CN102952167A - Method for dilution crystallizationelution and crystallization of cytidine 5'-disodium phosphate - Google Patents
Method for dilution crystallizationelution and crystallization of cytidine 5'-disodium phosphate Download PDFInfo
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- CN102952167A CN102952167A CN2012104989254A CN201210498925A CN102952167A CN 102952167 A CN102952167 A CN 102952167A CN 2012104989254 A CN2012104989254 A CN 2012104989254A CN 201210498925 A CN201210498925 A CN 201210498925A CN 102952167 A CN102952167 A CN 102952167A
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- cytidine
- cytidylic acid
- crystallization
- disodium phosphate
- dilution
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- 238000002425 crystallisation Methods 0.000 title claims abstract description 34
- 230000008025 crystallization Effects 0.000 title claims abstract description 24
- 238000010790 dilution Methods 0.000 title claims abstract description 16
- 239000012895 dilution Substances 0.000 title claims abstract description 16
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 title abstract description 9
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 title abstract description 9
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 title abstract description 9
- 238000000034 method Methods 0.000 title abstract description 7
- 239000001488 sodium phosphate Substances 0.000 title abstract description 7
- 229910000397 disodium phosphate Inorganic materials 0.000 title abstract 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000013078 crystal Substances 0.000 claims abstract description 14
- 238000000967 suction filtration Methods 0.000 claims abstract description 14
- 239000012296 anti-solvent Substances 0.000 claims abstract description 13
- 239000003960 organic solvent Substances 0.000 claims abstract description 13
- 238000001291 vacuum drying Methods 0.000 claims abstract description 8
- PNPLHKHBANFGMS-WFIJOQBCSA-N [Na].[Na].[C@@H]1([C@H](O)[C@H](O)[C@@H](COP(=O)(O)O)O1)N1C(=O)N=C(N)C=C1 Chemical compound [Na].[Na].[C@@H]1([C@H](O)[C@H](O)[C@@H](COP(=O)(O)O)O1)N1C(=O)N=C(N)C=C1 PNPLHKHBANFGMS-WFIJOQBCSA-N 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- IERHLVCPSMICTF-XVFCMESISA-N cytidine 5'-monophosphate Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(O)=O)O1 IERHLVCPSMICTF-XVFCMESISA-N 0.000 claims description 12
- 239000011734 sodium Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 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 claims description 11
- 229910052708 sodium Inorganic materials 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 7
- INTPYBRGLGSMRA-WFIJOQBCSA-L disodium cytidine 5'-monophosphate Chemical compound [Na+].[Na+].O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP([O-])([O-])=O)O1 INTPYBRGLGSMRA-WFIJOQBCSA-L 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 239000002245 particle Substances 0.000 abstract description 5
- 239000007864 aqueous solution Substances 0.000 abstract description 3
- 238000002156 mixing Methods 0.000 abstract 2
- 239000012467 final product Substances 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 229960000935 dehydrated alcohol Drugs 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 229960004756 ethanol Drugs 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- RAJMXAZJKUGYGW-POYBYMJQSA-N 2',3'-dideoxycytidine-5'-monophosphate Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](COP(O)(O)=O)CC1 RAJMXAZJKUGYGW-POYBYMJQSA-N 0.000 description 1
- ZWIADYZPOWUWEW-XVFCMESISA-N CDP Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(O)=O)O1 ZWIADYZPOWUWEW-XVFCMESISA-N 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- PCDQPRRSZKQHHS-CCXZUQQUSA-N Cytarabine Triphosphate Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 PCDQPRRSZKQHHS-CCXZUQQUSA-N 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- LPUQAYUQRXPFSQ-DFWYDOINSA-M monosodium L-glutamate Chemical compound [Na+].[O-]C(=O)[C@@H](N)CCC(O)=O LPUQAYUQRXPFSQ-DFWYDOINSA-M 0.000 description 1
- 235000013923 monosodium glutamate Nutrition 0.000 description 1
- 239000004223 monosodium glutamate Substances 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 235000008935 nutritious Nutrition 0.000 description 1
- 230000000050 nutritive effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention discloses a method for dilution crystallizationelution and crystallization of cytidine 5'-disodium phosphate. An organic solvent of 0.5-3.0 time(s) of aqueous solution of cytidine 5'-disodium phosphate is added as an anti-solvent into the aqueous solution of cytidine 5'-disodium phosphate with the pH value of 7.0-9.0 and the concentration of 10-300g/L, mixing is performed at temperature of 10-40 DEG C and at a controlled speed of 50-230rmp, suction filtration is performed after complete crystallization, the crystal is washed with ethanol, and vacuum drying is performed to obtained the cytidine 5'-disodium phosphate crystal. By adopting the method, the final product quality can be improved significantly, and the yield of the crystalline product can be increased stably. Moreover, the particle size of the crystal can be controlled by changing the mixing speed or temperature for crystallization. The method has the advantages of simpleness in operation and good repeatability and is suitable for industrial production of the cytidine 5'-disodium phosphate.
