CN101768124B - Medicine crystal, preparation method and purpose thereof - Google Patents
Medicine crystal, preparation method and purpose thereof Download PDFInfo
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- CN101768124B CN101768124B CN2008102467268A CN200810246726A CN101768124B CN 101768124 B CN101768124 B CN 101768124B CN 2008102467268 A CN2008102467268 A CN 2008102467268A CN 200810246726 A CN200810246726 A CN 200810246726A CN 101768124 B CN101768124 B CN 101768124B
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- difluorobenzyl
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- 239000013078 crystal Substances 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 239000003814 drug Substances 0.000 title claims description 18
- 229940079593 drug Drugs 0.000 title description 6
- 238000000034 method Methods 0.000 claims abstract description 24
- 206010015037 epilepsy Diseases 0.000 claims abstract description 10
- 239000000843 powder Substances 0.000 claims abstract description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- 238000010521 absorption reaction Methods 0.000 claims description 6
- 238000001228 spectrum Methods 0.000 claims description 6
- 238000001757 thermogravimetry curve Methods 0.000 claims description 6
- 238000004364 calculation method Methods 0.000 claims description 5
- 208000037921 secondary disease Diseases 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 238000013019 agitation Methods 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000006166 lysate Substances 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 abstract description 2
- 229960003014 rufinamide Drugs 0.000 abstract description 2
- POGQSBRIGCQNEG-UHFFFAOYSA-N rufinamide Chemical compound N1=NC(C(=O)N)=CN1CC1=C(F)C=CC=C1F POGQSBRIGCQNEG-UHFFFAOYSA-N 0.000 abstract description 2
- 238000002329 infrared spectrum Methods 0.000 abstract 1
- 238000002076 thermal analysis method Methods 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 14
- 238000005755 formation reaction Methods 0.000 description 14
- 206010010904 Convulsion Diseases 0.000 description 6
- 239000002775 capsule Substances 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 239000008188 pellet Substances 0.000 description 4
- 239000006187 pill Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 230000005611 electricity Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- GGRLKHMFMUXIOG-UHFFFAOYSA-M 2-acetyloxyethyl(trimethyl)azanium;hydroxide Chemical compound [OH-].CC(=O)OCC[N+](C)(C)C GGRLKHMFMUXIOG-UHFFFAOYSA-M 0.000 description 1
- -1 AMPA-kainate Chemical compound 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010009346 Clonus Diseases 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 208000034308 Grand mal convulsion Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241000282560 Macaca mulatta Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 1
- 102000004108 Neurotransmitter Receptors Human genes 0.000 description 1
- 108090000590 Neurotransmitter Receptors Proteins 0.000 description 1
- 206010061334 Partial seizures Diseases 0.000 description 1
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 230000036982 action potential Effects 0.000 description 1
- 210000004727 amygdala Anatomy 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000001037 epileptic effect Effects 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 235000013905 glycine and its sodium salt Nutrition 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000000936 membranestabilizing effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a new rufinamide crystal and a preparation method thereof. An infrared spectrum is determined by an X-ray powder map method and a KBr sheeting-transmission method, and thermal analysis determination is carried out by a differential scanning magnitude method. A preparation prepared by the new crystal has good dissolution degree and is more suitable for being used by a patient suffering from epilepsy at the stage of attack.
Description
Technical field
The present invention relates to technical field of pharmaceuticals, be specifically related to a kind of medicine new crystal.
Background technology
Medicine when crystallization owing to influenced by various factors; Intramolecularly or intermolecular bonding mode are changed; It is different to cause molecule or atom to be arranged at lattice vacancy; Form the crystals with different structure, the different crystal forms of same medicine possibly have remarkable difference at aspects such as outward appearance, solubleness, fusing point, dissulution, biological effectivenesses, thereby has influenced stability of drug, bioavailability and curative effect; This kind phenomenon shows particularly evidently aspect oral solid formulation, and medicine different crystal forms phenomenon is one of important factor that influences drug quality and clinical efficacy.Therefore, the research to the medicine crystal formation is the most important thing in the drug research process.
