WO1998056772A1 - Crystal modification of 1-(2,6-difluorobenzyl)-1h-1,2,3--triazole-4-carboxamide and its use as antiepileptic - Google Patents

Crystal modification of 1-(2,6-difluorobenzyl)-1h-1,2,3--triazole-4-carboxamide and its use as antiepileptic Download PDF

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Publication number
WO1998056772A1
WO1998056772A1 PCT/EP1998/003427 EP9803427W WO9856772A1 WO 1998056772 A1 WO1998056772 A1 WO 1998056772A1 EP 9803427 W EP9803427 W EP 9803427W WO 9856772 A1 WO9856772 A1 WO 9856772A1
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Prior art keywords
modification
weak
triazole
carboxamide
medium
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PCT/EP1998/003427
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French (fr)
Inventor
Robert Portmann
Urs Christoph Hofmeier
Andreas Burkhard
Walter Scherrer
Martin Szelagiewicz
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Novartis Ag
Novartis-Erfindungen Verwaltungsgesellschaft Mbh
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Priority to AU84371/98A priority Critical patent/AU725528B2/en
Priority to DE69811500T priority patent/DE69811500T2/en
Priority to CA002256013A priority patent/CA2256013C/en
Priority to DE122007000051C priority patent/DE122007000051I2/en
Priority to AT98934929T priority patent/ATE232852T1/en
Priority to US09/125,329 priority patent/US6740669B1/en
Priority to PL330764A priority patent/PL191943B1/en
Priority to IL12573398A priority patent/IL125733A/en
Priority to EP98934929A priority patent/EP0994863B1/en
Priority to HU0000798A priority patent/HU226107B1/en
Priority to SI9830405T priority patent/SI0994863T1/en
Application filed by Novartis Ag, Novartis-Erfindungen Verwaltungsgesellschaft Mbh filed Critical Novartis Ag
Priority to BR9804947A priority patent/BR9804947A/en
Priority to SK1093-98A priority patent/SK283685B6/en
Priority to NZ331371A priority patent/NZ331371A/en
Priority to DK98934929T priority patent/DK0994863T3/en
Priority to JP53628898A priority patent/JP3672574B2/en
Priority to NO19983667A priority patent/NO329315B1/en
Publication of WO1998056772A1 publication Critical patent/WO1998056772A1/en
Priority to HK00106804A priority patent/HK1028241A1/en
Priority to US11/329,945 priority patent/US7750028B2/en
Priority to NL300284C priority patent/NL300284I2/en
Priority to LU91345C priority patent/LU91345I2/en
Priority to FR07C0037C priority patent/FR07C0037I2/fr
Priority to CY200700014C priority patent/CY2007014I2/en
Priority to US12/767,003 priority patent/US8076362B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants

Definitions

  • 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-dif luorobenzyl)-1 H-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)-1 H-1 ,2,3- triazoie-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)-1 H-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 specially 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
  • the invention relates to the novel crystal modifications A and A', their preparation and use in pharmaceutical preparations comprising this crystal modification.
  • 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.
  • novel crystal modification A of 1-(2,6-difluorobenzyl)-1 H-1 ,2,3-triazole-4-carboxamide melts at 242 °C (239-245 °C).
  • 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. Figure 1], which are not present in the FT-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 .
  • the apparatus IFS 88 (Bruker) can be used for the recording of each of the FT-IR spectra.
  • 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. Figure 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 .
  • 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 A, 5.14 A, 4.84 A, 4.55 A, 4.34 A, 4.07 A, 3.51 A, 3.48 A, 3.25 A, 3.19 A, 3.15 A, 3.07 A, 2.81 A [cf. Table 1].
  • the patterns recorded on X-ray film were measured using an LS-18 line scanner from Johannsson, Taby (Sweden) and evaluated using the Scanpi software (P.E.Werner, University of Sweden).
  • 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 fo the modification 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 A and 3.64 A, 3.51 A and 3.48 A, 3.19 A and 3.15 A.
  • 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 . Figure 1 ], which is not to be observed in the corresponding spectra of the modifications A and C.
  • 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 .
  • the apparatus IFS 85 (Bruker) can be used for recording of each of the FT-IR spectra.
  • 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. Figure 2], which are not present in the Raman spectra of the modifications A and C.
  • 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 .
  • the apparatus RFS 100 (Bruker) can be used for recording of each of the FT Raman spectra.
  • the modification B has an X-ray powder pattern with characteristic lines with interplanar spacings (d values) of 11.0 A, 8.3 A, 5.18 A, 4.88 A, 4.80 A, 4.42 A, 4.33 A, 4.19 A, 4.12 A, 3.81 A, 3.50 A, 3.41 A, 3.36 A, 3.32 A, 3.28 A, 3.24 A, 3.05 A, 2.83 A [cf. Table 1].
  • 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.
  • 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. Figure 1], which is not to be observed in the corresponding spectra of the modifications A and B.
  • the following bands are obtained for the modification C: 3396, 3287, 3137, 1657, 1631 , 1602, 1559, 1475, 1392, 1323, 1287, 1237, 1122, 1104, 1047, 1035, 1012, 876, 839, 797, 773, 729 and 653 cm '1 .
  • the apparatus IFS 85 (Bruker) can be used for recording of each of the FT-IR spectra.
