The invention relates to 2apos; -deoxycytidine crystal, preparation method and device

Abstract

The invention relates to the technical field of preparation of 2 '-deoxycytidine crystals, and provides a 2'-deoxycytidine crystal, and a preparation method and device thereof. The method comprises the following steps: S100, dissolving 2 '-deoxycytidine in acetone to prepare a raw material solution, and adding the raw material solution into a preparation device; s200, stirring is conducted, so that a Taylor vortex flow field is formed in the preparation device, water is dropwise added into the preparation device and mixed with the raw material liquid, mixed liquid is obtained, and the volume ratio of the water to the raw material liquid is 1: 3-2: 3; s300, cooling the mixed solution at a cooling rate of 5.25 DEG C / h-6. 67 DEG C / h, cooling to 0-5 DEG C, and keeping for 8-14 hours to obtain a solid-liquid mixture; and S400, filtering and drying the solid-liquid mixture to obtain a 2 '-deoxycytidine crystal. The crystallization degree of the 2 '-deoxycytidine crystal is improved, the crystal coalescence is reduced, the operation is simple, and the cost is reduced.

Description

Technical Field

[0001] The present invention relates to the technical field of 2'-deoxycytidine crystal preparation, and in particular to a 2'-deoxycytidine crystal, a preparation method and a device. Background Art

[0002] With the continuous development and progress of biotechnology, nucleic acid drugs, as a new type of treatment, are gradually becoming a research hotspot in the medical field. Nucleic acid drugs have the advantages of high efficiency, strong targeting and low side effects, and are widely used in gene therapy, anti-tumor and immunomodulation. N4-benzoyl-5'-O-(4,4'-dimethoxytriphenyl)-2'-deoxycytidine is referred to as 2'-deoxycytidine. As an oligonucleotide, it can not only be used to synthesize oligodeoxynucleotides containing 3'-S-phosphorothioate (3'-PS) linkages, but also can be used as a DNA modifier, a DNA synthesis blocker and a tool for other biological activity research. It is also a useful tool for detecting enzyme-catalyzed cleavage processes in DNA.

[0003] However, no matter what method is used to produce 2'-deoxycytidine, impurities must be removed by purification to obtain a finished product with qualified purity. The existing purification methods in the industry are mainly column chromatography, reprecipitation, and crystallization. Among them, the crystallization method is simple to operate, low in cost, and can obtain high-purity products for industrial mass production.

[0004] The 2'-deoxycytidine crystallization method mentioned in Chinese patent CN1467216A mainly uses acetone as a good solvent and water as an anti-solvent to stand and crystallize at -15°C. The 2'-deoxycytidine crystals produced by this method are severely agglomerated, poor in crystallinity, and uneven in particle size distribution. The method is time-consuming and cannot be used for mass production.

[0005] In view of this, the most common method currently on the market is to use a crystallizer for stirred crystallization. However, the flow field generated by the crystallizer is a non-uniform turbulent flow field with uneven velocity distribution. The closer to the stirring paddle, the stronger the turbulence and the more violent the fluid flow. Although this will shorten the crystallization time, it will lead to different crystal product shapes and uneven particle size distribution. At the same time, since the two ends of the anchor-type stirring paddle are sharp, it will also cause additional crystal breakage during the stirring process. Summary of the invention

[0006] The present invention aims to solve at least one of the technical problems existing in the related art. To this end, the present invention provides a 2'-deoxycytidine crystal, a preparation method and a device, which can improve the crystallinity of the 2'-deoxycytidine crystal, reduce crystal agglomeration, simplify operation and reduce cost.

