CN115540503A - Programmed drying method under vincristine sulfate ternary solvent system - Google Patents
Programmed drying method under vincristine sulfate ternary solvent system Download PDFInfo
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- 238000001035 drying Methods 0.000 title claims abstract description 74
- 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 64
- 229960002110 vincristine sulfate Drugs 0.000 title claims abstract description 63
- 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 25
- 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 38
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 34
- 238000000859 sublimation Methods 0.000 claims description 11
- 230000008022 sublimation Effects 0.000 claims description 11
- 230000008014 freezing Effects 0.000 claims description 10
- 238000007710 freezing Methods 0.000 claims description 10
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 238000007670 refining Methods 0.000 claims description 7
- 238000003795 desorption Methods 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims 2
- 239000013078 crystal Substances 0.000 claims 2
- 238000002156 mixing Methods 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 30
- 238000009776 industrial production Methods 0.000 abstract description 3
- 229960001701 chloroform Drugs 0.000 description 21
- 230000000052 comparative effect Effects 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 230000000694 effects Effects 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 239000000843 powder Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 6
- 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
- 239000012535 impurity 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
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 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
- 240000001829 Catharanthus roseus Species 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 241000208327 Apocynaceae 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
- 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
- JYYOBHFYCIDXHH-UHFFFAOYSA-N carbonic acid;hydrate Chemical compound O.OC(O)=O JYYOBHFYCIDXHH-UHFFFAOYSA-N 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
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000004108 freeze drying Methods 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
- 230000035755 proliferation Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000013517 stratification 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 programmed drying; the mixed solvent comprises water and C in a specific ratio 3～4 Ketones and dimethyl carbonate. The drying method can reduce the solvent residue of the vincristine sulfate to the level meeting the pharmacopoeia regulation, 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 industrial production of the vincristine sulfate.
Description
Technical Field
The invention belongs to the field of compounds, and particularly relates to a programmed drying method under a vincristine sulfate ternary solvent system.
Background
Catharanthus roseus is the whole plant of Catharanthus roseus of Apocynaceae, and more than 70 kinds of alkaloids have been isolated so far, and vincristine (vincristine VCR) is the most valuable. Vincristine is a dimeric indole compound, interferes with 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 with the formation of a proliferation cell spindle, stops mitosis in the middle phase, has an immunosuppressive effect, and is a cell cycle specific antitumor drug.
The 2020 edition of Chinese pharmacopoeia stipulates that the related substances of vincristine sulfate are 2.0% of maximum single impurity and 5.0% of total amount of related substances. On the basis, in order to improve the safety of the use of the medicine and enable the medicine to be popularized and used in a wider range, the quality of the vincristine sulfate needs to be further improved to meet the requirement that the limit of unknown impurities of the raw material medicine needs to be less than 0.1% in the specification (ICH Q3A) of the raw material medicine impurities according to the international human medicine registration technical coordination guide. The existing preparation process of vincristine sulfate cannot meet the requirements of ICH Q3A, and is difficult to be popularized and used in a wider range such as international health assistance. If the unknown impurities in vincristine sulfate are reduced to be below 0.1%, trichloromethane is required to be used as a solvent in the preparation process, but trichloromethane is specified as a second type of solvent in 2020 edition of Chinese pharmacopoeia, and the residual limit value is very small and is 0.006%. Meanwhile, the thermal stability of the vincristine sulfate is poor, and related substances are remarkably increased after the vincristine sulfate is dried at a high temperature under reduced pressure for a long time, so that the quality of a finished product is greatly reduced; after the chloroform is dissolved in water, the chloroform is difficult to be reduced to the limit after the chloroform is frozen and dried.
Disclosure of Invention
The invention aims to solve the problems that related substances are easy to increase and trichloromethane residue is difficult to meet the requirements in the vincristine sulfate drying process 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, does not increase the content of related substances of a finished product, and is suitable for industrial production of the vincristine sulfate.
In the existing drying process, if the vincristine sulfate is directly dried at high temperature and reduced pressure, the related substances in the finished product are obviously increased. The sublimation principle is utilized, the material solution is quickly frozen under the relatively low temperature condition, then the material is heated under the proper vacuum environment, the frozen solvent molecules are directly sublimated into steam to overflow, the material is kept in an ice rack during freezing, and the program type drying method is suitable for preparing the material which is not high in temperature resistance. Since vincristine sulfate is soluble in water, it is theoretically possible to freeze-dry with water as a solvent, but the residual chloroform is difficult to reduce to within limits. Therefore, screening a mixed solvent system with a specific proportion required by the program type drying process can ensure that the quality (related substances and solvent residues) of the finished product meets the requirements and is stable and controllable, and becomes the key of the vincristine sulfate drying process.