  • 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 are the bands at 3137 cm “1 and 1602 cm '1 [cf. Figure 2], which are not present in the Raman spectra of the modifications A and B.
  • the following bands are obtained for the modification C: 3137, 3080, 3012, 2971 , 1673, 1629, 1602, 1561 , 1436, 1271 , 1248, 1105, 1065, 1035, 1013, 839, 800, 767, 726, 690, 672, 593, 549, 500, 492, 435 and 370 cm '1 .
  • the apparatus RFS 100 (Bruker) can be used for recording of each of the FT Raman spectra.
  • the modification C has an X-ray powder pattern with characteristic lines with interplanar spacings (d values) of 9.0 A, 4.73 A, 4.65 A, 3.75 A, 3.54 A, 3.42 A, 3.25 A [cf. Table 1].
  • the modification C has, in addition to an endothermic signal in the range of 230 °C to 260 °C (peak temperature 239-245 °C), a very broad, weak, exothermic signal in the region of 180 °C compared with the modifications A or A' and B.
  • Table 1 Characterization of the modifications A. B and C (X-rav powder patterns):
  • Modifications A, A', B and C have valuable pharmacological properties; in particular, they can be used for the treatment of epilepsy.
  • the modification A or A' has significant advantages compared with the modification B and compared with the modification C.
  • comprehensive thermodynamic investigations such as thermomicroscopy, X-ray powder diffractometry, DSC, solubility tests and other experiments, have shown that the modification A or A' surprisingly has substantially better thermodynamic stability than the modifications B and C.
  • Modification C which can be obtained only under specific conditions, is the least stable of the three modifications.
  • the crystals of the modification C are converted into modification B at as low as room temperature within a few weeks.
  • the modification C is converted either into the modification A or A' or into the modification B, depending on experimental conditions. It is particularly important for drug that its pharmaceutical formulation ensures high and reproducible stability over a long period.
  • a constant stability also permits reproducible bioavailability of an active ingredient. If an active ingredient is subjected to a conversion process, this may readily also cause the bioavailability to fluctuate, which is undesirable. Accordingly, pharmaceutical active ingredients or polymorphic forms thereof which are of primary interest for pharmaceutical developments are those which exhibit high stability and do not have the above-mentioned disadvantages.
  • the crystal modification A or A' fulfils these preconditions.
  • the modification A or A' has, for example, a slower dissolution rate in water or in gastric fluid (so-called “slow-release effect”). This effect can be utilized primarily for long- term therapy where a slow or delayed release is desired.
  • the invention relates to the modification A of 1 -(2,6-difluorobenzyl)-1 H-1 ,2,3-triazole-4- carboxamide, characterized by the following absorptions in the infrared spectrum (KBr pellet - transmission method): bands at 3092 cm '1 and 3412 cm "1 .
  • the invention relates to the modification A of 1 -(2,6-difluorobenzyl)-1 H-1 ,2,3-triazole-4- carboxamide, characterized by the characteristic lines with interplanar spacings (d values) as shown in Table 1.
  • the invention relates to the modification A of 1 -(2,6-dif luorobenzyl)-1 H-1 ,2,3-triazole-4- carboxamide, characterized by an endothermic peak in the range from 230 °C to 260 °C, the peak temperature being 239-245 °C and the endothermic signal being 209 J/g +/- 10 J/g.
  • the invention relates to the crystal modification A' which, compared with modification A, has defects in the crystal lattice.
  • the invention relates to the modification A' which, compared with modification A, has smaller line spacings between the pairs of lines with interplanar spacings 3.68 A and 3.64 A, 3.51 A and 3.48 A, and 3.19 A and 3.15 A.
  • the invention relates to the essentially pure form of the modification A or A' of 1 -(2,6- difluorobenzyl)-1 H-1 ,2,3-triazole-4-carboxamide.
  • the term "essentially pure form” means purity of >95%, in particular >98%, primarily >99%, based on the modification A or A'.
  • the invention relates to pharmaceutical preparations comprising the modification A or A' of 1-(2,6-difluorobenzyl)-1 H-1 ,2,3-triazole-4-carboxamide.
  • the invention relates in particular to corresponding pharmaceutical preparations for the treatment of epilepsy and subindications thereof.
  • the invention relates to the use of the modification A or A' of 1 -(2,6-difluorobenzyl)- 1 H-1 ,2,3-triazole-4-carboxamide for the preparation of pharmaceutical preparations, in particular for the treatment of epilepsy and subindications thereof.
  • novel modification A or A' of 1 -(2,6-difluorobenzyl)-1 H-1 ,2,3-triazole-4-carboxamide can be used, for example, in the form of pharmaceutical preparations which comprise a therapeutically effective amount of the active ingredient, if desired together with inorganic or organic, solid or liquid, pharmaceutically usable carriers, which are suitable for enteral, for example oral, or parenteral administration.
  • novel modification A or A' of 1- (2,6-difluorobenzyl)-1 H-1 ,2,3-triazole-4-carboxamide can be used in the form of preparations which can be administered parenterally or of infusion solutions.
  • the pharmaceutical preparations may be sterilized and/or may comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating the osmotic pressure and/or buffers.
  • excipients for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating the osmotic pressure and/or buffers.
  • the present pharmaceutical preparations comprise from about 0.1% to 100%, in particular from about 1% to about 50%, of lyophilisates to about 100% of the active ingredient.