[0007] The present invention provides a method for preparing 2'-deoxycytidine crystals, comprising the following steps: S100, dissolving 2'-deoxycytidine in acetone to prepare a raw material solution with a concentration of 100 mg / mL to 150 mg / mL, and adding the raw material solution to the preparation device; S200, stirring at a temperature of 25° C. to 30° C. to form a Taylor vortex flow field in the preparation device, adding water droplets into the preparation device, mixing with the raw material liquid, and obtaining a mixed liquid, wherein the volume ratio of water to the raw material liquid is 1:3 to 2:3; S300, cooling the mixed solution at a cooling rate of 5.25°C / h~6.67°C / h to 0°C~5°C, and then maintaining the temperature for 8h~14h to obtain a solid-liquid mixture; S400, filtering the solid-liquid mixture to obtain a solid product, and drying the solid product to obtain 2'-deoxycytidine crystals.

[0008] According to the method for preparing 2'-deoxycytidine crystals provided by the present invention, in step S200, the temperature of the water is 25°C to 30°C.

[0009] According to the method for preparing 2'-deoxycytidine crystals provided by the present invention, in the step S200, the dripping speed of the water is 0.1 ml / min to 0.3 ml / min.

[0010] According to a method for preparing 2'-deoxycytidine crystals provided by the present invention, in step S200, the stirring speed is 800 rpm to 1400 rpm.

[0011] According to a method for preparing 2'-deoxycytidine crystals provided by the present invention, in the step S400, the drying temperature is 30° C. to 60° C., and the drying time is 1 h to 5 h.

[0012] The present invention also provides a 2'-deoxycytidine crystal, which is prepared based on the preparation method of the 2'-deoxycytidine crystal as described above, and the particle size of the 2'-deoxycytidine crystal is 189 μm.

[0013] The present invention also provides a 2'-deoxycytidine crystal preparation device, which is used to implement the above-mentioned 2'-deoxycytidine crystal preparation method, comprising: An outer cylinder, wherein a cooling medium inlet is provided at the bottom side of the outer cylinder, and a cooling medium outlet is provided at the top side of the outer cylinder; An inner cylinder, wherein the inner cylinder is sleeved in the outer cylinder, a cooling cavity is formed between the inner cylinder and the outer cylinder, the inner cylinder is provided with a feed pipe, the outer cylinder is provided with a through hole, the feed pipe passes through the through hole and is exposed on the outside of the outer cylinder; The stirring assembly comprises a driving member and a stirring rod. The stirring rod is rotatably inserted in the inner cylinder. The driving member is connected to the stirring rod to drive the stirring rod to rotate.

[0014] According to the device for preparing 2'-deoxycytidine crystals provided by the present invention, the ratio between the diameter of the stirring rod and the inner diameter of the inner cylinder is 1:3-2:3.

[0015] According to the device for preparing 2'-deoxycytidine crystals provided by the present invention, the ratio between the outer diameter of the inner cylinder and the inner diameter of the outer cylinder is 1:3-2:3.

[0016] The device for preparing 2'-deoxycytidine crystals provided by the present invention further comprises a sealing cover, which is arranged on the top side of the inner cylinder and has a mounting hole, through which the stirring rod passes.

[0017] The above one or more technical solutions in the embodiments of the present invention have at least one of the following technical effects: The present invention provides a 2'-deoxycytidine crystal, a preparation method and a device. Water is added to a raw material solution and the mixed solution is gradually cooled to provide the supersaturation required for crystallization of 2'-deoxycytidine. At the same time, a Taylor vortex flow field is adopted, which is an axisymmetric annular vortex, and a uniformly distributed shear force is generated on the mixed solution, which can effectively accelerate the mass transfer and heat transfer efficiency, accelerate nucleation, and further improve the crystallinity of the 2'-deoxycytidine crystal, reduce crystal agglomeration, and has simple operation and low cost.

[0018] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the technical solutions in the present invention or the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0020] Figure 1 It is a schematic structural diagram of a device for preparing 2'-deoxycytidine crystals in the prior art.

[0021] Figure 2 It is a schematic structural diagram of a device for preparing 2'-deoxycytidine crystals provided by the present invention.

[0022] Figure 3This is a scanning electron microscope photograph of the 2'-deoxycytidine crystals prepared in Example 1 provided by the present invention.

[0023] Figure 4 This is a scanning electron microscope photograph of the 2'-deoxycytidine crystals prepared in Example 2 provided by the present invention.

