CN103040855B - Pharmaceutical composition of fludarabine phosphate and preparation method thereof - Google Patents
Pharmaceutical composition of fludarabine phosphate and preparation method thereof Download PDFInfo
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- CN103040855B CN103040855B CN201210589631.2A CN201210589631A CN103040855B CN 103040855 B CN103040855 B CN 103040855B CN 201210589631 A CN201210589631 A CN 201210589631A CN 103040855 B CN103040855 B CN 103040855B
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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
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, 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 intracellular deoxycytidine kinase phosphorylation.Thereby this metabolite can suppress the synthetic of DNA by suppressing the activity of ribonucleotide reductase, archaeal dna polymerase α, DNA primer enzyme and DNA ligase.Thereby the activity that can partly suppress in addition RNA polymerase II reduces the synthetic of albumen.
US2004006041 discloses a kind of fludarabine phosphate injection, and this injection is made up of fludarabine phosphate, alkali and water, and the pH scope of this fludarabine phosphate injection is between 5.5～7.1.Although this invention, by controlling the pH of injection, has strengthened the stability of injection in of short duration hot environment, the stability of this injection still has much room for improvement.
For the defect of 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 is mainly 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, 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 object of the present invention, the technical scheme of employing is:
A kind of pharmaceutical composition of fludarabine phosphate, in described pharmaceutical composition, contain fludarabine phosphate, sodium chloride and excipient, wherein, fludarabine phosphate: sodium chloride: the weight ratio of excipient is 10:1～5:6～12, preferably 10:1～3:6～10.
The first optimal technical scheme of the present invention is: described excipient is selected from least one in mannitol, glucose, dextran, sorbitol, lactose, preferably 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 solvent, add the ratio obtain solution of 50～120g fludarabine phosphate solid according to every liter of mixed solvent, be heated to 45～50 ℃, be stirred to completely by dissolving;
(2) distilling under reduced pressure under 45～55 ℃ of conditions, in the time that 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 after 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), and 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, preferably 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, preferably lyophilized injectable powder.
The 8th optimal technical scheme of the present invention is: the preparation method of described lyophilized injectable powder is:
1. take in proportion fludarabine phosphate, excipient and the sodium chloride of recipe quantity;
2. in Agitation Tank, add the water for injection of 80% full liquid measure, add excipient and the sodium chloride of recipe quantity, be stirred to completely and dissolve, then add the fludarabine phosphate of recipe quantity, after fully stirring, adding the pH value of the sodium hydroxide solution regulator solution of 2mol/L is 6.5～7.5;
3. add the medicinal carbon of 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, full and uniform, and the solution preparing carries out end-filtration degerming through the microporous filter membrane of 0.22 μ m, obtains filtrate;
4. filtrate is encased in injection bottle made, frozen drying, obtains freeze-dried powder.
Below technical scheme of the present invention is made further explanation.
The present invention adopts gentle method recrystallization, thereby improve the purity of fludarabine phosphate, guarantee the drug safety of its Pharmaceutical composition, detect through high performance liquid chromatography, its purity 99.5%, and no solvent residue, is therefore a kind of very safe crystal, is highly suitable for preparing various drug combination preparations.Confirm through stability study, the crystal of fludarabine phosphate prepared by the present invention 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 configures mixed solvent, adds the ratio obtain solution of 50～120g fludarabine phosphate solid according to every liter of mixed solvent, is heated to 45～50 ℃, is stirred to completely by dissolving;
(2) distilling under reduced pressure under 47～50 ℃ of conditions, in the time that 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, preferably 1～1.5 ℃/min; Leave standstill growing the grain 1～5 hour; Obtain filtering after 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 be 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 be in reducing the consumption of excipient, guarantee the lyophilizing form of Fludarabine phosphate freeze-dried powder injection and the effect of redissolving.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction pattern of the fludarabine phosphate crystal prepared of embodiment 1.