  • the invention also relates to the use of modification A or A' of 1-(2,6-difluorobenzyl)-1 H- 1 ,2,3-triazole-4-carboxamide as a drug, preferably in the form of pharmaceutical preparations.
  • the dosage may depend on various factors, such as method of administration, species, age and/or individual condition.
  • the doses to be administered daily are between about 0.25 and about 10 mg/kg in the case of oral administration, and preferably between about 20 mg and about 500 mg for warm-blooded species having a body weight of about 70 kg.
  • modification A or A' is carried out, for example, as described in the embodiments below.
  • a suspension of methyl 1-(2,6-difluorobenzyl)-1 H-1 ,2,3-triazole-4-carboxylate (about 62 parts by weight), methanol (475.2 parts by weight) and anhydrous ammonia (29.4 parts by weight) is stirred for about 24 hours at 50-55°C in a closed vessel.
  • the suspension is cooled to about 20°C and stirred for about a further 2 hours.
  • the product is isolated by filtration, washed with methanol (240 parts by weight) and dried at 40-60°C in vacuo. Yield:
  • the starting compounds can be prepared, for example, as follows: A mixture of 1 -(2,6-dif luorobenzyl)-1 H-1 ,2,3-triazole-4-carboxylic acid (167.1 parts by weight), methanol (552 parts by weight) and 96% sulfuric acid (35.7 parts by weight) is stirred for about 5 hours at 60-66°C. The suspension is cooled to about 20°C and stirred for about a further 2 hours. The product is isolated by filtration and washed with methanol (198 parts by weight). A yield of about 160 parts by weight is obtained by drying at 40-60°C in vacuo.
  • the starting material can be prepared, for example, as follows: 4-Cyano-1 -(2,6-dif luorobenzyl)-1 H-1 ,2,3-triazole
  • 1 -(2,6-dif luorobenzyl)-1 H-1 ,2,3-triazole-4-carboxamide (pure active ingredient; 4.0 g) is dissolved in 96% ethanol (500 ml, without denaturing agent) at about 80°C while stirring.
  • the solution is filtered into a suction bottle (1 litre) at about 20°C (glass suction filter, pore size 10-20 ⁇ m), a suspension forming. After stirring has been continued for 5 minutes at about 20°C and for 15 minutes at about 0°C, the product is isolated by filtration (about 0° to about 20°C).
  • the solvent-moist product (9.6 g) is investigated without subsequent drying. Modification A'.
  • Film-coated tablets each containing, for example, 100, 200 or 400 mg of modification A or A' of 1 -(2,6-difluorobenzyl)-1 H-1 ,2,3-triazole-4-carboxamide with the following composition per dosage unit:
  • Titanium dioxide 0.83 1.66 3.32
  • the active ingredient is granulated with demineralised water. Milled lactose, maize starch, Avicel PH 102, cellulose-HP-M-603 and sodium laurylsulfate are added to the above mixture and granulated with demineralised water.
  • the moist material is dried and milled. After the addition of the remaining ingredients, the homogeneous mixture is compressed to give tablet cores having the stated active ingredient content.
  • the tablet cores are coated with the film coat which is formed from the appropriate ingredients, the latter being dissolved or being suspended in water or in small amounts of ethanol with 5% of isopropanol.
  • Figure 1 shows the FT-IR spectra of the KBr pellets of modifications A, B and C.
  • Figure 2 shows the FT-Raman spectra of the powder of modification A, B and C.
  • the modification A is denoted by the symbol *
  • the modification B by the symbol **
  • the modification C by the symbol * * *.

Abstract

The invention relates to the novel modification A or A' of the compound 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide of formula (I), its use for the treatment of epilepsy, and pharmaceutical preparations comprising this crystal modification.

Description

CRYSTAL MODIFICATION OF l-(2,6-DIFLUOROBENZYL)-lH-l,2,3— TRIAZOLE-4-CARBOXAMIDE AND ITS USE AS ANTIEPILEPTIC
Background of the invention
The compound 1 -(2,6-difluorobenzyl)-1 H-1 ,2,3-triazole-4-carboxamide of the formula
Figure imgf000003_0001
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-dif luorobenzyl)-1 H-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)-1 H-1 ,2,3- triazoie-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)-1 H-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 specially 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-Dif luorobenzyl)-1 H-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', their preparation and use in pharmaceutical preparations comprising this crystal modification.
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)-1 H-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. Figure 1], which are not present in the FT-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. Figure 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 A, 5.14 A, 4.84 A, 4.55 A, 4.34 A, 4.07 A, 3.51 A, 3.48 A, 3.25 A, 3.19 A, 3.15 A, 3.07 A, 2.81 A [cf. Table 1]. The measurement can be carried out, for example, in transmission geometry on an FR 552 Guinier camera from Enraf-Nonius, Delft (The Netherlands), using copper Kαι radiation (wavelength λ = 1.54060 A). The patterns recorded on X-ray film were measured using an LS-18 line scanner from Johannsson, Taby (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 fo the modification 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 A and 3.64 A, 3.51 A and 3.48 A, 3.19 A and 3.15 A.
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 . Figure 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. Figure 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 FT Raman spectra.
