CN103360276A - Crystal form, preparation method and application of agomelatine, as well as medicine composition - Google Patents
Crystal form, preparation method and application of agomelatine, as well as medicine composition Download PDFInfo
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- CN103360276A CN103360276A CN2012100895296A CN201210089529A CN103360276A CN 103360276 A CN103360276 A CN 103360276A CN 2012100895296 A CN2012100895296 A CN 2012100895296A CN 201210089529 A CN201210089529 A CN 201210089529A CN 103360276 A CN103360276 A CN 103360276A
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- YJYPHIXNFHFHND-UHFFFAOYSA-N agomelatine Chemical compound C1=CC=C(CCNC(C)=O)C2=CC(OC)=CC=C21 YJYPHIXNFHFHND-UHFFFAOYSA-N 0.000 title claims abstract description 78
- 229960002629 agomelatine Drugs 0.000 title claims abstract description 78
- 239000013078 crystal Substances 0.000 title claims abstract description 65
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 239000003814 drug Substances 0.000 title claims abstract description 18
- 239000000203 mixture Substances 0.000 title claims abstract description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 39
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 14
- 238000001953 recrystallisation Methods 0.000 claims description 14
- 238000002425 crystallisation Methods 0.000 claims description 13
- 230000008025 crystallization Effects 0.000 claims description 13
- 239000012065 filter cake Substances 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 238000010992 reflux Methods 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 10
- 239000000706 filtrate Substances 0.000 claims description 10
- 238000000967 suction filtration Methods 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 8
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 7
- 208000024827 Alzheimer disease Diseases 0.000 claims description 6
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
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- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 claims description 5
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 claims description 5
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
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- OQRMWUNUKVUHQO-UHFFFAOYSA-N 2-naphthalen-1-ylacetonitrile Chemical compound C1=CC=C2C(CC#N)=CC=CC2=C1 OQRMWUNUKVUHQO-UHFFFAOYSA-N 0.000 description 1
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- UUXLZQRTGHEMET-UHFFFAOYSA-N COC1=CC=C2C=CC=C(C2=C1)CCNC(C)=O.C(C)(=O)N Chemical compound COC1=CC=C2C=CC=C(C2=C1)CCNC(C)=O.C(C)(=O)N UUXLZQRTGHEMET-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention provides a crystal form, a preparation method and an application of agomelatine, as well as a medicine composition. Compared with the prior art, the crystal form provided by the invention has the following advantages and positive effects that the new crystal form of the agomelatine obtained by the preparation method provided by the invention is high in purity, stable, good in repeatability, better than a plurality of existing crystal forms in purity and stability, and suitable for preparing medicament preparations. The preparation method of the new crystal form of the agomelatine provided by the invention is simpler and more convenient than the existing crystal form, is also moderate in condition, easy to be applied in actual production and low in cost, and satisfies the requirements of industrial production.
Description
Technical field
The present invention relates to chemical pharmacy field, in particular to a kind of crystal formation, preparation method and purposes of chemicals Agomelatine, and the pharmaceutical composition that contains the crystal formation of Agomelatine.
Background technology
Agomelatine (Agomelatine) is melatonin 1,2 (MT1, MT2) receptor stimulant, also be five hydroxytryptamine 2c (5HT2C) receptor antagonist simultaneously, can be directly and the 5HT2C receptors bind of nerve synapse caudacoria, thereby bring into play its antidepressant curative effect, and do not increase the 5HT concentration between cynapse, thereby do not have the common adverse effect of five hydroxytryptamine reuptake inhibitor class medicine and five hydroxytryptamine NRI class medicine.Another unique effect target spot of this medicine is at the MT acceptor, by the agonism to MT1 and MT2 acceptor, capable of regulating patient's 24 circadian rhythm 24s, improves patient's sleep quality, thereby promotes the improvement of patients with depression overall clinical situation.
A large amount of clinical studyes is verified: Agomelatine has desirable shot and long term curative effect, and this medicine onset is rapid, and significantly reduces the recurrence recrudescence rate of depressive patient; Security significantly is better than SSRI, SNRI class medicine, in alleviate depression disease core symptom, significantly improves patient's sleep quality, improves the daystart waking state, is one of ideal chose that satisfies patient and these demands of doctor.
