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Process for the preparation of 1,2-dichloroethane free crystals of zonisamide

a technology of zonisamide and free crystals, which is applied in the field of process for the preparation of 1, 2dichloroethane free crystals of zonisamide, can solve the problems of patient safety, inability to be useful, and the solvent used in the preparation of a drug substance cannot be completely removed by practical manufacturing techniques, and achieves high safety

Inactive Publication Date: 2004-07-15
UENO YOSHIKAZU +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

0007] The present inventors have intensively studied a process for the preparation of crystals of zonisamide having a high safety and complying with the above-mentioned guideline, and have found that the desired crystals of zonisamide containing residual 1,2-dichloroethane of not more than 5 ppm can easily be obtained even from crystals of zonisamide containing 1,2-dichloroethane in a high concentration by...

Problems solved by technology

The solvent used in the preparation of a drug substance cannot completely be removed by practical manufacturing techniques, which are in actuality employed in the production.
Further, solvents to residue in drug substance usually cannot be useful for the therapeutic benefits of drug substance, and contrarily, there may be caused a problem of safety of a patient according to the kinds of residual solvents and a concentration thereof.
Since a solvent may play an important role in increasing the yield rate or in determination of physical properties of drug substance such as crystal form, purity, solubility, etc., even if such a solvent is known to be toxic, there may be many cases that the use thereof in the preparation of drug substance cannot be avoided in terms of risk-benefits.
However, it is very difficult to completely remove an occluded solvent by a drying method being actually employed in the production.
On the other hand, zonisamide cannot melt even by heating in water, and hence, this method cannot be applied for removal of the solvent occluded in crystals of zonisamide.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0027] To wet crystals (60 g) containing zonisamide in an amount of about 85% by weight prepared by using 1,2-dichloroethane in the method disclosed in Reference Example 3 and Example 1 of JP-A-53-77057 was added 50 vol % aqueous isopropanol (500 ml), and 320 ml of the solvent was removed by evaporation at a temperature of from 76 to 100.degree. C. under stirring. To the residual mixture were added water (10 ml), isopropanol (200 ml) and activated carbon (8 g), and the mixture was dissolved with heating. The activated carbon was separated by filtration, and washed with 50% aqueous isopropanol (80 ml). The filtrate and the washing were combined and cooled. The precipitated crystals were collected by filtration, washed with water (100 ml), and dried at 80.degree. C. for 16 hours to give crystals of zonisamide (48.5 g). The content of 1,2-dichloroethane in the crystals was less than 1 ppm (less than detection limit).

examples 2-3

[0028] The same procedures as Example 1 were repeated except that the water content in the aqueous isopropanol and the amount of the aqueous isopropanol were changed. The results are shown in Table 1.

1 TABLE 1 Item Example 2 Example 3 Water content in aqueous 65 50 isopropanol (vol %) Amount of aqueous 450 310 isopropanol (ml) Evaporation temperature 76-100 80-100 (.degree. C.) Amount of 250 205 evaporated solvent (ml) Yield of crystals (g) 49.0 47.8 Content of residual 1,2- <1 <1 dichloroethane (ppm) (less than DL) (less than DL) (DL: detection limit)

example 4

[0029] To the same wet crystals (60 g) containing zonisamide in an amount of about 85% by weight as used in Example 1 were added 50 vol % aqueous isopropanol (300 ml), water (7.5 ml) and 1,2-dichloroethane (8.8 g), and 210 ml of the solvent was removed by evaporation at a temperature of from 79 to 100.degree. C. under stirring. The residual mixture was cooled, and the precipitated crystals were collected by filtration to give wet crystals of zonisamide (56.7 g). The content of 1,2-dichloroethane in the wet crystals of zonisamide was less than 1 ppm (less than detection limit). The wet crystals were dried at 80.degree. C. for 16 hours to give dried crystals of zonisamide (49.9 g).

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PUM

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Abstract

A process for the preparation of crystals of zonisamide containing residual 1,2-dichloroethane of not more than 5 ppm, which comprises adding an aqueous C2-4 alcohol to crystals of zonisamide containing residual 1,2-dichloroethane of more than 5 ppm, removing said 1,2-dichloroethane by azeotropic distillation, followed by collecting the precipitated crystals from the residual mixture.

Description

[0001] The present invention relates to a process for the preparation of crystals of zonisamide (chemical name: 1,2-benzisoxazole-3-methanesulfona-mide), which is useful as an antiepileptic agent. More particularly, the present invention relates to a process for efficiently preparing crystals of zonisamide containing residual 1,2-dichloroethane of not more than 5 ppm.[0002] Zonisamide has widely been used as an antiepileptic agent in Japan and United States. Zonisamide and processes for the preparation thereof are disclosed in JP-A-53-77057, U.S. Pat. No. 4,172,896 and JP-A-54-163823. In addition, Yakugaku-Zasshi, vol. 116, p. 533-547 (1996) discloses that zonisamide has actually been prepared using as an intermediate 1,2-benzisoxazole-3-methanesulfonyl chloride, which is obtained by sulfonation and decarboxylation of 1,2-benzisoxazol-3-acetic acid. Further, the solvent for the above sulfonation and decarboxylation is dichloromethane in the process disclosed in Yakugaku-Zasshi, vol....

Claims

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Application Information

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IPC IPC(8): A61P25/08C07D261/20
CPCC07D261/20A61P25/08
Inventor UENO, YOSHIKAZUKIMURA, YASUJIRO
Owner UENO YOSHIKAZU
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