CN103360276B - 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
- Publication number
- CN103360276B CN103360276B CN201210089529.6A CN201210089529A CN103360276B CN 103360276 B CN103360276 B CN 103360276B CN 201210089529 A CN201210089529 A CN 201210089529A CN 103360276 B CN103360276 B CN 103360276B
- Authority
- CN
- China
- Prior art keywords
- agomelatine
- preparation
- crystal form
- chloroform
- crystal formation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 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 74
- 229960002629 agomelatine Drugs 0.000 title claims abstract description 74
- 239000013078 crystal Substances 0.000 title claims abstract description 61
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 239000003814 drug Substances 0.000 title abstract description 16
- 239000000203 mixture Substances 0.000 title abstract description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 36
- 230000015572 biosynthetic process Effects 0.000 claims description 33
- 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
- 238000001035 drying Methods 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 238000001816 cooling Methods 0.000 claims description 10
- 239000000706 filtrate Substances 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 9
- 238000000967 suction filtration Methods 0.000 claims description 9
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract 1
- 230000008092 positive effect Effects 0.000 abstract 1
- 238000005755 formation reaction Methods 0.000 description 31
- 239000008194 pharmaceutical composition Substances 0.000 description 10
- 230000000694 effects Effects 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 238000011282 treatment Methods 0.000 description 5
- 208000024827 Alzheimer disease Diseases 0.000 description 4
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 description 4
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 4
- 206010022437 insomnia Diseases 0.000 description 4
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 4
- 229960003987 melatonin Drugs 0.000 description 4
- 239000002674 ointment Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- SNIXRMIHFOIVBB-UHFFFAOYSA-N N-Hydroxyl-tryptamine Chemical compound C1=CC=C2C(CCNO)=CNC2=C1 SNIXRMIHFOIVBB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000000935 antidepressant agent Substances 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 230000004064 dysfunction Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000007958 sleep Effects 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 208000000044 Amnesia Diseases 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- 208000027559 Appetite disease Diseases 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 208000020401 Depressive disease Diseases 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 208000019454 Feeding and Eating disease Diseases 0.000 description 2
- 239000001828 Gelatine Substances 0.000 description 2
- 208000019695 Migraine disease Diseases 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 206010029216 Nervousness Diseases 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- 206010033664 Panic attack Diseases 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- 206010039966 Senile dementia Diseases 0.000 description 2
- 201000001880 Sexual dysfunction Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 210000002249 digestive system Anatomy 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- -1 drageeing Substances 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- 206010016256 fatigue Diseases 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 208000026278 immune system disease Diseases 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 231100000863 loss of memory Toxicity 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 208000024714 major depressive disease Diseases 0.000 description 2
- 201000003995 melancholia Diseases 0.000 description 2
- 206010027599 migraine Diseases 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 208000019906 panic disease Diseases 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 208000012672 seasonal affective disease Diseases 0.000 description 2
- 231100000872 sexual dysfunction Toxicity 0.000 description 2
- 238000013456 study Methods 0.000 description 2
- 239000006190 sub-lingual tablet Substances 0.000 description 2
- 229940098466 sublingual tablet Drugs 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001519 thymoleptic effect Effects 0.000 description 2
- OQRMWUNUKVUHQO-UHFFFAOYSA-N 2-naphthalen-1-ylacetonitrile Chemical compound C1=CC=C2C(CC#N)=CC=CC2=C1 OQRMWUNUKVUHQO-UHFFFAOYSA-N 0.000 description 1
- 102000006902 5-HT2C Serotonin Receptor Human genes 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- BDRKSBXMFVDYBA-UHFFFAOYSA-N C1=CC=C(CCNC(C)=O)C2=CC(OC)=CC=C21.C1=CC=C(CCNC(C)=O)C2=CC(OC)=CC=C21 Chemical compound C1=CC=C(CCNC(C)=O)C2=CC(OC)=CC=C21.C1=CC=C(CCNC(C)=O)C2=CC(OC)=CC=C21 BDRKSBXMFVDYBA-UHFFFAOYSA-N 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 101150013372 Htr2c gene Proteins 0.000 description 1
- 229940121723 Melatonin receptor agonist Drugs 0.000 description 1
- 208000035999 Recurrence Diseases 0.000 description 1
- XURZGOTTZHKXTQ-UHFFFAOYSA-N acetonitrile;lithium Chemical compound [Li].CC#N XURZGOTTZHKXTQ-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 230000005260 alpha ray Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000006583 body weight regulation Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000027288 circadian rhythm Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 230000003001 depressive effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 238000010316 high energy milling Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 238000009115 maintenance therapy Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 239000013074 reference sample Substances 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 1
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 1
- 239000003775 serotonin noradrenalin reuptake inhibitor Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 230000003860 sleep quality Effects 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000002618 waking effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- 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 of chemicals Agomelatine, preparation method and purposes, and the pharmaceutical composition of crystal formation containing Agomelatine.