1-(2, the 6-difluorobenzyl)-1H-1,2,3-triazole-4-methane amide is the antiepileptic drug of new generation by Switzerland Novartis exploitation, these article are not still gone public and are sold in China; 1-(2, the 6-difluorobenzyl)-1H-1,2,3-triazole-4-methane amide belongs to insoluble drug, all insoluble or slightly soluble only in water, methyl alcohol, acetonitrile, ethanol, ETHYLE ACETATE, ether, sodium hydroxide, hydrochloric acid.Chinese patent 98800011.3 (open day is on May 26th, 1999), 98805675.5 (open day is on July 5th, 2000), 200410047367.5 (open day is on February 7th, 2007); Four kinds of different crystal forms of this medicine are studied; Wherein the dissulution of A, B, three kinds of crystal formations of C is better than A ' crystal formation, but still is not very desirable, particularly at 0-15 minute dissulution; Therefore, it is imperative to study the good crystal formation of a kind of dissulution.
Summary of the invention
For these reasons; Our scientific research personnel is through secular scientific experiment; Find a kind of new crystal formation; This new crystal is that the oral solid formulation of feedstock production has than existing crystal formation (A, A ', B, C in the publication) good dissolution degree, and the dissulution in particularly in 0-15 is publication A, B, more than 2 times of three kinds of crystal formations of C, is fit to the epileptic more and in stage of attack, uses.
The present invention realizes through following technical scheme.
Following compounds 1-(2, the 6-difluorobenzyl)-1H-1,2, the crystal of 3-triazole-4-methane amide,
It is characterized in that:
Measuring 2 θ angles with X-ray powder atlas calculation is: 8.28,13.32,15.56,16.82,18.14,19.30,20.30,21.70,24.06,25.30, and, 27.32,27.78,28.94,31.66,34.24,35.90,39.56 degree;
Above-mentioned numerical value can be by ± 2 error because of objective factors such as instrument, method, environment.
KBr compressing tablet-transmission method is measured ir spectra and is had following absorption: 3411,3189,3093,1634,1560,1474,1398,1325,1285,1236,1126,1081,1052,1037,1014,886,840,799,780,769,723, and 687cm
-1
Above-mentioned numerical value can be by ± 10 error because of objective factors such as instrument, method, environment.
In differential scanning amount method thermogram, in 230 ℃ of-250 ℃ of scopes, endothermic signal is arranged, peak temperature 240-246 ℃.
Above-mentioned numerical value can be by ± 2 error because of objective factors such as instrument, method, environment.
Above-mentioned crystal can obtain through crystallization process, also can prepare through the application's method, comprises but is limited to following preparation method: with 1-(2; The 6-difluorobenzyl)-and 1H-1,2,3-triazole-4-methane amide adds in the DMSO 99.8MIN., and heating for dissolving is complete; Lysate is under agitation dripped in the entry, drip and finish, continue to stir, filter; Water washing does not filter the material drying, obtains crystal.
Above-mentioned crystal, its purity more than or equal to 95% less than 100%.
The pharmaceutical prepn of above-mentioned crystal preparation.
Pharmaceutical prepn of the present invention comprises that load is not limited to conventional oral prepns such as tablet, capsule, pellet, granule, pill.
The application of above-mentioned crystal in preparation treatment epilepsy or epilepsy secondary disease medicine.
Description of drawings
1, Fig. 1 is the new crystal X-of a present invention ray powder collection of illustrative plates;
Measuring 2 θ angles is: 8.28,13.32,15.56,16.82,18.14,19.30,20.30,21.70,24.06,25.30, and, 27.32,27.78,28.94,31.66,34.24,35.90,39.56 degree.
2, Fig. 2 is that the new crystal KBr compressing tablet of the present invention-transmission method is measured infrared spectrogram;
Have following absorption: 3411,3189,3093,1634,1560,1474,1398,1325,1285,1236,1126,1081,1052,1037,1014,886,840,799,780,769,723,687cm
-1
3, Fig. 3 is a differential scanning amount method thermogram spectrum;
In 230 ℃ of-250 ℃ of scopes, endothermic signal is arranged, peak temperature 240-246 ℃.
