CN103040855A - Pharmaceutical composition of fludarabine phosphate and preparation method thereof - Google Patents

Pharmaceutical composition of fludarabine phosphate and preparation method thereof Download PDF

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CN103040855A
CN103040855A CN2012105896312A CN201210589631A CN103040855A CN 103040855 A CN103040855 A CN 103040855A CN 2012105896312 A CN2012105896312 A CN 2012105896312A CN 201210589631 A CN201210589631 A CN 201210589631A CN 103040855 A CN103040855 A CN 103040855A
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fludarabine phosphate
pharmaceutical composition
excipient
injection
fludarabine
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CN103040855B (en
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钟正明
刘春燕
王进宇
陈颖江
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HAINAN JINRUI PHARMACEUTICAL CO Ltd
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Abstract

The invention relates to fludarabine phosphate, in particular to a pharmaceutical composition of fludarabine phosphate. The pharmaceutical composition comprises fludarabine phosphate, sodium chloride and excipient in weight ratio of 10: (1-5): (6-12) and preferably 10: (1-3): (6-10). The excipient is selected from at least one type of mannite, glucose, dextran, sorbitol and lactose, and preferably mannite or sorbitol. The pharmaceutical composition of fludarabine phosphate has low impurity content, is highly stable, and is suitable for clinical application.

Description

Pharmaceutical composition of a kind of fludarabine phosphate and preparation method thereof
Technical field
The present invention relates to fludarabine phosphate, specifically, relate to Pharmaceutical composition of a kind of fludarabine phosphate and preparation method thereof.
Background technology
Fludarabine phosphate is the nucleotide analog of fluoridizing of antiviral agents vidarabine, and chemical name is 9-β-D-arabic acid-furanose-2-fluoroadenine-5-phosphate.Molecular formula is C10H13FN5O7P, and molecular weight is 365.2.Can relatively resist the deamination of adenine deaminase.
Fludarabine phosphate is a kind of antineoplastic agent, is used for the treatment of chronic lymphocytic leukemia.Fludarabine phosphate is become 2F-ara-A by dephosphorylation rapidly in vivo, and the latter can by cellular uptake, then be become activated triphosphate 2F-ara-ATP after the intracellular deoxycytidine kinase phosphorylation.Thereby this metabolite can suppress by the activity that suppresses ribonucleotide reductase, archaeal dna polymerase α, dna primer enzyme and dna ligase the synthetic of DNA.Thereby the activity that can partly suppress in addition the RNA polymerase II reduces the synthetic of albumen.
US2004006041 discloses a kind of fludarabine phosphate injection, and this injection is comprised of fludarabine phosphate, alkali and water, and the pH scope of this fludarabine phosphate injection is between 5.5~7.1.Although should invent the pH by the control injection, strengthened the stability of injection in of short duration hot environment, the stability of this injection still remains to be improved.
Defective for the fludarabine phosphate injection, the domestic freeze-dried powder that also discloses some fludarabine phosphates, for example patent application 201110447906.4 discloses a kind of injection phosphoric acid fludarabine lyophilized formulations and preparation method thereof, this fludarabine phosphate lyophilized formulations mainly is prepared from by active component fludarabine phosphate and excipient, and the mass ratio of fludarabine phosphate and excipient is: 1: 0.5~2.0.But the impurity content in the fludarabine phosphate of this patent application is higher, and clinical use can have certain potential safety hazard.
In view of this, special proposition the present invention.
Summary of the invention
Goal of the invention of the present invention has been to propose the pharmaceutical composition of fludarabine phosphate.
In order to realize purpose of the present invention, the technical scheme of employing is:
A kind of pharmaceutical composition of fludarabine phosphate, contain fludarabine phosphate, sodium chloride and excipient in the described pharmaceutical composition, wherein, fludarabine phosphate: sodium chloride: the weight ratio of excipient is 10:1~5:6~12, preferred 10:1~3:6~10.
The first optimal technical scheme of the present invention is: described excipient is selected from least a in mannitol, glucose, dextran, sorbitol, the lactose, preferred mannitol or sorbitol, more preferably sorbitol.
The second optimal technical scheme of the present invention is: described fludarabine phosphate is crystalline compounds, and the X-ray powder diffraction pattern that described crystalline compounds use Cu-K alpha ray measures as shown in Figure 1.