The modification B has an X-ray powder pattern with characteristic lines with interplanar spacings (d values) of 11.0 A, 8.3 A, 5.18 A, 4.88 A, 4.80 A, 4.42 A, 4.33 A, 4.19 A, 4.12 A, 3.81 A, 3.50 A, 3.41 A, 3.36 A, 3.32 A, 3.28 A, 3.24 A, 3.05 A, 2.83 A [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. Figure 1], 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, 1122, 1104, 1047, 1035, 1012, 876, 839, 797, 773, 729 and 653 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 C differs from the modifications A or A' and B predominantly in the shape and in the relative intensity of many bands. Particularly characteristic are the bands at 3137 cm"1 and 1602 cm'1 [cf. Figure 2], which are not present in the Raman spectra of the modifications A and B. In the range 3400-300 cm'1, inter alia the following bands are obtained for the modification C: 3137, 3080, 3012, 2971 , 1673, 1629, 1602, 1561 , 1436, 1271 , 1248, 1105, 1065, 1035, 1013, 839, 800, 767, 726, 690, 672, 593, 549, 500, 492, 435 and 370 cm'1. For example, the apparatus RFS 100 (Bruker) can be used for recording of each of the FT Raman spectra.
The modification C has an X-ray powder pattern with characteristic lines with interplanar spacings (d values) of 9.0 A, 4.73 A, 4.65 A, 3.75 A, 3.54 A, 3.42 A, 3.25 A [cf. Table 1]. In the thermogram in differential scanning calorimetry, the modification C has, in addition to an endothermic signal in the range of 230 °C to 260 °C (peak temperature 239-245 °C), a very broad, weak, exothermic signal in the region of 180 °C compared with the modifications A or A' and B. Table 1 : Characterization of the modifications A. B and C (X-rav powder patterns):
Figure imgf000008_0001
Figure imgf000009_0001
Single crystal X-rav analysis:
Crystal quality and unit cell of modifications A, B, and C were verified by Weissenberg and precession photographs. The intensities were measured on a four-axis Nonius CAD-4 diffractometer. The structures were solved with the SHELXS-97 and refined with the SHELXL-97 software.
Modification A
Space group: Pna2ι - orthorhombic Cell dimensions: a = 24.756 (5)A b = 23.069 (4)A c = 5.386 (1 )A v = 3075.9 A3 Z = 12 Dx = 1.543 gcm"; v per formula: V, = 256.3 A3
9011 unique reflections; 2479 thereof significant with I > 2σ (I). 557 parameters refined. Position of all H atoms found by difference Fourier maps and refined isotropically. Reliability index R,: 3.65% (wR2 for all 9011 reflections: 11.34%).
Modification B
Space group: P "1 -triclinic
Cell dimensions: a = 5.326(1 ) A b = 11.976(2) A c = 17.355(3) A α = 107.22(3)° β = 92.17(3)° γ = 102.11 (3)° v = 1027.9 A3 Z = 4 Dx = 1.539 gcm": v per formula Vz = 257.0 A3 4934 unique reflections; 834 thereof significant with I > 2σ (I). 232 parameters refined. Position of all H atoms found by difference Fourier maps and refined isotropically. Reliability index R,: 4.20% (wR2 for all 4934 reflections: 7.93%).
Modification C
Space group: P2JC - monoclinic Cell dimensions: a = 10.982(2) A b = 5.350(1 ) A c = 17.945(3) A β = 91.59(1)° v = 1053.9 A3 Z = 4 Dx = 1.501 gem'3 v per formula: Vz = 263.5 A3
3073 unique reflections; 1071 thereof significant with I > 2σ (I). 187 parameters refined. Position of all H atoms found by difference Fourier maps and refined isotropically. Reliability index R,: 5,02% (wR2 for all 3073 reflections: 14.55%).
Modifications A, A', B and C have valuable pharmacological properties; in particular, they can be used for the treatment of epilepsy.
The modification A or A' has significant advantages compared with the modification B and compared with the modification C. Thus, for example, comprehensive thermodynamic investigations, such as thermomicroscopy, X-ray powder diffractometry, DSC, solubility tests and other experiments, have shown that the modification A or A' surprisingly has substantially better thermodynamic stability than the modifications B and C. Modification C, which can be obtained only under specific conditions, is the least stable of the three modifications. The crystals of the modification C are converted into modification B at as low as room temperature within a few weeks. The modification C is converted either into the modification A or A' or into the modification B, depending on experimental conditions. It is particularly important for drug that its pharmaceutical formulation ensures high and reproducible stability over a long period. These preconditions are fulfilled by incorporation of the compound 1-(2,6-difluorobenzyl)-1H-1 ,2,3-triazole-4-carboxamide of the crystal modification A or A', owing to its high thermodynamic stability. In particular, this is displayed in a solid pharmaceutical dosage form.
A constant stability also permits reproducible bioavailability of an active ingredient. If an active ingredient is subjected to a conversion process, this may readily also cause the bioavailability to fluctuate, which is undesirable. Accordingly, pharmaceutical active ingredients or polymorphic forms thereof which are of primary interest for pharmaceutical developments are those which exhibit high stability and do not have the above-mentioned disadvantages. The crystal modification A or A' fulfils these preconditions.
Furthermore, the modification A or A' has, for example, a slower dissolution rate in water or in gastric fluid (so-called "slow-release effect"). This effect can be utilized primarily for long- term therapy where a slow or delayed release is desired.
