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Purification process for Iodixanol

A technology of iodixanol and purification method, which is applied in the field of purification of iodixanol, and can solve problems such as difficult to handle, expensive, and slightly toxic

Active Publication Date: 2012-08-29
ZHEJIANG HAIZHOU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In practical applications, the solvent 1-methoxy-2-propanol is not only expensive, but also a slightly toxic, high-boiling solvent. The use of the last step will cause the solvent residue in the product to be difficult to handle to the standards required by the Pharmacopoeia.

Method used

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  • Purification process for Iodixanol
  • Purification process for Iodixanol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Embodiment 1, the preparation of iodixanol crude product

[0019] The crude product of iodixanol was prepared according to the method in Chinese Patent Publication No. CN1340042.

[0020] Take 0.3 mol of raw compound A and dissolve it in 240 ml of 2-methoxyethanol containing 0.36 mol of sodium hydroxide at 50°C. After all the solids were dissolved, the temperature dropped below 15°C, and then 0.16mol of concentrated hydrochloric acid was added to the solution, and 0.086mol of epichlorohydrin was added at one time, and the reaction was tracked and monitored by HPLC.

[0021] After reacting for 46 hours, the content of iodixanol in the reaction mixture no longer increased, and 350ml of deionized water was added (the solution was clear at this moment, so it was unnecessary to add sodium hydroxide). After adjusting the pH to 10.8 with 18% hydrochloric acid, an appropriate amount (about 0.2 g) of compound A was added to the solution as a seed crystal, and the obtained suspe...

Embodiment 2～7

[0025] Embodiment 2~7, the purification of iodixanol

[0026] The HPLC method and chemical titration method used in the following examples are all carried out with reference to the method recorded in "Pharmacopia" (USP 29 edition).

[0027] Take about 135 g of the iodixanol crude product prepared in Example 1 respectively, add about 1000 ml of a large polar solvent as listed in Table 1, heat up to reflux, keep warm, and stir until the crude product is completely dissolved;

[0028] According to the color of the solution, selectively add an appropriate amount of activated carbon for decolorization, stir under reflux for 30 minutes, and filter while it is hot;

[0029] The filtrate was added dropwise with a small polar solvent (Table 1) under reflux until the system became turbid, then stopped the dropwise addition, and slowly cooled down until the crystallization was complete, then filtered, the filter cake was washed with an appropriate amount of cold methanol, and dried in va...

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Abstract

The invention provides a method for purifying iodixanol. The invention adopts a recrystallization method to purify crude iodixanol prepared from dipolymer of 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo isophthalamide, after several times of repeated purification, an iodixanol product qualified to Pharmacopoeia standards is obtained. The inventive purification method can be effectivelyused for purification of crude iodixanol prepared from dipolymer of 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo isophthalamide, and the used solvent has low cost, so as to remarkably reduce cost compared with the prior purification method. In addition, the inventive purification method is a non-chromatographic solvent purification method and can obtain iodixanol with high purity and high content after several times of repeated purification, so as to meet the industrial production requirements of iodixanol product, as well as Pharmacopoeia standards.

Description

technical field [0001] The invention belongs to the field of chemical medicines, and in particular relates to a method for purifying iodixanol. Background technique [0002] Iodixanol (Iodixanol, trade name Visipaque) is a kind of non-ionic X-ray contrast agent developed by Norway Nycomed company, listed in 1993, its chemical name is 1,3-bis(acetamido)-N , N'-bis[3,5-bis(2,3-dihydroxypropylaminocarbonyl)-2,4,6-triiodophenyl]-2-hydroxypropane, the chemical structural formula is as shown in (I): [0003] [0004] Since iodixanol injection is directly injected into human blood vessels, and the dosage is high, the raw material drug iodixanol must be thoroughly purified, and the product quality must meet the requirements of the Pharmacopoeia. [0005] The iodixanol purification methods can be basically divided into chromatographic purification methods and non-chromatographic purification methods. [0006] In the chromatographic purification method: Nycomed's patent EP108638B...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C237/46C07C231/24
Inventor 史命锋
Owner ZHEJIANG HAIZHOU PHARMA CO LTD
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