The 3rd optimal technical scheme of the present invention is: the preparation method of described fludarabine phosphate crystal is:
(1) according to water: the volume ratio of acetone, ethanol is 5:1~2:1~3 preparation mixed solvents, and the ratio obtain solution according to every liter of mixed solvent adding 50~120g fludarabine phosphate solid is heated to 45~50 ℃, is stirred to fully by dissolving;
(2) distilling under reduced pressure under 45~55 ℃ of conditions when the volume of mixed solvent is reduced to 10~20%, stops distilling under reduced pressure, and mixed solvent is cooled to 1~5 ℃, leaves standstill growing the grain 1~5 hour; Obtain filtering behind the crystal, vacuum drying 2~4 hours obtains the crystalline compounds of fludarabine phosphate.
The 4th optimal technical scheme of the present invention is: in step (1), water: the volume ratio of acetone, ethanol is 5:1~2:1~2, further preferred 5:1:1~2.
The 5th optimal technical scheme of the present invention is: in step (2), described cooling rate is 0.5~2 ℃/min, preferred 1~1.5 ℃/min.
The 6th optimal technical scheme of the present invention is: in step (2), the temperature of distilling under reduced pressure is 47~50 ℃.
The 7th optimal technical scheme of the present invention is: described Pharmaceutical composition is lyophilized injectable powder and aqueous injection, preferred lyophilized injectable powder.
The 8th optimal technical scheme of the present invention is: the preparation method of described lyophilized injectable powder is:
1. take by weighing in proportion fludarabine phosphate, excipient and the sodium chloride of recipe quantity;
2. the water for injection that in Agitation Tank, adds 80% full liquid measure, the excipient and the sodium chloride that add recipe quantity, be stirred to fully dissolving, add the fludarabine phosphate of recipe quantity again, the pH value that adds the sodium hydroxide solution regulator solution of 2mol/L after fully stirring is 6.5~7.5;
3. the medicinal carbon that adds 0.01%g/mL, stirring and adsorbing 20 minutes, through 0.45 μ m filtering with microporous membrane carbon removal, filtrate adds to the full amount of water for injection, and is full and uniform, and the solution for preparing carries out the end-filtration degerming through the microporous filter membrane of 0.22 μ m, gets filtrate;
4. filtrate is encased in the injection bottle made, frozen drying obtains freeze-dried powder.
The below makes further explanation technical scheme of the present invention.
The present invention adopts gentle method recrystallization, thereby improved the purity of fludarabine phosphate, guaranteed the drug safety of its Pharmaceutical composition, detect through high performance liquid chromatography, its purity 99.5%, and therefore no solvent residue is a kind of very safe crystal, is highly suitable for preparing various drug combination preparations.Confirm through stability study, the crystal of the fludarabine phosphate of the present invention's preparation and pharmaceutical composition all possess good stability.
Fludarabine phosphate crystal of the present invention, the X-ray powder diffraction pattern that use Cu-K alpha ray measures is as shown in Figure 1; Its preparation method is:
(1) according to water: the volume ratio of acetone, ethanol is that 5:1~2:1 disposes mixed solvent, and the ratio obtain solution according to every liter of mixed solvent adding 50~120g fludarabine phosphate solid is heated to 45~50 ℃, is stirred to fully by dissolving;
(2) distilling under reduced pressure under 47~50 ℃ of conditions when the volume of mixed solvent is reduced to 10~20%, stops distilling under reduced pressure, and mixed solvent is cooled to 1~5 ℃, and cooling rate is 0.5~2 ℃/min, preferred 1~1.5 ℃/min; Left standstill growing the grain 1~5 hour; Obtain filtering behind the crystal, vacuum drying 2~4 hours obtains the crystalline compounds of fludarabine phosphate.
Fludarabine phosphate pharmaceutical composition of the present invention can be prepared into lyophilized injectable powder and aqueous injection, and preferred lyophilized injectable powder.Because fludarabine phosphate is not suitable for adopting high temperature sterilize, thereby is not suitable for being prepared into aqueous injection.
Fludarabine phosphate pharmaceutical composition of the present invention has added a certain amount of sodium chloride in compositions, can accelerate fludarabine phosphate and be absorbed the speed that enters blood, thereby improve curative effect.And, by adding a small amount of sodium chloride, can in the consumption that reduces excipient, guarantee the lyophilizing form of Fludarabine phosphate freeze-dried powder injection and the effect of redissolving.
