CN115540503B - Programme drying method of vincristine sulfate in ternary solvent system - Google Patents
Programme drying method of vincristine sulfate in ternary solvent system Download PDFInfo
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- 238000001035 drying Methods 0.000 title claims abstract description 67
- AQTQHPDCURKLKT-JKDPCDLQSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-JKDPCDLQSA-N 0.000 title claims abstract description 63
- 229960002110 vincristine sulfate Drugs 0.000 title claims abstract description 62
- 239000002904 solvent Substances 0.000 title claims abstract description 37
- 239000012046 mixed solvent Substances 0.000 claims abstract description 28
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims abstract description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 25
- 150000002576 ketones Chemical class 0.000 claims abstract description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 41
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 34
- 238000000034 method Methods 0.000 claims description 11
- 238000000859 sublimation Methods 0.000 claims description 11
- 230000008022 sublimation Effects 0.000 claims description 11
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 8
- 238000010981 drying operation Methods 0.000 claims description 4
- 238000003795 desorption Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 32
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 229960001701 chloroform Drugs 0.000 description 18
- 230000000052 comparative effect Effects 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 238000007689 inspection Methods 0.000 description 9
- 238000007670 refining Methods 0.000 description 9
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000000843 powder Substances 0.000 description 7
- 239000003814 drug Substances 0.000 description 5
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 4
- 238000004108 freeze drying Methods 0.000 description 3
- 230000008014 freezing Effects 0.000 description 3
- 238000007710 freezing Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- 229960004528 vincristine Drugs 0.000 description 3
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 3
- JYYOBHFYCIDXHH-UHFFFAOYSA-N carbonic acid;hydrate Chemical compound O.OC(O)=O JYYOBHFYCIDXHH-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 240000001829 Catharanthus roseus Species 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 230000010190 G1 phase Effects 0.000 description 1
- 230000027311 M phase Effects 0.000 description 1
- 244000187664 Nerium oleander Species 0.000 description 1
- 230000018199 S phase Effects 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- -1 indole compound Chemical class 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F26—DRYING
- F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
- F26B1/00—Preliminary treatment of solid materials or objects to facilitate drying, e.g. mixing or backmixing the materials to be dried with predominantly dry solids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D519/04—Dimeric indole alkaloids, e.g. vincaleucoblastine
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F26—DRYING
- F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
- F26B5/00—Drying solid materials or objects by processes not involving the application of heat
- F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
- F26B5/06—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing
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- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Mechanical Engineering (AREA)
- General Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a drying method of vincristine sulfate, which comprises the following steps: dissolving vincristine sulfate in a mixed solvent, and carrying out program drying; the mixed solvent comprises water, C 3～4 ketone and dimethyl carbonate in a specific proportion. The drying method can reduce the solvent residue of the vincristine sulfate to a level meeting the pharmacopoeia regulations, simultaneously keep the content of relevant substances of the vincristine sulfate not to be obviously increased, ensure the quality of the finished product of the vincristine sulfate, and is suitable for the industrialized production of the vincristine sulfate.
Description
Technical Field
The invention belongs to the field of compounds, and particularly relates to a procedural drying method of vincristine sulfate in a ternary solvent system.
Background
The vinca rosea is the whole plant of the oleander family, and more than 70 alkaloids have been isolated so far, of which vincristine (VINCRISTINE VCR) is the most valuable. Vincristine is a dimeric indole compound, which can interfere tumor cell metabolism by acting on tumor cell tubulin, has wide clinical application, mainly acts on G1, S and M phases of a cell proliferation cycle, has a delay effect on the M phase, can interfere the formation of a spindle body of the proliferation cell, can stop mitosis in the middle phase, has an immunosuppressive effect, and is a cell cycle specific antitumor drug.