[0024] Figure 5 This is a scanning electron microscope photograph of the 2'-deoxycytidine crystals prepared in Example 3 provided by the present invention.

[0025] Figure 6 This is a scanning electron microscope photograph of the 2'-deoxycytidine crystals prepared in Example 4 provided by the present invention.

[0026] Figure 7 This is a scanning electron microscope photograph of the 2'-deoxycytidine crystals prepared in Example 5 provided by the present invention.

[0027] Figure 8 This is a scanning electron microscope photograph of the 2'-deoxycytidine crystals prepared in Comparative Example 1 provided by the present invention.

[0028] Fig. 9 This is a scanning electron microscope photograph of the 2'-deoxycytidine crystals prepared in Comparative Example 2 provided by the present invention.

[0029] Fig.10 This is a scanning electron microscope photograph of the 2'-deoxycytidine crystals prepared in Comparative Example 5 provided by the present invention.

[0030] Fig.11 This is a comparison chart of X-ray diffraction of 2'-deoxycytidine crystals prepared in Example 1, Example 2, and Example 3 provided by the present invention and commercially available 2'-deoxycytidine crystals.

[0031] Fig.12 This is a comparison chart of the particle size distribution of the 2'-deoxycytidine crystals prepared in Examples 1, 2, and 3 provided by the present invention and commercially available 2'-deoxycytidine crystals.

[0032] Fig.13 This is a comparison chart of X-ray diffraction of 2'-deoxycytidine crystals prepared in Example 2 and Comparative Example 2 provided by the present invention and commercially available 2'-deoxycytidine crystals.

[0033] Fig.14 This is a comparison chart of the particle size distribution of 2'-deoxycytidine crystals prepared in Example 2 and Comparative Example 2 provided by the present invention and commercially available 2'-deoxycytidine crystals.

[0034] Reference numerals: 1. Outer cylinder; 2. Inner cylinder; 3. Cooling medium inlet; 4. Cooling medium outlet; 5. Feed pipe; 6. Stirring rod; 7. Sealing cover. DETAILED DESCRIPTION

[0035] In order to make the purpose, technical scheme and advantages of the present invention clearer, the technical scheme in the present invention will be clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present invention. The following embodiments are used to illustrate the present invention, but cannot be used to limit the scope of the present invention.

[0036] In the description of the embodiments of the present invention, it should be noted that the terms “first”, “second” and “third” are only used for descriptive purposes and cannot be understood as indicating or implying relative importance.

[0037] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the embodiment of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0038] Combine the following Figures 2 to 14 The present invention describes a 2'-deoxycytidine crystal, a preparation method and a device.

[0039] The present invention provides a method for preparing 2'-deoxycytidine crystals, comprising the following steps: S100, dissolving 2'-deoxycytidine in acetone to prepare a raw material solution with a concentration of 100 mg / mL to 150 mg / mL, and adding the raw material solution to the preparation device.

[0040] S200. Stir at a temperature of 25°C to 30°C at a speed of 800rpm to 1400rpm to form a Taylor vortex flow field in the preparation device, add water droplets into the preparation device at a dropping speed of 0.1ml / min to 0.3ml / min, mix the water and the raw material liquid to obtain a mixed liquid, wherein the volume ratio of water to the raw material liquid is 1:3 to 2:3; the temperature of the water is 25°C to 30°C.

[0041] S300, cooling the mixed liquid at a cooling rate of 5.25°C / h~6.67°C / h by a cooling medium, and cooling the mixed liquid to 0°C~5°C, and then maintaining the temperature for 8h~14h to obtain a solid-liquid mixture.

[0042] S400, filtering the solid-liquid mixture to obtain a solid product, drying the solid product at a drying temperature of 30° C. to 60° C. for a drying time of 1 h to 5 h to obtain 2'-deoxycytidine crystals.

[0043] The present invention also provides a 2'-deoxycytidine crystal, which is prepared based on the preparation method of the 2'-deoxycytidine crystal as described above, and the average particle size of the 2'-deoxycytidine crystal is 189 μm.