The invention relates to the modification A of 1 -(2,6-difluorobenzyl)-1 H-1 ,2,3-triazole-4- carboxamide, characterized by the following absorptions in the infrared spectrum (KBr pellet - transmission method): bands at 3092 cm'1 and 3412 cm"1.
The invention relates to the modification A of 1 -(2,6-dif iuorobenzyl)-1 H-1 ,2,3-triazole-4- carboxamide, characterized by characteristic lines with interplanar spacings (d values) of 10.5 A, 5.14 A, 4.84 A, 4.55 A, 4.34 A, 4.07 A, 3.51 A, 3.48 A, 3.25 A, 3.19 A, 3.15 A, 3.07 A and 2.81 A, determined by means of an X-ray powder pattern.
The invention relates to the modification A of 1 -(2,6-difluorobenzyl)-1 H-1 ,2,3-triazole-4- carboxamide, characterized by the characteristic lines with interplanar spacings (d values) as shown in Table 1.
The invention relates to the modification A of 1 -(2,6-dif luorobenzyl)-1 H-1 ,2,3-triazole-4- carboxamide, characterized by an endothermic peak in the range from 230 °C to 260 °C, the peak temperature being 239-245 °C and the endothermic signal being 209 J/g +/- 10 J/g.
Furthermore, the invention relates to the crystal modification A' which, compared with modification A, has defects in the crystal lattice.
The invention relates to the modification A' which, compared with modification A, has smaller line spacings between the pairs of lines with interplanar spacings 3.68 A and 3.64 A, 3.51 A and 3.48 A, and 3.19 A and 3.15 A.
The invention relates to the essentially pure form of the modification A or A' of 1 -(2,6- difluorobenzyl)-1 H-1 ,2,3-triazole-4-carboxamide. The term "essentially pure form" means purity of >95%, in particular >98%, primarily >99%, based on the modification A or A'.
The invention relates to pharmaceutical preparations comprising the modification A or A' of 1-(2,6-difluorobenzyl)-1 H-1 ,2,3-triazole-4-carboxamide. The invention relates in particular to corresponding pharmaceutical preparations for the treatment of epilepsy and subindications thereof. The invention relates to the use of the modification A or A' of 1 -(2,6-difluorobenzyl)- 1 H-1 ,2,3-triazole-4-carboxamide for the preparation of pharmaceutical preparations, in particular for the treatment of epilepsy and subindications thereof.
The novel modification A or A' of 1 -(2,6-difluorobenzyl)-1 H-1 ,2,3-triazole-4-carboxamide can be used, for example, in the form of pharmaceutical preparations which comprise a therapeutically effective amount of the active ingredient, if desired together with inorganic or organic, solid or liquid, pharmaceutically usable carriers, which are suitable for enteral, for example oral, or parenteral administration. Furthermore, the novel modification A or A' of 1- (2,6-difluorobenzyl)-1 H-1 ,2,3-triazole-4-carboxamide can be used in the form of preparations which can be administered parenterally or of infusion solutions. The pharmaceutical preparations may be sterilized and/or may comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating the osmotic pressure and/or buffers. The present pharmaceutical preparations comprise from about 0.1% to 100%, in particular from about 1% to about 50%, of lyophilisates to about 100% of the active ingredient.
The invention also relates to the use of modification A or A' of 1-(2,6-difluorobenzyl)-1 H- 1 ,2,3-triazole-4-carboxamide as a drug, preferably in the form of pharmaceutical preparations. The dosage may depend on various factors, such as method of administration, species, age and/or individual condition. The doses to be administered daily are between about 0.25 and about 10 mg/kg in the case of oral administration, and preferably between about 20 mg and about 500 mg for warm-blooded species having a body weight of about 70 kg.
The preparation of modification A or A' is carried out, for example, as described in the embodiments below.
Preparation of 1-(2.6-difluorobenzyl)-1 H-1 ,2.3-triazole-4-carboxamide
Example 1 :
A suspension of methyl 1-(2,6-difluorobenzyl)-1 H-1 ,2,3-triazole-4-carboxylate (about 62 parts by weight), methanol (475.2 parts by weight) and anhydrous ammonia (29.4 parts by weight) is stirred for about 24 hours at 50-55°C in a closed vessel. The suspension is cooled to about 20°C and stirred for about a further 2 hours. The product is isolated by filtration, washed with methanol (240 parts by weight) and dried at 40-60°C in vacuo. Yield:
57.2 parts by weight = 98%. Modification A.
The starting compounds can be prepared, for example, as follows: A mixture of 1 -(2,6-dif luorobenzyl)-1 H-1 ,2,3-triazole-4-carboxylic acid (167.1 parts by weight), methanol (552 parts by weight) and 96% sulfuric acid (35.7 parts by weight) is stirred for about 5 hours at 60-66°C. The suspension is cooled to about 20°C and stirred for about a further 2 hours. The product is isolated by filtration and washed with methanol (198 parts by weight). A yield of about 160 parts by weight is obtained by drying at 40-60°C in vacuo.
Example 2:
1 N sodium hydroxide solution (0.11 ml) is added to a mixture of 4-cyano-1 -(2,6-dif luorobenzyl)- 1 H-1 ,2,3-triazole (2.20 g) and water (44 ml) at an external temperature of 95-100°C while stirring. After 90 minutes, the suspension is cooled to 10°C and the product is isolated by filtration, washed with water and dried at about 60°C in vacuo. 1-(2,6-Difluorobenzyl)-1H-1 ,2,3- triazole-4-carboxamide is obtained in this manner; yield: 99.2% by weight. Modification A.