The 2020 edition of Chinese pharmacopoeia prescribes that the related substances of vincristine sulfate are less than 2.0% of the maximum single impurity, and the total amount of the related substances is less than 5.0%. However, in order to improve the safety of the use of the medicine and promote the use of the medicine in a wider range, the quality of vincristine sulfate needs to be further improved to meet the requirement that the unknown impurity limit of the raw medicine is less than 0.1% in the regulation (ICH Q3A) of the impurity of the raw medicine according to the guidelines of the international human medicine registration technology coordination. The prior preparation process of vincristine sulfate can not meet the requirement of ICH Q3A, and is difficult to be used for popularization and application in a larger range such as international health assistance. If the content of unknown impurities in vincristine sulfate is reduced to below 0.1%, chloroform is used as a solvent in the preparation process, but the 2020 edition of Chinese pharmacopoeia prescribes that chloroform is a second-class solvent, and the residual limit value is very small and is 0.006%. Meanwhile, the vincristine sulfate has poor thermal stability, and related substances are obviously increased after the vincristine sulfate is dried for a long time by using a high temperature under reduced pressure, so that the quality of a finished product is greatly reduced; and freeze-drying is carried out after the dissolution with water, so that the residual chloroform is difficult to be reduced to the limit.
Disclosure of Invention
The invention aims to solve the problems that related substances are easy to increase and chloroform residues are difficult to meet the requirements in the drying process of vincristine sulfate in the prior art. Therefore, the invention provides the drying method of the vincristine sulfate, which can ensure that the vincristine sulfate solvent residue is qualified, and meanwhile, the content of related substances of a finished product cannot be increased, so that the method is suitable for the industrialized production of the vincristine sulfate.
In the existing drying process, if vincristine sulfate is directly dried at high temperature and under reduced pressure, related substances in the finished product can be obviously increased. By utilizing the principle of sublimation, the material solution is quickly frozen under the condition of relatively low temperature, then the material is heated under the proper vacuum environment, the frozen solvent molecules are directly sublimated into steam to overflow, and the material itself is remained in an ice frame during freezing, so that the program type drying method is suitable for preparing the material which is not resistant to high temperature. Since vincristine sulfate is soluble in water, freeze-drying can be theoretically performed with water as a solvent, but residual chloroform is difficult to fall within limits. Therefore, the mixed solvent system with a specific proportion required by the program type drying process is screened, the quality (related substances and solvent residues) of the finished product can be ensured to meet the requirements, and the method is stable and controllable and becomes the key of the vincristine sulfate drying process.
In order to solve the technical problems, the invention adopts the following technical scheme:
A method for procedural drying of vincristine sulfate in ternary solvent system, comprising the steps of: dissolving the crystallized and refined vincristine sulfate in a mixed solvent, wherein the mixed solvent comprises water, C3-4 ketone and dimethyl carbonate, and performing program drying to finally obtain a refined vincristine sulfate finished product.
After the crystallization and refining of the vincristine sulfate are completed, drying is needed, and at this time, if the vincristine sulfate is directly dried at a high temperature under vacuum, the purity of the vincristine sulfate may be reduced, and the quality may be deteriorated. According to research, the crystallization refined vincristine sulfate is dissolved in a ternary solvent system comprising water, C3-4 ketone and dimethyl carbonate, and is subjected to program drying, so that the trichloromethane can be effectively reduced on the premise that related substances are not increased, but the related substances of the vincristine sulfate are not changed before and after drying.
Preferably, the mixed solvent comprises water, C3-4 ketone and dimethyl carbonate according to the volume ratio of 7-12: 0.3 to 0.8:1, and mixing.
Preferably, the C 3～4 ketone comprises one or more of acetone and butanone.
Preferably, the volume mass ratio of the mixed solvent to the crystallized and refined vincristine sulfate is 8-20 mL:1g.
Preferably, the volume mass ratio of the mixed solvent to the crystallized and refined vincristine sulfate is 10-15 mL:1g.
Preferably, the program drying comprises prefreezing, sublimation drying and resolution drying steps; the temperatures of the prefreezing, the sublimation drying and the resolution drying are sequentially increased.
Preferably, the pre-freezing temperature is-60 to-30 ℃; the sublimation drying temperature is-10-0 ℃; the temperature of the desorption drying is 25-40 ℃.
Preferably, the prefreezing operation is to cool to-60 to-30 ℃ and keep the temperature for 30-180 min; the sublimation drying operation is that the temperature is raised to-10 to 0 ℃ within 30 to 180min and the temperature is kept for 300 to 720min; the operation of resolving and drying is that the temperature is raised to 25-40 ℃ within 30-120 min and the temperature is kept for 300-1200 min.