The Agomelatine untoward reaction is less, common are headache, feels sick and weak etc.No matter be the treatment of short or long term maintenance, its adverse reaction rate is similar to placebo, and the untoward reaction of long-term treatment than short more still less, and this is also similar to placebo.Agomelatine does not cause the change of body weight, and gastrointestinal side effect is also seldom arranged.
Agomelatine goes on the market as thymoleptic.The Agomelatine sheet of France Shi Weiya company development is film coated tablet, and its commodity are called Valdoxan
/ Thymanax
Specification is 25mg.It is that first obtains the melatonin receptor agonist thymoleptic of European Union's listing approval in the world.
In European patent document EP0447285, describe the preparation method of agomelatine I crystal formation, described respectively II, III, IV, V, the VI crystal formation of Agomelatine in the Chinese patent literature 200510071611.6,200610108396.7,200610108394.8,200610108395.2,200810174918.2.
Wherein, the I crystal formation is to make by recrystallization in isopropyl ether.The II crystal formation is to make by recrystallization in the second alcohol and water.The III crystal formation be by 110 ℃ the heating Agomelatines until fully the fusing, then Slow cooling until crystallization make.The IV crystal formation be by at 110 ℃ of heating Agomelatines until fully fusing, then rapidly cooling between 50-70 ℃, and kept approximately 5 hours until crystallization makes at 70 ℃.The V crystal formation is to make by " high energy " mechanical mill.The VI crystal formation is by being dissolved in the heating under boiling of isopropyl ether solution, being quickly cooled to 0 ℃; Water-soluble under the high pressure/alcohol mixture (50/50), crystallization made in 24 hours.
Above crystal formation part preparation method is complicated, and preparation process needs high temperature or " high energy mechanical grinding ", can not satisfy the demand of suitability for industrialized production.Some stable crystal form is not high, and is high to temperature, light, humidity and oxygen level requirement in the storage, can not satisfy the preparation of medicine preparation and the needs that transportation stores.
Summary of the invention
For solving above-mentioned problems of the prior art, the invention provides a kind of crystal formation, preparation method and purposes of Agomelatine, and the pharmaceutical composition that contains the crystal formation of Agomelatine
Particularly, the invention provides:
(1) a kind of crystal formation of Agomelatine, in the powder x-ray diffraction spectrogram of the crystal formation of described Agomelatine, 2 θ angles, Prague, spacing d and relative intensity are as follows:
Wherein said relative intensity represents with the percentage ratio of strong ray.
(2) preparation method of the crystal formation of the described Agomelatine of a kind of basis (1), the method comprises:
1) with the ratio of weight/volume be 1: 2 to 1: 3 Agomelatine and chloroform reflux to described Agomelatine dissolving, filter gained solution, obtain filtrate, the unit of the ratio of wherein said weight/volume is g/ml;
2) with described filtrate cooling crystallization, then carry out suction filtration, obtain filter cake; And
3) with described filtration cakes torrefaction to constant weight.
(3) according to (2) described preparation method, wherein, in step 1) in, the ratio of the weight/volume of described Agomelatine and described chloroform is 1: 2.5.
(4) according to (2) described method, wherein, in step 3) in, described drying is drying under reduced pressure.
(5) according to (4) described method, wherein, described drying under reduced pressure carries out under 60 ℃.
(6) according to (2) described method, wherein, in step 2) in, described filter cake is carried out recrystallization second time with chloroform, and the amount of used chloroform is the 50-100% of the recrystallization first time in the described second time recrystallization.
(7) according to the crystal formation of (1) described Agomelatine for the preparation of the purposes in the medicine for the treatment of melatonin dysfunction.
(8) purposes of crystal formation in the medicine of making the following illness for the treatment of of basis (1) described Agomelatine: sleep disordered; nervous; anxiety; seasonal affective disorder or severe depression; cardiovascular disorder; digestive system; the insomnia and the fatigue that are caused by the time difference; schizophrenia; panic attack; melancholia; appetite disorder; obesity; insomnia; abalienation; epilepsy; diabetes; Parkinson's disease; senile dementia; with various disorders normal or that pathologic is aging relevant; migraine; the loss of memory; alzheimer's disease; cerebral circulation is disorderly; sexual dysfunction; immune dysfunction; and cancer.
(9) a kind of pharmaceutical composition, it comprises crystal formation and one or more pharmaceutically acceptable auxiliary material or the vehicle of the described Agomelatine of basis (1) as activeconstituents.
