Crystallization method of uridine monophosphate disodium
By adjusting the pH value and temperature of the aqueous disodium uridate solution, adding anti-solvent and vacuum-growing and stirring crystallization, the problems of low bulk density and poor fluidity during the crystallization of disodium uridate were solved, and high bulk density, good fluidity and high purity disodium uridate crystals were achieved.
Patent Information
- Application Number
- CN202411727052.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-28
- Publication Date
- 2025-02-28
AI Technical Summary
In the prior art, there are problems of low bulk density and poor liquidity during the crystallization process of disodium uridine, resulting in poor product quality and inconvenient storage and transportation.
By adjusting the pH and temperature of the crude aqueous solution of disodium uridate, adding anti-solvent, vacuum cultivation and stirring of crystallization, finally, disodium uridate crystals were obtained by solid-liquid separation.
It improves the bulk density and fluidity of disodium uridine crystals, ensures the high purity and good flow performance of the product, and avoids the problems of easy clumping and inconvenient storage and transportation.
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of crystallization and relates to a crystallization method of disodium uridine monophosphate. Background Art
[0002] With the development of biotechnology industry and pharmaceutical industry, the research and development of nucleotides and their derivatives has become a hot topic and has gradually formed another major industry after amino acids. Nucleotides are a class of biochemical substances with high added value and are widely used, supporting the development of some large industries, such as high-end dairy industry and pharmaceutical industry. As a functional additive in the dairy industry, its addition can make milk powder closer to breast milk, effectively enhance the ability of infants and young children to resist bacterial dysentery, and reduce the occurrence of diarrhea; in the pharmaceutical field, nucleotides are the raw materials for the production of many nucleotide derivatives as pharmaceutical intermediates, and are used to synthesize hundreds of compounds such as CDP, UDP, GTP, CDP-choline, SAM, cGMP, CTP, UTP, cAMP, UDP-acetylglucosamine, GDP-mannose, GDP-glucose, UDP-glucose, etc. Nucleotide drugs have unique therapeutic effects in anti-cancer, anti-viral, treatment of cardiovascular diseases, diabetes and interference induction, and have good application effects and a huge application market.
[0003] Generally, nucleotide crystallization is carried out by low-temperature alcohol precipitation. This method is prone to heterogeneous nucleation, resulting in impurities being embedded, uneven product size, and poor product quality. Nucleotides with low bulk density and poor fluidity not only cannot ensure uniform loading during the production process, but also have a large packaging volume that is inconvenient for storage and transportation. Therefore, it is particularly important to find a method for preparing nucleotide crystals with high bulk density and good fluidity. Summary of the invention
[0004] The technical problem to be solved by the present invention is to provide a crystallization method for improving the bulk density and fluidity of disodium uridine monophosphate in view of the problems existing in the crystallization process of disodium uridine monophosphate in the prior art.
[0005] In order to solve the above technical problems, the technical solution adopted by the present invention is as follows:
[0006] The present invention discloses a crystallization method of disodium uridine monophosphate, comprising the following steps:
[0007] (1) adjusting the pH of the aqueous solution of the crude disodium uridine monophosphate and then cooling it, and adding an anti-solvent to the aqueous solution of the crude disodium uridine monophosphate at a controlled stirring speed;
[0008] (2) When the aqueous solution of the crude disodium uridine monophosphate becomes turbid, the stirring is stopped, the addition of the anti-solvent is stopped, and vacuum crystal growth is performed;
[0009] (3) After the crystal growth is completed, the vacuum is removed, the temperature is continued to be lowered, the stirring speed is controlled to perform stirring crystallization, and the anti-solvent is continued to be added;
[0010] (4) After the anti-solvent is added, continue to control the stirring speed and stir, and finally separate the solid and liquid to obtain disodium uridine monophosphate crystals.
[0011] In some embodiments, in step (1), the concentration of crude disodium uridine monophosphate in the crude disodium uridine monophosphate aqueous solution is 10-30 wt%; the pH is adjusted to 6.0-8.0; the temperature is lowered to 15-20°C; and the stirring speed is less than 100 rpm.
[0012] In some embodiments, preferably, in step (1), the concentration of crude disodium uridine monophosphate in the crude disodium uridine monophosphate aqueous solution is 18-30 wt %, more preferably 18 wt %.
