CN111777525A - Refining method of iodixanol - Google Patents
Refining method of iodixanol Download PDFInfo
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- CN111777525A CN111777525A CN201910272601.0A CN201910272601A CN111777525A CN 111777525 A CN111777525 A CN 111777525A CN 201910272601 A CN201910272601 A CN 201910272601A CN 111777525 A CN111777525 A CN 111777525A
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- iodixanol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention provides a refining method of iodixanol, which is characterized in that a mixed solvent of ethylene glycol monoethyl ether and water is used for recrystallizing a crude iodixanol product to obtain a pure iodixanol product. The mixed solvent of ethylene glycol monoethyl ether and water is adopted to purify the crude iodixanol, so that the yield of iodixanol is improved; the crystallization time of iodixanol is shortened, the crystallization period of 48-72 hours is shortened to 9-17 hours, and the production efficiency is greatly improved; and the solvent can be efficiently recovered, the cost is saved, the method is environment-friendly and convenient for industrial popularization and application.
Description
Technical Field
The invention relates to the field of medicine synthesis, in particular to a refining method of iodixanol.
Background
Iodixanol quotientThe product name is Wei Vivipaque (Visipaque)TM) The iodine contrast medium is a third-generation isotonic nonionic iodine contrast medium, has the osmotic pressure consistent with the osmotic pressure of human blood, small injection irritation and good patient compliance, has a recent annual increase trend in global sales, and reaches $ 3.86 hundred million in 2015 for global sales of iodixanol preparations.
Since iodixanol molecule has a plurality of configurational isomers and has a large molecular weight reaching 1550.18, crystal growth of the iodixanol has high activation energy (more than 50KJ/mol), and crystallization and purification are difficult.
By now, a number of recrystallization processes have been explored to refine iodixanol so that it can be refined to give pharmaceutical grade iodixanol drug substance.
WO9918054 discloses a process for the recrystallization of iodixanol under water-methanol-isopropanol conditions under pressure. Since it needs to be operated at high pressure, equipment cost and production risk are increased.
US7968745 discloses refining iodixanol in 2-5mL n-propanol/g crude iodixanol with crystallization time of 72 hours, long time consumption and low production efficiency. WO2007064220 discloses refining iodixanol in 2-6mL ethanol/g crude iodixanol with crystallization times between 52 hours and 82 hours, still long time consuming.
CN101001831 discloses refining iodixanol in the presence of propylene glycol methyl ether, the crystallization time is between 40 and 96 hours, and the toxicity data of the propylene glycol methyl ether used in the method is not sufficiently studied, so that no corresponding solvent classification can be found in the ICHQ3C, which brings trouble to the establishment of limit standards of residual solvents in the bulk drugs.
CN102725249 discloses recrystallization of iodixanol in a water-ethylene glycol monomethyl ether-n-butanol system with a crystallization time of 44 hours. Because the solubility of the water-ethylene glycol monomethyl ether system to the crude iodixanol is more than 200mg/mL, a solvent with lower solubility is added to reduce the solubility of the mixed solvent, so that the iodixanol can be crystallized and separated out. N-butanol is a good choice, but since the boiling point of ethylene glycol monomethyl ether is 124.5 ℃, the boiling point of n-butanol is 117.25 ℃, the boiling points of the ethylene glycol monomethyl ether and the n-butanol are close to each other, the solvent recovery is difficult, the production cost is increased, and the environmental friendliness is reduced.
It can be seen that the existing methods for refining iodixanol by recrystallization have respective problems, and therefore, a feasible method for recrystallizing iodixanol, which is short in time consumption, easy in solvent recovery, safe, economical and easy in production process amplification, is urgently needed.
Disclosure of Invention
The invention aims to provide a method for recrystallizing iodixanol by using a mixed solvent of ethylene glycol monoethyl ether and water.
The invention provides a refining method of iodixanol, which is characterized by comprising the following steps: the method comprises the step of recrystallizing a crude product of iodixanol by using a mixed solvent of glycol monoethyl ether and water to obtain a pure product of iodixanol.
