Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-09-08
2004-05-25
Morris, Patricia L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S255000
Reexamination Certificate
active
06740669
ABSTRACT:
BACKGROUND OF THE INVENTION
The compound 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide of the formula
is described in the European Patent Application with the Publication No. 0 199 262 A2 (EP 199262), for example in Example 4. Valuable pharmacological properties are attributed to this compound; thus, it can be used, for example, as an antiepileptic. The compound 1-(2,6-difluorobenyl)-1H-1,2,3-triazole-4-carboxamide is obtained according to EP 199262, starting from 2,6-difluorobenzyl azide via the formation of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid, the procedure being analogous to Example 2.
EP 199262 provides no information at all about possible crystal modifications obtained. If the method according to the Example 4 is used in conjunction with Example 2, the crude 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide product obtained is finally crystallized from ethanol. However, EP 199262 gives no indication that such recrystallization is specifically to be applied, or on particular conditions that might be adopted. It has now surprisingly been found that the different crystal modifications (polymorphism) characterized below can be prepared by choice of specialty selected process conditions, for example through the choice of an appropriate solvent for the recrystallization or the duration of the recrystallization.
DESCRIPTION OF THE INVENTION
1-(2,6-Difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide can be obtained in the novel crystal modifications A, A′, B and C. These crystal modifications differ with respect to their thermodynamic stability, in their physical parameters, such as the absorption pattern of IR and Raman spectra, in X-ray structure investigations and in their preparation processes.
The invention relates to the novel crystal modifications A and A′ preparation and use in pharmaceutical preparations comprising the crystal modifications.
The modification A′, compared with A, has defects in the crystal lattice. These are detectable, for example, by X-ray analysis, e.g. by smaller line spacings with otherwise predominantly identical lines or bands.
The novel crystal modification A of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide melts at 242° C. (239-245° C.).
In the FT infrared (FT-IR) spectrum (KBr pellet—transmission method), modification A or A′ differs from modifications B and C predominantly in the shape and in the relative intensity of many bands. Particularly characteristic are the bands at 3412 cm
−1
and 3092 cm
−1
[cf. FIG.
1
], which are not present in the Fr-IR spectra of the modifications B and C. In the range 4000-600 cm
−1
, inter alia the following bands are obtained for modification A: 3412, 3189, 3092, 1634, 1560, 1473, 1397, 1325, 1300, 1284, 1235, 1125, 1053, 1036, 1014, 885, 840, 799, 781, 723, 688 and 640 cm
−1
. For example, the apparatus IFS 88 (Bruker) can be used for the recording of each of the FT-IR spectra.
In the FT Raman spectrum (powder—reflection method 180°), the modification A or A′ differs from modifications B and C predominantly in the shape and in the relative intensity of many bands. Particularly characteristic are the band at 1080 cm
−1
[cf. FIG.
2
], which is not present in the Raman spectra of the modifications B and C. In the range 3400-300 cm
−1
, inter alia the following bands are obtained for the modification A: 3093, 2972, 1628, 1614, 1558, 1465, 1446, 1393, 1279, 1245, 1147, 1080, 1061, 1036, 1014, 840, 724, 691, 667, 550, 499, 437 and 368 cm
−1
. For example, the apparatus RFS 100 (Bruker) can be used for the recording of each of the FT Raman spectra.
The novel modification A has an X-ray powder pattern with characteristic lines with interplanar spacings (d values) of 10.5 Å, 5.14 Å, 4.84 Å, 4.55 Å, 4.34 Å, 4.07 Å, 3.51 Å, 3.48 Å, 3.25 Å, 3.19 Å, 3.15 Å, 3.07 Å, 2.81 Å [cf. Table 1]. The measurement can be carried out, for example, in transmission geometry on an FR 552 Guinier camera from Enraf-Nonius, Deft (The Netherlands), using copper K&agr;
1
radiation (wavelength &lgr;=1.54060 Å). The patterns recorded on X-ray film were measured using an LS-18 line scanner from Johannsson, Täby (Sweden) and evaluated using the Scanpi software (P. E. Werner, University of Stockholm).