Background technology
Agomelatine (Agomelatine) is melatonin 1,2 (MT1, MT2) receptor stimulant, also be five hydroxytryptamine 2c (5HT2C) receptor antagonist simultaneously, can directly and the 5HT2C receptors bind of nerve synapse caudacoria, thus play its antidepressant curative effect, and do not increase the 5HT concentration between cynapse, thus there is no 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, at MT acceptor, by the agonism to MT1 and MT2 acceptor, 24 circadian rhythm 24s of adjustable patient, improves the sleep quality of patient, thus 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 is significantly better than SSRI, SNRI class medicine, while alleviate depression disease core symptom, significantly improves patient sleeps's quality, and improving daystart waking state, is one of ideal chose meeting patient and these demands of doctor.
Agomelatine untoward reaction is less, common are headache, to feel sick and weak etc.No matter be short or long term maintenance therapy, its adverse reaction rate is similar to placebo, and the untoward reaction of long-term treatment comparatively short is less, this is also similar to placebo.Agomelatine does not cause the change of body weight, seldom has gastrointestinal side effect yet.
Agomelatine goes on the market as thymoleptic.The agomelatine tablet of Shi Weiya company of France development is film coated tablet, and its commodity are called Valdoxan
/ Thymanax
specification is 25mg.It is the melatonin receptor agonist thymoleptic of first acquisition European Union listing approval in the world.
In European patent document EP0447285, describe the preparation method of agomelatine I crystal formation, in Chinese patent literature 200510071611.6,200610108396.7,200610108394.8,200610108395.2,200810174918.2, respectively describe II, III, IV, V, VI crystal formation of Agomelatine.
Wherein, I crystal is obtained by recrystallization in isopropyl ether.II crystal formation is obtained by recrystallization in second alcohol and water.III crystal formation is that then Slow cooling is until crystallization obtains by heating Agomelatines until melt completely at 110 DEG C.IV crystal formation is by heating Agomelatines until melt completely at 110 DEG C, then cooling rapidly between 50-70 DEG C, and maintains about 5 hours until crystallization obtains at 70 DEG C.V crystal formation is obtained by " high energy " mechanical mill.VI crystal formation heats at the boil by being dissolved in isopropyl ether solution, is quickly cooled to 0 DEG C; Water-soluble under high pressure/alcohol mixture (50/50), crystallization obtains for 24 hours.
Above crystal formation part preparation method is complicated, and preparation process needs high temperature or " high energy mechanical grinding ", can not meet the demand of suitability for industrialized production.Some stability of crystal form is not high, requires high, can not meet the preparation of medicine preparation and the needs of shipping storage in storage to temperature, light, humidity and oxygen level.
Summary of the invention
For solving above-mentioned problems of the prior art, the invention provides a kind of crystal formation of Agomelatine, preparation method and purposes, and the pharmaceutical composition of crystal formation containing Agomelatine
Specifically, the invention provides:
(1) crystal formation for Agomelatine, in the powder x-ray diffraction spectrogram of the crystal formation of described Agomelatine, θ angle, Prague 2, spacing d and relative intensity are as follows:
Wherein said relative intensity represents with the percentage ratio of the strongest ray.
