HK1020051A - Crystal modification of a pharmaceutical agent - Google Patents

Description

Crystal modification of drug

no marking

Background

A compound 1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxamide represented by the formula:it is described in European patent application publication No.0199262A2(EP199262), for example, example 4. The compounds exhibit valuable pharmacological properties; it can be used, for example, as an antiepileptic drug. The compound 1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxamide is prepared according to the method of EP199262 starting from 2, 6-difluorobenzyl azide and by forming 1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxylic acid, analogously to example 2.

EP199262 does not describe any information on the possibility of obtaining crystalline modifications. If the procedure of example 4 is followed in combination with example 2, the crude 1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxamide is finally recrystallized from ethanol. However, it is not clear from EP199262 that such recrystallization is to be particularly useful or to be carried out under specific conditions. It has now surprisingly been found that by selecting specifically selected reaction conditions, for example by selecting suitable recrystallization solvents and recrystallization times, different crystal modifications (polymorphs) can be prepared which are characterized as follows. Detailed Description

The resulting 1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxamide is available as a new crystalline modification-A, A', B and C. These crystal modifications are distinguished from: their thermodynamic stability, physical parameters such as IR and raman spectral absorption spectra, X-ray structural analysis and methods for their preparation.

The present invention relates to novel crystalline modifications A and A', processes for their preparation and their use in pharmaceutical formulations comprising the crystalline modifications.

Compared to a, modifier a' has a defect in its lattice. This can be determined by methods such as X-ray analysis, for example by analysis of a reduction in the line spacing and other substantially identical lines or bands.

The novel crystal modification A of 1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxamide melts at 242 deg.C (239-.

In the FT infrared (FT-IR) spectrum (KBr pellet-transmission method), modification A or A' is significantly different from modification B and C in the shape and relative intensity of many bands. The features that were not present in the FT-IR spectra of modifications B and C are: 3412cm^-1And 3092cm^-1Band of (c) [ see: FIG. 1 of the drawings]. At 4000-^-1The following characteristic bands were determined from modification A: 3412. 3189, 3092, 1634, 1560, 1473, 1397, 1325, 1300, 1284, 1235, 1125, 1053, 1036,1014, 885, 840, 799, 781, 723, 688 and 640cm^-1. FT-IR spectra of each modification can be recorded using, for example, an IFS88(Bruker) instrument.

In the FT raman spectrum (powder-reflectance method 180 °), modified form a or a' is significantly different from modified forms B and C in the shape and relative intensity of many bands. The characteristic features of the modified B and C which do not exist in the Raman spectrum are: 1080cm^-1Band of (c) [ see: FIG. 2 of the drawings]. At 3400 and 300cm^-1The following characteristic bands were determined from 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 368cm^-1. FT raman spectra of each modification can be recorded using, for example, RFS100(Bruker) instruments.

The novel modification A has an interplanar spacing (d value) in its X-ray powder spectrum of: characteristic spectral lines of 10.5 ,5.14 ,4.84 ,4.55 ,4.34 ,4.07 ,3.51 ,3.48 ,3.25 ,3.19 ,3.15 ,3.07  and 2.81  [ see attached Table 1]. The measurement may be in, for example, transmission geometryScientific method, using a FR 552 Teni camera produced by Enraf-Nonius, Delft (the Netherlands) and using copper Ka₁Radiation (wavelength =1.54060 ). The spectra recorded on the X-ray films were measured with an LS-18 linear scanner produced by Johannsson, Taby (Sweden) and calculated with Scanpi software (university of Stockholm, P.E. Werner).

The novel modification A is characterized by its thermogram measured by differential scanning calorimetry. An endothermic peak is shown in the graph between the 230-260 ℃ range. The peak temperature was 239-. The measurements were performed using a Perkin Elmer DSC 7 in a closed pan with a heating rate of 20K/min. The standard sample amount was about 4 mg. Typical distinguishing features that are different from modifications B and C are: there were no other thermal signals in the thermogram of modified form a.

The crystal of modification A' has the same crystal structure as modification A. However, it differs from modification A in the X-ray powder spectrum: the line spacing between its characteristic spectral line pairs is slightly reduced. They are pairs of lines with the following interplanar spacings: 3.68  and 3.64 ,3.51  and 3.48 ,3.19  and 3.15 .

