Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-05-23
2003-12-16
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S113000, C546S156000
Reexamination Certificate
active
06664268
ABSTRACT:
This application is the 371 of PCT/EP99/08776, filed on Nov. 15, 1999.
The present invention relates to a defined crystal modification of 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, to processes for its preparation and to its use in pharmaceutical preparations.
Hereinbelow, 8-cyano-1-cyclopropyl-7-(1 S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of the formula (I) is referred to as CCDC.
CCDC is known from DE-A 19 633 805 or PCT Appl. No. 97 903 260.4. According to these publications, it is prepared by reacting 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid with (1S,6S)-2,8-diaza-bicyclo[4.3.0]nonane in a mixture of dimethylformamide and acetonitrile in the presence of an auxiliary base. Water is added to the mixture and CCDC is then extracted from water using dichloromethane and is isolated by removing the extractant. This gives a powder whose crystal modification is not unambiguous. On the contrary, the powder is largely amorphous and can contain mixtures of different crystal modifications. If, by chance, a uniform crystal modification is formed, it is not clear how it can be extracted and obtained in a defined form. However, it is the precondition for preparing medicaments that, for an active compound which can be present in different crystal modifications, it can be stated unamibiguously which of its crystal modifications is used for preparing the medicament.
The partially amorphous powder which is obtained by the preparation process outlined above is furthermore hygroscopic. However, amorphous solids, and in particular hygroscopic solids, are difficult to handle when being processed pharmaceutically since, for example, they have low bulk densities and unsatisfactory flow properties. Moreover, the handling of hygroscopic solids requires special work techniques and apparatuses to obtain reproducible results, for example with respect to the active compound content or the stability of the solid formulations produced.
It is therefore an object of the invention to prepare a crystalline form of a defined modification of CCDC which, owing to its physical properties, in particular its crystal properties and its behaviour towards water, is easy to handle in pharmaceutical formulations.
This object is achieved according to the invention by a novel crystalline form of CCDC which is referred to as modification B hereinbelow.
The invention accordingly provides the crystalline modification B of CCDC which is characterized in that it has an X-ray powder diffractogram with the reflection signals (2 theta) of high and medium intensity (>30% relative intensity) listed in Table 1 below.
TABLE 1
X-ray powder diffractogram of CCDC of the modification B
2&thgr; (2 theta)
8.91
13.23
14.26
14.40
15.34
17.88
19.70
20.78
21.86
28.13
30.20
REFERENCES:
patent: 6278013 (2001-08-01), Bartel
patent: 96/16055 (1996-05-01), None
patent: 97/31001 (1997-08-01), None
patent: 00/31075 (2000-06-01), None
patent: 00/52009 (2000-09-01), None
patent: 00/52010 (2000-09-01), None
Hallenbach Werner
Himmler Thomas
Rast Hubert
Bayer Aktiengesellschaft
Huang Evelyn Mei
Pellegrino Susan M.
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