Further, the recrystallization process comprises the following steps: dissolving the crude iodixanol product in a mixed solvent of ethylene glycol monoethyl ether and water to obtain a mixed solution, adding crystal seeds, stirring at a constant temperature, then continuously adding the ethylene glycol monoethyl ether, and crystallizing to obtain a pure iodixanol product.
The preparation method of the seed crystal comprises the following steps: and (3) preparing a crystal as a seed crystal by taking iodixanol which is prepared by self or sold on the market according to a conventional method.
Further, the dissolving method comprises the following steps: dissolving a crude product of iodixanol in water, adding ethylene glycol monoethyl ether, and performing azeotropic concentration to obtain a mixed solution;
or taking a mixed solvent of ethylene glycol monoethyl ether and water, adding a crude product of iodixanol into the mixed solvent, and dissolving to obtain a mixed solution.
Further, in the mixed solvent, the weight ratio of ethylene glycol monoethyl ether to water is (1.75-15.89): 1, preferably (2.12-8.52): 1, more preferably (2.55-8.52): 1.
further, in the mixed solution, the weight ratio of the iodixanol crude product to water and ethylene glycol monoethyl ether is 1: (0.17-0.57): (1.00-2.70), preferably 1: (0.27-0.47): (1.00-2.30), more preferably 1: (0.27-0.47): (1.20-2.30).
Further, the adding amount of the seed crystal is 2-8 percent of the weight of the crude iodixanol, and preferably 5-8 percent.
Further, the temperature of the heat preservation stirring is 90-120 ℃, and the time is 1-3 hours; preferably, the temperature is 90-110 ℃ and the time is 1-2 hours.
Further, the time for continuously adding the ethylene glycol monoethyl ether is within 2-8 hours after the heat preservation and stirring are finished, and the adding mode is dropwise adding.
Further, the amount of the ethylene glycol monoethyl ether continuously added is 2.0-8.0 times, preferably 2.5-6.0 times, and more preferably 2.5-4.0 times of the weight of the crude iodixanol product.
Further, the crystallization process comprises the following steps: stirring at 90-120 deg.C for 2-8 hr, preferably at 90-110 deg.C for 3-7 hr; more preferably, the stirring is carried out at 90-100 ℃ for 6-7 hours.
Further, the iodixanol crude product comprises the following components: greater than 97% iodixanol, less than 2% iohexol, less than 1% over-alkylated impurities.
Further, the ingredients are HPLC area normalized percent content as determined by iodixanol USP method.
Further, the recrystallization process also comprises washing the obtained iodixanol pure product.
Further, the washing reagent is ethylene glycol monoethyl ether; the temperature during washing is maintained at 80-120 deg.C, preferably 90-100 deg.C.
The invention adopts the mixed solvent of ethylene glycol monoethyl ether and water to purify the crude iodixanol, thereby improving the yield of iodixanol; the crystallization time of iodixanol is shortened, the crystallization period of 48-72 hours is shortened to 9-17 hours, and the production efficiency is greatly improved; and the solvent can be efficiently recovered, the cost is saved, the method is environment-friendly and convenient for industrial popularization and application.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention is described in further detail below with reference to examples, but it should not be construed that the scope of the above subject matter is limited to the examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The raw materials and reagents used in the present invention are known products, and are obtained by purchasing commercially available products.
Example 1 preparation of a refined product of iodixanol according to the invention
Taking 1000L of aqueous solution (containing 100kg of iodixanol crude product) with the content of 10% of iodixanol crude product (the percentage content of each component in the iodixanol crude product: iodixanol more than 97%, iohexol less than 2%, over-alkylated impurity less than 1%, and a small amount of other impurities), and concentrating until the weight ratio of the iodixanol crude product to water in the solution is 1: A. then adding ethylene glycol monoethyl ether (the addition amount is calculated according to the azeotropic ratio and the water content), removing water by azeotropy, and continuing to concentrate. And sampling to test the water content in the solution, stopping concentration when the water content in the solution reaches B times of the weight of the iodixanol, and calculating according to the azeotropic ratio, wherein the amount of the ethylene glycol monoethyl ether is C times of the weight of the iodixanol. Maintaining the heating temperature at 110 ℃, adding seed crystals (the seed crystal adding amount is H% of the weight of the crude iodixanol), and stirring for D hours under the condition of heat preservation after the seed crystal adding is finished. And continuously dropwise adding ethylene glycol monoethyl ether into the crystallization system within E hours, wherein the addition amount is F times of the weight of iodixanol, and stirring for G hours under the condition of heat preservation. Then the mixture is filtered under the condition of heat preservation, and filter cakes are washed by 30kg of ethylene glycol monoethyl ether heated to 100 ℃ to obtain a refined iodixanol product.