In the FT-IR (KBr pellet-Transmission) spectrum, modification B is significantly different from modification A, A' and C in the shape and relative intensity of many bands, and is characterized by 1678cm^-1Band of (c) [ see: FIG. 1 of the drawings]This was not found in the corresponding maps for modifications a and C. At 4000-^-1The following characteristic bands were obtained from modification B: 3404,3199,3125,1678,1635,1560,1475,1393,1357,1322,1286,1237,1051,1036,1028,889,837,800,719,667 and 645cm^-1. FT-IR spectra of each modification can be recorded using, for example, an IFS85(Bruker) instrument.

In the FT-Raman spectrum (powder-reflectance 180 ℃ C.), modification B is significantly different from modification A, A' and modification C in the shape and relative intensity of many bands, and is characterized by 1678cm^-1And 1086cm^-1Band of (c) [ see: FIG. 2 of the drawings]In modifications of A and CAnd does not exist in the raman spectrum. At 3400 and 300cm^-1The following characteristic bands were obtained from 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 365cm^-1。

FT-Raman spectra of each modification can be recorded using, for example, an RFS100(Bruker) instrument.

Modification B has an interplanar spacing (d value) in its X-ray powder pattern of: characteristic lines of 11.0 ,8.3 ,5.18 ,4.88 ,4.80 ,4.42 ,4.33 ,4.19 ,4.12 ,3.81 ,3.50 ,3.41 ,3.36 ,3.32 ,3.28 ,3.24 ,3.05 ,2.83  [ see: attached Table 1 ].

In the thermogram measured by differential scanning calorimetry, modification B had a weak thermal signal at 205 ℃ (180-.

In the FT-IR (KBr pellet-Transmission) spectrum, modification C is clearly different from modifications A, A' and B in the shape and relative intensity of many bands. It is characterized by 3137cm^-1Band of (c) [ see: FIG. 1 of the drawings]This was not found in the corresponding maps for modifications a and B.

At 4000-^-1The following characteristic bands were obtained from 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 653cm^-1. FT-IR spectra of each modification can be recorded using, for example, an IFS85(Bruker) instrument.

In the FT-raman spectrum (powder-reflectance method 180 °), modified bulk C is significantly different from modified bulk a or a' and B in the shape and relative intensity of many bands. The characteristics which do not exist in the Raman spectra of the modified forms A and B are as follows: 3137 and 1602cm^-1Band of (c) [ see: FIG. 2 of the drawings]. At 3400 and 300cm^-1The following characteristic bands were obtained from 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 370cm^-1. FT raman spectra of each modification can be recorded using, for example, an RFS100(Bruker) instrument.

Modified form C has an interplanar spacing (d value) in its X-ray powder spectrum of: characteristic spectral lines of 9.0 ,4.73 ,4.65 ,3.75 ,3.54 ,3.42  and 3.25  [ see attached Table 1]. In the thermogram measured by differential scanning calorimetry, modification C has a very broad and weak exothermic signal different from modification A or A' and B in the 180 ℃ region in addition to an endothermic signal (peak temperature 239-245 ℃) in the range of 230-260 ℃. Table 1: characterization of modified A, B and C (X-ray powder pattern)

Improvement A:		improvement B:		improvement body C:
						d[]	strength of	d[]	Strength of	d[]	Strength of
10.9	Weak (weak)	11.0	Medium and high grade	9.0	Medium and high grade
						10.5	Medium and high grade	8.3	Medium and high grade	7.0	Weak (weak)
6.6	Weak (weak)	8.1	Is very weak	5.49	Weak (weak)
						5.63	Weak (weak)	5.68	Is very weak	5.11	Is very weak
5.25	Weak (weak)	5.18	Is very strong	4.80	Weak (weak)
						5.14	Medium and high grade	5.11	Weak (weak)	4.73	High strength
4.94	Weak (weak)	4.88	Medium and high grade	4.65	Is very strong
						4.84	Is very strong	4.80	High strength	4.47	Is very weak
4.55	High strength	4.71	Is very weak	4.19	Is very weak
						4,42	Is very weak	4.61	Weak (weak)	4.11	Is very weak
4.34	Medium and high grade	4.45	Weak (weak)	3.98	Is very weak
						4.23	Is very weak	4.42	High strength	3.83	Is very weak
4.16	Weak (weak)	4.33	Is very strong	3.75	High strength
						4.07	Medium and high grade	4.19	Medium and high grade	3.73	Weak (weak)
4.01	Weak (weak)	4.12	High strength	3.54	Medium and high grade
						3.68	Is very weak	4.09	Weak (weak)	3.50	Weak (weak)
3.64	Is very weak	3.99	Is very weak	3.42	High strength
						3.60	Weak (weak)	3.95	Very muchWeak (weak)	3.25	Medium and high grade
3.56	Weak (weak)	3.84	Weak (weak)	2.88	Is very weak
						3.51	Medium and high grade	3.81	Medium and high grade	2.80	Is very weak
3.48	Medium and high grade	3.65	Weak (weak)	2.74	Is very weak
						3.38	Is very weak	3.61	Is very weak	2.67	Is very weak
3.25	High strength	3.58	Is very weak	2.64	Weak (weak)
						3.19	Medium and high grade	3.54	Weak (weak)