The starting material can be prepared, for example, as follows: 4-Cyano-1 -(2,6-dif luorobenzyl)-1 H-1 ,2,3-triazole
A mixture of 2,6-dif luorobenzyl azide (34.2 g), 2-chloroacrylonitrile (17.73 g) and water (125 ml) is stirred for 24 hours at about 80°C. By increasing the external temperature to about 130°C, excess 2-chloroacrylonitrile is distilled off. The semisolid mixture is cooled to about 40°C, cyclohexane (50 ml) is added to the suspension and the mixture is brought to about 20°C and stirred for about 2 hours. The product is isolated by filtration and washed with cyclohexane (75 ml) and then with water (50 ml). The moist product is mixed with water (100 ml), the suspension is filtered and the product is washed with water (50 ml) and dried at about 60°C in vacuo. Yield: 38.04 g = 86%.
Examples of the recrystallization of 1 -(2,6-dif luorobenzyl)-1 H-1.2.3-triazole-4-carboxamide
Example 3:
1-(2,6-Difluorobenzyl)-1 H-1 ,2,3-triazole-4-carboxamide (75.0 g) is dissolved in formic acid (360 ml) at 50-55°C by stirring. The solution is discharged in the course of 1 hour onto stirred methanol (375 ml) at about 20°C, a suspension forming. After stirring has been continued for 2 hours at about 20°C, the product is isolated by filtration, washed with methanol (750 ml) and dried at about 60°C in vacuo. Yield: 69.6 g = 92.8%. Modification A.
Example 4:
1 -(2,6-Dif luorobenzyl)-1 H-1 ,2,3-triazole-4-carboxamide (22.86 kg) is dissolved in formic acid (111.6 kg) at 58-63°C while stimng. The solution is discharged in the course of about 2 hours onto stirred methanol (131.9 1) at 20-25°C, after which washing with formic acid (7.6 kg) is carried out. A suspension forms. After stirring has been continued for at least 3 hours at about 20°C, the product is isolated by filtration and washed with methanol (187.5 I). By drying in vacuo at about 60°C, the product is obtained as modification A in a yield of 93-94%.
Example 5:
1 -(2,6-dif luorobenzyl)-1 H-1 ,2,3-triazole-4-carboxamide (pure active ingredient; 4.0 g) is dissolved in 96% ethanol (500 ml, without denaturing agent) at about 80°C while stirring. The solution is filtered into a suction bottle (1 litre) at about 20°C (glass suction filter, pore size 10-20 μm), a suspension forming. After stirring has been continued for 5 minutes at about 20°C and for 15 minutes at about 0°C, the product is isolated by filtration (about 0° to about 20°C). The solvent-moist product (9.6 g) is investigated without subsequent drying. Modification A'.
Formulation Example 1 :
Film-coated tablets each containing, for example, 100, 200 or 400 mg of modification A or A' of 1 -(2,6-difluorobenzyl)-1 H-1 ,2,3-triazole-4-carboxamide with the following composition per dosage unit:
Core material mg mg mg Active ingredient 100.00 200.00 400.00
Anhydrous, colloidal silica 0.88 1.75 3.5
Microcrystalline cellulose 36.62 73.25 146.50
Hydroxypropylmethyl- 5.00 10.00 20.00 cellulose
Lactose 20.00 40.00 80.00
Magnesium stearate 2.00 4.00 8.00
Maize starch 10.00 20.00 40.00
Sodium carboxymethyl- 5.00 10.00 20.00 cellulose
Sodium laurylsulfate 0.50 1.00 2.00
Film coat mg mg mg
Hydroxypropylmethyl- 3.22 6.43 12.87 cellulose
Red iron oxide 0.04 0.09 0.18
Polyethylene glycol 8000, 0.58 1.16 2.32 flakes
Talc 2.33 4.66 9.31
Titanium dioxide 0.83 1.66 3.32
The active ingredient is granulated with demineralised water. Milled lactose, maize starch, Avicel PH 102, cellulose-HP-M-603 and sodium laurylsulfate are added to the above mixture and granulated with demineralised water.
The moist material is dried and milled. After the addition of the remaining ingredients, the homogeneous mixture is compressed to give tablet cores having the stated active ingredient content. The tablet cores are coated with the film coat which is formed from the appropriate ingredients, the latter being dissolved or being suspended in water or in small amounts of ethanol with 5% of isopropanol.
Description of the Figures
Figure 1 shows the FT-IR spectra of the KBr pellets of modifications A, B and C.
Figure 2 shows the FT-Raman spectra of the powder of modification A, B and C.
In both Figures, the modification A is denoted by the symbol *, the modification B by the symbol ** and the modification C by the symbol ***.

Claims

Patent Claims
1. Modification A of the compound 1 -(2,6-dif luorobenzyl)-1 H-1 ,2,3-triazole-4- carboxamide of the formula
Figure imgf000018_0001
characterized by characteristic lines at inteφlanar spacings (d values) of 10.5 A, 5.14 A, 4.84 A, 4.55 A, 4.34 A, 4.07 A, 3.51 A, 3.48 A, 3.25 A, 3.19 A, 3.15 A, 3.07 A, 2.81 A, determined by means of an X-ray powder pattern.
