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Crystalline composition containing escitalopram oxalate

A technology of escitalopram and its mixture, applied in the field of crystalline composition containing escitalopram oxalate, can solve the problems of large energy consumption, expensive equipment, and complexity

Inactive Publication Date: 2009-07-29
H LUNDBECK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] Both wet granulation and melt granulation are energy intensive unit operations requiring complex and expensive equipment and technical expertise

Method used

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  • Crystalline composition containing escitalopram oxalate
  • Crystalline composition containing escitalopram oxalate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0094] Example 1: Removal of hydroxyl-containing impurities by succinic anhydride

[0095] R- and S-carboxylates containing 0.6% of Z-4-(4-dimethylamino-1-(4-fluorophenyl)-but-1-enyl)-3-hydroxymethyl-benzonitrile A mixture of phthalopram (55,5 g) was dissolved in anhydrous toluene (145,0 g). Succinic anhydride (0,5 g) was added to the solution, the mixture was stirred at 45° C. for 120 minutes, water (230 ml) and ammonia (25% by weight) (3 ml) were added (pH=10,5-11,0). The phases were separated and the toluene phase was washed with water (3x120ml). Evaporation of the toluene phase yielded 53,0 g (95%). The product contains 0,06% of Z-4-(4-dimethylamino-1-(4-fluorophenyl)-but-1-enyl)-3-hydroxymethyl-benzonitrile.

Embodiment 2

[0096] Example 2: Crystallization of escitalopram oxalate on a production scale

[0097] A number of crude batches of escitalopram oxalate were recrystallized on a production scale according to the procedure described below. Each batch includes:

[0098] a) The preparation of escitalopram is as follows: according to WO03 / 000672, the acidic ring-closing reaction of the R-shaped diol precursor is carried out, and then according to the method described in Example 1, impurities containing hydroxyl groups are removed by a production-scale method, Racemic citalopram and escitalopram were then isolated as described in WO03 / 000672. These batches contained Z-4-(4-dimethylamino-1-(4-fluorophenyl)-but-1-enyl)-3-hydroxymethyl-benzonitrile, usually relative to escitalopram 0.05% (w / w). These batches are referred to as R-diol batches.

[0099] b) Preparation of escitalopram by ring closure from S-shaped diol precursor via activated ester form under basic conditions as described in US Pa...

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Abstract

The present invention discloses crystalline particles of escitalopram oxalate which either have a broad particle size distribution or comprise at least 0.01 % (w / w) of Z-4-(4-dimethylamino-1-(4-fluorophenyl)-but-1-enyl)-3-hydroxymethyl-benzonitrile, said particles being suitable for use in direct compression. Furthermore, the invention discloses a novel pharmaceutical unit dosage form containing such crystalline particles of escitalopram oxalate as well as methods for manufacture of such crystalline particles of escitalopram oxalate. Finally, the invention provides a method for reduction of the amount of hydroxyl containing impurities in a solution of citalopram or escitalopram.

Description

[0001] This application is a Chinese patent application (National Application No. 200580006940.0, International Application No. PCT / DK2005 / 000115) divisional application. technical field [0002] The present invention relates to a crystalline preparation of the oxalate salt of the compound escitalopram (INN-named), which is the S-enantiomer of the known antidepressant citalopram, i.e. , (S)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuronitrile oxalate. Background technique [0003] Citalopram is a well known antidepressant with the following structure: [0004] [0005] It is a selective centrally active serotonin (5-HT) reuptake inhibitor and therefore has antidepressant activity. [0006] Citalopram was first disclosed in DE 2,657,013 (corresponding to US 4,136,193), which patent publication describes the preparation of citalopram by a method and briefly describes other methods that can be used for the preparation of citalopram. The prepar...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/87A61K9/20A61K9/48A61K31/343A61P25/24
CPCA61K9/14A61K9/2095A61K9/28A61K9/4825A61K31/343A61K2121/00
Inventor K·B·詹森R·E·亨布尔K·利耶格伦T·V·克里斯滕森
Owner H LUNDBECK AS
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