[0013] In some embodiments, preferably, in step (1), the pH is adjusted to 7.0 to 7.5, and more preferably to 7.2.
[0014] In some embodiments, preferably, in step (1), the cooling is to reduce the temperature to 15-18°C, more preferably to 18°C.
[0015] In some embodiments, in step (1), the anti-solvent is any one or a combination of methanol, ethanol, isopropanol and n-butanol; the anti-solvent is added at a rate of 8% to 14% of the crude aqueous solution of disodium uridine monophosphate by volume / h.
[0016] In some embodiments, in step (3), the anti-solvent is any one or a combination of methanol, ethanol, isopropanol and n-butanol; the anti-solvent is added at a rate of 8% to 14% of the crude aqueous solution of disodium uridine monophosphate by volume / h.
[0017] In some embodiments, preferably, in step (1) or step (3), the anti-solvent is ethanol.
[0018] Wherein, the anti-solvents are all anhydrous solvents.
[0019] In some embodiments, preferably, in step (1), the anti-solvent is added at a rate of 10% crude disodium uridine monophosphate aqueous solution volume / h.
[0020] In some embodiments, preferably, in step (3), the anti-solvent is added at a rate of 10% crude disodium uridine monophosphate aqueous solution volume / h.
[0021] In some embodiments, in step (2), the crystal growing is carried out at -0.080MPa to -0.098MPa; the crystal growing temperature is 15 to 20°C, and the crystal growing time is 1 to 10 hours.
[0022] In some embodiments, preferably, in step (2), the crystal growing is carried out at -0.085 MPa to -0.097 MPa, more preferably at -0.090 MPa to -0.097 MPa, and even more preferably at -0.095 MPa.
[0023] In some embodiments, preferably, in step (2), the crystal growing temperature is 15-20°C, more preferably 15-18°C, and even more preferably 18°C.
[0024] In some embodiments, preferably, in step (2), the crystal growing time is 1 to 6 hours, more preferably 1 to 3 hours, and even more preferably 3 hours.
[0025] In some embodiments, in step (3), the cooling is to reduce the temperature to 10-15°C; the stirring speed is less than 100 rpm; and the stirred crystallization is carried out under normal pressure.
[0026] In some embodiments, preferably, in step (3), the cooling is to reduce the temperature to 10-12°C, more preferably to 10°C.
[0027] In some embodiments, in step (3), the stirring crystallization time is based on the amount of anti-solvent added, and the crystallization time is until the total amount of anti-solvent added reaches 2.0 to 3.5 times the volume of the crude sodium disodium uridine monophosphate aqueous solution.
[0028] In some embodiments, preferably, in step (3), the stirring crystallization time is based on the amount of anti-solvent added, and the crystallization time is until the total amount of anti-solvent added reaches 2.0 to 3.0 times the volume of the crude sodium disodium uridine monophosphate aqueous solution.
[0029] In some embodiments, further preferably, in step (3), the stirring crystallization time is based on the amount of anti-solvent added, and the crystallization time is until the total amount of anti-solvent added reaches 2.5 times the volume of the crude sodium disodium uridine monophosphate aqueous solution.
[0030] In some embodiments, in step (4), the stirring is performed at 8-12°C.
[0031] In some embodiments, preferably, in step (4), the stirring is performed at 10-12°C.
[0032] In some embodiments, further preferably, in step (4), the stirring is performed at 10°C.
[0033] In some embodiments, in step (4), the stirring speed is less than 100 rpm and the stirring time is 1.5 to 3.0 h.
[0034] In some embodiments, preferably, in step (4), the stirring speed is less than 100 rpm, and the stirring time is 2.0 to 3.0 h, more preferably 3.0 h.
[0035] In some embodiments, preferably, a 10-30 wt% crude disodium uridine monophosphate aqueous solution is adjusted to pH 6.0-8.0 and then added to a crystallizer, cooled to 15-20° C., and an antisolvent is added dropwise to the crude disodium uridine monophosphate aqueous solution at a flow rate of 8-12% of the crude disodium uridine monophosphate aqueous solution volume / h, while stirring at a stirring speed of less than 100 rpm; when the crude disodium uridine monophosphate aqueous solution becomes turbid, stirring is stopped, the addition of the antisolvent is stopped, and the internal pressure of the crystallizer is evacuated to vacuum for vacuum crystal cultivation; After the crystal growing is completed, the vacuum is removed, the temperature is lowered to 10-15°C, and the solution is stirred at a stirring speed of less than 100 rpm for stirring crystallization, while the anti-solvent is continuously added at a flow rate of 8-12% of the volume of the crude sodium uridine monophosphate aqueous solution / h until the total amount of the anti-solvent added reaches 2.0-3.5 times the volume of the crude sodium uridine monophosphate aqueous solution; after the anti-solvent is added, the solution is stirred at 8-12°C at a stirring speed of less than 100 rpm for 1.5-3.0 hours, and then solid-liquid separation is performed, the solid is washed, and dried to obtain sodium uridine monophosphate crystals.