3.15	Medium and high grade	3.50	Medium and high grade
						3.11	Weak (weak)	3.47	Is very weak
3.07	Medium and high grade	3.41	Medium and high grade
						2.93	Is very weak	3.36	Is very strong
2.87	Is very weak	3.32	High strength
						2.81	Medium and high grade	3.28	Medium and high grade
2.76	Weak (weak)	3.24	Medium and high grade
						2.73	Is very weak	3.10	Weak (weak)
2.68	Weak (weak)	3.07	Weak (weak)
						2.62	Is very weak	3.05	Medium and high grade
2.53	Weak (weak)	2.93	Weak (weak)
						2.43	Weak (weak)	2.88	Weak (weak)
2.40	Is very weak	2.87	Is very weak
								2.83	Medium and high grade
		2.66	Weak (weak)
								2.63	Is very weak
		2.55	Weak (weak)
								2.50	Weak (weak)
		2.46	Weak (weak)
								2.44	Weak (weak)
		2.37	Weak (weak)
								2.35	Weak (weak)

Single crystal X-ray analysis:

the crystal mass and unit cell of modifications A, B and C will be identified by wesenberg and loiter photographs. The intensity was measured with a four-axis Nonius CAD-4 diffractometer. The crystal structure was resolved using SHELXS-97 and refined using SHELXL-97 software. Improved body a space group: pan2₁-unit cell size of orthorhombic crystals: a =24.756(5)  b =23.069(4)  c =5.386(1)  v =3075.9 ³ Z=12 D_x=1.543gcm^-3V/molecular formula: v_z=256.3³9011 characteristic reflections; of these 2479 reflections had significance of I > 2 σ (I). 557 parameters were accurate. The positions of all H atoms were determined by differential fourier mapping and refined isotropically. Reliability index R₁3.65% (wR of all 9011 reflections)₂11.34 percent). Improved body B space group: unit cell size of P-1-triclinic: a =5.326(1)  b =11.976(2)  c =17.355(3)  α =107.22(3) ° β =92.17(3) ° γ =102.11(3) ° v =1027.9 ³ Z=4 D_x=1.539gcm^-3V/formula V_z=257.0³4934 characteristic reflections; of these 834 had significance with I > 2 σ (I). 232 parameters are accurate. The positions of all H atoms were determined by differential fourier mapping and refined isotropically. Reliability index R₁4.20% (wR of all 4934 reflections₂7.93%) improved volume C space group: p2₁Unit cell size of/C-monoclinic: a =10.982(2)  b =5,350(1)  c =17.945(3) 

β=91.59(1)°v=1053.9³ Z=4 D_x=1.501gcm^-3V/molecular formula: v_z=263.5³3073 characteristic reflections; of these 1071 had significance with I > 2 σ (I). 187 parameters were accurate. All H atom positions were determined by differential fourier mapping and refined isotropically. ReliabilityIndex of sex R₁5.02% (wR of all 3073 reflections)₂:14.55％)

Modifications A, A', B and C have valuable pharmacological properties: they are particularly useful in the treatment of epilepsy.