(10) according to (9) described pharmaceutical composition, the formulation of this pharmaceutical composition is tablet, drageeing, granule, Sublingual tablet, gelatine capsule, lozenge, suppository, ointment, ointment, skin gel, injectable formulation, drinkable suspensoid or disintegratable paste.
New crystal of the present invention compared with prior art has the following advantages and positively effect:
The new crystal of the Agomelatine that is obtained by the present invention, purity is high, stable crystal form, favorable reproducibility, purity and stable aspect more be better than existing several crystal formation, be suitable for preparing medicine preparation.And the preparation method of the new crystal of Agomelatine provided by the invention is also easier than existing crystal formation, and mild condition, do not need High Temperature High Pressure, do not need so-called " high energy milling " yet, be easy in actual production, use, with low cost, meet the requirement of suitability for industrialized production.
Description of drawings
Fig. 1. the powder x-ray diffraction spectrum (instrument: PANalytical X ' Pert Pro powder x-ray diffraction of the crystal formation of Agomelatine of the present invention; Condition: Cu K α, 40kV, 35mA).
Embodiment
Below the invention will be further described by the description of embodiment and with reference to accompanying drawing, but this is not to be limitation of the present invention, those skilled in the art are according to basic thought of the present invention, can make various modifications or improvement, but only otherwise break away from basic thought of the present invention, all within the scope of the present invention.
The chemical name of Agomelatine involved in the present invention (Agomelatine) is N-[2-(7-methoxy-1-naphthyl) ethyl] and ethanamide (N-[2-(7-methoxynaphth-l-yl) ethyl] acetamide), its chemical formula is C
15H
17NO
2, molecular weight is 243.31, and has suc as formula the chemical structural formula shown in the I:
One object of the present invention is to provide a kind of New crystal form of agomelatine.This crystal formation demonstrates valuable characteristic aspect medicine preparation.This crystal formation purity is high and stable, can standing storage, and to temperature, light, humidity and oxygen level without particular requirement.Another object of the present invention is to provide a kind of preparation method of this new crystal, and the method is simple to operate, favorable reproducibility.Another object of the present invention is to provide a kind of pharmaceutical composition, and it comprises: as this new crystal and one or more pharmaceutically acceptable auxiliary material or the vehicle of activeconstituents.Another object of the present invention is to provide this new crystal for the preparation of the purposes in the medicine for the treatment of melatonin dysfunction.
Particularly, the present invention at first provides a kind of crystal formation of Agomelatine, and wherein, in the powder x-ray diffraction spectrogram of the crystal formation of described Agomelatine, 2 θ angles, d value and relative intensity are as shown in table 1 below:
Table 1
The present invention also provides a kind of preparation method of the crystal formation according to Agomelatine of the present invention, and the method comprises:
1) with weight/volume be 1: 2 to 1: 3 Agomelatine and chloroform reflux to described Agomelatine dissolving, filter gained solution, obtain filtrate, the unit of the ratio of wherein said weight/volume is g/ml;
2) with described filtrate cooling crystallization, then carry out suction filtration, obtain filter cake; With
3) with described filtration cakes torrefaction to constant weight.
Preferably, in step 1) in, the ratio of the weight of described Agomelatine and described chloroform (g)/volume (ml) is 1: 2.5.
Preferably, in step 1) in, carrying out while hot described filtration, crystallization effect is better like this.
In step 3) in, hypobaric drying method is preferred.Preferably at 60 ℃ of drying under reduced pressure.
Preferably, in step 2) in, described filter cake is carried out the recrystallization second time with chloroform, for the second time operation of recrystallization comprises: reflux, filtered while hot, cooling crystallization, suction filtration, obtain filter cake; For the second time the amount of the used chloroform of recrystallization be the 50-100% of the recrystallization first time.
The invention still further relates to a kind of pharmaceutical composition, it comprises as the crystal formation of the above-mentioned Agomelatine of activeconstituents and one or more pharmaceutically acceptable auxiliary material or vehicle.In pharmaceutical composition of the present invention, preferably, be suitable for those formulations of oral, gi tract outer (intravenously or subcutaneous) or nasal administration, for example tablet, drageeing, granule, Sublingual tablet, gelatine capsule, lozenge, suppository, ointment, ointment, skin gel, injectable formulation, drinkable suspensoid or disintegratable paste.Regulate useful dosage according to the character of disorder and seriousness, route of administration and patient's age and body weight, use once a day or repeatedly.