[0036] In some embodiments, it is further preferred that the 18-30 wt% crude sodium uridine monophosphate aqueous solution is adjusted to pH 7.0-7.5 and then added to the crystallizer, cooled to 15-18° C., and an anti-solvent is added dropwise to the crude sodium uridine monophosphate aqueous solution at a flow rate of 8-12% of the crude sodium uridine monophosphate aqueous solution volume / h, while stirring at a stirring speed of less than 100 rpm; when the crude sodium uridine monophosphate aqueous solution becomes turbid, stirring is stopped, the addition of the anti-solvent is stopped, and the internal pressure of the crystallizer is evacuated to vacuum for vacuum crystal cultivation After the crystal growing is completed, the vacuum is removed, the temperature is lowered to 10-12°C and the solution is stirred at a stirring speed of less than 100 rpm for stirring crystallization, and the anti-solvent is continuously added at a flow rate of 8-12% of the volume of the crude aqueous solution of disodium uridine monophosphate / h until the total amount of the anti-solvent added reaches 2.0-3.0 times the volume of the crude aqueous solution of disodium uridine monophosphate; after the anti-solvent is added, the solution is stirred at 10-12°C at a stirring speed of less than 100 rpm for 1.5-3.0 hours, and then solid-liquid separation is performed, the solid is washed, and dried to obtain disodium uridine monophosphate crystals.
[0037] In some embodiments, it is further preferred that the 18 wt% crude disodium uridine monophosphate aqueous solution is adjusted to pH 7.2 and then added to a crystallizer, cooled to 18°C, and an anti-solvent is added dropwise to the crude disodium uridine monophosphate aqueous solution at a flow rate of 10% of the crude disodium uridine monophosphate aqueous solution volume / h, and stirred at a stirring speed of less than 100 rpm; when the crude disodium uridine monophosphate aqueous solution becomes turbid, stirring is stopped, the addition of the anti-solvent is stopped, and the internal pressure of the crystallizer is evacuated to vacuum for vacuum crystal cultivation; after the crystal cultivation is completed, the vacuum is removed, the temperature is reduced to 10°C and stirred at a stirring speed of less than 100 rpm for stirred crystallization, and the anti-solvent is continued to be added dropwise at a flow rate of 10% of the crude disodium uridine monophosphate aqueous solution volume / h until the total amount of the anti-solvent added reaches 2.5 times the volume of the crude disodium uridine monophosphate aqueous solution; after the anti-solvent is added dropwise, stirring is continued at 10°C at a stirring speed of less than 100 rpm for 3.0 hours, and then solid-liquid separation, solid washing, and drying are performed to obtain disodium uridine monophosphate crystals.
[0038] In some embodiments, the pH of the crude disodium uridine monophosphate aqueous solution is adjusted to 6.0-8.0, and the pH is adjusted to 6.0-8.0 using an alkaline solution, wherein the alkaline solution is a conventionally used alkaline aqueous solution, such as an aqueous sodium carbonate solution, an aqueous sodium bicarbonate solution, or an aqueous sodium hydroxide solution, preferably an aqueous sodium hydroxide solution, further preferably a 25-50 wt % aqueous sodium hydroxide solution, and further preferably a 30 wt % aqueous sodium hydroxide solution.
[0039] In some embodiments, the drying is vacuum drying, the drying temperature is 30-50° C., and the drying time is 5-15 hours.
[0040] In some embodiments, preferably, the drying is vacuum drying, the drying temperature is 35-45°C, more preferably 38-42°C, and further preferably 40°C; the drying time is 5-12h, more preferably 8-12h, and further preferably 10h.
[0041] In some embodiments, the bulk density of the disodium uridine monophosphate crystals is 0.60 g / mL to 0.92 g / mL, and the purity is 99.0% to 99.5%.
