Crystal form of anhydrous luoro-1-(2,4-difluorophenyl)-1,4-dihyd

Details Crystal form of anhydrous luoro-1-(2,4-difluorophenyl)-1,4-dihyd Crystal form of anhydrous luoro-1-(2,4-difluorophenyl)-1,4-dihyd

1997-05-21

1998-06-09

Dees, Jose G.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514312, 514 19, 546123, 546156, A61K 31435, A61K 3147, C07D47104, C07D215312

Patent

active

057634548

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

The invention is directed to a novel crystal form of anhydrous oro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonic acid salt, a method of using said compound in the treatment of a bacterial infection in mammals, especially humans, and to pharmaceutical compositions useful therefor.
U.S. Pat. No. 5,229,396, which is incorporated herein by reference, discloses oro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonic acid salt of the formula ##STR1## wherein Y is o,p-difluorophenyl and R.sup.2 is ##STR2## having antibacterial activity.


SUMMARY OF THE INVENTION

The invention is directed to a novel crystal form of anhydrous oro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonic acid salt which possesses valuable and nonobvious properties. Since the anhydrate is substantially hydrophobically stable, formulation problems of the active ingredient during tableting or capsulation operations are alleviated.


DETAILED DESCRIPTION OF THE INVENTION

The oro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonic acid salt referred to in U.S. Pat. No. 5,229,396 characterized by the major peaks in the following X-ray powder diffraction pattern


__________________________________________________________________________ Peak no. 1 2 3 4 5 6 7 8 9 10 __________________________________________________________________________ 2.theta.(.degree.) Cu 5.0 9.8 13.0 14.8 19.7 20.9 22.0 23.0 28.1 29.3 d space 17.9 9.0 6.8 6.0 4.5 4.2 4.0 3.9 3.2 3.0 __________________________________________________________________________ form a monohydrate. The monohydrate is characterized by the major peaks in the following X-ray powder diffraction pattern


______________________________________ Peak no. 1 2 3 4 5 6 7 8 ______________________________________ 2.theta.(.degree.) Cu 4.7 9.4 12.4 13.1 13.6 14.2 17.0 17.9 d space 18.7 9.4 7.1 6.7 6.5 6.3 5.2 5.0 ______________________________________ Peak no. 9 10 11 12 12 14 15 ______________________________________ 2.theta.(.degree.) Cu 18.7 21.0 22.0 24.2 24.2 26.6 27.2 d space 4.7 42 4.0 3.7 3.7 3.5 3.3 ______________________________________
The novel crystal form of oro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonic acid salt (hereinafter "the anhydrate") is hydrophobically stable and characterized by the major peaks in the following X-ray powder diffraction pattern.


______________________________________ Peak no. 1 2 3 4 5 6 7 8 ______________________________________ 2.theta.(.degree.) Cu 4.5 7.7 9.1 13.6 15.0 18.2 18.6 22.8 d space 19.5 11.5 9.7 6.5 5.9 4.9 4.8 3.9 ______________________________________
The anhydrate may be prepared by heating oro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonic acid salt or its derived monohydrate in an organic solvent or a mixture thereof with an aprotic co-solvent, such as isopropanol, dimethylsulfoxide, n-propanol, tetrahydrofuran or n-butanol, preferably n-butanol or tetrahydrofuran
-butanol, to reflux or to a temperature between about 70.degree. C. to about 90.degree. C., preferably about 85.degree. C. Depending on the reaction temperature and other conditions, the reaction time generally ranges from about 1 hour to about 20 hours, preferably about 2 hours to about 16 hours.
The crystal slurry formed is cooled to a temperature between about 20.degree. C. to about 30.degree. C., preferably about 25.degree. C., for a time period between about 2 hours to about 24 hours, preferably about 2 hours to about 12 hours. The crystalline product is then filtered from the mother liquid and dried under vacuum until all the solvent has been removed.
The anhydrate may be administered as an antibacterial agent as described in above-mentioned U.S. Pat. No. 5,229,396. Administration to a subje

REFERENCES:
patent: 5164402 (1992-11-01), Brighty
patent: 5229396 (1993-07-01), Brighty

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