Wherein, the values of the A-G parameters are shown in the table 1:
TABLE 1 values of the parameters in example 1
The content and yield of the related substances in the crude iodixanol and the refined iodixanol prepared by the invention are shown in table 2:
TABLE 2. content and yield of related substances
| Serial number | Iohexol | Iodixanol | Over alkylated impurities | Other impurities | Yield of |
| Crude product | 1.52％ | 97.21％ | 0.73％ | 0.54％ | - |
| 1 | 0.12％ | 99.51％ | 0.33％ | 0.04％ | 85.1％ |
| 2 | 0.07％ | 99.62％ | 0.28％ | 0.03％ | 76.3％ |
| 3 | 0.25％ | 99.04％ | 0.60％ | 0.11％ | 91.4％ |
| 4 | 0.13％ | 99.53％ | 0.30％ | 0.04％ | 85.9％ |
| 5 | 0.11％ | 99.57％ | 0.29％ | 0.03％ | 83.7％ |
| 6 | 0.13％ | 99.54％ | 0.29％ | 0.04％ | 85.6％ |
| 7 | 0.13％ | 99.54％ | 0.28％ | 0.05％ | 86.0％ |
| 8 | 0.12％ | 99.54％ | 0.30％ | 0.04％ | 85.8％ |
Example 2 recovery of ethylene glycol monomethyl ether
According to the method of the embodiment 1, 1000kg of iodixanol recrystallization mother liquor is taken, the water content is measured, the distillation is carried out, after the water is azeotropically removed, the distilled ethylene glycol monoethyl ether is received, 910kg of ethylene glycol monoethyl ether with the water content of less than 0.05 percent is obtained, the recovery rate is 91 percent, and the ethylene glycol monoethyl ether can be directly used for recrystallization of the next batch of crude iodixanol.
Comparative example 1 preparation of a refined product of iodixanol
Taking 1000L of aqueous solution (containing 100kg of iodixanol crude product) with the content of 10% of iodixanol crude product (the percentage content of each component in the iodixanol crude product: iodixanol more than 97%, iohexol less than 2%, over-alkylated impurity less than 1%, and a small amount of other impurities), and concentrating until the weight ratio of the iodixanol crude product to water in the solution is 1: 2. adding propylene glycol monomethyl ether (calculated according to azeotropic ratio and water content), removing water by azeotropic distillation, and concentrating. Sampling and testing the water content, stopping concentration when the water content reaches 0.22 times of the weight of iodixanol, and calculating according to the azeotropic ratio, wherein the weight of propylene glycol monomethyl ether is 0.60 times of that of iodixanol. Maintaining the heating temperature at 110 ℃, adding seed crystals accounting for 8 percent of the weight of the crude iodixanol into the mixture, and keeping the temperature and stirring for 10.5 hours after the addition. Then, the rest propylene glycol monomethyl ether is dropwise added into the crystallization system within 24.5 hours, the addition amount is 1.20 times of that of iodixanol, and the stirring is carried out for 5 hours under the condition of heat preservation after the addition is finished. Then the mixture is filtered under the condition of heat preservation, and a filter cake is washed by 30kg of propylene glycol monomethyl ether heated to 100 ℃ to obtain a refined iodixanol product.
The yield was 75.3%, as determined by HPLC, iohexol 0.12%, iodixanol 99.51%, over alkylated impurity 0.33%, other impurities 0.04%.