(2) a kind of preparation method of crystal formation of the Agomelatine Gen Ju (1), the method comprises:
1) by the ratio of weight/volume be 1: 2 to 1: 3 Agomelatine and chloroform reflux dissolve to described Agomelatine, filter gained solution, obtain filtrate, the unit of the ratio of wherein said weight/volume is g/ml;
2) by described filtrate cooling crystallization, then carry out suction filtration, obtain filter cake; And
3) by described filtration cakes torrefaction to constant weight.
(3) preparation method Gen Ju (2), wherein, in step 1) in, the ratio of the weight/volume of described Agomelatine and described chloroform is 1: 2.5.
(4) method Gen Ju (2), wherein, in step 3) in, described drying is drying under reduced pressure.
(5) method Gen Ju (4), wherein, described drying under reduced pressure carries out at 60 DEG C.
(6) method Gen Ju (2), wherein, in step 2) in, described filter cake chloroform is carried out second time recrystallization, and the amount of chloroform used in described second time recrystallization is the 50-100% of first time recrystallization.
(7) purposes of crystal formation in the medicine for the preparation of the dysfunction for the treatment of melatonin of the Agomelatine Gen Ju (1).
(8) purposes of crystal formation in the medicine manufacturing the following illness for the treatment of of the Agomelatine Gen Ju (1): sleep disordered, nervous, anxiety, seasonal affective disorder or severe depression, cardiovascular disorder, digestive system, the insomnia caused by the time difference and fatigue, schizophrenia, panic attack, melancholia, appetite disorder, obesity, insomnia, abalienation, epilepsy, diabetes, Parkinson's disease, senile dementia, with the normal or aging relevant various disorders of pathologic, migraine, the loss of memory, alzheimer's disease, cerebral circulation is disorderly, sexual dysfunction, immune dysfunction, and cancer.
(9) pharmaceutical composition, it comprises crystal formation as the Agomelatine Gen Ju (1) of activeconstituents and one or more pharmaceutically acceptable auxiliary material or vehicle.
(10) pharmaceutical composition Gen Ju (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.
New crystal of the present invention compared with prior art has the following advantages and positively effect:
The new crystal of the Agomelatine obtained by the present invention, purity is high, stable crystal form, favorable reproducibility, is more better than existing several crystal formation, is suitable for preparing medicine preparation in purity and stability.And the preparation method of the new crystal of Agomelatine provided by the invention, also easier than existing crystal formation, and mild condition, do not need High Temperature High Pressure, also do not need so-called " high energy milling ", be easy to apply in actual production, with low cost, meet the requirement of suitability for industrialized production.
Accompanying drawing explanation
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 by way of embodiment description and the invention will be further described with reference to accompanying drawing, but this is not limitation of the present invention, those skilled in the art are according to basic thought of the present invention, various amendment or improvement can be made, but only otherwise depart from basic thought of the present invention, all within the scope of the present invention.
The chemical name of Agomelatine (Agomelatine) involved in the present invention is N-[2-(7-methoxy-1-naphthyl) ethyl] ethanamide (N-[2-(7-methoxynaphth-l-yl) ethyl] acetamide), and its chemical formula is C
15h
17nO
2, molecular weight is 243.31, and has such as formula the chemical structural formula shown in I:
One object of the present invention is to provide a kind of New crystal form of agomelatine.This crystal formation demonstrates valuable characteristic in medicine preparation.This crystal form 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 the preparation method providing this new crystal a kind of, 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 the purposes of this new crystal in the medicine for the preparation of the dysfunction for the treatment of melatonin.
Specifically, the present invention provide firstly 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
Present invention also offers a kind of preparation method of the crystal formation according to Agomelatine of the present invention, the method comprises:
1) by weight/volume be 1: 2 to 1: 3 Agomelatine and chloroform reflux dissolve to described Agomelatine, filter gained solution, obtain filtrate, the unit of the ratio of wherein said weight/volume is g/ml;
2) by described filtrate cooling crystallization, then carry out suction filtration, obtain filter cake; With
3) by described filtration cakes torrefaction to constant weight.