[0042] Beneficial effects:
[0043] (1) In the crystallization method of disodium uridine monophosphate crystals provided by the present invention, vacuum crystal cultivation and step temperature crystallization are introduced in the process of disodium uridine monophosphate crystallization, and the obtained disodium uridine monophosphate crystals have high bulk density, good fluidity and high purity, avoiding the problems of easy agglomeration of the later product, uneven filling amount and excessive volume.
[0044] (2) The method provided by the present invention is simple and easy to operate, and is simple to industrially scale up and transform, thus being suitable for large-scale industrial applications. DETAILED DESCRIPTION
[0045] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.
[0046] The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials described are commercially available unless otherwise specified.
[0047] In the following embodiments, the method for detecting the parameters of the crystal is as follows:
[0048] 1. Crystal bulk density detection method:
[0049] Take a quantity of powder sufficient to complete the test and pass it through a sieve with an aperture greater than 1.0 mm. Place it in a dry, graduated 250 mL measuring cylinder (readable to 2 mL) and gently introduce, without compacting, about 100 grams (m) of the test sample, with an accuracy of 0.1%. Spread the powder carefully, without compression, and read the unit volume (V) to the nearest scale mark when untreated. Bulk density = m / V g / mL.
[0050] 2. The bulk density and purity parameters of the crude disodium uridine monophosphate used in the following examples of the present invention are as follows: the bulk density of the crude disodium uridine monophosphate is 0.22 g / mL, and the purity is 95.0%.
[0051] Embodiment 1:
[0052] Take 100g of crude disodium uridine monophosphate, prepare 555mL of aqueous solution with a concentration of 180g / L, stir and dissolve, use 30wt% sodium hydroxide aqueous solution to adjust pH to 7.2, obtain disodium uridine monophosphate aqueous solution, and place in a crystallizer; cool the disodium uridine monophosphate aqueous solution crystallization system to 18°C, add anhydrous ethanol at a rate of 55.5mL / h, and stir at a speed of less than 100rpm; when the disodium uridine monophosphate aqueous solution becomes turbid, stop stirring, stop adding anhydrous ethanol, start to evacuate the internal pressure of the crystallization container to -0.095MPa, and grow crystals at 18°C for 3h. After growing crystals, remove the vacuum, then reduce the temperature of the crystallization system to 10°C, stir and crystallize at normal pressure and a speed of less than 100rpm, and continue to add anhydrous ethanol at a flow rate of 55.5mL / h, and finally add anhydrous ethanol The total volume of 1387.5mL. After the addition of anhydrous ethanol was completed, the mixture was stirred at a speed of less than 100 rpm and 10° C. for 3 h, separated by a centrifuge, the solid was washed with anhydrous ethanol, and vacuum dried at 40° C. for 10 h to obtain disodium uridine monophosphate crystals with a bulk density of 0.92 g / mL and a purity of 99.5%.
[0053] Embodiment 2:
[0054] Take 100g of crude disodium uridine monophosphate, prepare 500mL of aqueous solution with a concentration of 200g / L, stir and dissolve, use 30wt% sodium hydroxide aqueous solution to adjust the pH to 7.4, obtain disodium uridine monophosphate aqueous solution, and place it in a crystallizer; cool the disodium uridine monophosphate aqueous solution crystallization system to 15°C, add anhydrous ethanol at a rate of 50mL / h, and stir at a speed of less than 100rpm; when the disodium uridine monophosphate aqueous solution becomes turbid, stop stirring, stop adding anhydrous ethanol, start to evacuate the internal pressure of the crystallization container to -0.093MPa, and grow crystals at 15°C for 2h. After growing crystals, remove the vacuum, then reduce the temperature of the crystallization system to 12°C, stir and crystallize at normal pressure and a speed of less than 100rpm, and continue to add anhydrous ethanol at a flow rate of 50mL / h, and finally add anhydrous ethanol to a total volume of 1250mL. After the addition of anhydrous ethanol was completed, the mixture was stirred at a speed of less than 100 rpm and 12° C. for 3 h, separated by a centrifuge, the solid was washed with anhydrous ethanol, and vacuum dried at 40° C. for 8 h to obtain disodium uridine monophosphate crystals with a bulk density of 0.75 g / mL and a purity of 99.2%.