Preferably, the prefreezing operation is to cool to-40 to-30 ℃ and keep the temperature for 90-180 min; the sublimation drying operation is that the temperature is raised to-10 to 0 ℃ within 60 to 180min and the temperature is kept for 360 to 600min.
The finished product of refined vincristine sulfate obtained by the procedural drying method under the ternary solvent system of vincristine sulfate is characterized in that the trichloromethane residue in the finished product of refined vincristine sulfate is not higher than 0.006%, the dimethyl carbonate residue is not higher than 0.5%, and the C 3～4 ketone residue is not higher than 0.2%.
Compared with the prior art, the implementation of the invention has the following beneficial effects:
The invention provides a ternary solvent system program drying process of vincristine sulfate, which can ensure high quality of the vincristine sulfate finished product without increasing the content of related substances while the solvent residue of the vincristine sulfate finished product is qualified, and is suitable for industrialized production of vincristine sulfate.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the concept and technical effects of the present invention will be clearly and completely described below in connection with specific embodiments so as to fully understand the objects, features and effects of the present invention. It is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments, and that other embodiments obtained by those skilled in the art without inventive effort are within the scope of the present invention based on the embodiments of the present invention.
Example 1
5G of vincristine sulfate after crystallization and purification was weighed, mixed solvent (64 mL of water, 4mL of acetone and 7mL of dimethyl carbonate) was added, stirred to dissolve completely, placed in a dish, and subjected to a drying procedure according to the parameters shown in Table 1. After drying, the sample powder was collected, sampled and inspected for solvent residues and related substances.
Table 1 example 1 drying parameters and sample quality inspection table
As can be seen from Table 1, the content of the related substances before and after the refining of example 1 was unchanged, but the content of chloroform was successfully reduced to 0.0026%, which is significantly lower than the residual limit value specified in the Chinese pharmacopoeia.
Example 2
5G of vincristine sulfate after crystallization and purification was weighed, mixed solvent (70 mL of water, 2.5mL of butanone and 6.5mL of dimethyl carbonate) was added, stirred to dissolve completely, placed in a dish, and dried according to the parameters shown in Table 2. After drying, the sample powder was collected, sampled and inspected for solvent residues and related substances.
Table 2 example 2 drying parameters and sample quality inspection table
As can be seen from Table 2, the content of the related substances before and after refining in example 2 was unchanged, but the content of chloroform was successfully reduced to 0.0032%, which is significantly lower than the residual limit value specified in the Chinese pharmacopoeia.
Example 3
20G of crystallized and refined vincristine sulfate was weighed, mixed solvent (197 mL of water, 8mL of acetone and 15mL of dimethyl carbonate) was added, stirred to dissolve completely, and placed in a tray, and a drying procedure was performed according to the parameters shown in Table 3. After drying, the sample powder was collected, sampled and inspected for solvent residues and related substances.
Table 3 example 3 drying parameters and sample quality inspection table
It can be seen from table 3 that the content of the related substances is not changed before and after the refining of example 3, but the content of chloroform is successfully reduced to 0.0018%, which is significantly lower than the residual limit value specified in the chinese pharmacopoeia.
Example 4
50G of the crystallized and purified vincristine sulfate was weighed, mixed solvent (700 mL of water, 50mL of acetone and 80mL of dimethyl carbonate) was added thereto, stirred to be completely dissolved, and placed in a dish, and a drying procedure was performed according to the parameters shown in Table 4. After drying, the sample powder was collected, sampled and inspected for solvent residues and related substances.
Table 4 example 4 drying parameters and sample quality inspection table
As can be seen from Table 4, the content of the related substances before and after the refining of example 4 was unchanged, but the content of chloroform was successfully reduced to 0.0006%, which is significantly lower than the residual limit value specified in the Chinese pharmacopoeia.
Example 5
200G of the crystallized and purified vincristine sulfate was weighed, mixed solvent (1700 mL of water, 70mL of acetone and 170mL of dimethyl carbonate) was added thereto, stirred to be completely dissolved, and placed in a dish, and a drying procedure was performed according to the parameters shown in Table 5. After drying, the sample powder was collected, sampled and inspected for solvent residues and related substances.