Modifications A and A' are particularly advantageous over modifications B and C. Both modifications a or a' surprisingly have significantly better thermodynamic stability than modifications B and C, for example in comprehensive thermodynamic analyses such as thermal microscopy, X-ray powder diffraction, Differential Scanning Calorimetry (DSC), solubility tests and other experiments. Modification C, which could be obtained only under specific conditions, was the least stable of the three modifications. The crystals of modification C were transformed into modification B even at such a low temperature at room temperature within several weeks. Modification C can be converted to modification A or A' or modification B depending on the test conditions. Ensuring a high and reproducible stability of a pharmaceutical formulation over a prolonged period of time is of utmost importance for the drug. These prerequisites are met by the crystals of modification A or A' which incorporate 1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxamide, owing to their higher thermodynamic stability. Especially in solid pharmaceutical dosage forms.

The constant stability also allows reproducible bioavailability of the active ingredient. Adverse bioavailability fluctuations are easily caused if a conversion of the active ingredient occurs. Thus, the pharmaceutically active ingredients or their substantially pharmaceutically suitable polymorphs should all be substances which have good stability and do not suffer from the above-mentioned drawbacks. Modifications A and A' meet these prerequisites.

In addition, modifications A and A' also have slow dissolution rates, for example in water or gastric juice (so-called "slow release action"). This effect is often applicable to long-term therapies requiring slow or delayed release.

The invention relates to an improved form A of 1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxamide, characterized in that it has the following absorptions in the infrared spectrum (KBr pellet-transmission method): 3092cm^-1And 3412cm^-1Band(s).

The present invention relates to an improved 1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxamide A, characterized in that: characteristic lines having an interplanar spacing (d value) of 10.5 ,5.14 ,4.84 ,4.55 ,4.34 ,4.07 ,3.51 ,3.48 ,3.25 ,3.19 ,3.15 ,3.07  and 2.81 , as determined by X-ray powder spectrometry.

The invention relates to a modification A of 1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxamide, which is characterized by the characteristic spectral lines with the interplanar spacings (values of d) shown in Table 1.

The present invention relates to an improved 1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxamide A, characterized in that: an endotherm between 230 ℃ and 260 ℃, a peak temperature of 239 ℃ and 245 ℃ and an endotherm of 209J/g +/-10J/g.

Further, the present invention relates to a crystal modification a' having lattice defects as compared with the modification a.

The present invention relates to a modified body a' in which the line spacing between the line pairs is reduced and the line pairs have an interplanar spacing of 3.68  and 3.64 ,3.51  and 3.48 ,3.19  and 3.15  as compared with the modified body a.

The invention relates to substantially pure modifications A or A' of 1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxamide. The term "substantially pure" means a purity of > 95%, preferably > 98%, most preferably > 99%, based on modifications A or A'.

The invention relates to pharmaceutical preparations containing 1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxamide modifications A or A'. The invention relates in particular to pharmaceutical preparations suitable for the treatment of epilepsy and its secondary disorders. The invention also relates to the application of the 1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-formamide modifications A and A' in preparing medicinal preparations, in particular to the application in preparing medicinal preparations for treating epilepsy and secondary symptoms thereof.

The novel 1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxamide modifications A or A' can be employed, for example, in the form of pharmaceutical preparations containing therapeutically effective amounts of the active ingredient, if desired in combination with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers suitable for enteral, intragastric, e.g. oral, or parenteral administration. In addition, the novel 1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxamide modifications A or A' can be administered in the form of preparations which are administered parenterally or as infusion solutions. The above-mentioned pharmaceutical preparations may be sterilized and/or contain excipients such as preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for osmotic pressure regulation and/or buffers. The pharmaceutical formulations of the present invention contain from about 0.1 to 100%, preferably from about 1 to 50%, of the lyophilizate to about 100% of the active ingredient.

The invention also relates to the use of the 1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxamide modifications A or A', in particular in pharmaceutical preparations. The dosage used will depend on a variety of factors, such as mode of administration, species, age of the patient and/or individual condition. The daily dose in the case of oral administration is between about 0.25 and 10mg/Kg, and preferably in the range of about 20 to 50mg for a warm-blooded species weighing about 70 Kg. The preparation of modifications A and A' can be carried out, for example, by the following embodiments. Preparation of 1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxamide example 1:

a suspension of methyl 1- (2, 6-difluorobenzyl) -1H-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) was stirred in a closed vessel for about 24 hours. The suspension was cooled to 20 ℃ and stirring was continued for about 2 hours. The product was isolated by filtration, washing with methanol (240 parts by weight) and vacuum drying at 40-60 ℃. Yield: 57.2% part by weight = 98% of modification a.