Description of drawings
Fig. 1 is the X-ray powder diffraction pattern of the fludarabine phosphate crystal of embodiment 1 preparation.
The specific embodiment of the present invention only limits to further explain and explanation the present invention, not to Composition of contents restriction of the present invention.
The specific embodiment
Embodiment 1
(1) according to water: the volume ratio of acetone, ethanol is 5:1:1 configuration mixed solvent, and the ratio obtain solution according to every liter of mixed solvent adding 80g fludarabine phosphate solid is heated to 45 ℃, is stirred to fully by dissolving;
(2) distilling under reduced pressure under 50 ℃ of conditions when the volume of mixed solvent is reduced to 20%, stops distilling under reduced pressure, and mixed solvent is cooled to 1 ℃, and cooling rate is 2 ℃/min; Left standstill growing the grain 5 hours; Obtain filtering behind the crystal, vacuum drying 4 hours obtains the white crystalline powder of fludarabine phosphate.
The X-ray powder diffraction pattern that the fludarabine phosphate for preparing measures by the Cu-K alpha ray as shown in Figure 1; Detect through high performance liquid chromatography, its purity is 99.5%; Fusing point is: 206~207 ℃.
Embodiment 2
(1) according to water: the volume ratio of acetone, ethanol is 5:2:2 configuration mixed solvent, and the ratio obtain solution according to every liter of mixed solvent adding 100g fludarabine phosphate solid is heated to 50 ℃, is stirred to fully by dissolving;
(2) distilling under reduced pressure under 50 ℃ of conditions when the volume of mixed solvent is reduced to 10%, stops distilling under reduced pressure, and mixed solvent is cooled to 5 ℃, and cooling rate is 1.5 ℃/min, leaves standstill growing the grain 2 hours; Obtain filtering behind the crystal, vacuum drying 2 hours obtains the white crystalline powder of fludarabine phosphate.
The X-ray powder diffraction pattern that the fludarabine phosphate for preparing measures by the Cu-K alpha ray as shown in Figure 1; Detect through high performance liquid chromatography, its purity is 99.5%; Fusing point is: 206~207 ℃.
Embodiment 3
(1) according to water: the volume ratio of acetone, ethanol is 5:2:1 configuration mixed solvent, and the ratio obtain solution according to every liter of mixed solvent adding 50~120g fludarabine phosphate solid is heated to 45 ℃, is stirred to fully by dissolving;
(2) distilling under reduced pressure under 45 ℃ of conditions when the volume of mixed solvent is reduced to 15%, stops distilling under reduced pressure, and mixed solvent is cooled to 2 ℃, and cooling rate is 1 ℃/min; Left standstill growing the grain 4 hours; Obtain filtering behind the crystal, vacuum drying 3 hours obtains the white crystalline powder of fludarabine phosphate.
The X-ray powder diffraction pattern that the fludarabine phosphate for preparing measures by the Cu-K alpha ray as shown in Figure 1; Detect through high performance liquid chromatography, its purity is 99.5%; Fusing point is: 206~207 ℃.
Embodiment 4
(1) according to water: the volume ratio of acetone, ethanol is 5:2:3 configuration mixed solvent, and the ratio obtain solution according to every liter of mixed solvent adding 70g fludarabine phosphate solid is heated to 48 ℃, is stirred to fully by dissolving;
(2) distilling under reduced pressure under 47 ℃ of conditions when the volume of mixed solvent is reduced to 12%, stops distilling under reduced pressure, and mixed solvent is cooled to 2 ℃, and cooling rate is 2 ℃/min; Left standstill growing the grain 5 hours; Obtain filtering behind the crystal, vacuum drying 4 hours obtains the white crystalline powder of fludarabine phosphate.
The X-ray powder diffraction pattern that the fludarabine phosphate for preparing measures by the Cu-K alpha ray as shown in Figure 1; Detect through high performance liquid chromatography, its purity is 99.5%; Fusing point is: 206~207 ℃.
Embodiment 5:
A kind of Pharmaceutical composition of fludarabine phosphate, its prescription is: fludarabine phosphate 50mg, sodium chloride 5mg, mannitol 60mg.
Embodiment 6:
A kind of Pharmaceutical composition of fludarabine phosphate, its prescription is: fludarabine phosphate 50mg, sodium chloride 15mg, sorbitol 30mg.
Embodiment 7:
A kind of Pharmaceutical composition of fludarabine phosphate, its prescription is: fludarabine phosphate 50mg, sodium chloride 5mg, sorbitol 50mg.