[0044] like Figure 2 As shown, the present invention also provides a 2'-deoxycytidine crystal preparation device, which is used to implement the above-mentioned 2'-deoxycytidine crystal preparation method, comprising: The outer cylinder 1 has a cooling medium inlet 3 at the bottom side of the outer cylinder 1 and a cooling medium outlet 4 at the top side of the outer cylinder 1; the cooling medium can be water, coolant or salt water. Specifically, the cooling medium enters the outer cylinder from the cooling medium inlet located beside the bottom end of the outer cylinder and is discharged from the cooling medium outlet located beside the top end of the outer cylinder, ensuring that the cooling medium can always immerse the inner cylinder and ensure cooling uniformity.

[0045] The inner cylinder 2 is sleeved in the outer cylinder, a cooling cavity is formed between the inner cylinder and the outer cylinder, the inner cylinder is provided with a feed pipe 5, the outer cylinder is provided with a through hole, the feed pipe passes through the through hole and is exposed outside the outer cylinder; specifically, the cooling cavity is filled with cooling medium. Raw material liquid and water are added to the inner cylinder through the feed pipe without interfering with the cooling cavity.

[0046] The stirring assembly includes a driving member and a stirring rod 6. The stirring rod is rotatably inserted in the inner cylinder. The driving member is connected to the stirring rod to drive the stirring rod to rotate. The driving member can be a driving motor or a motor to output power, thereby driving the stirring rod to stir the raw material liquid and water in the inner cylinder, so that the raw material liquid and water are in a Taylor vortex flow field of annular vortices in an axisymmetric direction, and a uniformly distributed shear force is generated on the raw material liquid and water, which can effectively accelerate the mass transfer and heat transfer efficiency and accelerate nucleation.

[0047] According to a 2'-deoxycytidine crystal preparation device provided by the present invention, the ratio between the diameter of the stirring rod and the inner diameter of the inner cylinder is 1:3-2:3, which improves the stirring effect and helps to quickly form a Taylor vortex flow field.

[0048] According to a 2'-deoxycytidine crystal preparation device provided by the present invention, the ratio between the outer diameter of the inner cylinder and the inner diameter of the outer cylinder is 1:3-2:3, ensuring that the cooling cavity has sufficient space to expand the temperature control range of the cooling medium.

[0049] According to the present invention, a 2'-deoxycytidine crystal preparation device further comprises a sealing cover 7, which is arranged on the top side of the inner cylinder, and the sealing cover is provided with a mounting hole, through which the stirring rod passes. By providing the sealing cover, the relative sealing of the inner cylinder, the inner cylinder and the stirring rod is ensured, and the accuracy of temperature control is improved.

[0050] It should also be noted that the preparation device of 2'-deoxycytidine crystals provided by the present invention is specifically a Taylor vortex crystallizer (CT crystallizer), such as Figure 2 As shown, compared with the existing ordinary turbulent crystallizer (MT crystallizer), such as Figure 1 As shown, the preparation device for 2'-deoxycytidine crystals provided by the present invention not only improves crystallinity and reduces agglomeration, but also has simple operation and low cost, and can quickly obtain high-quality 2'-deoxycytidine crystals.

[0051] Example 1 S100, dissolve 2'-deoxycytidine in acetone to prepare a stock solution with a concentration of 150 mg / mL, and add 6 mL of the stock solution into the inner cylinder through the feed tube. The outer diameter of the inner cylinder is 20 mm, the inner diameter of the outer cylinder is 30 mm, and the diameter of the stirring rod is 10 mm.

[0052] S200. Under the condition of a temperature of 30°C, the driving motor drives the stirring rod to stir at a speed of 800 rpm, so that the raw material liquid in the inner cylinder forms a Taylor vortex flow field, and 4 mL of water at a temperature of 30°C is added to the preparation device at a dropping speed of 0.2 ml / min to mix the water and the raw material liquid to obtain a mixed liquid.