The present invention also provides the purposes of crystal formation in the medicine of making the dysfunction for the treatment of melatonin according to Agomelatine of the present invention.
The present invention also provides the purposes of crystal formation in the medicine of the following disease of preparation treatment according to Agomelatine of the present invention: sleep disordered; nervous; anxiety; seasonal affective disorder or severe depression; cardiovascular disorder; digestive system; the insomnia and the fatigue that are caused by the time difference; schizophrenia; panic attack; melancholia; appetite disorder; obesity; insomnia; abalienation; epilepsy; diabetes; Parkinson's disease; senile dementia; with various disorders normal or that pathologic is aging relevant; migraine; the loss of memory; alzheimer's disease; cerebral circulation is disorderly; sexual dysfunction; immune dysfunction; and cancer.
Mode by the following examples further explains and describes content of the present invention, but these embodiment are not to be construed as limiting the scope of the invention.
In the following embodiments, chloroform can derive from Tianjin Fu Yu Fine Chemical Co., Ltd.
In the following embodiments, the Agomelatine crude product can be the Agomelatine crude product compound that uses various prior aries to prepare, for example: with 7-methoxyl group-1-tetralone and the reaction of acetonitrile lithium, product is through dehydrogenation, tosic acid dehydration aromizing, get naphthalene acetonitrile, Lithium Aluminium Hydride reduces afterwards and the product of excess acetyl chloride gained; The Agomelatine crude product also can be existing agomelatine crystal form in the various prior aries.
In the following embodiments, purity is measured by efficient liquid-phase chromatography method, and concrete condition determination can be referring to test example 1.
Embodiment 1
30g Agomelatine crude product, 75ml chloroform, 1g gac are joined in the 250ml reaction flask, and reflux to Agomelatine dissolves, and keeps refluxing filtered while hot 10 minutes.Filtrate cooling crystallization, suction filtration, 60 ℃ of drying under reduced pressure of filter cake be to constant weight, thereby obtain the crystal of Agomelatine.Wherein, the purity of Agomelatine is 99.80%.
Embodiment 2
30g Agomelatine crude product, 60ml chloroform are joined in the 250ml reaction flask, and reflux to Agomelatine dissolves, and keeps refluxing filtered while hot 10 minutes.Filtrate cooling crystallization, suction filtration, 60 ℃ of drying under reduced pressure of filter cake be to constant weight, thereby obtain the crystal of Agomelatine.Wherein, the purity of Agomelatine is 99.79%.
Embodiment 3
30g Agomelatine crude product, 90ml chloroform are joined in the 250ml reaction flask, and reflux to Agomelatine dissolves, and keeps refluxing filtered while hot 10 minutes.Filtrate cooling crystallization, suction filtration, 60 ℃ of drying under reduced pressure of filter cake be to constant weight, thereby obtain the crystal of Agomelatine.Wherein, the purity of Agomelatine is 99.78%.
Embodiment 4
30g Agomelatine crude product, 75ml chloroform, 1g gac are joined in the 250ml reaction flask, and reflux to Agomelatine dissolves, and keeps refluxing filtered while hot 10 minutes.The filtrate cooling crystallization, suction filtration, filter cake carries out secondary recrystallization with the 40ml chloroform, and secondary recrystallization operation comprises: reflux, filtered while hot, cooling crystallization, suction filtration, obtain filter cake; 60 ℃ of drying under reduced pressure of filter cake, thus the crystal of Agomelatine obtained.Wherein, the purity of Agomelatine is 99.90%.
Embodiment 5
Use powder x-ray diffraction that the agomelatine crystal form that embodiment 4 obtains is measured, what measure employing is Cu K alpha-ray, and design parameter is: 40kV, 35mA.Obtain powder x-ray diffraction spectrogram shown in Figure 1.Wherein, 2 θ angles, Prague, spacing d and relative intensity are as shown in table 2.
Table 2
Embodiment 6: pharmaceutical composition
The prescription of 1000 tablets of tablets of preparation, every contains 25mg dosage:
Test example 1
Stability study:
Respectively agomelatine crystal form II, III, IV, agomelatine crystal form of the present invention are put into 40 ℃ thermostat container, placed 20 days, by high performance liquid chromatography the stability of these crystal formations is studied.
