CN102241608A - Retigabine compound and composition thereof - Google Patents
Retigabine compound and composition thereof Download PDFInfo
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- CN102241608A CN102241608A CN2011101214038A CN201110121403A CN102241608A CN 102241608 A CN102241608 A CN 102241608A CN 2011101214038 A CN2011101214038 A CN 2011101214038A CN 201110121403 A CN201110121403 A CN 201110121403A CN 102241608 A CN102241608 A CN 102241608A
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- retigabine
- semihydrate
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- 0 CC*C(Nc(c(CC)c1)ccc1NCc(cc1)ccc1F)O Chemical compound CC*C(Nc(c(CC)c1)ccc1NCc(cc1)ccc1F)O 0.000 description 1
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Abstract
The invention relates to a retigabine compound in a semihydrate crystal form and a preparation method thereof. The compound in the crystal form has the following good characteristics: the purity is high; and the stability is good, and the compound has superiority in industrial production and is suitable for preparation technological process and long-term storage. The invention also relates to a pharmaceutical composition of the retigabine compound in the semihydrate crystal form and an application of the compound in preparation of antiepileptic medicaments.
Description
Technical field
Pharmaceutical composition, preparation method and this crystal formation that the present invention relates to contain retigabine (retigabine) compound semihydrate crystal formation is used for making the application of the medicine of treatment epilepsy.
Background technology
Retigabine (Retigabine) for a kind of neurone potassium channel openers and GABA toughener, can reduce the neuronal excitation agent, and anticonvulsant action has mechanism and multiple.Its mechanism of action is different from the anticonvulsant drug of present batrachotoxin, calcium channel, GABA acceptor, clinically is used for the neuralgic treatment that the local outbreak of epilepsy and zoster cause.
Retigabine (Retigabine), chemical name, 2-amino-4-(4-luorobenzyl amino)-1-ethoxy carbonyl amino-benzene, molecular formula is C16H18FN3O2, its molecular weight is 303.33.Chemical structural formula is:
Retigabine has polymorphism, and CN98801733.4 discloses its 3 kinds of crystal formations.The inventor finds that also there is a kind of crystal formation in retigabine in research process, be different from disclosed those 3 kinds of crystal formations in the above-mentioned patent, and this crystal formation is the semihydrate of retigabine, and surprisingly, this crystal formation has excellent characteristic: the purity height; Good stability has superiority on industrial production, be fit to preparation technical process and standing storage.
Summary of the invention
One object of the present invention discloses a kind of crystal formation of retigabine semihydrate.
Another object of the present invention discloses the preparation method of retigabine semihydrate crystal formation.
Another purpose of the present invention discloses the pharmaceutical composition that comprises retigabine semihydrate crystal formation.
The invention also discloses the application of crystal formation in making treatment epilepsy medicine of retigabine semihydrate.
Now content of the present invention is specifically described in conjunction with purpose of the present invention.
The invention provides a kind of retigabine semihydrate (shown in the formula I),
（Ⅰ）
Karl Fischer method (Karl Fischer method) is in a kind of all kinds of chemical processes of measuring moisture in the material, and, the most accurately method the most single-minded to water has been listed in the standard method of moisture determination in many materials, organic compound especially, reliable results.Through 6 batches of mensuration, the moisture that described invention crystal formation contains is between 2.80%-2.95% (weight percent).The theoretical content of water is 2.88% in the retigabine semihydrate, can assert that the invention compound contains crystal water half.
。
The invention provides a kind of new crystal of retigabine semihydrate, adopt D/Max-2500.9161 type x-ray diffractometer to measure condition determination: Cu Ka target, tube voltage 40KV, tube current 100mA.X-ray powder diffraction charateristic avsorption band (2 θ) and D value are as follows, see Fig. 1.
| Peak number | Diffraction angle (2 θ) | The D value | I/ |
| 1 | 14.880 | 5.9487 | 7 |
| 2 | 18.240 | 4.8597 | 88 |
| 3 | 21.800 | 4.0735 | 5 |
| 4 | 23.740 | 3.7448 | 2 |
| 5 | 25.500 | 3.4902 | 20 |
| 6 | 27.140 | 3.2829 | 5 |
| 7 | 27.580 | 3.2315 | 4 |
| 8 | 28.900 | 3.0869 | 27 |
| 9 | 30.080 | 2.9684 | 75 |
| 10 | 30.340 | 2.9436 | 100 |
| 11 | 33.280 | 2.6899 | 16 |
| 12 | 33.780 | 2.6512 | 2 |
| 13 | 34.400 | 2.6049 | 67 |
| 14 | 37.220 | 2.4137 | 3 |
| 15 | 38.960 | 2.3098 | 18 |
| 16 | 40.660 | 2.2171 | 21 |
| 17 | 44.460 | 2.0360 | 33 |
| 18 | 45.540 | 1.9902 | 13 |
| 19 | 46.000 | 1.9714 | 13 |
| 20 | 46.820 | 1.9387 | 14 |
| 21 | 47.680 | 1.9058 | 24 |
| 22 | 48.440 | 1.8776 | 15 |
The mensuration of 2 θ values is used light source among the present invention, and precision is ± 0.2 °, therefore represents above-mentioned value of getting to allow certain reasonably limit of error, and its limit of error is ± 0.2 °.