4, Fig. 4 is existing patent 1-(2, the 6-difluorobenzyl)-1H-1,2, the stripping curve figure of 3-triazole-4-methane amide A crystal, B crystal, C crystal, the new crystalline solids preparation of the present invention; Wherein X-coordinate is the time, and ordinate zou is a dissulution, and the crystal formation of different curve representatives is as follows:
crystal formation of the present invention
Experiment conclusion: through stripping curve figure; We can learn; The dissulution of the preparation of the new crystal preparation of the present invention will be higher than the dissulution of existing patent crystal formation, and particularly in 0-15 minute, crystal of the present invention will exceed more than 2 times than existing A, B, C crystal formation dissulution; Patient's use proved absolutely that the present invention has scientific meaning when the preparation of the new crystal preparation of the present invention was more suitable for epileptic seizures.
Pharmacological testing
Crystal of the present invention be prepared into pharmaceutical prepn effectively several electricity irritation of antagonism and chemical epileptic seizures animal pattern tetanic reach the epileptic seizures of clonic spasm phase mutually.Crystal of the present invention is prepared into the oral ED that pharmaceutical prepn suppresses rodent maximal electroshock property tonic-clonic seizures
50Be 5～17mg/kg, but relatively poor to Yetrazol inductive outbreak curative effect.This medicine can effectively suppress epileptic seizures that stimulation test cat brain amygdala cause and the hippocampus that non-exciting cat electricity irritation is caused and the back release of cortex.Can alleviate or cancel the chronic recurrence type of the rhesus monkey epilepsy partial seizures due to the white lake heeling-in at cortical motor area heeling-in rufinamide, curative effect is better than other anticonvulsant drug usually.
It is to work through suppressing sodium dependency action potential frequency that crystal of the present invention is prepared into pharmaceutical prepn, points out its drug effect to come from membrane stabilizing action.Experiment shows, its concentration does not have obvious influence to monoamine, suprarenin, histamine, vagusstoff, glycocoll, AMPA-kainate, NMDA or GABA neurotransmitter-receptor system during greater than 10umol/L.
Preparation embodiment
The new crystal of the present invention
Measuring 2 θ angles with X-ray powder atlas calculation is: 8.17,13.16,15.20,16.09,18.13,19.12,20.880,21.07,23.50,25.01,27.64,28.30,29.79,31.92,35.23,35.37,39.30 degree;
KBr compressing tablet-transmission method is measured ir spectra and is had following absorption: 3409,3172,3081,1637,1566,1464,1396,1318,1280,1238,1124,1071,1062,1035,1011,889,851,793,789,761,723, and 686cm
-1
In differential scanning amount method thermogram, in 230 ℃ of-252 ℃ of scopes, endothermic signal is arranged, peak temperature 243-247 ℃.
Above-mentioned crystal, its purity more than or equal to 95% less than 100%.
The pharmaceutical prepn of above-mentioned crystal preparation.
Pharmaceutical prepn of the present invention comprises that load is not limited to conventional oral prepns such as tablet, capsule, pellet, granule, pill.
The application of above-mentioned crystal in preparation treatment epilepsy or epilepsy secondary disease medicine.
The new crystal of the present invention
Measuring 2 θ angles with X-ray powder atlas calculation is: 8.21,13.19,15.47,16.15,18.07,19.10,20.89,21.04,23.52,25.11,27.72,28.35,29.75,32.04,35.19,35.04,39.37 degree;
KBr compressing tablet-transmission method is measured ir spectra and is had following absorption: 3404,3179,3085,1630,1561,1468,1399,1321,1283,1234,1128,1074,1059,1038,1015,881,849,794,782,765,721, and 685cm
-1
In differential scanning amount method thermogram, in 231 ℃ of-249 ℃ of scopes, endothermic signal is arranged, peak temperature 241-246 ℃.
Above-mentioned crystal, its purity more than or equal to 95% less than 100%.
The pharmaceutical prepn of above-mentioned crystal preparation.
Pharmaceutical prepn of the present invention comprises that load is not limited to conventional oral prepns such as tablet, capsule, pellet, granule, pill.
Embodiment 3
The new crystal of the present invention
Measuring 2 θ angles with X-ray powder atlas calculation is: 8.28,13.32,15.56,16.82,18.14,19.30,20.30,21.70,24.06,25.30, and, 27.32,27.78,28.94,31.66,34.24,35.90,39.56 degree;
KBr compressing tablet-transmission method is measured ir spectra and is had following absorption: 3411,3189,3093,1634,1560,1474,1398,1325,1285,1236,1126,1081,1052,1037,1014,886,840,799,780,769,723, and 687cm
-1
In differential scanning amount method thermogram, in 230 ℃ of-250 ℃ of scopes, endothermic signal is arranged, peak temperature 240-246 ℃.