[0053] S300, using water as a cooling medium, passing it into the cooling cavity between the outer cylinder and the inner cylinder through the cooling medium inlet of the outer cylinder, and cooling the mixed liquid at a cooling rate of 6.25°C / h, and cooling it to 5°C, and then maintaining it for 10 hours to complete crystallization and obtain a solid-liquid mixture.

[0054] After completing the heat exchange, the water is discharged from the outer cylinder through the cooling medium outlet.

[0055] S400, filtering the solid-liquid mixture to obtain a solid product, drying the solid product at a drying temperature of 50° C. for 4 hours to obtain 2'-deoxycytidine crystals.

[0056] like Figure 3As shown, the morphology of the 2'-deoxycytidine crystals obtained in this example was obtained by scanning electron microscopy.

[0057] Example 2 S100, dissolve 2'-deoxycytidine in acetone to prepare a stock solution with a concentration of 140 mg / mL, and add 6 mL of the stock solution into the inner cylinder through the feed tube. The outer diameter of the inner cylinder is 20 mm, the inner diameter of the outer cylinder is 30 mm, and the diameter of the stirring rod is 10 mm.

[0058] S200. Under the condition of a temperature of 28°C, the driving motor drives the stirring rod to stir at a speed of 1000 rpm, so that the raw material liquid in the inner cylinder forms a Taylor vortex flow field, and 4 mL of water at a temperature of 28°C is added to the preparation device at a dropping speed of 0.25 ml / min to mix the water and the raw material liquid to obtain a mixed liquid.

[0059] S300, using the coolant as a cooling medium, passing it into the cooling cavity between the outer cylinder and the inner cylinder through the cooling medium inlet of the outer cylinder, and cooling the mixed liquid at a cooling rate of 5.25°C / h, and cooling it to 4°C, and then maintaining it for 12 hours to complete crystallization and obtain a solid-liquid mixture.

[0060] After completing the heat exchange, the water is discharged from the outer cylinder through the cooling medium outlet.

[0061] S400, filtering the solid-liquid mixture to obtain a solid product, drying the solid product at a drying temperature of 30° C. for 5 hours to obtain 2'-deoxycytidine crystals.

[0062] like Figure 4 As shown, the morphology of the 2'-deoxycytidine crystals obtained in this example was obtained by scanning electron microscopy.

[0063] Example 3 S100, dissolve 2'-deoxycytidine in acetone to prepare a stock solution with a concentration of 130 mg / mL, and add 6 mL of the stock solution into the inner cylinder through the feed tube. The outer diameter of the inner cylinder is 20 mm, the inner diameter of the outer cylinder is 30 mm, and the diameter of the stirring rod is 10 mm.

[0064] S200. Under the condition of a temperature of 27°C, the driving motor drives the stirring rod to stir at a speed of 1400 rpm, so that the raw material liquid in the inner cylinder forms a Taylor vortex flow field, and 4 mL of water at a temperature of 27°C is added to the preparation device at a dropping speed of 0.3 ml / min to mix the water and the raw material liquid to obtain a mixed liquid.

[0065] S300, using brine as a cooling medium, passing it into the cooling cavity between the outer cylinder and the inner cylinder through the cooling medium inlet of the outer cylinder, and cooling the mixed liquid at a cooling rate of 6.67°C / h, and cooling it to 3°C, and then maintaining it for 8 hours to complete crystallization and obtain a solid-liquid mixture.

[0066] After completing the heat exchange, the water is discharged from the outer cylinder through the cooling medium outlet.

[0067] S400, filtering the solid-liquid mixture to obtain a solid product, drying the solid product at a drying temperature of 40° C. for 3 hours to obtain 2'-deoxycytidine crystals.

[0068] like Figure 5 As shown, the morphology of the 2'-deoxycytidine crystals obtained in this example was obtained by scanning electron microscopy.

[0069] Example 4 S100, dissolve 2'-deoxycytidine in acetone to prepare a stock solution with a concentration of 120 mg / mL, and add 6 mL of the stock solution into the inner cylinder through the feed tube. The outer diameter of the inner cylinder is 10 mm, the inner diameter of the outer cylinder is 30 mm, and the diameter of the stirring rod is 4 mm.