Characteristic for the novel modification A is the thermogram in differential scanning calorimetry. It has an endothermic peak in the range from 230° C. to 260° C. The peak temperature is 239-245° C., and the endothermic signal is 209 J/g+/−10 J/g. The measurement was carried out on a Perkin Elmer DSC 7 in a closed pan with a heating rate of 20 K/minute. The typical sample quantity is about 4 mg. As a typical distinguishing feature compared with the modifications B and C, the thermogram of the modification A has no further thermal signal.
Crystals of the modfication A′ have the same crystal structure as modification A. They differ from the modification A in the X-ray powder pattern in that they have slightly smaller line spacings between specific pairs of lines. These are the pairs of lines with the following interplanar spacings: 3.68 Å and 3.64 Å, 3.51 Å and 3.48 Å, 3.19 Å and 3.15 Å.
In the FT-IR spectrum (KBr pellet—transmission method), the modification B differs from the modification A or A′ and C predominantly in the shape and in the relative intensity of many bands. Particularly characteristic is a band at 1678 cm
−1
[cf. FIG.
1
], which is not to be observed in the corresponding spectra of the modifications A and C. In the range 4000-600 cm
−1
, inter alia the following bands are obtained for the modification B: 3404, 3199, 3125, 1678, 1635, 1560, 1475, 1393, 1357, 1322, 1286, 1237, 1051, 1036, 1028, 889, 837, 800, 719, 667 and 645 cm
−1
. For example, the apparatus IFS 85 (Bruker) can be used for recording of each of the FT-IR spectra.
In the FT Raman spectrum (powder—reflection method 180°), the modification B differs from the modifications A or A′ and C predominantly in the shape and in the relative intensity of many bands. Particularly characteristic are the bands at 3166 cm
−1
and 1086 cm
−1
[cf. FIG.
2
], which are not present in the Raman spectra of the modifications A and C. In the range 3400-300 cm
−1
, inter alia the following bands are obtained for the modification B: 3166, 3089, 2970, 1678, 1628, 1614, 1559, 1464, 1441, 1391, 1275, 1244, 1147, 1086, 1062, 1036, 1014, 839, 773, 724, 690, 668, 595, 549, 500, 493, 430 and 365 cm
−1
. For example, the apparatus RFS 100 (Bruker) can be used for recording of each of the Fr Raman spectra.
The modification B has an X-ray powder pattern with characteristic lines with interplanar spacings (d values) of 11.0 Å, 8.3 Å, 5.18 Å, 4.88 Å, 4.80 Å, 4.42 Å, 4.33 Å, 4.19 Å, 4.12 Å, 3.81 Å, 3.50 Å, 3.41 Å, 3.36 Å, 3.32 Å, 3.28 Å, 3.24 Å, 3.05 Å, 2.83 Å [cf. Table 1].
In the thermogram in differential scanning calorimetry, the modification B has, in addition to an endothermic signal in the range from 230° C. to 260° C. (peak temperature 239-245° C.), a weak thermal signal at 205° C. (180-220° C.) as a typical distinguishing feature compared with the modifications A or A′ and C.
In the FT-IR spectrum (KBr pellet—transmission method), the modification C differs from the modifications A or A′ and B predominantly in the shape and in the relative intensity of many bands. Particularly characteristic is a band at 3137 cm
−1
[cf. FIG.
11
], which is not to be observed in the corresponding spectra of the modifications A and B.
In the range 4000-600 cm
−1
, inter alia the following bands are obtained for the modification C: 3396, 3287, 3137, 1657, 1631, 1602, 1559, 1475, 1392, 1323, 1287, 1237,
Burkhard Andreas
Hofmeier Urs Christoph
Portmann Robert
Scherrer Walter
Szelagiewicz Martin
Borovian Joseph J.
Morris Patricia L.
Novartis AG
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