Table 5 example 5 drying parameters and sample quality inspection table
As can be seen from Table 5, the content of the related substances before and after the refining of example 5 was unchanged, but the content of chloroform was successfully reduced to 0.0043%, which is significantly lower than the residual limit value specified in the Chinese pharmacopoeia.
Comparative example 1
20G of crystallized and refined vincristine sulfate is weighed and placed in a vacuum drying oven for vacuum drying according to the parameters of Table 6. After drying, samples were collected, sampled and inspected for solvent residues and related substances.
Table 6 comparative example 1 drying parameters and sample quality inspection table
As can be seen from Table 6, in comparative example 1, although the chloroform content was successfully reduced below the residual limit value specified in the "Chinese pharmacopoeia" after drying, the content of the relevant substances before and after drying was significantly improved, and the quality of vincristine sulfate was rather lowered.
Comparative example 2
20G of vincristine sulfate after crystallization and refining are weighed, placed in a vacuum drying oven and vacuum dried according to the parameters of Table 7. After drying, samples were collected, sampled and inspected for solvent residues and related substances.
Table 7 comparative example 2 drying parameters and sample quality inspection table
As can be seen from Table 7, although the related substances before and after drying were not significantly increased in comparative example 2, the chloroform content after drying was still 0.027%, which was difficult to reduce below the residual limit value specified in the Chinese pharmacopoeia.
Comparative example 3
20G of the crystallized and purified vincristine sulfate was weighed, added with a solvent (140 mL of water+60 mL of t-butanol) and stirred to be completely dissolved, and placed in a tray, and a drying procedure was performed according to the parameters shown in Table 8. After drying, the sample powder was collected, sampled and inspected for solvent residues and related substances.
Table 8 comparative example 3 drying parameters and sample quality inspection table
As can be seen from Table 8, the content of the related substances was not changed before and after drying in comparative example 3, but the content of chloroform was still 0.06%, which was difficult to reduce below the residual limit value specified in the "Chinese pharmacopoeia".
Effect example 1
The drying results of example 1 and example 2 and comparative examples 1 to 3 were compared together, as shown in table 9.
Table 9 summary of results for example 1, example 2 and comparative example
As can be seen from Table 9, it was found that, in example 1 and example 2, compared with comparative examples 1 to 3, the use of water, acetone (or butanone) and dimethyl carbonate as solvents, the solvent residue of vincristine sulfate after crystallization purification was eventually satisfactory and the relevant substances were not significantly increased. The vincristine sulfate after the crystallization refining is directly dried under reduced pressure, related substances are obviously increased when the temperature is higher, and the chloroform residue cannot be reduced below a limit value even if the temperature is lower and the vincristine sulfate is dried for a long time. The mixed solvent composed of tert-butanol and water which is commonly used in freeze drying is used for carrying out programmed drying on the vincristine sulfate after the crystallization refining, so that the chloroform residue cannot be reduced below a limit value.
Effect example 2
Weighing 20g of crystallized and refined vincristine sulfate, adding 200mL of mixed solvent composed of water, acetone and dimethyl carbonate in different proportions according to Table 10, stirring to dissolve completely, performing program drying, collecting sample powder, sampling, and inspecting solvent residue and related substances.