1. sample purity is measured
The HPLC chromatographic condition: octadecylsilane chemically bonded silica is weighting agent; 10mM/L phosphate buffered saline buffer (sodium hydroxide regulate pH to 7.0) and acetonitrile volume ratio are that 2: 7 mixing solutions is as moving phase; Column temperature is 40 ℃; The detection wavelength is 220nm.Internal mark method determination purity.
Respectively II, III, IV, VI, agomelatine crystal form of the present invention are configured to the solution of 1mg/ml with moving phase, respectively get 10 μ L injection liquid chromatographies, the record color atlas.
2. samples contg is measured
Measuring method reference sample method for detecting purity is measured with external standard method, the results are shown in Table 3.
Table 3
According to above-mentioned test-results, New crystal form of agomelatine of the present invention more has superiority than existing crystal formation on purity and stability, is more suitable for the preparation needs.
Claims (10)
1. the crystal formation of an Agomelatine, in the powder x-ray diffraction spectrogram of the crystal formation of described Agomelatine, 2 θ angles, Prague, spacing d and relative intensity are as follows:
Wherein said relative intensity represents with the percentage ratio of strong ray.
2. the preparation method of the crystal formation of an Agomelatine according to claim 1, the method comprises:
1) with the ratio of weight/volume be 1: 2 to 1: 3 Agomelatine and chloroform reflux to described Agomelatine dissolving, filter gained solution, obtain filtrate, the unit of the ratio of wherein said weight/volume is g/ml;
2) with described filtrate cooling crystallization, then carry out suction filtration, obtain filter cake; And
3) with described filtration cakes torrefaction to constant weight.
3. preparation method according to claim 2, wherein, in step 1) in, the ratio of the weight/volume of described Agomelatine and described chloroform is 1: 2.5.
4. method according to claim 2, wherein, in step 3) in, described drying is drying under reduced pressure.
5. method according to claim 4, wherein, described drying under reduced pressure carries out under 60 ℃.
6. method according to claim 2 is wherein, in step 2) in, described filter cake is carried out the recrystallization second time with chloroform, and the amount of used chloroform is the 50-100% of recrystallization for the first time in the described second time recrystallization.
7. the crystal formation of Agomelatine according to claim 1 is for the preparation of the purposes in the medicine for the treatment of melatonin dysfunction.
8. the purposes of the crystal formation of Agomelatine according to claim 1 in the medicine of making the following illness for the treatment of: sleep disordered; nervous; anxiety; seasonal affective disorder or severe depression; cardiovascular disorder; digestive system; the insomnia and the fatigue that are caused by the time difference; schizophrenia; panic attack; melancholia; appetite disorder; obesity; insomnia; abalienation; epilepsy; diabetes; Parkinson's disease; senile dementia; with various disorders normal or that pathologic is aging relevant; migraine; the loss of memory; alzheimer's disease; cerebral circulation is disorderly; sexual dysfunction; immune dysfunction; and cancer.
9. pharmaceutical composition, it comprises as the crystal formation of the Agomelatine according to claim 1 of activeconstituents and one or more pharmaceutically acceptable auxiliary material or vehicle.
10. pharmaceutical composition according to claim 9, the formulation of this pharmaceutical composition is tablet, drageeing, granule, Sublingual tablet, gelatine capsule, lozenge, suppository, ointment, ointment, skin gel, injectable formulation, drinkable suspensoid or disintegratable paste.
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| CN101735091A (en) * | 2009-12-30 | 2010-06-16 | 北京德众万全药物技术开发有限公司 | Preparation method of Agomelatine |
| CN101792400A (en) * | 2010-03-16 | 2010-08-04 | 华东师范大学 | Synthetic method for agomelatine |
| CN102050755A (en) * | 2009-10-29 | 2011-05-11 | 重庆医药工业研究院有限责任公司 | Novel agomelatine crystal forms and preparation methods of agomelatine crystal forms |
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| CN102050755A (en) * | 2009-10-29 | 2011-05-11 | 重庆医药工业研究院有限责任公司 | Novel agomelatine crystal forms and preparation methods of agomelatine crystal forms |
| CN101735091A (en) * | 2009-12-30 | 2010-06-16 | 北京德众万全药物技术开发有限公司 | Preparation method of Agomelatine |
| CN101792400A (en) * | 2010-03-16 | 2010-08-04 | 华东师范大学 | Synthetic method for agomelatine |
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