[0070] S200. Under the condition of a temperature of 26°C, the driving motor drives the stirring rod to stir at a speed of 1200 rpm, so that the raw material liquid in the inner cylinder forms a Taylor vortex flow field, and 4 mL of water at a temperature of 26°C is added to the preparation device at a dropping speed of 0.15 ml / min to mix the water and the raw material liquid to obtain a mixed liquid.

[0071] S300, using alkaline water as a cooling medium, passing it into the cooling cavity between the outer cylinder and the inner cylinder through the cooling medium inlet of the outer cylinder, and cooling the mixed liquid at a cooling rate of 6.00°C / h, and cooling it to 2°C, and then maintaining it for 13 hours to complete crystallization and obtain a solid-liquid mixture.

[0072] After completing the heat exchange, the water is discharged from the outer cylinder through the cooling medium outlet.

[0073] S400, filtering the solid-liquid mixture to obtain a solid product, drying the solid product at a drying temperature of 60° C. for 1 h to obtain 2'-deoxycytidine crystals.

[0074] like Figure 6 As shown, the morphology of the 2'-deoxycytidine crystals obtained in this example was obtained by scanning electron microscopy.

[0075] Example 5 S100, dissolve 2'-deoxycytidine in acetone to prepare a stock solution with a concentration of 100 mg / mL, and add 6 mL of the stock solution into the inner cylinder through the feed tube. The outer diameter of the inner cylinder is 20 mm, the inner diameter of the outer cylinder is 30 mm, and the diameter of the stirring rod is 10 mm.

[0076] S200. Under the condition of a temperature of 25°C, the driving motor drives the stirring rod to stir at a speed of 900 rpm, so that the raw material liquid in the inner cylinder forms a Taylor vortex flow field, and 2 mL of water at a temperature of 25°C is added to the preparation device at a dropping speed of 0.1 ml / min to mix the water and the raw material liquid to obtain a mixed liquid.

[0077] S300, using water as a cooling medium, passing it into the cooling cavity between the outer cylinder and the inner cylinder through the cooling medium inlet of the outer cylinder, and cooling the mixed liquid at a cooling rate of 5.75°C / h, and cooling it to 0°C, and then maintaining it for 14 hours to complete crystallization and obtain a solid-liquid mixture.

[0078] After completing the heat exchange, the water is discharged from the outer cylinder through the cooling medium outlet.

[0079] S400, filtering the solid-liquid mixture to obtain a solid product, drying the solid product at a drying temperature of 45° C. for 3 hours to obtain 2'-deoxycytidine crystals.

[0080] like Figure 7 As shown, the morphology of the 2'-deoxycytidine crystals obtained in this example was obtained by scanning electron microscopy.

[0081] See also Fig.11 As shown, the X-ray diffraction comparison diagrams of Example 1, Example 2 and Example 3 and commercially available 2'-deoxycytidine crystals show that, compared with commercially available 2'-deoxycytidine crystals, the crystallinity of the 2'-deoxycytidine crystals prepared in Example 1, Example 2 and Example 3 of the present invention are improved, and the crystallization effect of the 2'-deoxycytidine crystals prepared in Example 2 is the most obvious.

[0082] See also Fig.12 As shown, the particle size distribution comparison diagram of the 2'-deoxycytidine crystals prepared in Example 1, Example 2, and Example 3 and the commercially available 2'-deoxycytidine crystals shows that, compared with the commercially available 2'-deoxycytidine crystals, the crystal particle size distribution of the 2'-deoxycytidine crystals prepared in Example 1, Example 2, and Example 3 of the present invention is more uniform, and the effect of the 2'-deoxycytidine crystals prepared in Example 2 is the most obvious, with an average particle size of 189 μm.