In order to solve the technical problem, the invention adopts the following technical scheme:
a programmed drying method under a vincristine sulfate ternary solvent system comprises the following steps: dissolving the crystallized and refined vincristine sulfate into a mixed solvent, and carrying out programmed drying on the mixed solvent comprising water, C3-4 ketones and dimethyl carbonate to finally obtain a refined vincristine sulfate finished product.
After the vincristine sulfate crystallization is refined, drying is needed, and at the moment, if direct high-temperature vacuum drying is carried out, the purity of the vincristine sulfate may be reduced, and the quality of the vincristine sulfate is poor. Researches show that the crystallized and refined vincristine sulfate is dissolved in a ternary solvent system comprising water, C3-4 ketones and dimethyl carbonate, and is subjected to programmed 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 do not change before and after drying.
Preferably, the mixed solvent comprises water, C3-4 ketones and dimethyl carbonate according to a volume ratio of 7-12: 0.3 to 0.8:1 are mixed.
Preferably, said C 3～4 The ketones comprise one or more of acetone and butanone.
Preferably, the volume mass ratio of the mixed solvent to the crystallized and purified vincristine sulfate is 8-20 mL:1g.
Preferably, the volume mass ratio of the mixed solvent to the crystallized and purified vincristine sulfate is 10-15 mL:1g of the total weight of the composition.
Preferably, the programmed drying comprises the steps of pre-freezing, sublimation drying and desorption drying; the temperatures of the prefreezing, the sublimation drying and the desorption drying are increased in sequence.
Preferably, the pre-freezing temperature is-60 to-30 ℃; the temperature of sublimation drying is-10 to 0 ℃; the temperature for resolving and drying is 25-40 ℃.
Preferably, the pre-freezing operation is to cool the temperature to-60 to-30 ℃ and preserve the temperature for 30 to 180min; the operation of sublimation drying 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 to heat up to 25-40 ℃ within 30-120 min and keep the temperature for 300-1200 min.
Preferably, the pre-freezing operation is to cool the temperature to-40 to-30 ℃ and preserve the temperature for 90 to 180min; the operation of sublimation drying is that the temperature is raised to-10-0 ℃ within 60-180 min and the temperature is kept for 360-600 min.
The finished product of the refined vincristine sulfate is obtained by a programmed drying method under the vincristine sulfate ternary solvent system, wherein the finished product of the refined vincristine sulfate has the trichloromethane residue of not more than 0.006 percent, the dimethyl carbonate residue of not more than 0.5 percent and C 3～4 The 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 type drying process of vincristine sulfate, which can ensure high quality of the finished product of vincristine sulfate without increasing related substance content when the solvent residue of the finished product of vincristine sulfate is qualified, and is suitable for industrial production of vincristine sulfate.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention clearer, the conception and the technical effects of the present invention will be clearly and completely described below with reference to specific embodiments so as to fully understand the objects, features and effects of the present invention. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments, and those skilled in the art can obtain other embodiments without inventive effort based on the embodiments of the present invention, and all embodiments are within the protection scope of the present invention.
Example 1
5g of crystallized and refined vincristine sulfate is weighed, mixed solvent (64 mL of water, 4mL of acetone and 7mL of dimethyl carbonate) is added, stirred to be completely dissolved, placed in a tray, and dried according to parameters in Table 1. After drying, the sample powder was collected, sampled and examined for solvent residues and related substances.
Table 1 example 1 drying parameters and sample quality test chart
As can be seen from Table 1, the content of related substances before and after the refining of example 1 is not changed, but the content of trichloromethane is successfully reduced to 0.0026%, which is significantly lower than the residual limit value specified in the Chinese pharmacopoeia.
Example 2
5g of crystallized and refined vincristine sulfate is weighed, mixed solvent (70 mL of water, 2.5mL of butanone and 6.5mL of dimethyl carbonate) is added, stirred to be completely dissolved, placed in a tray, and dried according to the parameters in Table 2. After drying, the sample powder was collected, sampled and examined for solvent residues and related substances.
Table 2 example 2 drying parameters and sample quality test chart
As can be seen from Table 2, the content of related substances before and after the refining in example 2 is not changed, but the content of trichloromethane is successfully reduced to 0.0032%, which is significantly lower than the residue limit value specified in the Chinese pharmacopoeia.