The starting compounds can be prepared, for example, by the following methods:

a mixture of 1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxylic acid (167.2 parts by weight), methanol (552 parts by weight), and 96% sulfuric acid (35.7 parts by weight) was stirred at 60-66 ℃ for about 5 hours. The suspension was cooled to 20 ℃ and stirring was continued for about 2 hours. The product was isolated by filtration and washing with methanol (198 parts by weight). 160 parts by weight of the product are obtained by vacuum drying at 40-60 ℃. Example 2

To a mixture of 4-cyano-1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole (2.20g) and water (44ml) was added 1N sodium hydroxide solution (0.11ml) at an external temperature of 95-100 ℃ with stirring. After 90 minutes the suspension was cooled to 10 ℃ and the product was isolated by filtration, water washing and vacuum drying at 60 ℃. This procedure gave 1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxamide: the yield was 99.2% of modified form a.

The starting reactants can be prepared, for example, by the following methods:

4-cyano-1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole

A mixture of 2, 6-difluorobenzyl azide (34.2g), 2-chloroacrylonitrile (17.73g) and water (125ml) was stirred at about 80 ℃ for 24 hours. The external temperature was raised to about 130 ℃ to distill off the excess 2-chloroacrylonitrile. The semi-solid mixture was cooled to about 40 ℃ and cyclohexane (50ml) was added to the suspension, then the mixture was cooled to 20 ℃ and stirring was continued for about 2 hours. The product was isolated by filtration, washing sequentially with cyclohexane (75ml) and water (50 ml). The wet product was mixed with water (100ml), the suspension filtered and washed with water (50ml) and dried under vacuum at 60 ℃ to give the product. Yield: 38.04= 86%. Recrystallization of 1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxamide example 3:

1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxamide (75.0g) was dissolved in formic acid with stirring at 50-55 ℃. The above solution was added to stirred methanol (375ml) at about 20 ℃ for 1 hour to form a suspension. After stirring at 20 ℃ for about 2 hours, the product was obtained by filtration, washing with methanol (750ml) and drying under vacuum at 60 ℃. Yield: 69.6g = 92.8% of modification a. Example 4:

1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxamide (22.86kg) was dissolved in formic acid with stirring at 58-63 ℃. The solution was added to stirred methanol (131.9L) over about 2 hours at 20-25 deg.C, then washed with formic acid (7.6 kg). A suspension is formed. After stirring at about 20 ℃ for at least 3 hours, the product was isolated by filtration and washing with methanol (187.5L). The improved A product was obtained in 93-94% yield by vacuum drying at about 60 ℃. Example 5:

1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxamide (pure active ingredient, 4.0g) was dissolved in 96% ethanol with stirring and at about 80 ℃. The solution was then filtered at 20 ℃ into a suction flask (1L) (glass suction filter: pore size 10-20 μm) to give a suspension. After stirring at about 20 ℃ for 5 minutes and at 0 ℃ for 15 minutes, the product can be filtered (about 0-20 ℃). The solvent-containing product (9.6g) was tested without further drying. Preparation of modified form a' example 1:

film-coated tablets containing 100, 200 or 400mg of 1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxamide modification A or A' and the following components, respectively, per dosage unit: core material mg mg of active ingredient 100.00200.00400.00 anhydrous, colloidal silicon dioxide 0.881.753.5 microcrystalline cellulose 36.6273.25146.50 hydroxypropyl methylcellulose 5.0010.0020.00 lactose 20.0040.0080.00 magnesium stearate 2.004.008.00 corn starch 10.0020.0040.00 sodium carboxymethylcellulose 5.0010.0020.00 sodium lauryl sulfate 0.501.002.00 coating film mg of hydroxypropyl methylcellulose 3.226.4312.87 red iron oxide 0.040.090.18 polyethylene glycol 80000.581.162.32 flake talc 2.334.669.31 titanium dioxide 0.831.663.32

The active ingredient is granulated with deionized water. The ground lactose, corn starch, Avicel PH 102, cellulose-HP-M-603, and sodium lauryl sulfate were then added to the above mixture and further granulated with deionized water.