[0083] Comparative Example 1 Use Figure 1 The preparation device shown in the figure prepares 2'-deoxycytidine crystals, which specifically includes the following steps: Towards Figure 1 6 mL of 2'-deoxycytidine crystallization raw material solution was added to the preparation device shown (the outer diameter of the outer cylinder was 30 mm, and the outer diameter of the inner cylinder was 20 mm). The raw material solution was obtained by dissolving 2'-deoxycytidine in acetonitrile. The concentration of the 2'-deoxycytidine crystallization stock solution was 150 mg / mL. Stirring was started at a speed of 1000 rpm. The temperature was 30°C. 4 mL of water was added dropwise to the inner cylinder at a flow rate of 0.2 mL / min, and then the temperature was lowered to 5°C at a rate of 6.25°C / h. The temperature was maintained at 5°C for 10 hours. After the crystallization was completed, the product was separated from the solid phase and dried at 50°C. The morphology was obtained by scanning electron microscopy as shown in the figure. Figure 8 shown.

[0084] Comparative Example 2 In this comparative example 2, 2'-deoxycytidine crystals were prepared according to the method of Example 2. The difference from Example 2 is that the device used in this comparative example 2 is Figure 1 The preparation device is shown in the figure, and the other steps are exactly the same; the morphology of the obtained 2'-deoxycytidine crystal obtained by scanning electron microscopy is shown in Fig. 9 shown.

[0085] Comparative Example 3 Towards Figure 1 6 mL of 2'-deoxycytidine crystal stock solution was added to the preparation device shown (the outer diameter of the outer cylinder was 30 mm, and the outer diameter of the inner cylinder was 20 mm). The concentration of the 2'-deoxycytidine crystal stock solution was 200 mg / mL, stirring was started, and the speed was 1000 rpm. The temperature was 30°C, and 8 mL of water was added dropwise to the inner cylinder at a flow rate of 0.2 mL / min. After the addition was completed, the temperature was maintained at 30°C for 12 hours. The final product was found to be a colloid amorphous.

[0086] Comparative Example 4 Towards Figure 1 6 mL of 2'-deoxycytidine crystal stock solution was added to the preparation device shown (the outer diameter of the outer cylinder was 30 mm, and the outer diameter of the inner cylinder was 20 mm). The concentration of the 2'-deoxycytidine crystal stock solution was 200 mg / mL, and stirring was started at a speed of 1000 rpm. The temperature was 30°C, and 6 mL of water was added dropwise to the inner cylinder at a flow rate of 0.2 mL / min, and then the temperature was reduced to 5°C at a rate of 6.25°C / h, and maintained at 5°C for 10 hours. The product was finally found to be a colloid amorphous.

[0087] Comparative Example 5 Towards Figure 16 mL of 2'-deoxycytidine crystal stock solution was added to the preparation device shown (the outer diameter of the outer cylinder was 30 mm, and the outer diameter of the inner cylinder was 20 mm). The concentration of the 2'-deoxycytidine crystal stock solution was 150 mg / mL. Stirring was started at a speed of 1600 rpm. The temperature was 30°C. 6 mL of water was added to the inner cylinder at a flow rate of 0.2 mL / min. Then the temperature was lowered to 5°C at a rate of 6.25°C / h and maintained at 5°C for 10 hours. The morphology of the obtained product obtained by scanning electron microscopy is shown in FIG. Fig.10 shown.

[0088] like Fig.13 As shown, the X-ray diffraction comparison diagrams of 2'-deoxycytidine crystals prepared in Example 2 of the present invention and Comparative Example 2 and commercially available 2'-deoxycytidine crystals show that the crystallinity of the crystals prepared by the preparation device provided by the present invention is much better than that of the crystals prepared by the existing preparation device.

[0089] like Fig.14 As shown in the figure, the particle size distribution comparison diagram of 2'-deoxycytidine crystals prepared in Example 2 of the present invention and Comparative Example 2 and commercially available 2'-deoxycytidine crystals shows that the particle size distribution of the crystals prepared by the preparation device provided by the present invention is much more uniform than that of the crystals prepared by the existing preparation device.