TABLE 10 Mixed solvent State and sample quality inspection Table for different proportions
The mixed solvent consisting of water, acetone and dimethyl carbonate is used as a solvent for program drying, and a finished product with qualified quality can not be obtained in any proportion, and the mixed solvent with different proportions is required to be set for carrying out investigation on the dissolution condition, solvent residue and the results of related substances. When water alone was used as the solvent, the samples were soluble as shown in group 1 of the table, but after drying the chloroform residue could not be reduced below the limit. When only dimethyl carbonate was used as a solvent, as shown in group 2 of the table, the sample was not dissolved, and thus, the drying procedure was not performed. When water and dimethyl carbonate are used as the mixed solvent, as shown in group 3 in the table, the sample can be dissolved in the water layer, but the solvent layering affects the drying effect, and neither dimethyl carbonate nor chloroform can be reduced below the limit, so acetone is required to promote the mutual dissolution of water and dimethyl carbonate into homogeneous phases (generally, acetone is also used in the process of separating and purifying vincristine sulfate, and the addition of acetone in the drying process does not bring about new solvent residues to be controlled). When water, acetone and dimethyl carbonate are used as a mixed solvent, but the dosage of the acetone is small, as shown in the 4 th group in the table, similar to the 3 rd group, the mixed system still has layering phenomenon, and the dimethyl carbonate and chloroform in the finished product exceed the limit, so that the drying effect is affected; when the amount of acetone in the mixture system is large, as shown in group 5, the pre-freezing condition is poor because the solidifying point of the acetone is high, and the residual amount of acetone and chloroform in the final product exceeds the limit, so that the drying effect is affected. When the amount of dimethyl carbonate in the mixed system is large, as shown in the 6 th group in the table, the mixed solvent system is obviously layered, and the solvent residues of the dimethyl carbonate and the chloroform do not meet the requirements. When the amount of dimethyl carbonate in the mixed system is small, as shown in the 7 th group in the table, the mixed solvent system is more uniform like the 1 st group, but the solvent residue of chloroform after drying still does not meet the specified requirements. Therefore, the aim of meeting the standard of the dissolution residue and not increasing related substances can be achieved only by adopting the mixed solvent of water, C 3～4 ketone and dimethyl carbonate in a specific proportion.
The foregoing disclosure is merely illustrative of the preferred embodiments of the present invention and is not intended to limit the scope of the claims herein, as equivalent changes may be made in the claims herein without departing from the scope of the invention.
Claims (8)
1. A method for procedural drying of vincristine sulfate in ternary solvent system, characterized in that it comprises the following steps: dissolving the crystallized and refined vincristine sulfate in a mixed solvent, wherein the mixed solvent comprises water, C3-4 ketone and dimethyl carbonate, and performing program drying to finally obtain a refined vincristine sulfate finished product; the mixed solvent comprises water, C3-4 ketone and dimethyl carbonate according to the volume ratio of 7-12: 0.3 to 0.8:1, mixing; the program type drying comprises the steps of prefreezing, sublimation drying and resolution drying; the temperatures of the prefreezing, the sublimation drying and the resolution drying are sequentially increased.
2. The method of claim 1, wherein the C3-4 ketones comprise one or more of acetone and butanone.
3. The method of claim 1, wherein the volume mass ratio of the mixed solvent to the crystallized and refined vincristine sulfate is 8-20 mL:1 g.
4. The method of claim 3, wherein the volume mass ratio of the mixed solvent to the crystallized and refined vincristine sulfate is 10-15 mL:1 g.
5. The method of claim 1, wherein the pre-frozen temperature is-60 to-30 ℃; the sublimation drying temperature is-10-0 ℃; the temperature of the desorption drying is 25-40 ℃.
6. The method according to claim 1, wherein the prefreezing operation is to cool to-60 to-30 ℃ and keep the temperature for 30-180 min; the sublimation drying operation is that the temperature is raised to-10-0 ℃ within 30-180 min, and the temperature is kept for 300-720 min; the operation of resolving and drying is that the temperature is raised to 25-40 ℃ within 30-120 min, and the temperature is kept for 300-1200 min.
7. The method according to claim 6, wherein the prefreezing is performed by cooling to-40 to-30 ℃ and preserving heat for 90-180 min; the sublimation drying operation is that the temperature is raised to-10-0 ℃ within 60-180 min, and the temperature is kept for 360-600 min.
8. A finished product of refined vincristine sulfate obtained by a procedural drying method under a ternary solvent system of vincristine sulfate according to claim 1, wherein in the finished product of refined vincristine sulfate, chloroform residue is not higher than 0.006%, dimethyl carbonate residue is not higher than 0.5%, and C 3~4 ketone residue is not higher than 0.2%.
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|---|---|---|---|---|
| US4375432A (en) * | 1981-05-12 | 1983-03-01 | Eli Lilly And Company | Method of preparing vincristine |
| CN103965219A (en) * | 2014-05-14 | 2014-08-06 | 湖北宏中药业有限公司 | Vincristine and method for synthesizing vincristine sulfate |
| CN104262362A (en) * | 2014-09-01 | 2015-01-07 | 海南希源化工科技有限公司 | Vinblastine extraction and purification method |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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