for 1h; filtering with 0.22 μm microporous membrane at room temperature;
2) In the A-level clean area, controlling the temperature of the solution obtained in the step (1) at 15 ℃, maintaining for 1h, filling into a freeze-dried tube injection bottle (500 mg amifostine/bottle), pre-freezing, vacuum drying, inflating and tamponade to obtain a freeze-dried preparation A;
the method for pre-freezing and vacuum drying comprises the following steps: placing a tube-made injection bottle filled with sterile amifostine solution on a plate layer of a freeze dryer, freezing by setting the temperature of the plate layer, cooling to the temperature of minus 25 ℃ at 3-10 min/DEG C, maintaining for 3h, starting a condensing chamber of the freeze dryer to cool to the temperature of minus 45 ℃, and starting a vacuum pump to increase the vacuum degree in the freeze dryer to 0.2mbarHeating the plate layer slowly to dry the plate layer at-25deg.C to-5deg.C for 15 hr, and performing pressure rise test at certain time interval until the pressure rise test result is lower than 0.7pa/m 2 And/120 s, ending the drying.
EXAMPLE 2 preparation of the amifostine lyophilized powder of the invention
1) In the C-level clean zone, 10kg of amifostine trihydrate is added with 40L of water for injection, after stirring and dissolving at 35 ℃, 16L of ethanol is added under the stirring state, and the water for injection is added to be constant in volume to 80L; cooling the solution to 20 ℃ and maintaining for 1h; filtering with 0.22 μm microporous membrane at room temperature;
2) In the A-level clean area, controlling the temperature of the solution obtained in the step (1) at 20 ℃, maintaining for 1h, filling into a freeze-dried tube injection bottle (500 mg amifostine/bottle), pre-freezing, vacuum drying, inflating and tamponade to obtain a freeze-dried preparation B;
the method for pre-freezing and vacuum drying comprises the following steps: placing a tube-made injection bottle filled with sterile amifostine solution on a plate layer of a freeze dryer, freezing by setting the temperature of the plate layer, cooling to the temperature of minus 25 ℃ at 3-10 min/DEG C, maintaining for 3 hours, starting a condensing chamber of the freeze dryer to cool to a temperature of lower than minus 45 ℃, starting a vacuum pump to increase the vacuum degree in the freeze dryer to above 0.2mbar, slowly heating the tube-made injection bottle through the plate layer, drying the tube-made injection bottle from the temperature of minus 25 ℃ to the temperature of minus 5 ℃ for 15 hours, and performing a pressure rise test at intervals until the pressure rise test result is lower than 0.1pa/m 2 And/120 s, ending the drying.
EXAMPLE 3 preparation of the amifostine lyophilized powder of the invention
1) In the C-level clean zone, 10kg of amifostine trihydrate is added with 40L of water for injection, after stirring and dissolving at 35 ℃, 8L of ethanol is added under the stirring state, and the water for injection is added to be constant in volume to 80L; cooling the solution to 10 ℃ and maintaining for 2 hours; filtering with 0.22 μm microporous membrane at room temperature to clarify;
2) In the A-level clean area, controlling the temperature of the solution obtained in the step (1) at 10 ℃, maintaining for 2 hours, filling into a freeze-dried tube injection bottle (500 mg amifostine/bottle), pre-freezing, vacuum drying, inflating and tamponade to obtain a freeze-dried preparation C;
wherein the method comprises the steps ofThe method for pre-freezing and vacuum drying comprises the following steps: placing a tube-made injection bottle filled with sterile amifostine solution on a plate layer of a freeze dryer, freezing by setting the temperature of the plate layer, cooling to the temperature of minus 25 ℃ at 3-10 min/DEG C, maintaining for 3 hours, starting a condensing chamber of the freeze dryer to cool to a temperature of lower than minus 45 ℃, starting a vacuum pump to increase the vacuum degree in the freeze dryer to above 0.2mbar, slowly heating the tube-made injection bottle through the plate layer, drying the plate layer at the temperature of minus 25 ℃ to minus 5 ℃ for 15 hours, and performing a pressure rise test at intervals until the pressure rise test result is lower than 0.2pa/m 2 And/120 s, ending the drying.