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, add the ratio obtain solution of 80g fludarabine phosphate solid according to every liter of mixed solvent, be heated to 45 ℃, be stirred to completely by dissolving;
(2) distilling under reduced pressure under 50 ℃ of conditions, in the time that 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; Leave standstill growing the grain 5 hours; Obtain filtering after crystal, vacuum drying 4 hours, obtains the white crystalline powder of fludarabine phosphate.
The X-ray powder diffraction pattern that the fludarabine phosphate preparing measures by 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, add the ratio obtain solution of 100g fludarabine phosphate solid according to every liter of mixed solvent, be heated to 50 ℃, be stirred to completely by dissolving;
(2) distilling under reduced pressure under 50 ℃ of conditions, in the time that 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 after crystal, vacuum drying 2 hours, obtains the white crystalline powder of fludarabine phosphate.
The X-ray powder diffraction pattern that the fludarabine phosphate preparing measures by 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, add the ratio obtain solution of 50～120g fludarabine phosphate solid according to every liter of mixed solvent, be heated to 45 ℃, be stirred to completely by dissolving;
(2) distilling under reduced pressure under 45 ℃ of conditions, in the time that 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; Leave standstill growing the grain 4 hours; Obtain filtering after crystal, vacuum drying 3 hours, obtains the white crystalline powder of fludarabine phosphate.
The X-ray powder diffraction pattern that the fludarabine phosphate preparing measures by 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, add the ratio obtain solution of 70g fludarabine phosphate solid according to every liter of mixed solvent, be heated to 48 ℃, be stirred to completely by dissolving;
(2) distilling under reduced pressure under 47 ℃ of conditions, in the time that 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; Leave standstill growing the grain 5 hours; Obtain filtering after crystal, vacuum drying 4 hours, obtains the white crystalline powder of fludarabine phosphate.
The X-ray powder diffraction pattern that the fludarabine phosphate preparing measures by 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 Pharmaceutical composition for fludarabine phosphate, its formula is: fludarabine phosphate 50mg, sodium chloride 5mg, mannitol 60mg.
Embodiment 6:
A Pharmaceutical composition for fludarabine phosphate, its formula is: fludarabine phosphate 50mg, sodium chloride 15mg, sorbitol 30mg.
Embodiment 7:
A Pharmaceutical composition for fludarabine phosphate, its formula is: fludarabine phosphate 50mg, sodium chloride 5mg, sorbitol 50mg.
Embodiment 8:
In embodiment 5～7, the preparation method of the Pharmaceutical composition of fludarabine phosphate is:
1. take fludarabine phosphate, sodium chloride and the excipient of recipe quantity according to ratio in embodiment 5～7;
2. in Agitation Tank, add the water for injection of 80% full liquid measure, add excipient and the sodium chloride of recipe quantity, be stirred to completely and dissolve, then add the fludarabine phosphate of recipe quantity, after fully stirring, adding the pH value of the sodium hydroxide solution regulator solution of 0.2mol/L is 6.5～7.5;
3. add the medicinal carbon of 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, full and uniform, and the solution preparing carries out end-filtration degerming through the microporous filter membrane of 0.22 μ m, obtains filtrate;
4. filtrate is encased in 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, then be down to-45 ℃ with the speed of 0.72 ℃/min; Freezing 4 hours;
(2) the distillation phase
After medicine freezes, the temperature of condenser is controlled to-45 ℃, to whole system evacuation, low vacuum is in 15pa, and the speed of intensification is 0.35 ℃/min, in the time that temperature rises to-1 ℃, continues insulation 5 hours;
(3) dry period
Control temperature and vacuum, shelf temperature is warming up to 20～30 ℃ with the speed of 0.6 ℃/min, be incubated 5～7 hours, total head plug after passed examination, outlet.
Experimental example 1: influence factor's test
Three batches 101,102,103 of the fludarabine phosphate that the embodiment of the present invention 1 is prepared, prepare freeze-dried powder according to embodiment 8 methods, and simulation listing packing, carries out stability test.