[0055] Embodiment 3:
[0056] Take 100g of crude disodium uridine monophosphate, prepare 333mL of aqueous solution with a concentration of 300g / L, stir and dissolve, use 30wt% sodium hydroxide aqueous solution to adjust pH to 7.1, obtain disodium uridine monophosphate aqueous solution, and place in a crystallizer; cool the disodium uridine monophosphate aqueous solution crystallization system to 16°C, add anhydrous ethanol at a rate of 33.3mL / h, and stir at a speed of less than 100rpm; when the disodium uridine monophosphate aqueous solution becomes turbid, stop stirring, stop adding anhydrous ethanol, start to evacuate the internal pressure of the crystallization container to -0.090MPa, and grow crystals at 16°C for 3h. After growing crystals, remove the vacuum, then reduce the temperature of the crystallization system to 11°C, stir and crystallize at normal pressure and a speed of less than 100rpm, and continue to add anhydrous ethanol at a flow rate of 33.3mL / h, and finally add anhydrous ethanol to a total volume of 832.5mL. After the addition of anhydrous ethanol was completed, the mixture was stirred at a speed of less than 100 rpm and 11° C. for 3 h, separated by centrifuge, the solid was washed with anhydrous ethanol, and vacuum dried at 40° C. for 9 h to obtain disodium uridine monophosphate crystals with a bulk density of 0.72 g / mL and a purity of 99.0%.
[0057] Embodiment 4:
[0058] Take 100g of crude disodium uridine monophosphate, prepare 555mL of aqueous solution with a concentration of 180g / L, stir and dissolve, use 30wt% sodium hydroxide aqueous solution to adjust pH to 7.2, obtain disodium uridine monophosphate aqueous solution, and place in a crystallizer; cool the disodium uridine monophosphate aqueous solution crystallization system to 18°C, add anhydrous ethanol at a rate of 77.7mL / h, and stir at a speed of less than 100rpm; when the disodium uridine monophosphate aqueous solution becomes turbid, stop stirring, stop adding anhydrous ethanol, start to evacuate the internal pressure of the crystallization container to -0.095MPa, and grow crystals at 18°C for 1h. After growing crystals, remove the vacuum, then reduce the temperature of the crystallization system to 10°C, stir and crystallize at normal pressure and a speed of less than 100rpm, and continue to add anhydrous ethanol at a flow rate of 77.7mL / h, and finally add anhydrous ethanol to a total volume of 1387.5mL. After the addition of anhydrous ethanol was completed, the mixture was stirred at a speed of less than 100 rpm and 10° C. for 3 h, separated by a centrifuge, the solid was washed with anhydrous ethanol, and vacuum dried at 40° C. for 10 h to obtain disodium uridine monophosphate crystals with a bulk density of 0.79 g / mL and a purity of 99.4%.
[0059] Embodiment 5:
[0060] The preparation method of disodium uridine monophosphate crystals is the same as that of Example 1, except that the anti-solvent anhydrous ethanol is replaced by anhydrous methanol. The bulk density of the obtained disodium uridine monophosphate crystals is 0.68 g / mL and the purity is 99.0%.
[0061] Embodiment 6:
[0062] The preparation method of disodium uridine monophosphate crystals is the same as that of Example 1, except that the anti-solvent anhydrous ethanol is replaced by anhydrous isopropanol. The obtained disodium uridine monophosphate crystals have a bulk density of 0.73 g / mL and a purity of 99.2%.
[0063] Embodiment 7:
[0064] The preparation method of disodium uridine monophosphate crystals is the same as that of Example 1, except that the anti-solvent anhydrous ethanol is replaced by anhydrous n-butanol. The obtained disodium uridine monophosphate crystals have a bulk density of 0.75 g / mL and a purity of 99.1%.