The correction polystyrene film of instrument when infrared spectrogram is measured meets the regulation of Chinese Pharmacopoeia.
This crystal formation infrared spectrogram (KBr pressed disc method mensuration) is at 3407 ± 5cm
-13288 ± 5cm
-12983 ± 5cm
-12959 ± 5cm
-12577 ± 5cm
-11739 ± 2cm
-11652 ± 2cm
-11596 ± 2cm
-11422 ± 2cm
-1There is characteristic peak at the place, sees Fig. 2.
Another object of the present invention discloses retigabine semihydrate crystalline preparation method, by with retigabine heating for dissolving in acetonitrile-acetic acid-aqueous solution, naturally cools to room temperature, is incubated for some time again to obtain.
Specifically comprise the following steps: in the mixed solution of the acetonitrile-acetate-water=5-6:1-2:3-2 by retigabine being added 6-7 times of weight or measurement (WM) ratio, be heated to 80 ℃-85 ℃, filtered while hot naturally cools to 45 ℃-50 ℃, is incubated 1-2 hour, reduce to 25 ℃-30 ℃ again, be incubated 3-4 hours, separate out crystallization, filter, drying obtains retigabine semihydrate white crystal of the present invention, content 99.8%.
Used retigabine, synthetic according to the method that document DE4200259 provides, needn't make hydrochloride, the chemical structure of synthetic retigabine is proved conclusively through ultimate analysis.
Another purpose of the present invention provides the pharmaceutical composition that comprises retigabine semihydrate crystal formation.Preparation of pharmaceutical compositions of the present invention is as follows: use standard and conventional technology; acceptable solid or liquid vehicle are combined, and make it at random to combine and be prepared into particulate or microballoon with acceptable auxiliary and vehicle on the technology of pharmaceutics.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet or the like.Solid carrier can be at least a material, and it can serve as thinner, flavouring agent, solubilizing agent, lubricant, suspension agent, tackiness agent, disintegrating agent and coating agent.Inert solid carrier comprises trimagnesium phosphate, Magnesium Stearate, smoothers sugar, lactose, pectin, propylene glycol, Polysorbate 80, dextrin, starch, gelatin, cellulose substances for example methylcellulose gum, Microcrystalline Cellulose, low melt point paraffin, polyoxyethylene glycol, N.F,USP MANNITOL, theobroma oil etc.
The amount of the active ingredient that contains in pharmaceutical composition and the unit dosage form (The compounds of this invention) can be according to patient's the state of an illness, specific being applied of situation of diagnosis, the amount of used compound or concentration are regulated in the scope of a broad, and the weight range of active compound is 1%～40%(weight of composition).
The present invention also provides the application of retigabine semihydrate in making treatment epilepsy medicine.
Test at body through rat, in traditional electroshock test,, adopt super-large current to stimulate the ED of its anticonvulsant action to behind the rats by intraperitoneal injection retigabine semihydrate new crystal
50Be 4.9mg/kg, can be used for making the medicine of treatment epilepsy.
Stability test
Retigabine semihydrate crystal at high light (under 4500lx ± 500lx), high temperature (60 ± 2 ℃), high humidity (RH92.5%) condition from 0-10 days, outward appearance does not change, in addition, X powder diffraction, infrared absorption spectrum, thermogram spectrum all do not change, stable crystal form is described, do not have the trichite of commentaries on classics and give birth to, still keep original crystal formation; Related substance, content do not change in addition, illustrate that the new crystal chemical stability is good, are fit to the manufacturing and the standing storage of pharmaceutical preparation.
At 40 ℃, under different relative humidity (RH) conditions (75%, 92.5%), the mensuration of moisture in the retigabine semihydrate crystal:
The result: at 40 ℃, under different relative humidity (RH) conditions (75%, 92.5%), it is constant that moisture keeps, and explanation has good stability, and is fit to the manufacturing and the standing storage of pharmaceutical preparation.
Figure of description:
Fig. 1 retigabine semihydrate X-ray diffraction in crystals figure;
Fig. 2 retigabine semihydrate crystalline infrared spectrogram;
Embodiment:
The present invention is described further below in conjunction with embodiment, makes this area professional and technical personnel better understand the present invention.Embodiment only is indicative, means that never it limits the scope of the invention by any way.
