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Crystalline composition containing escitalopram

a technology of crystalline composition and escitalopram, which is applied in the field of antidepressant drugs, can solve the problems of poor flow properties, poor cohesiveness or poor flow properties of active substances, and complex and expensive equipment and technical skill, and achieves the effects of improving the efficiency of escitalopram and improving the effect of escitalopram absorption and absorption

Inactive Publication Date: 2005-09-08
H LUNDBECK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0028] A fifth aspect of the invention is to provide a method for manufacture of large crystalline particles of escitalopram oxalate comprising reduction of the amount of hydroxyl containing impurities in a solution of escitalopram

Problems solved by technology

However, in many cases the particle size of the active substance is small, the active substance is cohesive or has poor flow properties.
Wet granulation as well as melt granulation are energy intensive unit operations requiring complicated and expensive equipment as well as technical skill.
The process used for the preparation of citalopram hydrobromide results in a product with a very small particle size around 2-20 μm that, as many other particulate products with a small particle size, has very poor flow properties.
The escitalopram oxalate product prepared by crystallisation from acetone as outlined in U.S. Pat. No. 4,943,590 has, as the citalopram hydrobromide product described above, a very small particle size around 2-20 μm resulting in similarly poor flow properties.

Method used

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  • Crystalline composition containing escitalopram

Examples

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Effect test

example 1

Scavenging of Hydroxyl Containing Impurity by Succinic Anhydride

[0082] A mixture of R— and S-Citalopram (55.5 g) containing 0.6% of Z-4-(4-dimethylamino-1-(4-fluorophenyl)-but-1-enyl)-3-hydroxymethyl-benzonitrile is dissolved in dry toluene (145.0 g). Succinic anhydride (0.5 g) is added to the solution and the mixture is stirred at 45° C. (120 minutes). Water (230 ml) and aqueous ammonia (25% by weight) (3 ml) is added (pH=10.5-11.0). The phases are separated and the toluene phase is washed with water (3×120 ml). The toluene phase is evaporated and the yield is 53.0 g (95%). The product contains 0.06% of Z-4-(4-dimethylamino-1-(4-fluorophenyl)-but-1-enyl)-3-hydroxymethyl-benzonitrile.

example 2

Production Scale Crystallisation of Escitalopram Oxalate

[0083] A large number of batches of crude escitalopram oxalate have been recrystallised in production scale according to the procedure described below. The batches comprises: [0084] a) Escitalopram prepared by acidic ring-closure of the R-form of the diol precursor as described in WO03 / 000672 followed by scavenging of hydroxyl containing impurity by a production scale version of the process described in example 1 followed by separation of racemic citalopram and escitalopram as described in WO03 / 000672. These batches contain Z-4-(4-dimethylamino-1-(4-fluorophenyl)-but-1-enyl)-3-hydroxymethyl-benzonitrile, typically in the range of 0.05% (w / w) relative to escitalopram. These batches are referred to as R-diol batches. [0085] b) Escitalopram prepared by ring-closure of the S-form of the diol precursor via an activated ester under alkaline conditions as described in U.S. Pat. No. 4,943,590. These batches do not contain Z-4-(4-dimet...

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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] Under 35 U.S.C. § 119(e), this application claims the benefit of prior U.S Provisional Application No. 60 / 550,909, filed Mar. 5, 2004, which is incorporated herein by reference in its entirety.[0002] The present invention relates to crystalline preparations of the oxalate salt of the compound escitalopram (INN-name), which is the S-enantiomer of the well-known antidepressant drug citalopram, i.e. (S)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile oxalate. BACKGROUND OF THE INVENTION [0003] Citalopram is a well-known antidepressant drug that has the following structure: It is a selective, centrally active serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, accordingly having antidepressant activities. [0004] Citalopram was first disclosed in DE 2,657,013, corresponding to U.S. Pat. No. 4,136,193. This patent publication describes the preparation of citalopram by one method and outlines a further method, which may be used for prep...

Claims

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Application Information

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IPC IPC(8): A61K9/14A61K31/343C07D307/87
CPCA61K31/343A61K9/2054C07D307/87
Inventor JENSEN, KIM B.HUMBLE, RIKKE E.LILJEGREN, KENCHRISTENSEN, TROELS V.
Owner H LUNDBECK AS
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