1. hot test
By the freeze-dried powder preparing, put in sealing clean container, at 40 ℃ of temperature, place 10 days, in the 5th day and sampling in the 10th day, detect result and comparison in 0 day by stability high spot reviews project.
2. high humidity experiment
By the freeze-dried powder preparing, put in sealing clean container, in 25 ± 2 ℃ of temperature, under the condition of relative humidity 90 ± 5%, place 10 days, in the 5th day and sampling in the 10th day, detect result and comparison in 0 day by stability high spot reviews project.
3. strong illumination test
By the freeze-dried powder preparing, put in sealing clean container, under the condition that is 4500lx in illumination, place 10 days, in the 5th day and sampling in the 10th day, detect result and comparison in 0 day by stability high spot reviews project.
Result of the test is as shown in table 1.
Table 1: influence factor's result of the test
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 present invention 2 is prepared, method according to embodiment 8 is prepared freeze-dried powder, simulation listing packing, carry out following stability test: in 40 ℃ ± 2 ℃, under the condition of 75% ± 5%RH, place 6 months,, respectively at sampling once 1,2,3,6 the end of month each stability high spot reviews project is tested at duration of test.Experimental result is as shown in table 2.
Table 2: accelerated test result
From accelerated test result, freeze-dried powder prepared by fludarabine phosphate crystal of the present invention, investigates through accelerated test for 6 months, and related substance and content slightly change, and significant change does not occur all the other indices.Confirm that freeze-dried powder stability prepared by fludarabine phosphate crystal 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
Prepare lyophilized powder according to experimental example 8 methods for 3 batches 301,302,303 of the fludarabine phosphate crystalline compounds that the embodiment of the present invention 3 is prepared, simulation listing packing, carry out following stability test: put in sealing clean container, at 30 ℃ ± 2 ℃, under 60% ± 5%RH part, place 24 months,, respectively at sampling once the 3rd, 6,9,12,18,24 the end of month each stability high spot reviews project is tested at duration of test.Result of the test is as shown in table 3:
Table 3: the long-term test results of fludarabine phosphate composition powder injection
From long-term test results, freeze-dried powder prepared by fludarabine phosphate compositions of the present invention is investigated through long term test for 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 example 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 example 2: fludarabine phosphate freeze-dried powder prepared by patent application 201110447906 embodiment 13;
Comparative example 3: phosphoric acid fluorine prepared by patent ZL201110036856 embodiment 1 reaches and draws freeze-dried powder;
Get the fludarabine phosphate crystalline compounds that the embodiment of the present invention 4 prepares simultaneously and prepare freeze-dried powder according to the method for embodiment 8, simulation listing packing, put in sealing clean container simultaneously, in 40 ℃ ± 2 ℃, under 75% ± 5%RH condition, place 6 months,, respectively at sampling once 1,2,3,6 the end of month each stability high spot reviews project is tested at duration of test, experimental result is as shown in table 4.
Table 4: the accelerated test result of fludarabine phosphate composition powder injection and drugs compared
From speed-up ratio, compared with result of the test, this product is investigated through accelerated test for 6 months, and related substance and content have no significant change.And related substance in comparative example, content all significantly increase.
Experimental example 5: the impact of the ratio of solvent on fludarabine phosphate crystalline compounds in investigation reaction
Adopt the preparation condition of embodiment 1, comparison of design example 4～11, only changes listed condition in table, and all the other steps and condition are with embodiment 1; Specifically as shown in Table 5,6.
Table 5:
| ? | Embodiment 1 | Comparative example 4 | Comparative example 5 | Comparative example 6 | Comparative example 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:
From above-mentioned experiment, 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, and the consumption of screening active carbon.The inspection of clarity adopts two clarity inspection techniques of Chinese Pharmacopoeia version in 2000, 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 | Conform with the regulations |
| 0.05 | 98.9 | Conform with the regulations |
| 0.03 | 99.7 | Conform with the regulations |
| 0.02 | 99.8 | Conform with the regulations |
| 0.01 | 100.0 | Conform with the regulations |
By drawing in table, 0.01% active carbon can make the clarity of lyophilizing liquid qualified, 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 lyophilizing experiment according to freeze drying process in embodiment 8, experimental result is in table 8.