Description
Technical field
The invention belongs to the biological products manufacture field, be specifically related to the dilution crystallization method of 5'-cytidylic acid disodium.
Background technology
5'-cytidylic acid disodium (5 ' Cytidine Monophosphate Disodium Salt, 5 '-CMPNa
2) chemical formula is C
9H
12N
3Na
2O
8P.Molecular weight 367.16 is colourless to white crystals or white crystalline powder, and chemical structural formula is as follows.
Cytidine 5'-Di-Sodium Phosphate has peculiar taste, and fusing point is 300 ° of C.Water-soluble, stable in the aqueous solution.Solubleness is little in organic solvent, is dissolved in hardly the organic solvents such as methyl alcohol, ethanol.0.01mol/L the maximum absorption spectrum of hydrochloric acid soln is 279nm ± 2nm.
Cytidine 5'-disodic alkaliine can be used as the seasonings monosodium glutamate and uses with 5'-GMP2Na salt, as foodstuff additive.The 5'-cytidylic acid disodium not only can use as nutritious supplementary, nutritive food additive or makeup with other Nucleotide collocation, and it more can be used as intermediate and prepares the bio-pharmaceuticals such as cytidine diphosphate, cytosine arabinoside, cytidine triphosphate(CTP).Domestic demand to this kind biological product is larger, but because its initial raw materials for production cytidine 5'-phosphoric acid relatively lacks, need large quantities of from external import every year.
Domestic production 5'-cytidylic acid disodium is amorphous body substantially at present, the size-grade distribution of crystalline product and brilliant practise second-rately, for example product poor fluidity, proportion are little, and the amorphous products water content is lower, and unstable, make troubles for follow-up storage, transportation and use.Domestic very few to the correlative study of cytidine 5'-disodic alkaliine crystallisation process at present, and do not have relevant bibliographical information.
Summary of the invention
Technical problem to be solved by this invention provides a kind of dilution crystallization method of 5'-cytidylic acid disodium, adopt the dilution crystallization technology, improve domestic production 5'-cytidylic acid disodium size-grade distribution and brilliant practise second-rate, product dispersiveness, poor fluidity, proportion are little, make troubles for follow-up storage, transportation and use.
For solving the problems of the technologies described above, thinking of the present invention is: with an organic solvent as anti-solvent, and by control temperature and organic solvent add-on, stable 5'-cytidylic acid disodium crystalline product and the yield of improving.
Concrete technical scheme is as follows:
A kind of dilution crystallization method of 5'-cytidylic acid disodium, the pH value be 7.0 ~ 9.0 and concentration be in 5'-cytidylic acid two sodium water solutions of 10 ~ 300g/L, add volume and be the organic solvent of 0.5 ~ 3.0 times of 5'-cytidylic acid two sodium water solution as anti-solvent, temperature is at 10 ~ 40 ℃, stirring velocity is controlled at 50 ~ 250rmp, suction filtration after the crystallization fully, the washing with alcohol crystal, vacuum-drying namely gets 5'-cytidylic acid disodium salt crystal.
Wherein, the volume that adds organic solvent is preferably 0.9 ~ 2.5 times of 5'-cytidylic acid two sodium water solution volumes.
Wherein, described organic solvent is any one or a few the mixture in methyl alcohol, ethanol or the acetone.
Wherein, Tc is preferably 20 ~ 40 ℃.
Wherein, stirring velocity preferably is controlled at 80 ~ 250rmp.
Beneficial effect: the present invention has following advantage:
1, the present invention has obvious raising to crystalline product quality and yield than conventional crystallization processes, and the crystalline product stable yield is 96%, and product purity reaches more than 99%.