The resulting wet wood was dried and ground. The homogeneous mixture is compressed after the addition of the remaining ingredients to produce a tablet core having the above active ingredient content.

The tablet cores are coated with a coating consisting of suitable ingredients, dissolved or suspended in water or a small amount of ethanol containing 5% isopropanol. FIG. 1 is a graphical representation of the FT-IR spectra of KBr pellets of modified A, B and C. FIG. 2 is a graphical representation of FT-Raman spectra of powders of modified A, B and C. In the two figures, the symbol for modified body A^*Symbol for indicating, improving body B^**The modified body C is represented by a symbol^***And (4) showing.

Claims (15)

1. Modified 1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxamide represented by the following formula:the method is characterized in that: characteristic lines of 10.5 ,5.14 ,4.84 ,4.55 ,4.34 ,4.07 ,3.51 ,3.48 ,3.25 ,3.19 ,3.15 ,3.07  and 2.81  in the aspect of d value measured by an X-ray powder spectrum method.

2. The improvement of claim 1, characterized by an X-ray powder pattern having the following interplanar spacing (d value) characteristic lines: 10.9 (weak), 10.5 (medium), 6.6 (weak), 5.63 (weak), 5.25 (weak), 5.14 (medium), 4.94 (weak), 4.84 (strong), 4.55 (strong), 4.42 (weak), 4.34 (medium), 4.23 (weak), 4.16 (weak), 4.07 (medium), 4.01 (weak), 3.68 (weak), 3.64 (weak), 3.60 (weak), 3.56 (weak), 3.51 (medium), 3.48 (medium), 3.38 (weak), 3.25 (strong), 3.19 (medium), 3.15 (medium), 3.11 (weak), 3.07 (medium), 2.93 (weak), 2.87 (weak), 2.81 (medium), 2.76 (weak), 2.73 (weak), 2.68 (weak), 2.62 (weak), 2.53 (weak), 2.43 (weak), 2.40 (weak).

3. The improvement according to claim 1 or 2, characterized in that its FT-IR spectrum (KBr tablet-transmission method) has the following absorption: 3092cm^-1And 3412cm^-1。

4. The improvement of claim 3, characterized by the FT-IR spectrum (KBr pellet-transmission) having the following absorptions: 3412. 3189, 3092, 1634, 1560, 1473, 1397, 1325, 1300, 1284, 1235, 1125, 1053, 1036,1014, 885, 840, 799, 781, 723, 688 and 640cm^-1。

5. The improvement according to any one of claims 1 to 4, characterized in that its FT-Raman spectrum (powder-reflectance 180 ℃) has the following absorption: 3093. 2972, 1628,1614, 1558, 1465, 1446, 1393, 1279, 1245, 1147, 1080, 1061, 1036,1014, 840, 724, 691, 667, 550, 499, 437 and 368cm^-1。

6. The improvement of any one of claims 1-5, wherein: an endothermic peak in the range of 230-.

7. An improved form A' of the compound 1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxamide, characterized in that: the modified form A of any one of claims 1 to 6, which is the same as modified form A except that defects are present in the crystal lattice.

8. The improvement of claim 7, wherein: there is a reduced line spacing between pairs of spectral lines with an interplanar spacing of 3.68  and 3.64 ,3.51  and 3.48 ,3.19  and 3.15  as compared to the modified form a of any one of claims 1 to 6.

9. The modified form A or A' of any one of claims 1 to 8 in substantially pure form.

10. A pharmaceutical formulation comprising 1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxamide modification a or a' as claimed in any of claims 1 to 9, together with pharmaceutically acceptable excipients and additives.

11. Use of the 1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxamide modification a or a' as claimed in any of claims 1 to 9 as a pharmaceutical preparation.

12. Use of the 1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxamide modifier a or a' according to any of claims 1 to 9 for the preparation of a pharmaceutical preparation for the treatment of epilepsy and its secondary disorders.

13. An improved form of the compound 1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxamide characterized by an FT-IR spectrum having 3412cm^-1And 3092cm^-1The band of (2).

14. An improved compound 1- (2, 6-difluorobenzyl) -1H-1,2, 3-triazole-4-carboxamide characterized by having an FT-Raman spectrum of 1080cm^-1The band of (2).

15. A pharmaceutical preparation comprising the modified form of claim 13 or 14 and pharmaceutically acceptable excipients and additives.