[0090] The above one or more technical solutions in the embodiments of the present invention have at least one of the following technical effects: The present invention provides a 2'-deoxycytidine crystal, a preparation method and a device. Water is added to a raw material solution and the mixed solution is gradually cooled to provide the supersaturation required for crystallization of 2'-deoxycytidine. At the same time, a Taylor vortex flow field is adopted, which is an axisymmetric annular vortex, and a uniformly distributed shear force is generated on the mixed solution, which can effectively accelerate the mass transfer and heat transfer efficiency, accelerate nucleation, and further improve the crystallinity of the 2'-deoxycytidine crystal, reduce crystal agglomeration, and has simple operation and low cost.

[0091] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing 2'-deoxycytidine crystals, characterized in that: The steps include: S100, dissolving 2'-deoxycytidine in acetone to prepare a raw material solution with a concentration of 100 mg / mL to 150 mg / mL, and adding the raw material solution to the preparation device; S200, stirring at a temperature of 25° C. to 30° C. to form a Taylor vortex flow field in the preparation device, adding water droplets into the preparation device, mixing with the raw material liquid, and obtaining a mixed liquid, wherein the volume ratio of water to the raw material liquid is 1:3 to 2:3; S300, cooling the mixed solution at a cooling rate of 5.25°C / h~6.67°C / h to 0°C~5°C, and then maintaining the temperature for 8h~14h to obtain a solid-liquid mixture; S400, filtering the solid-liquid mixture to obtain a solid product, and drying the solid product to obtain 2'-deoxycytidine crystals.

2. The method for preparing 2'-deoxycytidine crystals according to claim 1, characterized in that: In the step S200, the temperature of the water is 25°C to 30°C.

3. The method for preparing 2'-deoxycytidine crystals according to claim 1, characterized in that: In the step S200, the water is added at a dropping speed of 0.1 ml / min to 0.3 ml / min.

4. The method for preparing 2'-deoxycytidine crystals according to claim 1, characterized in that: In the step S200, the stirring speed is 800 rpm to 1400 rpm.

5. The method for preparing 2'-deoxycytidine crystals according to claim 1, characterized in that: In the step S400, the drying temperature is 30°C to 60°C, and the drying time is 1 hour to 5 hours.

6. A 2'-deoxycytidine crystal, characterized in that: The 2'-deoxycytidine crystals are prepared according to the method for preparing the 2'-deoxycytidine crystals according to any one of claims 1 to 5, wherein the particle size of the 2'-deoxycytidine crystals is 189 μm.

7. A device for preparing 2'-deoxycytidine crystals, characterized in that: A method for preparing the 2'-deoxycytidine crystal according to any one of claims 1 to 5, comprising: An outer cylinder, wherein a cooling medium inlet is provided at the bottom side of the outer cylinder, and a cooling medium outlet is provided at the top side of the outer cylinder; An inner cylinder, wherein the inner cylinder is sleeved in the outer cylinder, a cooling cavity is formed between the inner cylinder and the outer cylinder, the inner cylinder is provided with a feed pipe, the outer cylinder is provided with a through hole, the feed pipe passes through the through hole and is exposed on the outside of the outer cylinder; The stirring assembly comprises a driving member and a stirring rod. The stirring rod is rotatably inserted in the inner cylinder. The driving member is connected to the stirring rod to drive the stirring rod to rotate.

8. The device for preparing 2'-deoxycytidine crystals according to claim 7, characterized in that: The ratio between the diameter of the stirring rod and the inner diameter of the inner cylinder is 1:3 to 2:

3.

9. The device for preparing 2'-deoxycytidine crystals according to claim 7, characterized in that: The ratio between the outer diameter of the inner cylinder and the inner diameter of the outer cylinder is 1:3 to 2:

3.

10. The device for preparing 2'-deoxycytidine crystals according to claim 7, characterized in that: It also includes a sealing cover, which is arranged on the top side of the inner cylinder. The sealing cover is provided with a mounting hole, and the stirring rod passes through the mounting hole.

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