Used retigabine among the present invention, synthetic according to the method that document DE4200259 provides, needn't make hydrochloride, purity 98.1% (HPLC normalization method).Chemical structure is proved conclusively through ultimate analysis, proves that chemical structure is correct.Molecular formula is C16H18FN3O2, results of elemental analyses:
Measured value (calculated value),
C:63.26(63.35),H:5.99(5.98),N:13.77(13.85)?,F6.20(6.26)。
In the 50l reactor, add 6 kilograms of retigabines, add in the mixed solution of 40 liters of acetonitrile-acetate-water=6:2:2, be heated to 82 ℃, filtered while hot naturally cools to 45 ℃-47 ℃, is incubated 1.5 hours, reduce to 25 ℃-30 ℃ again, be incubated 3 hours, separate out crystallization, filter, drying obtains 5.5 kilograms of retigabine semihydrate white crystals of the present invention, content 99.8%.Measure 3 times through the karl Fischer method, computation of mean values contains the moisture of 2.86% (weight percent).
Results of elemental analyses:
Measured value (calculated value),
C:61.41(61.53),H:6.15(6.13),N:13.49(13.45),F:6.11(6.08)。
This crystalline X-ray diffractogram is seen Fig. 1.Instrument model and condition determination: Japanese D/max 2500 type diffractometers of science; CuKa 40Kv 100mA; 2 θ sweep limit: 0-50
°
This crystalline infrared spectrogram is seen Fig. 2, uses the KBr compressing tablet during mensuration.
Embodiment 2
The capsule that contains retigabine semihydrate new crystal
Prescription: retigabine semihydrate 45 grams of new crystal, propylene glycol 20ml, lactose 100 grams, Magnesium Stearate 25 grams, colloidal silica 35 grams are made 1000.
Technology: new crystal retigabine semihydrate, lactose, Magnesium Stearate, colloidal silica is wetting with 15% aqueous solution of propylene glycol, the granulation of sieving behind the mixing, 60 ℃ of dryings, whole grain, filled capsules.
Embodiment 3
The tablet that contains retigabine semihydrate new crystal
Prescription: retigabine semihydrate 20 grams of new crystal, Microcrystalline Cellulose 30 grams, lactose 130 grams, 15 gram PEG-4000, Magnesium Stearate 15 grams, 22 gram 30 POVIDONE K 30 BP/USPs 30, croscarmellose sodium 45 grams, talcum powder 10 grams, distilled water is an amount of, makes 1000.
The retigabine semihydrate of technology: PEG-4000 and new crystal is pulverized jointly, crosses 80 mesh sieves, with behind other material mixing with distilled water system softwood, 16 mesh sieve system particles are put in the loft drier in 40-45 ℃ of drying, the whole grain of 16 mesh sieves, Magnesium Stearate adds mixing in the dried particle, compressing tablet.
Claims (6)
1. the semihydrate of retigabine compound shown in the formula I,
（Ⅰ）
Measure with the karl Fischer method, described hydrate contains the moisture of 2.78%-2.98% (weight percent);
The crystal of described retigabine semihydrate is characterized in that: use the CuKa ray as characteristic X-ray
During powder was measured, its collection of illustrative plates had following 2 θ diffraction angle and D value,
The error of 2 θ diffraction angle is 0.2.
2. the described retigabine semihydrate of claim 1 crystalline preparation method by with retigabine heating for dissolving in acetonitrile-acetic acid-aqueous solution, naturally cools to room temperature, is incubated for some time again to obtain.
3. the described preparation method of claim 2, it is characterized in that comprising the following steps: in the mixed solution of the acetonitrile-acetate-water=5-6:1-2:3-2 by retigabine being added 6-7 times of weight or measurement (WM) ratio, be heated to 80 ℃-85 ℃, filtered while hot naturally cools to 45 ℃-50 ℃, be incubated 1-2 hour, reduce to 25 ℃-30 ℃ again, be incubated 3-4 hours, separate out crystallization, filter, drying obtains.
4. one kind contains the retigabine of the described crystal formation of claim 1 and the retigabine composition that one or more pharmaceutically acceptable carriers are formed.
5. right requires 4 described compositions, it is characterized in that said composition is used to prepare oral preparations.
6. the application of the retigabine of the described crystal formation of claim 1 in the medicine of making the treatment epilepsy.