[0065] Comparative Example 1: No real pressure
[0066] Take 100g of crude disodium uridylate, prepare 555mL of aqueous solution with a concentration of 180g / L, stir and dissolve, use 30wt% sodium hydroxide aqueous solution to adjust the pH to 7.2, obtain disodium uridylate aqueous solution, and place it in a crystallizer; cool the disodium uridylate aqueous solution crystallization system to 18°C, add anhydrous ethanol at a rate of 55.5mL / h, and stir at a speed of less than 100rpm; when the disodium uridylate aqueous solution becomes turbid, stop stirring, stop adding anhydrous ethanol, and grow crystals at 18°C for 3h. After the crystal growth is completed, the temperature of the crystallization system is lowered to 10°C, and stirred crystallization is carried out at normal pressure and a speed of less than 100rpm, while continuing to add anhydrous ethanol at a flow rate of 55.5mL / h, and the total volume of anhydrous ethanol added is finally 1387.5mL. After the addition of anhydrous ethanol was completed, the mixture was stirred at a speed of less than 100 rpm and 10° C. for 3 h, separated by a centrifuge, the solid was washed with anhydrous ethanol, and vacuum dried at 40° C. for 10 h to obtain disodium uridine monophosphate crystals with a bulk density of 0.74 g / mL and a purity of 99.1%.
[0067] Comparative Example 2: No stage temperature control
[0068] Take 100g of crude disodium uridine monophosphate, prepare 555mL of aqueous solution with a concentration of 180g / L, stir and dissolve, use 30wt% sodium hydroxide aqueous solution to adjust pH to 7.2, obtain disodium uridine monophosphate aqueous solution, and place in a crystallizer; cool the disodium uridine monophosphate aqueous solution crystallization system to 18°C, add anhydrous ethanol at a rate of 55.5mL / h, and stir at a speed of less than 100rpm; when the disodium uridine monophosphate aqueous solution becomes turbid, stop stirring, stop adding anhydrous ethanol, start to evacuate the internal pressure of the crystallization container to -0.095MPa, and grow crystals at 18°C for 3h. After growing crystals, remove the vacuum, stir and crystallize at normal pressure and a speed of less than 100rpm, and continue to add anhydrous ethanol at a flow rate of 55.5mL / h, and finally add anhydrous ethanol to a total volume of 1387.5mL. After the addition of anhydrous ethanol was completed, the mixture was stirred at a speed of less than 100 rpm and 18° C. for 3 h, separated by a centrifuge, the solid was washed with anhydrous ethanol, and vacuum dried at 40° C. for 10 h to obtain disodium uridine monophosphate crystals with a bulk density of 0.73 g / mL and a purity of 99.0%.
[0069] Comparative Example 3: No crystal growth
[0070] 100 g of crude disodium uridylate was prepared into 555 mL of an aqueous solution with a concentration of 180 g / L, which was stirred and dissolved, and a 30 wt % sodium hydroxide aqueous solution was used to adjust the pH to 7.2 to obtain an aqueous solution of disodium uridylate, which was placed in a crystallizer; the crystallization system of the aqueous solution of disodium uridylate was cooled to 18° C., and anhydrous ethanol was added dropwise at a rate of 55.5 mL / h, while stirring at a speed of less than 100 rpm; when the aqueous solution of disodium uridylate became turbid, the temperature of the crystallization system was lowered to 10° C., and stirred and crystallized at normal pressure and a speed of less than 100 rpm, while anhydrous ethanol was continuously added dropwise at a flow rate of 55.5 mL / h, and the total volume of anhydrous ethanol added dropwise was finally 1387.5 mL. After the addition of anhydrous ethanol was completed, the mixture was stirred at a speed of less than 100 rpm and 10° C. for 3 h, separated by a centrifuge, the solid was washed with anhydrous ethanol, and vacuum dried at 40° C. for 10 h to obtain disodium uridine monophosphate crystals with a bulk density of 0.68 g / mL and a purity of 98.7%.
[0071] The present invention provides a method and idea for the crystallization of disodium uridine monophosphate. There are many methods and approaches to realize the technical solution. The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the protection scope of the present invention. All components not specified in this embodiment can be realized by existing technologies.
Claims
1. A method for crystallizing disodium uridine monophosphate, characterized in that: The steps include: (1) adjusting the pH of the crude disodium uridine monophosphate aqueous solution, cooling it, and adding an antisolvent to the crude disodium uridine monophosphate aqueous solution at a controlled stirring speed; (2) When the aqueous solution of the crude disodium uridine monophosphate becomes turbid, the stirring is stopped, the addition of the anti-solvent is stopped, and vacuum crystal growth is performed; (3) After the crystal growth is completed, the vacuum is removed, the temperature is continued to be lowered, the stirring speed is controlled to perform stirring crystallization, and the anti-solvent is continued to be added; (4) After the anti-solvent is added, continue to control the stirring speed and stir, and finally separate the solid and liquid to obtain disodium uridine monophosphate crystals.