Table 8. effect comparative test result
Essence 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 redissolution effect is better.
Claims (9)
1. a pharmaceutical composition for fludarabine phosphate, is characterized in that, contains fludarabine phosphate, sodium chloride and excipient in described pharmaceutical composition, and described Pharmaceutical composition is lyophilized injectable powder; Wherein, fludarabine phosphate: sodium chloride: the weight ratio of excipient is 5:1:6, and excipient is selected from mannitol or sorbitol; 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.
2. the Pharmaceutical composition of fludarabine phosphate according to claim 1, is characterized in that, excipient is selected from sorbitol.
3. the Pharmaceutical composition of fludarabine phosphate according to claim 1, is characterized in that, 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 solvent, add the ratio obtain solution of 50～120g fludarabine phosphate solid according to every liter of mixed solvent, be heated to 45～50 ℃, be stirred to completely by dissolving;
(2) distilling under reduced pressure under 45～55 ℃ of conditions, in the time that 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 after crystal, vacuum drying 2～4 hours, obtains the crystalline compounds of fludarabine phosphate.
4. the Pharmaceutical composition of fludarabine phosphate according to claim 3, is characterized in that, in step (1), and water: the volume ratio of acetone, ethanol is 5:1～2:1～2.
5. the Pharmaceutical composition of fludarabine phosphate according to claim 4, is characterized in that, in step (1), and water: the volume ratio of acetone, ethanol is 5:1:1～2.
6. the Pharmaceutical composition of fludarabine phosphate according to claim 3, is characterized in that, in step (2), described cooling rate is 0.5～2 ℃/min.
7. the Pharmaceutical composition of fludarabine phosphate according to claim 6, is characterized in that, in step (2), described cooling rate is 1～1.5 ℃/min.
8. the Pharmaceutical composition of fludarabine phosphate according to claim 7, is characterized in that, in step (2), the temperature of distilling under reduced pressure is 47～50 ℃.
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) take in proportion fludarabine phosphate, excipient and the sodium chloride of recipe quantity;
(2) in Agitation Tank, add the water for injection of 80% full liquid measure, add excipient and the sodium chloride of recipe quantity, be stirred to completely and dissolve, then add the fludarabine phosphate of recipe quantity, after fully stirring, adding the pH value of the sodium hydroxide solution regulator solution of 0.2mol/L is 6.5～7.5;
(3) add the medicinal carbon of 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, full and uniform, and the solution preparing carries out end-filtration degerming through the microporous filter membrane of 0.22 μ m, obtains filtrate;
(4) filtrate is encased in injection bottle made, frozen drying, obtains freeze-dried powder.
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| EP3406729A4 (en) * | 2016-01-20 | 2019-08-28 | Zhejiang Hisun Pharmaceutical Co., Ltd. | Method for enzymatic preparation of 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 |
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| US6046322A (en) * | 1997-12-11 | 2000-04-04 | Schering Aktiengesellschaft | Process for the production of fludarabine-phosphate lithium, sodium, potassium, calcium and magnesium salts and purification process for the production of fludarabine-phosphate and fludarabine-phosphate with a purity of at least 99.5% |
| CN102552175A (en) * | 2011-12-28 | 2012-07-11 | 辰欣药业股份有限公司 | Fludarabine phosphate lyophilized preparation for injection and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6046322A (en) * | 1997-12-11 | 2000-04-04 | Schering Aktiengesellschaft | Process for the production of fludarabine-phosphate lithium, sodium, potassium, calcium and magnesium salts and purification process for the production of fludarabine-phosphate and fludarabine-phosphate with a purity of at least 99.5% |
| CN102552175A (en) * | 2011-12-28 | 2012-07-11 | 辰欣药业股份有限公司 | Fludarabine phosphate lyophilized preparation for injection and preparation method thereof |
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