Embodiment 8:
The preparation method of the Pharmaceutical composition of fludarabine phosphate is among the embodiment 5~7:
1. take by weighing fludarabine phosphate, sodium chloride and the excipient of recipe quantity according to ratio among the embodiment 5~7;
2. the water for injection that in Agitation Tank, adds 80% full liquid measure, the excipient and the sodium chloride that add recipe quantity, be stirred to fully dissolving, add the fludarabine phosphate of recipe quantity again, the pH value that adds the sodium hydroxide solution regulator solution of 0.2mol/L after fully stirring is 6.5~7.5;
3. the medicinal carbon that adds 0.01%g/mL, stirring and adsorbing 20 minutes, through 0.45 μ m filtering with microporous membrane carbon removal, filtrate adds to the full amount of water for injection, and is full and uniform, and the solution for preparing carries out the end-filtration degerming through the microporous filter membrane of 0.22 μ m, gets filtrate;
4. filtrate is encased in the injection bottle made, frozen drying obtains freeze-dried powder; Wherein said frozen drying process is:
(1) freezing period
Shelf temperature is down to-3 ℃ with the speed of 0.5 ℃/min, is incubated 0.5 hour, be down to-45 ℃ with the speed of 0.72 ℃/min again; Freezing 4 hours;
(2) the distillation phase
After medicine freezes, the temperature of condenser is controlled at-45 ℃, to the whole system evacuation, low vacuum is in 15pa, and the speed of intensification is 0.35 ℃/min, when treating that temperature rises to-1 ℃, continues insulation 5 hours;
(3) dry period
Control temperature and vacuum are warming up to 20~30 ℃ with shelf temperature with the speed of 0.6 ℃/min, are incubated 5~7 hours, total head plug after the passed examination, outlet.
Experimental example 1: influence factor's test
Three batches 101,102,103 of the fludarabine phosphate that the embodiment of the invention 1 is prepared prepare freeze-dried powder according to embodiment 8 methods, and simulation listing packing is carried out stability test.
1. hot test
With the freeze-dried powder for preparing, put in the sealing clean container, under 40 ℃ of temperature, placed 10 days,, detect result and comparison in 0 day in the 5th day and sampling in the 10th day by stable high spot reviews project.
2. high humidity experiment
With the freeze-dried powder for preparing, put in the sealing clean container, in 25 ± 2 ℃ of temperature, placed 10 days under the condition of relative humidity 90 ± 5%,, detect result and comparison in 0 day in the 5th day and sampling in the 10th day by stable high spot reviews project.
3. strong illumination test
With the freeze-dried powder for preparing, put in the sealing clean container, be to place 10 days under the condition of 4500lx in illumination,, detect result and comparison in 0 day in the 5th day and sampling in the 10th day by stable high spot reviews project.
Result of the test is as shown in table 1.
Table 1: influence factor's result of the test
Figure BDA00002673523700061
The result shows: the freeze-dried powder of preparation of the present invention, under the condition of simulation listing packing, under illumination, hot conditions, to place 10 days, and indices is without significant change.
The fludarabine phosphate crystal that other embodiment of the present invention is prepared has also carried out identical test, has obtained similar result.
Experimental example 2: accelerate experiment
Three batches 301,302,303 of the fludarabine phosphate crystalline compounds that the embodiment of the invention 2 is prepared, method according to embodiment 8 prepares freeze-dried powder, simulation listing packing, carry out following stability test: in 40 ℃ ± 2 ℃, placed 6 months under the condition of 75% ± 5%RH, at duration of test respectively at 1,2,3,6 sampling at the end of month once, each stable high spot reviews project is tested.Experimental result is as shown in table 2.
Table 2: accelerated test result
Figure BDA00002673523700072
Figure BDA00002673523700081
By the accelerated test result as can be known, the freeze-dried powder of fludarabine phosphate crystal preparation of the present invention was investigated through accelerated test in 6 months, and related substance and content slightly change, and significant change does not occur all the other indices.The freeze-dried powder stability that confirms fludarabine phosphate crystal preparation of the present invention is good.
The fludarabine phosphate crystalline compounds that other embodiment of the present invention is prepared has also carried out identical test, and the result of its acquisition is similar.