2. Modification according to Claim 1 , characterized by an X-ray powder pattern having the following characteristic lines at inteφlanar spacings (d values) of 10.9 A (weak), 10.5 A (medium), 6.6 A (weak), 5.63 A (weak), 5.25 A (weak), 5.14 A (medium), 4.94 A (weak), 4.84 A (very strong), 4.55 A (strong), 4.42 A (very weak), 4.34 A (medium), 4.23 A (very weak), 4.16 A (weak), 4.07 A (medium), 4.01 A (weak), 3.68 A (very weak), 3.64 A (very weak), 3.60 A (weak), 3.56 A (weak), 3.51 A (medium), 3.48 A (medium), 3.38 A (very weak), 3.25 A (strong), 3.19 A (medium), 3.15 A (medium), 3.11 A (weak), 3.07 A (medium), 2.93 A (very weak), 2.87 A (very weak), 2.81 A (medium), 2.76 A (weak), 2.73 A (very weak), 2.68 A (weak), 2.62 A (very weak), 2.53 A (weak), 2.43 A (weak), 2.40 A (very weak).
3. Modification according to Claim 1 or 2, characterized by the following absoφtions in the FT-IR spectrum (KBr pellet - transmission method) 3092 cm"1 and 3412 cm"1.
4. Modification according to Claim 3, characterized by the following absorptions in the FT-IR spectrum (KBr pellet - transmission method): 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.
5. Modification according to any one of Claims 1 -4, characterized by the following absoφtions in the FT-Raman spectrum (powder - reflection method 180°): 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.
6. Modification A according to any one of Claims 1 -5, characterized by an endothermic peak in the range from 230 ┬░C to 260 ┬░C, the peak temperature being 239-245 ┬░C and the endothermic signal being 209 J/g +/- 10 J/g.
7. Modification A' of the compound 1 -(2,6-dif luorobenzyl)-1 H-1 ,2,3-triazole-4- carboxamide, characterized in that it is identical to the modification A according to any one of Claims 1-6 but has defects in the crystal lattice.
8. Modification A' according to Claim 7, characterized by line spacings, smaller compared to modification A according to any one of Claims 1 -6, between the pairs of lines at inteφlanar spacings 3.68 A and 3.64 A, 3.51 A and 3.48 A, and 3.19 A and 3.15 A.
9. Modification A or A' according to any one of Claims 1 -8 in essentially pure form.
10. Pharmaceutical preparations comprising the modification A or A' of the compound 1- (2,6-dif luorobenzyl)-1 H-1 ,2,3-triazole-4-carboxamide according to any one of Claims 1 -9 and pharmaceutically usable excipients and additives.
11. Use of the modification A or A' of 1 -(2,6-dif luorobenzyl)-1 H-1 ,2,3-triazole-4- carboxamide according to any one of Claims 1-9 as a pharmaceutical preparation.
12. Use of the modification A or A' of 1 -(2,6-dif luorobenzyl)-1 H-1 ,2,3-triazole-4- carboxamide according to any one of Claims 1-9 for the preparation of pharmaceutical preparations for the treatment of epilepsy and subindications thereof.
13. A modification of the compound 1 -(2,6-dif luorobenzyl)-1 H-1 ,2,3-triazole-4- carboxamide characterized by bands at 3412 cm"1 and 3092 cm"1 in the FT-IR spectrum.
14. A modification of the compoundl -(2,6-dif luorobenzyl)-1 H-1 ,2,3-triazole-4- carboxamide characterized by a band at 1080 cm"1 in the FT-Raman spectrum.
15. A pharmaceutical preparation comprising a modification according to claim 13 or 14 and pharmaceutically usable excipients and additives.
PCT/EP1998/003427 1997-06-10 1998-06-08 Crystal modification of 1-(2,6-difluorobenzyl)-1h-1,2,3--triazole-4-carboxamide and its use as antiepileptic WO1998056772A1 (en)

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BR9804947A BR9804947A (en) 1997-06-10 1998-06-08 Crystal modification of a pharmaceutical agent
SK1093-98A SK283685B6 (en) 1997-06-10 1998-06-08 Crystal modification of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole- 4-carboxamide, pharmaceutical compositions containing it and use thereof
DE69811500T DE69811500T2 (en) 1997-06-10 1998-06-08 CRYSTAL MODIFICATION OF 1- (2,6-DIFLUORBENZYL) -1H-1,2,3-TRIAZOL-4-CARBONIC ACID AMIDE AND ITS USE AS AN ANTI-PILEPTIC
NZ331371A NZ331371A (en) 1997-06-10 1998-06-08 Crystal modification of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide and use thereof
AT98934929T ATE232852T1 (en) 1997-06-10 1998-06-08 CRYSTAL MODIFICATION OF 1-(2,6-DIFLUORBENZYL)-1H-1,2,3-TRIAZOLE-4-CARBON AUREAMIDE AND ITS USE AS AN ANTI-EPILEPTIC