2, adopt suitable organic solvent as anti-solvent, can guarantee the requirement of crystallization the finished product microbiological indicator, and the 5'-cytidylic acid disodium that obtains has even particle size, be quicksand like, glossiness is good, and yield is high, easily the advantage of suction filtration.
3, crystallizing system of the present invention and preparation method's operating time short, production process is carried out at normal temperatures, need not special heating and cooling device, saves the cost fund, is easier to operation control, good reproducibility.
4, this technique can be controlled granular size by changing crystallization stirring velocity or temperature, and is simple to operate, is fit to 5'-cytidylic acid disodium suitability for industrialized production.
Description of drawings
Fig. 1 is that the present invention adopts methyl alcohol to carry out the particle photo of gained behind the dilution crystallization as anti-solvent.
Fig. 2 is that the present invention adopts ethanol to carry out the particle photo of gained behind the dilution crystallization as anti-solvent.
Fig. 3 is that the present invention adopts acetone to carry out the particle photo of gained behind the dilution crystallization as anti-solvent.
Fig. 4 is that the present invention adopts 3 kinds of different organic solvents to carry out gained crystal powder diffracting spectrum behind the dilution crystallization.
Embodiment
According to following embodiment, the present invention may be better understood.Yet, those skilled in the art will readily understand, the described content of embodiment only is used for explanation the present invention, and should also can not limit the present invention described in detail in claims.
Embodiment 1:
Be the 5'-cytidylic acid two sodium water solution 10L of 10g/L with concentration, pH7.9, water-bath is controlled at 20 ℃, under the stir speed (S.S.) condition of 150rpm, slowly adds anti-solvent dehydrated alcohol 29L.With the suspension liquid suction filtration, obtain white crystal with a small amount of washing with alcohol during suction filtration after the crystallization fully, place vacuum-drying under the interior 45 ℃ of conditions of baking oven.Crystallization yield is 95.1%, and purity is 99.1%.
Embodiment 2:
Be the 5'-cytidylic acid two sodium water solution 6L of 100g/L with concentration, pH7.0, water-bath is controlled at 10 ℃, under the stir speed (S.S.) condition of 250rpm, slowly adds anti-solvent methanol 14L.With the suspension liquid suction filtration, obtain white crystal with a small amount of washing with alcohol during suction filtration after the crystallization fully, place vacuum-drying under the interior 45 ℃ of conditions of baking oven.Crystallization yield is 96.2%, and purity is 99.3%.
Embodiment 3:
Be the 5'-cytidylic acid two sodium water solution 2L of 180g/L with concentration, pH8.0, water-bath is controlled at 30 ℃, under the stir speed (S.S.) condition of 200rpm, slowly adds anti-solvent dehydrated alcohol 4.4L.With the suspension liquid suction filtration, obtain white crystal with a small amount of washing with alcohol during suction filtration after the crystallization fully, place vacuum-drying under the interior 45 ℃ of conditions of baking oven.Crystallization yield is 95.7%, and purity is 99.5%.
Embodiment 4:
Be the 5'-cytidylic acid two sodium water solution 100L of 250g/L with concentration, pH7.6, water-bath is controlled at 35 ℃, under the stir speed (S.S.) condition of 230rpm, slowly adds anti-solvent acetone 210L.With the suspension liquid suction filtration, obtain white crystal with a small amount of washing with alcohol during suction filtration after the crystallization fully, place vacuum-drying under the interior 45 ℃ of conditions of baking oven.Crystallization yield is 96.3%, and purity is 99.3%.
Embodiment 5:
Be the 5'-cytidylic acid two sodium water solution 150L of 300g/L with concentration, pH7.0, water-bath is controlled at 40 ℃, under the stir speed (S.S.) condition of 200rpm, slowly adds anti-solvent dehydrated alcohol 280L.With the suspension liquid suction filtration, obtain white crystal with a small amount of washing with alcohol during suction filtration after the crystallization fully, place vacuum-drying under the interior 45 ℃ of conditions of baking oven.Crystallization yield is 95.8%, and purity is 99.3%.