2. The crystallization method according to claim 1, characterized in that In step (1), the concentration of the crude disodium uridine monophosphate in the crude disodium uridine monophosphate aqueous solution is 10-30wt%; the pH is adjusted to 6.0-8.0; the temperature is lowered to 15-20°C; and the stirring speed is less than 100rpm.
3. The crystallization method according to claim 1, characterized in that In step (1) or step (3), the anti-solvent is any one of methanol, ethanol, isopropanol and n-butanol or a combination thereof; the anti-solvent is added at a rate of 8% to 14% of the crude aqueous solution of disodium uridine monophosphate by volume / h.
4. The crystallization method according to claim 1, characterized in that In step (2), the crystal growing is carried out at -0.080MPa to -0.098MPa; the crystal growing temperature is 15 to 20°C and the crystal growing time is 1 to 10 hours.
5. The crystallization method according to claim 1, characterized in that In step (3), the cooling is to reduce the temperature to 10-15° C.; the stirring speed is less than 100 rpm; and the stirred crystallization is carried out under normal pressure.
6. The crystallization method according to claim 1, characterized in that In step (3), the stirring crystallization time is based on the amount of anti-solvent added, and the crystallization time is until the total amount of anti-solvent added reaches 2.0 to 3.5 times the volume of the crude disodium uridine monophosphate aqueous solution.
7. The crystallization method according to claim 1, characterized in that In step (4), the stirring is carried out at 8-12°C.
8. The crystallization method according to claim 1, characterized in that In step (4), the stirring speed is less than 100 rpm and the stirring time is 1.5 to 3.0 h.
9. The crystallization method according to claim 1, characterized in that A 10-30 wt% aqueous solution of crude disodium uridine monophosphate is adjusted to pH 6.0-8.0 and then added to a crystallizer, cooled to 15-20° C., and an antisolvent is added dropwise to the aqueous solution of crude disodium uridine monophosphate at a flow rate of 8-12% of the aqueous solution volume / h, while stirring at a stirring speed of less than 100 rpm; when the aqueous solution of crude disodium uridine monophosphate becomes turbid, stirring and adding the antisolvent are stopped, and the internal pressure of the crystallizer is evacuated to vacuum for vacuum crystal cultivation; after the crystal cultivation is completed, the crystallizer is unloaded; The vacuum is removed, the temperature is lowered to 10-15° C. and the mixture is stirred at a stirring speed of less than 100 rpm for stirring crystallization, while the anti-solvent is continuously added dropwise at a flow rate of 8-12% of the volume of the crude sodium uridine monophosphate aqueous solution / h until the total amount of the anti-solvent added reaches 2.0-3.5 times the volume of the crude sodium uridine monophosphate aqueous solution; after the anti-solvent is added dropwise, the mixture is stirred at a stirring speed of less than 100 rpm for 1.5-3.0 h at 8-12° C., and then solid-liquid separation is performed, the solid is washed, and the solid is dried to obtain sodium uridine monophosphate crystals.
10. The crystallization method according to claim 1, characterized in that The 18-30wt% crude disodium uridine monophosphate aqueous solution is adjusted to pH 7.0-7.5 and then added to a crystallizer, cooled to 15-18°C, and an anti-solvent is added dropwise to the crude disodium uridine monophosphate aqueous solution at a flow rate of 8-12% of the crude disodium uridine monophosphate aqueous solution volume / h, while stirring at a stirring speed of less than 100 rpm; when the crude disodium uridine monophosphate aqueous solution becomes turbid, stirring and adding the anti-solvent are stopped, and the internal pressure of the crystallizer is evacuated to vacuum crystal growth; after the crystal growth is completed, the anti-solvent is unloaded. The method comprises the following steps: vacuum, reducing the temperature to 10-12° C., stirring at a stirring speed of less than 100 rpm for stirring crystallization, and continuously adding an anti-solvent at a flow rate of 8-12% of the volume of the crude aqueous solution of disodium uridine monophosphate / h until the total amount of the anti-solvent added reaches 2.0-3.0 times the volume of the crude aqueous solution of disodium uridine monophosphate; after the anti-solvent is added, stirring is continued at 10-12° C. at a stirring speed of less than 100 rpm for 1.5-3.0 hours, followed by solid-liquid separation, washing the solid, and drying to obtain disodium uridine monophosphate crystals.