US09/125,329 US6740669B1 (en) 1997-06-10 1998-06-08 Crystal modification of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide and its use as antiepileptic
PL330764A PL191943B1 (en) 1997-06-10 1998-06-08 Crystalline for of a pharmaceutic agent
IL12573398A IL125733A (en) 1997-06-10 1998-06-08 Crystal modification of the compound 1-(2,6-difluorobenzyl)-1h-1,2,3-triazole-4-carboxamide and pharmaceutical compositions for treating epilepsy comprising the same
EP98934929A EP0994863B1 (en) 1997-06-10 1998-06-08 Crystal modification of 1-(2,6-difluorobenzyl)-1h-1,2,3-triazole-4-carboxamide and its use as antiepileptic
HU0000798A HU226107B1 (en) 1997-06-10 1998-06-08 New crystal modifications of 1-(2,6-difluorobenzyl)-1h-1,2,3-triazole-4-carboxamide and pharmaceutical compositions containing them
SI9830405T SI0994863T1 (en) 1997-06-10 1998-06-08 Crystal modification of 1-(2,6-difluorobenzyl)-1h-1,2,3-triazole-4-carboxamide and its use as antiepileptic
AU84371/98A AU725528B2 (en) 1997-06-10 1998-06-08 Crystal modification of 1-(2,6-difluorobenzyl)-1H-1,2,3- triazole-4-carboxamide and its use as antiepileptic
JP53628898A JP3672574B2 (en) 1997-06-10 1998-06-08 Drug crystal deformation
CA002256013A CA2256013C (en) 1997-06-10 1998-06-08 Crystal modification of 1-(2,6-difluorobenzyl)-1h-1,2,3-triazole-4-carboxamide and its use as antiepileptic
DE122007000051C DE122007000051I2 (en) 1997-06-10 1998-06-08 CRYSTAL MODIFICATION OF 1- (2,6-DIFLUORBENZYL) -1H-1,2,3-TRIAZOL-4-CARBOXYL ACID AND ITS USE AS ANTIEPILEPTICUM
DK98934929T DK0994863T3 (en) 1997-06-10 1998-06-08 Crystal modification of 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4-carboxamide and its use as an antiepileptic agent
NO19983667A NO329315B1 (en) 1997-06-10 1998-08-11 Crystal modification of compound, pharmaceutical compositions containing it and use of the crystal modification.
HK00106804A HK1028241A1 (en) 1997-06-10 2000-10-25 Crystal modification of 1-(2,6-difluorobenzyl)-1h-1,2,3-triazole-4-carboxamide and its use as antiepileptic
US11/329,945 US7750028B2 (en) 1997-06-10 2006-01-11 Crystal modifications of 1-(2,6-difluorobenzyl)-1H-1, 2,3-triazole-4-carboxamide
NL300284C NL300284I2 (en) 1997-06-10 2007-07-03 Crystal modification of
LU91345C LU91345I2 (en) 1997-06-10 2007-07-04 Rufinamide and its pharmaceutically acceptable salts (inovelon)
FR07C0037C FR07C0037I2 (en) 1997-06-10 2007-07-06
CY200700014C CY2007014I2 (en) 1997-06-10 2007-07-13 CONVERSION IN CRYSTALLINE FORM OF 1-(2,6-DIFLUOROBENZYL)-1H-1,2,3-TRIAZOLE-4-CARBOXAMIDE AND THEIR USE AS AN ANTI-SEPILLANT
US12/767,003 US8076362B2 (en) 1997-06-10 2010-04-26 Crystal modification A of 1-(2,6-difluorobenzyI)-1 H-1,2,3-triazole-4-carboxamide and dosage forms and formulations thereof

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ITMI20091412A1 (en) * 2009-08-04 2011-02-05 Dipharma Francis Srl CRYSTALLINE FORMS OF RUFINAMIDE
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US8183269B2 (en) 2008-10-13 2012-05-22 Cipla Limited Process for the preparation of rufinamide
EP2334653A1 (en) 2008-10-13 2011-06-22 Cilpa Limited Process for the preparation of rufinamide
JP2012505191A (en) * 2008-10-13 2012-03-01 シプラ・リミテッド Method for producing rufinamide
WO2010043849A1 (en) * 2008-10-13 2010-04-22 Cipla Limited Process for the preparation of rufinamide
ITMI20091412A1 (en) * 2009-08-04 2011-02-05 Dipharma Francis Srl CRYSTALLINE FORMS OF RUFINAMIDE
EP2292609A1 (en) 2009-08-04 2011-03-09 Dipharma Francis S.r.l. Crystalline forms of rufinamide
WO2011135105A1 (en) * 2010-04-30 2011-11-03 Laboratorios Lesvi, S.L. Improved process for preparing rufinamide intermediate
EP2727914A1 (en) * 2010-04-30 2014-05-07 Laboratorios Lesvi, S.L. Polymorph of 1-(2,6-difluorobenzyl)-1h-1,2,3-triazole-carboxamide
US8884026B2 (en) 2010-04-30 2014-11-11 Laboratorios Lesvi, S.L. Process for preparing rufinamide intermediate
EP2465853A1 (en) * 2010-12-14 2012-06-20 Laboratorios Lesvi, S.L. Polymorph of rufinamide and process for obtaining it
ITMI20110718A1 (en) * 2011-04-29 2012-10-30 Dipharma Francis Srl PROCEDURE FOR PURIFICATION OF RUFINAMIDE
EP2518057A1 (en) 2011-04-29 2012-10-31 Dipharma Francis S.r.l. Process for the purification of rufinamide
US8461190B2 (en) 2011-04-29 2013-06-11 Dipharma Francis S.R.L. Process for the purification of rufinamide

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