Claims (5)
1. the dilution crystallization method of a 5'-cytidylic acid disodium, it is characterized in that, the pH value be 7.0 ~ 9.0 and concentration be in 5'-cytidylic acid two sodium water solutions of 10 ~ 300g/L, add volume and be the organic solvent of 0.5 ~ 3.0 times of 5'-cytidylic acid two sodium water solution as anti-solvent, temperature is at 10 ~ 40 ℃, and stirring velocity is controlled at 50 ~ 250rmp, suction filtration after the crystallization fully, washing with alcohol crystal, vacuum-drying namely get 5'-cytidylic acid disodium salt crystal.
2. the dilution crystallization method of 5'-cytidylic acid disodium according to claim 1 is characterized in that, the volume that adds organic solvent is 0.9 ~ 2.5 times of 5'-cytidylic acid two sodium water solution volumes.
3. the dilution crystallization method of 5'-cytidylic acid disodium according to claim 1 and 2 is characterized in that, described organic solvent is any one or a few the mixture in methyl alcohol, ethanol or the acetone.
4. the dilution crystallization method of 5'-cytidylic acid disodium according to claim 1 is characterized in that, Tc is 20 ~ 40 ℃.
5. the dilution crystallization method of 5'-cytidylic acid disodium according to claim 1 is characterized in that, stirring velocity is controlled at 80 ~ 250rmp.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103319557A (en) * | 2013-07-17 | 2013-09-25 | 南京工业大学 | Crystallization method of cyclic adenosine monophosphate |
| CN103435669A (en) * | 2013-09-09 | 2013-12-11 | 南京工业大学 | Solvent-out crystallization method for uridine-5'-monophosphate disodium |
| CN104163842A (en) * | 2014-07-15 | 2014-11-26 | 南通香地生物有限公司 | Method for producing cytidine monophosphate disodium salt |
| CN106928297A (en) * | 2017-03-10 | 2017-07-07 | 南京工业大学 | A kind of method of oil analysis conversion regulation and control Sodium guanylate crystallization process |
| CN107712345A (en) * | 2017-10-17 | 2018-02-23 | 南京工业大学 | A kind of mixture of ribonucleotides crystal powder and preparation method thereof |
| CN110790684A (en) * | 2019-12-09 | 2020-02-14 | 武汉科技大学 | Method for producing urea phosphate by using wet-process phosphoric acid as raw material through elution crystallization |
| CN112521436A (en) * | 2020-12-08 | 2021-03-19 | 吉林百年汉克制药有限公司 | Preparation method of 5' -cytidylic acid derivative and application of derivative in citicoline, citicoline sodium and injection thereof |
| CN114044526A (en) * | 2021-12-10 | 2022-02-15 | 郑州中科新兴产业技术研究院 | Separation method of mixed salt containing sodium sulfate and sodium chloride |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103319557A (en) * | 2013-07-17 | 2013-09-25 | 南京工业大学 | Crystallization method of cyclic adenosine monophosphate |
| CN103435669A (en) * | 2013-09-09 | 2013-12-11 | 南京工业大学 | Solvent-out crystallization method for uridine-5'-monophosphate disodium |
| CN104163842A (en) * | 2014-07-15 | 2014-11-26 | 南通香地生物有限公司 | Method for producing cytidine monophosphate disodium salt |
| CN106928297A (en) * | 2017-03-10 | 2017-07-07 | 南京工业大学 | A kind of method of oil analysis conversion regulation and control Sodium guanylate crystallization process |
| CN106928297B (en) * | 2017-03-10 | 2019-10-29 | 南京工业大学 | A kind of method of oil analysis conversion regulation Sodium guanylate crystallization process |
| CN107712345A (en) * | 2017-10-17 | 2018-02-23 | 南京工业大学 | A kind of mixture of ribonucleotides crystal powder and preparation method thereof |
| CN110790684A (en) * | 2019-12-09 | 2020-02-14 | 武汉科技大学 | Method for producing urea phosphate by using wet-process phosphoric acid as raw material through elution crystallization |
| CN112521436A (en) * | 2020-12-08 | 2021-03-19 | 吉林百年汉克制药有限公司 | Preparation method of 5' -cytidylic acid derivative and application of derivative in citicoline, citicoline sodium and injection thereof |
| CN114044526A (en) * | 2021-12-10 | 2022-02-15 | 郑州中科新兴产业技术研究院 | Separation method of mixed salt containing sodium sulfate and sodium chloride |
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Application publication date: 20130306 |