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| CN2011101214038A CN102241608A (en) | 2011-05-12 | 2011-05-12 | Retigabine compound and composition thereof |
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| CN2011101214038A CN102241608A (en) | 2011-05-12 | 2011-05-12 | Retigabine compound and composition thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102531966A (en) * | 2011-12-23 | 2012-07-04 | 山东创新药物研发有限公司 | Novel crystal form D of Retigabine and preparation method thereof |
| WO2013008250A2 (en) * | 2011-07-01 | 2013-01-17 | Dr.Reddys Laboratories Limited. | Crystalline form of retigabine and processes for mixture of retigabine crystalline modifications |
| CN102964273A (en) * | 2012-12-06 | 2013-03-13 | 北京英科博雅科技有限公司 | Novel retigabine crystal form F and preparation method thereof |
| CN103271899A (en) * | 2012-12-30 | 2013-09-04 | 北京阜康仁生物制药科技有限公司 | Application of Retigabine dihydrochloride crushing granularity in preparation |
| CN108403652A (en) * | 2018-05-21 | 2018-08-17 | 威海贯标信息科技有限公司 | A kind of retigabine tablet composition |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5384330A (en) * | 1992-01-08 | 1995-01-24 | Asta Medica Aktiengesellschaft | Pharmaceutically active 1,2,4-triamino-benzene derivatives, processes for their preparation and pharmaceutical compositions containing them |
| CN1243506A (en) * | 1997-01-20 | 2000-02-02 | Asta药物股份公司 | Novel modifications to 2-amino-4 (4-fluorobenzylamino)-1-ethoxycarbonyl-aminobenzene and processes for preparing said compound |
| WO2009018466A1 (en) * | 2007-08-01 | 2009-02-05 | Valeant Pharmaceuticals International, Inc. | Naphthyridine derivatives as potassium channel modulators |
| WO2009023677A1 (en) * | 2007-08-13 | 2009-02-19 | Valeant Pharmaceuticals International, Inc. | Derivatives of 5-amino-4, 6-disubstituted indole and 5-amino-4,6-disubstituted indoline as potassium channel modulators |
| WO2011039369A2 (en) * | 2009-10-02 | 2011-04-07 | Medichem S.A. | Amorphous forms of a 2-amino-4-(4-fluorobenzylamino)phenylcarbamate derivative |
-
2011
- 2011-05-12 CN CN2011101214038A patent/CN102241608A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5384330A (en) * | 1992-01-08 | 1995-01-24 | Asta Medica Aktiengesellschaft | Pharmaceutically active 1,2,4-triamino-benzene derivatives, processes for their preparation and pharmaceutical compositions containing them |
| CN1243506A (en) * | 1997-01-20 | 2000-02-02 | Asta药物股份公司 | Novel modifications to 2-amino-4 (4-fluorobenzylamino)-1-ethoxycarbonyl-aminobenzene and processes for preparing said compound |
| WO2009018466A1 (en) * | 2007-08-01 | 2009-02-05 | Valeant Pharmaceuticals International, Inc. | Naphthyridine derivatives as potassium channel modulators |
| WO2009023677A1 (en) * | 2007-08-13 | 2009-02-19 | Valeant Pharmaceuticals International, Inc. | Derivatives of 5-amino-4, 6-disubstituted indole and 5-amino-4,6-disubstituted indoline as potassium channel modulators |
| WO2011039369A2 (en) * | 2009-10-02 | 2011-04-07 | Medichem S.A. | Amorphous forms of a 2-amino-4-(4-fluorobenzylamino)phenylcarbamate derivative |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013008250A2 (en) * | 2011-07-01 | 2013-01-17 | Dr.Reddys Laboratories Limited. | Crystalline form of retigabine and processes for mixture of retigabine crystalline modifications |
| WO2013008250A3 (en) * | 2011-07-01 | 2013-03-07 | Dr.Reddys Laboratories Limited. | Crystalline form of retigabine and processes for mixture of retigabine crystalline modifications |
| CN102531966A (en) * | 2011-12-23 | 2012-07-04 | 山东创新药物研发有限公司 | Novel crystal form D of Retigabine and preparation method thereof |
| CN102531966B (en) * | 2011-12-23 | 2013-07-24 | 山东创新药物研发有限公司 | Novel crystal form D of Retigabine and preparation method thereof |
| CN102964273A (en) * | 2012-12-06 | 2013-03-13 | 北京英科博雅科技有限公司 | Novel retigabine crystal form F and preparation method thereof |
| CN102964273B (en) * | 2012-12-06 | 2014-04-02 | 北京英科博雅科技有限公司 | Novel retigabine crystal form F and preparation method thereof |
| CN103271899A (en) * | 2012-12-30 | 2013-09-04 | 北京阜康仁生物制药科技有限公司 | Application of Retigabine dihydrochloride crushing granularity in preparation |
| CN108403652A (en) * | 2018-05-21 | 2018-08-17 | 威海贯标信息科技有限公司 | A kind of retigabine tablet composition |
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Application publication date: 20111116 |