Experimental example 3: long term test
3 batches 301,302,303 of the fludarabine phosphate crystalline compounds that the embodiment of the invention 3 is prepared prepare lyophilized powder according to experimental example 8 methods, simulation listing packing, carry out following stability test: put in the sealing clean container, at 30 ℃ ± 2 ℃, placed 24 months under the 60% ± 5%RH spare, at duration of test respectively at the 3rd, 6,9,12,18,24 sampling at the end of month once, each stable high spot reviews project is tested.Result of the test is as shown in table 3:
Table 3: the long-term test results of fludarabine phosphate composition powder injection
Figure BDA00002673523700082
Figure BDA00002673523700091
By long-term test results as can be known, the freeze-dried powder of fludarabine phosphate compositions preparation of the present invention was investigated through long term test in 24 months, and significant change does not all occur indices.The stability of freeze-dried powder that confirms fludarabine phosphate compositions of the present invention is good.
The fludarabine phosphate crystal that other embodiment of the present invention is prepared has also carried out long term test, has obtained identical result of the test.
Experimental example 4: the comparative experiments of accelerated test
Comparative Examples 1: adopt commercially available fludarabine phosphate freeze-dried powder (authentication code: the accurate word H20065121 of traditional Chinese medicines; Production unit: Guangdong Lingnan Pharmaceutical Ltd. );
Comparative Examples 2: the fludarabine phosphate freeze-dried powder of patent application 201110447906 embodiment 13 preparations;
Comparative Examples 3: the phosphoric acid fluorine of patent ZL201110036856 embodiment 1 preparation reaches and draws freeze-dried powder;
Get simultaneously fludarabine phosphate crystalline compounds that the embodiment of the invention 4 prepares and prepare freeze-dried powder according to the method for embodiment 8, simulation listing packing, put simultaneously in the sealing clean container, in 40 ℃ ± 2 ℃, placed 6 months under 75% ± 5%RH condition, at duration of test respectively at 1,2,3,6 sampling at the end of month once, each stable high spot reviews project is tested, experimental result is as shown in table 4.
Table 4: the accelerated test result of fludarabine phosphate composition powder injection and drugs compared
Figure BDA00002673523700092
Figure BDA00002673523700101
By speed-up ratio than result of the test as can be known, this product was investigated through accelerated test in 6 months, and related substance and content have no significant change.And the related substance in the Comparative Examples, content all significantly increase.
Experimental example 5: investigate the ratio of solvent in the reaction to the impact of fludarabine phosphate crystalline compounds
Adopt the preparation condition of embodiment 1, comparison of design example 4~11 only changes listed condition in the table, and all the other steps and condition are with embodiment 1; Specifically shown in table 5,6.
Table 5:
? Embodiment 1 Comparative Examples 4 Comparative Examples 5 Comparative Examples 6 Comparative Examples 7
Water: the volume ratio of acetone, ethanol 5:1:1 5:3:3 5:4:4 1:1:1 6:1:1
Purity (HPLC) 99.2% 99.0% 98.5% 95.4% 93.3%
Yield 93.6% 90.5% 88.6% 83.7% 85.4%
Table 6:
Figure BDA00002673523700111
By above-mentioned experiment as can be known, the condition of employing of the present invention makes purity and two index optimizations of yield.
The screening experiment of experimental example 6 activated carbon concentration
Other component technological parameter all with implementing 8, selects respectively the injection active carbon of variable concentrations to adsorb, take fludarabine phosphate content, clarity as investigating index, the consumption of screening active carbon.Two clarity inspection techniques of Chinese Pharmacopoeia version in 2000 are adopted in the inspection of clarity, the results are shown in Table 7:
Table 7: activated carbon dosage screening test
Concentration of activated carbon (%) Fludarabine phosphate content (%) Clarity
0.1 97.8 Up to specification
0.05 98.9 Up to specification
0.03 99.7 Up to specification
0.02 99.8 Up to specification
0.01 100.0 Up to specification
By drawing in the table, 0.01% active carbon can make the clarity of lyophilizing liquid qualified, and is less to principal agent absorption, and pollutes minimumly, is 0.01%(g/ml so select concentration) active carbon adsorb.
Experimental example 7. effect comparative experimentss
Select glucose, dextran, mannitol, sorbitol to carry out the lyophilizing experiment according to freeze drying process among the embodiment 8, experimental result sees Table 8.
Table 8. effect comparative test result
Figure BDA00002673523700112
Figure BDA00002673523700121
Smart adjuvant screening comparative test, the present invention adopts the effect of mannitol and sorbitol better, and not only the apparent condition of freeze-dried products is better, and the redissolution effect is better.