Compared with the mixed solvent of propylene glycol monomethyl ether and water adopted in the comparative example 1, the invention can be seen that the mixed solvent of ethylene glycol monoethyl ether and water is adopted to purify the crude iodixanol, so that the crystallization time of iodixanol is effectively shortened, the crystallization period of 2-3 days is shortened to 9-17 hours, and the production efficiency is greatly improved; the yield of the method is also obviously improved from 75.3 percent to 76.3 to 91.4 percent.
In conclusion, the invention adopts the mixed solvent of ethylene glycol monoethyl ether and water to purify the crude iodixanol, thereby improving the yield of iodixanol; the crystallization time of iodixanol is shortened, the crystallization period of 48-72 hours is shortened to 9-17 hours, and the production efficiency is greatly improved; and the solvent can be efficiently recovered, the cost is saved, the method is environment-friendly and convenient for industrial popularization and application.
Claims (14)
1. A refining method of iodixanol is characterized in that: the method comprises the step of recrystallizing a crude product of iodixanol by using a mixed solvent of glycol monoethyl ether and water to obtain a pure product of iodixanol.
2. The method of claim 1, wherein: the recrystallization process comprises the following steps: dissolving the crude iodixanol product in a mixed solvent of ethylene glycol monoethyl ether and water to obtain a mixed solution, adding crystal seeds, stirring at a constant temperature, then continuously adding the ethylene glycol monoethyl ether, and crystallizing to obtain a pure iodixanol product.
3. The method of claim 2, wherein: the dissolving method comprises the following steps: dissolving a crude product of iodixanol in water, adding ethylene glycol monoethyl ether, and performing azeotropic concentration to obtain a mixed solution;
or taking a mixed solvent of ethylene glycol monoethyl ether and water, adding a crude product of iodixanol into the mixed solvent, and dissolving to obtain a mixed solution.
4. A method according to claim 2 or 3, characterized in that: in the mixed solvent, the weight ratio of ethylene glycol monoethyl ether to water is (1.75-15.89): 1, preferably (2.12-8.52): 1, more preferably (2.55-8.52): 1.
5. a method according to claim 2 or 3, characterized in that: in the mixed solution, the weight ratio of the iodixanol crude product to water to ethylene glycol monoethyl ether is 1: (0.17-0.57): (1.00-2.70), preferably 1: (0.27-0.47): (1.00-2.30), more preferably 1: (0.27-0.47): (1.20-2.30).
6. The method of claim 2, wherein: the addition amount of the seed crystal is 2-8 percent of the weight of the crude iodixanol product, preferably 5-8 percent.
7. The method of claim 2, wherein: the temperature of the heat preservation stirring is 90-120 ℃, and the time is 1-3 hours; preferably, the temperature is 90-110 ℃ and the time is 1-2 hours.
8. The method of claim 2, wherein: the time for continuously adding the ethylene glycol monoethyl ether is within 2-8 hours after the heat preservation and stirring are finished, and the adding mode is dropwise adding.
9. The method according to claim 2 or 8, characterized in that: the amount of the ethylene glycol monoethyl ether continuously added is 2.0 to 8.0 times, preferably 2.5 to 6.0 times, and more preferably 2.5 to 4.0 times of the weight of the crude iodixanol product.
10. The method of claim 2, wherein: the crystallization process comprises the following steps: stirring at 90-120 deg.C for 2-8 hr, preferably at 90-110 deg.C for 3-7 hr; more preferably, the stirring is carried out at 90-100 ℃ for 6-7 hours.
11. The method of claim 2, wherein: the iodixanol crude product comprises the following components: greater than 97% iodixanol, less than 2% iohexol, less than 1% over-alkylated impurities.
12. The method of claim 11, wherein: the ingredients are HPLC area normalized percentage content determined according to iodixanol USP method.
13. The method according to any one of claims 1-12, wherein: the recrystallization process also comprises washing the obtained iodixanol pure product.
14. The method of claim 13, wherein: the washing reagent is ethylene glycol monoethyl ether; the temperature during washing is maintained at 80-120 deg.C, preferably 90-100 deg.C.
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