Example 3
20g of crystallized and refined vincristine sulfate is weighed, mixed solvent (197 mL of water, 8mL of acetone and 15mL of dimethyl carbonate) is added, stirred to be completely dissolved, placed in a tray, and dried according to the parameters in Table 3. After drying, the sample powder was collected, sampled and examined for solvent residues and related substances.
Table 3 example 3 drying parameters and sample quality test chart
As can be seen from Table 3, the content of related substances before and after the refining in example 3 is not changed, but the content of trichloromethane is successfully reduced to 0.0018%, which is significantly lower than the residual limit value specified in the Chinese pharmacopoeia.
Example 4
50g of crystallized and refined vincristine sulfate is weighed, mixed solvent (700 mL of water, 50mL of acetone and 80mL of dimethyl carbonate) is added, stirred to be completely dissolved, placed in a tray, and dried according to the parameters in Table 4. After drying, the sample powder was collected, sampled and examined for solvent residues and related substances.
Table 4 example 4 drying parameters and sample quality test table
As can be seen from Table 4, the content of related substances before and after the refining of example 4 is not changed, but the content of trichloromethane is successfully reduced to 0.0006%, which is significantly lower than the residual limit value specified in the Chinese pharmacopoeia.
Example 5
200g of crystallized and refined vincristine sulfate is weighed, mixed solvent (1700 mL of water, 70mL of acetone and 170mL of dimethyl carbonate) is added, stirred to be completely dissolved, placed in a tray, and dried according to the parameters in Table 5. After drying, the sample powder was collected, sampled and examined for solvent residues and related substances.
Table 5 example 5 drying parameters and sample quality test chart
As can be seen from Table 5, the content of related substances before and after the refining in example 5 was not changed, 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, placed in a vacuum drying oven and dried in vacuum according to the parameters in the table 6. After drying, samples were collected, sampled and examined for solvent residues and related materials.
Table 6 comparative example 1 drying parameters and sample quality test table
As can be seen from table 6, in comparative example 1, although the content of chloroform after drying is successfully reduced to below the residual limit value specified in the chinese pharmacopoeia, the content of related substances before and after drying is significantly increased, and the quality of vincristine sulfate is rather reduced.
Comparative example 2
20g of crystallized and refined vincristine sulfate is weighed, placed in a vacuum drying oven and dried in vacuum according to the parameters in the table 7. After drying, samples were collected, sampled and examined for solvent residues and related materials.
Table 7 comparative example 2 drying parameters and sample quality test table
As can be seen from Table 7, in comparative example 2, although the substances before and after drying did not increase significantly, the content of chloroform after drying was still 0.027%, which is difficult to decrease below the residue limit value specified in the Chinese pharmacopoeia.
Comparative example 3
20g of crystallized and refined vincristine sulfate was weighed, added with a solvent (140 mL of water +60mL of t-butanol) and stirred to be completely dissolved, placed in a dish, and subjected to a drying procedure according to the parameters in Table 8. After drying, the sample powder was collected, sampled and examined for solvent residues and related substances.
Table 8 comparative example 3 drying parameters and sample quality test table
As can be seen from Table 8, the content of the related substances before and after the comparative example 3 is dried is not changed, but the content of the trichloromethane still remains 0.06%, which is difficult to be reduced below the residue limit value specified in the Chinese pharmacopoeia.
Effect example 1
The drying results of example 1 and example 2 were compared with those of comparative examples 1 to 3 in a summary manner, and are shown in table 9.
Table 9 summary of the results of examples 1 and 2 and comparative examples
As can be seen from table 9, in examples 1 and 2, it was found that, compared with comparative examples 1 to 3, the solvent residue of vincristine sulfate after crystallization purification was able to meet the limit requirement by the procedure drying using water, acetone (or butanone), and dimethyl carbonate as solvents, and the related substances were not significantly increased. The refined vincristine sulfate after crystallization is directly dried under reduced pressure, substances related to the vincristine sulfate obviously rise when the temperature is high, and the residual trichloromethane can not be reduced below a limit value even if the vincristine sulfate is dried for a long time when the temperature is low. The process drying of the purified vincristine sulfate by freeze drying is carried out by using a mixed solvent of tert-butanol and water which is commonly used, and the chloroform residue can not be reduced below the 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 according to different proportions in the table 10, stirring to completely dissolve, performing programmed drying, collecting sample powder, sampling, and checking solvent residue and related substances.