Comparative example 1
According to ZL93117436.8, "example 2: method for preparing crystalline amifostine free of mannitol "lyophilized formulation D of the present invention was prepared in the clean zone (grade C zone formulation, grade a zone fill and lyophilization).
Comparative example 2
1) In the C-level clean zone, 10kg of amifostine trihydrate is added with 40L of water for injection, after stirring and dissolving at 35 ℃, 12L of ethanol is added under the stirring state, and the water for injection is added to be constant in volume to 80L; filtering through a 0.22 μm microporous filter membrane;
2) Filling the solution obtained in the step (1) into a freeze-dried tube injection bottle (500 mg amifostine/bottle) in a class A clean area, pre-freezing, vacuum drying, inflating and tamponading to obtain a freeze-dried preparation E;
the method for pre-freezing and vacuum drying comprises the following steps: placing a tube-made injection bottle filled with sterile amifostine solution on a plate layer of a freeze dryer, freezing by setting the temperature of the plate layer, cooling to the temperature of minus 25 ℃ at 3-10 min/DEG C, maintaining for 3 hours, starting a condensing chamber of the freeze dryer to cool to a temperature of lower than minus 45 ℃, starting a vacuum pump to increase the vacuum degree in the freeze dryer to above 0.2mbar, slowly heating the tube-made injection bottle through the plate layer, drying the tube-made injection bottle from the temperature of minus 25 ℃ to the temperature of minus 5 ℃ for 15 hours, and performing a pressure rise test at intervals until the pressure rise test result is lower than 0.7pa/m 2 And/120 s, ending the drying.
The beneficial effects of the invention are further illustrated by the following test examples:
test example lyophilized preparation quality analysis
1. Method of
The freeze-dried preparations A, B, C, D and E were subjected to conditions of 25 ℃ + -2 ℃ and 60% + -5% relative humidity, and were sampled at 0,1,3,6 and 12 months, respectively, and analyzed for properties, pH, moisture, related substances and content by USP operation.
1) Content (USP 43)
Buffer salt: 0.94g/L of sodium 1-hexane sulfonate, and the pH was adjusted to 3.0 with phosphoric acid.
Mobile phase: methanol-buffer salt (7:18)
Control solution: 3mg/ml amifostine reference aqueous solution (prepared for temporary use or refrigerated storage)
Test solution: 3mg/ml amifostine aqueous solution (prepared for fresh use or stored in cold storage)
Chromatographic conditions:
a detector: 220nm UV
Chromatographic column: phenanthron Luna C8250 x 4.6mm 5 μm
Injector temperature: 4 DEG C
Flow rate: 1.0ml/min
Sample injection amount: 10 μl of
System applicability:
the control solution is continuously injected for 5 needles, the peak area RSD is not more than 2.0%, the main peak tailing factor is not more than 2.0, and the theoretical plate number is not less than 1000.
2) Related substance 1 and related substance 2 (USP 43)
a. Related substance 1
The detection method of the same content of the related substance 1 in chromatographic conditions and flow.
Control solution 1:70 μg/ml amifostine mercaptan aqueous solution (New preparation for clinical use)
Test solution: 2.4mg/ml amifostine aqueous solution (New preparation for clinical use)
System applicability:
the reference substance solution 1 is continuously injected for 6 needles, the peak area RSD is not more than 10.0 percent, the reference substance solution 2 is continuously injected for 6 needles, and the peak area RSD is not more than 4.0 percent.
b. Related substance 2
Buffer salt: 0.4g/L of 1-octane sodium sulfonate aqueous solution, with trifluoroacetic acid to adjust the pH 2.5.+ -. 0.1.
Mobile phase: acetonitrile-buffer salt (1:3)
Control solution: 46 μg/ml amifostine disulfide aqueous solution (New preparation for clinical use)
Test solution: 10mg/ml amifostine aqueous solution (New preparation for clinical use)
Chromatographic conditions:
a detector: 247nm UV
Chromatographic column: phenanthron Luna C18250 x 4.6mm 5 μm
Injector temperature: 4 DEG C
Flow rate: 1.0ml/min
Sample injection amount: 10 μl of
System applicability:
the control solution is continuously injected for 6 needles, the peak area RSD is not more than 4.0%, and the main peak tailing factor is not more than 2.5.
Limit: less than 2.0% total impurities including amifostine thiol and amifostine disulfide.