Above-mentioned crystal, its purity more than or equal to 95% less than 100%.
The pharmaceutical prepn of above-mentioned crystal preparation.
Pharmaceutical prepn of the present invention comprises that load is not limited to conventional oral prepns such as tablet, capsule, pellet, granule, pill.
The application of above-mentioned crystal in preparation treatment epilepsy or epilepsy secondary disease medicine.
The new crystal of the foregoing description 1, embodiment 2, embodiment 3 can obtain through crystallization process, also can prepare through the application's method, comprises but is limited to following preparation method: with 1-(2, the 6-difluorobenzyl)-1H-1; 2,3-triazole-4-methane amide adds in the DMSO 99.8MIN., and heating for dissolving is complete, under agitation drips lysate in the entry; Drip and finish, continue to stir, filter; Water washing does not filter the material drying, obtains crystal.
Annotate: the present invention's concrete technical scheme required for protection is not limited to the concrete combination of the expressed technical scheme of the foregoing description.
Claims (5)
1. following compounds 1-(2, the 6-difluorobenzyl)-1H-1,2, the crystal of 3-triazole-4-methane amide,
It is characterized in that:
Measuring 2 θ angles with X-ray powder atlas calculation is: 8.28,13.32,15.56,16.82,18.14,19.30,20.30,21.70,24.06,25.30,27.32,27.78,28.94,31.66,34.24,35.90,39.56 degree;
KBr compressing tablet-transmission method is measured ir spectra and is had following absorption: 3411,3189,3093,1634,1560,1474,1398,1325,1285,1236,1126,1081,1052,1037,1014,886,840,799,780,769,723, and 687cm
-1
In differential scanning amount method thermogram, in 230 ℃ of-250 ℃ of scopes, endothermic signal is arranged, peak temperature 240-246 ℃.
2. one kind prepares the said crystalline method of claim 1, it is characterized in that carrying out as follows:
With 1-(2, the 6-difluorobenzyl)-1H-1,2,3-triazole-4-methane amide adds in the DMSO 99.8MIN., and heating for dissolving is complete, and lysate is under agitation dripped in the entry, drips and finishes, and continues to stir, and filters, and water washing does not filter the material drying, obtains crystal.
3. crystal according to claim 1, its purity more than or equal to 95% less than 100%.
4. the pharmaceutical prepn of crystal preparation according to claim 1.
5. the application of crystal according to claim 1 in preparation treatment epilepsy or epilepsy secondary disease medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN2008102467268A CN101768124B (en) | 2008-12-30 | 2008-12-30 | Medicine crystal, preparation method and purpose thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2008102467268A CN101768124B (en) | 2008-12-30 | 2008-12-30 | Medicine crystal, preparation method and purpose thereof |
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| CN101768124A CN101768124A (en) | 2010-07-07 |
| CN101768124B true CN101768124B (en) | 2012-01-04 |
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| CN102219752B (en) * | 2011-04-21 | 2013-04-10 | 华润赛科药业有限责任公司 | Crystal form D of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4789680A (en) * | 1982-12-23 | 1988-12-06 | Ciba-Geigy Corporation | Aralkyltriazole compounds |
| CN1217716A (en) * | 1997-06-10 | 1999-05-26 | 诺瓦提斯公司 | Crystal modified body of medicine |
| CN1225087A (en) * | 1996-07-11 | 1999-08-04 | 诺瓦提斯公司 | Process for preparing 1-substituted 4-cyano-1,2,3-triazoles |
-
2008
- 2008-12-30 CN CN2008102467268A patent/CN101768124B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4789680A (en) * | 1982-12-23 | 1988-12-06 | Ciba-Geigy Corporation | Aralkyltriazole compounds |
| CN1225087A (en) * | 1996-07-11 | 1999-08-04 | 诺瓦提斯公司 | Process for preparing 1-substituted 4-cyano-1,2,3-triazoles |
| CN1217716A (en) * | 1997-06-10 | 1999-05-26 | 诺瓦提斯公司 | Crystal modified body of medicine |
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