TABLE 10 examination table for different proportions of mixed solvents and sample quality
The mixed solvent consisting of water, acetone and dimethyl carbonate is used as a solvent for program drying, a finished product with qualified quality can not be obtained in any proportion, and the mixed solvent with different proportions is set for result investigation of dissolution conditions, solvent residues and related substances. When water alone was used as the solvent, the sample was soluble but did not reduce the chloroform residue below the limit after drying as shown in table 1. When only dimethyl carbonate was used as a solvent, as shown in group 2 of the table, the sample could not be dissolved, and thus the programmed drying could not be performed. When water and dimethyl carbonate were used as the mixed solvent, as shown in group 3 of the table, the sample was soluble in the water layer, but solvent stratification affected the drying effect, neither dimethyl carbonate nor chloroform could be reduced to the limit, and acetone was required to promote water and dimethyl carbonateMutual solubility is homogeneous (generally, acetone is also used in the separation and purification process of vincristine sulfate, and the addition of acetone in the drying process does not bring new solvent residue to be controlled). When water, acetone and dimethyl carbonate are used as a mixed solvent, but the use amount of acetone is small, as shown in group 4 in the table, a layering phenomenon still occurs in a mixed system similar to that in group 3, and both dimethyl carbonate and chloroform in a finished product exceed the limit, so that the drying effect is influenced; when the amount of acetone in the mixture system is large, as shown in group 5, pre-freezing is not good because the freezing point of acetone is high, and the residue of acetone and chloroform in the final product exceeds the limit, which affects the drying effect. When the amount of dimethyl carbonate in the mixed system was large, as shown in group 6 in the table, the mixed solvent system was clearly layered, and the solvent residues of dimethyl carbonate and chloroform did not meet the requirements. When the amount of dimethyl carbonate in the mixed system is small, as shown in group 7 in the table, the mixed solvent system is more uniform like group 1, but the solvent residue of chloroform after drying still does not meet the specified requirements. It can be seen that only water and C in specific proportion are used 3～4 The mixed solvent of the ketone and the dimethyl carbonate can achieve the aim that the dissolved residue meets the standard and related substances are not increased.
The above disclosure is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the scope of the present invention, therefore, the present invention is not limited by the appended claims.
Claims (10)
1. A programmed drying method under a vincristine sulfate ternary solvent system is characterized by comprising the following steps: dissolving the crystallized and refined vincristine sulfate into a mixed solvent, and carrying out programmed drying on the mixed solvent comprising water, C3-4 ketones and dimethyl carbonate to finally obtain a refined vincristine sulfate finished product.
2. The method according to claim 1, wherein the mixed solvent comprises water, C3-4 ketones and dimethyl carbonate in a volume ratio of 7-12: 0.3 to 0.8:1 by mixing.
3. The method according to claim 1, wherein C is 3～4 The ketones include one or more of acetone and butanone.
4. The method according to claim 1, wherein the mixed solvent and the crystals are mixedAfter refiningThe volume-mass ratio of the vincristine sulfate is 8-20 mL:1g of the total weight of the composition.
5. The method according to claim 4, wherein the mixed solvent and the crystals are mixedAfter refiningThe volume-mass ratio of the vincristine sulfate is 10-15 mL:1g.
6. The method of claim 1, wherein the programmed drying comprises the steps of pre-freezing, sublimation drying, and desorption drying; the temperatures of the prefreezing, the sublimation drying and the desorption drying are increased in sequence.
7. The method of claim 6, wherein the prefreezing temperature is from-60 ℃ to-30 ℃; the temperature of sublimation drying is-10 to 0 ℃; the temperature for desorption drying is 25-40 ℃.
8. The preparation method according to claim 6, wherein the pre-freezing operation is cooling to-60 to-30 ℃ and keeping the temperature for 30 to 180min; the operation of sublimation drying 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 to heat up to 25-40 ℃ within 30-120 min and keep the temperature for 300-1200 min.
9. The preparation method of claim 8, wherein the pre-freezing is performed by cooling to-40 to-30 ℃ and keeping the temperature for 90 to 180min; the operation of sublimation drying is that the temperature is raised to-10-0 ℃ within 60-180 min and the temperature is kept for 360-600 min.
10. A as inThe finished product of the refined vincristine sulfate is obtained by a programmed drying method in a vincristine sulfate ternary solvent system, and is characterized in that the finished product of the refined vincristine sulfate has trichloromethane residue of not higher than 0.006%, dimethyl carbonate residue of not higher than 0.5%, and C 3～4 The ketone residue is not higher than 0.2%.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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| 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 |
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Non-Patent Citations (1)
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| 乔延江: "中华医学百科全书 中药制剂学", vol. 1, 中国协和医科大学出版社, pages: 32 * |
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