3) pH value of
Re-dissolving with 0.9% sodium chloride injection. Taking the re-dissolved solution, wherein the pH value of the solution is 6.5-7.5. (USP 791)
4) Moisture content
Taking 100.0mg of amifostine freeze-dried powder, placing the amifostine freeze-dried powder into a centrifuge tube with a plug, adding 10.0ml of methanol solution (100- > 4) of N-ethylmaleimide, carrying out ultrasonic treatment for 15 minutes, shaking, carrying out ultrasonic treatment for 15 minutes, taking 1.0ml of supernatant, and detecting according to a method IC of USP921, wherein the water content is 18.0% -22.0%.
2. Results
The specific results are shown in Table 1.
Table 1 results of room temperature stability test of inventive lyophilized formulations and comparative examples
Note that: "/" means that the freeze-dried powder injection is unstable in API in the observation test, degradation occurs, observation is finished, and no record is made.
As can be seen from table 1: after long-term 12-month inspection, samples A to C have no obvious change, and the stability is good. And the moisture of the samples D and E is unqualified, related substances are obviously changed, poor stability is shown, and the investigation is finished in advance. The results prove that the improved technology can solve the problem of the difference of stability of the product after the amifostine is amplified in a clean area, and realize the mass production of amifostine powder injection.
Claims (9)
1. A method for industrially preparing amifostine freeze-dried preparation is characterized in that: it comprises the following steps:
(1) Dissolving amifostine in water in a C-level clean area, adding ethanol, mixing uniformly, standing at 0-25 ℃ for 0.5-10 h, and filtering;
(2) And (3) in the A-level clean area, taking the filtrate obtained in the step (1), standing for 0.5-10 h at the temperature of 0-25 ℃, and freeze-drying to obtain the product.
2. The method according to claim 1, characterized in that: the temperature of the dissolution in the step (1) is more than 30 ℃.
3. The method according to claim 1, characterized in that: the filtration in step (1) is carried out by using a microporous membrane with the size of 0.22 μm.
4. The method according to claim 1, characterized in that: the freeze-drying in the step (2) is to firstly cool to-18 to-48 ℃ at 1-15 min/DEG C, pre-freeze for 1-10 h, and then vacuum-dry at the temperature of-30 to 0 ℃ to the pressure of 0.05-2 pa/m at the vacuum degree of more than 0.2mbar 2 /120s。
5. The method according to claim 4, wherein: the freeze-drying in the step (2) is to firstly cool to-20 to-30 ℃ at 3-10 min/DEG C, pre-freeze for 2-4 h, and then vacuum-dry at the temperature of-30 to 0 ℃ until the pressure is tested to be 0.05-2 pa/m at the vacuum degree of more than 0.2mbar 2 /120s。
6. The method according to claim 5, wherein: the freeze-drying in the step (2) is carried out by cooling to-25 ℃ at 3-10 min/DEG CPre-freezing for 2-4 h, vacuum drying at-20-0deg.C under vacuum degree of above 0.2mbar to pressure of 0.05-2 pa/m 2 /120s。
7. The method according to claim 1, characterized in that: the standing temperature is 5-20 ℃ and the time is 1-2 h.
8. The method according to claims 1-7, characterized in that: the mass volume ratio of the amifostine to the water to the ethanol is 80-200 mg: 0.78-0.9 ml:0.1 to 0.25ml.
9. The method according to claim 8, wherein: the mass volume ratio of the amifostine to the water to the ethanol is 125mg: 0.8-0.9 ml:0.1 to 0.2ml, preferably 125mg:0.85ml:0.15ml.
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| CN202211193414.1A CN117815189A (en) | 2022-09-28 | 2022-09-28 | Preparation method for industrially preparing amifostine freeze-dried preparation |
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| CN202211193414.1A CN117815189A (en) | 2022-09-28 | 2022-09-28 | Preparation method for industrially preparing amifostine freeze-dried preparation |
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| CN202211193414.1A Pending CN117815189A (en) | 2022-09-28 | 2022-09-28 | Preparation method for industrially preparing amifostine freeze-dried preparation |
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| Country | Link |
|---|---|
| CN (1) | CN117815189A (en) |
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2022
- 2022-09-28 CN CN202211193414.1A patent/CN117815189A/en active Pending
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