Claims (9)

1. the pharmaceutical composition of a fludarabine phosphate, it is characterized in that, contain fludarabine phosphate, sodium chloride and excipient in the described pharmaceutical composition, wherein, fludarabine phosphate: sodium chloride: the weight ratio of excipient is 10:1~5:6~12, preferred 10:1~3:6~10.
2. the pharmaceutical composition of fludarabine phosphate according to claim 1 is characterized in that, described excipient is selected from least a in mannitol, glucose, dextran, sorbitol, the lactose, preferred mannitol or sorbitol, more preferably sorbitol.
3. the pharmaceutical composition of fludarabine phosphate according to claim 1 is characterized in that, described fludarabine phosphate is crystalline compounds, and the X-ray powder diffraction pattern that described crystalline compounds use Cu-K alpha ray measures as shown in Figure 1.
4. the Pharmaceutical composition of fludarabine phosphate according to claim 3 is characterized in that, described fludarabine phosphate crystal
Preparation method be:
(1) according to water: the volume ratio of acetone, ethanol is 5:1~2:1~3 preparation mixed solvents, and the ratio obtain solution according to every liter of mixed solvent adding 50~120g fludarabine phosphate solid is heated to 45~50 ℃, is stirred to fully by dissolving;
(2) distilling under reduced pressure under 45~55 ℃ of conditions when the volume of mixed solvent is reduced to 10~20%, stops distilling under reduced pressure, and mixed solvent is cooled to 1~5 ℃, leaves standstill growing the grain 1~5 hour; Obtain filtering behind the crystal, vacuum drying 2~4 hours obtains the crystalline compounds of fludarabine phosphate.
5. the Pharmaceutical composition of fludarabine phosphate according to claim 4 is characterized in that, in step (1), water: the volume ratio of acetone, ethanol is 5:1~2:1~2, further preferred 5:1:1~2.
6. the Pharmaceutical composition of fludarabine phosphate according to claim 4 is characterized in that, in step (2), described cooling rate is 0.5~2 ℃/min, preferred 1~1.5 ℃/min.
7. the Pharmaceutical composition of fludarabine phosphate according to claim 4 is characterized in that, in step (2), the temperature of distilling under reduced pressure is 47~50 ℃.
8. the Pharmaceutical composition of fludarabine phosphate according to claim 1 is characterized in that, described Pharmaceutical composition is lyophilized injectable powder and aqueous injection, preferred lyophilized injectable powder.
9. the Pharmaceutical composition of fludarabine phosphate according to claim 1 is characterized in that, the preparation method of described lyophilized injectable powder is:
(1) takes by weighing in proportion fludarabine phosphate, excipient and the sodium chloride of recipe quantity;
(2) water for injection of adding 80% full liquid measure in Agitation Tank, the excipient and the sodium chloride that add recipe quantity, be stirred to fully dissolving, add the fludarabine phosphate of recipe quantity again, the pH value that adds the sodium hydroxide solution regulator solution of 0.2mol/L after fully stirring is 6.5~7.5;
(3) medicinal carbon of adding 0.01%g/mL, stirring and adsorbing 20 minutes, through 0.45 μ m filtering with microporous membrane carbon removal, filtrate adds to the full amount of water for injection, and is full and uniform, and the solution for preparing carries out the end-filtration degerming through the microporous filter membrane of 0.22 μ m, gets filtrate;
(4) filtrate is encased in the injection bottle made, frozen drying obtains freeze-dried powder.
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US10669302B2 (en) 2015-08-28 2020-06-02 Zhejianf Hisun Pharmaceutical Co., Ltd. Crystal form of fludarabine phosphate, preparation method therefor, and application thereof
CN109072272A (en) * 2016-01-20 2018-12-21 浙江海正药业股份有限公司 A kind of method that enzyme process prepares fludarabine phosphate
CN110028538A (en) * 2019-05-17 2019-07-19 连云港杰瑞药业有限公司 A kind of drying means of fludarabine phosphate bulk pharmaceutical chemicals
CN110974789A (en) * 2019-12-27 2020-04-10 瀚晖制药有限公司 Fludarabine phosphate freeze-drying agent and preparation method thereof
CN110974789B (en) * 2019-12-27 2020-08-25 瀚晖制药有限公司 Fludarabine phosphate freeze-drying agent and preparation method thereof

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