Preferably, in step 1) in, the ratio of weight (the g)/volume (ml) of described Agomelatine and described chloroform is 1: 2.5.
Preferably, in step 1) in, carry out described filtration while hot, such crystallization effect is better.
In step 3) in, hypobaric drying method is preferred.Preferably at 60 DEG C of drying under reduced pressure.
Preferably, in step 2) in, described filter cake chloroform is carried out second time recrystallization, and the operation of second time recrystallization comprises: reflux, filtered while hot, cooling crystallization, suction filtration, obtain filter cake; The amount of the chloroform that second time recrystallization is used is the 50-100% of first time recrystallization.
The invention still further relates to a kind of pharmaceutical composition, it comprises crystal formation as 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, such as tablet, drageeing, granule, Sublingual tablet, gelatine capsule, lozenge, suppository, ointment, ointment, skin gel, injectable formulation, drinkable suspensoid or disintegratable paste.According to age and the useful dosage of weight regulation of the character of disorder and seriousness, route of administration and patient, use once a day or repeatedly.
Present invention also offers the purposes of crystal formation in the medicine manufacturing the dysfunction for the treatment of melatonin according to Agomelatine of the present invention.
Present invention also offers 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 caused by the time difference and fatigue, schizophrenia, panic attack, melancholia, appetite disorder, obesity, insomnia, abalienation, epilepsy, diabetes, Parkinson's disease, senile dementia, with the normal or aging relevant various disorders of pathologic, 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 embodiments 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, Agomelatine crude product can be the Agomelatine crude Compound using various prior art to prepare, such as: react with 7-methoxyl group-1-tetralone and acetonitrile lithium, product is through dehydrogenation, tosic acid dehydration aromizing, obtain naphthalene acetonitrile, Lithium Aluminium Hydride reduces afterwards and the product of excess acetyl chloride gained; Agomelatine crude product also can be existing agomelatine crystal form in various prior art.
In the following embodiments, purity is measured by efficient liquid-phase chromatography method, and concrete condition determination can see test example 1.
Embodiment 1
30g Agomelatine crude product, 75ml chloroform, 1g gac are joined in 250ml reaction flask, reflux is dissolved to Agomelatine, keeps backflow 10 minutes, filtered while hot.Filtrate cooling crystallization, suction filtration, filter cake 60 DEG C of drying under reduced pressure to constant weight, thus obtain the crystal of Agomelatine.Wherein, the purity of Agomelatine is 99.80%.
Embodiment 2
30g Agomelatine crude product, 60ml chloroform are joined in 250ml reaction flask, reflux is dissolved to Agomelatine, keeps backflow 10 minutes, filtered while hot.Filtrate cooling crystallization, suction filtration, filter cake 60 DEG C of drying under reduced pressure to constant weight, thus obtain the crystal of Agomelatine.Wherein, the purity of Agomelatine is 99.79%.
Embodiment 3
30g Agomelatine crude product, 90ml chloroform are joined in 250ml reaction flask, reflux is dissolved to Agomelatine, keeps backflow 10 minutes, filtered while hot.Filtrate cooling crystallization, suction filtration, filter cake 60 DEG C of drying under reduced pressure to constant weight, thus 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 250ml reaction flask, reflux is dissolved to Agomelatine, keeps backflow 10 minutes, filtered while hot.Filtrate cooling crystallization, suction filtration, filter cake carries out secondary recrystallization with 40ml chloroform, and secondary recrystallization operation comprises: reflux, filtered while hot, cooling crystallization, suction filtration, obtain filter cake; Filter cake 60 DEG C of drying under reduced pressure, thus obtain the crystal of Agomelatine.Wherein, the purity of Agomelatine is 99.90%.
Embodiment 5
Use powder x-ray diffraction to measure the agomelatine crystal form that embodiment 4 obtains, what measure employing is Cu K alpha-ray, and design parameter is: 40kV, 35mA.Obtain the powder x-ray diffraction spectrogram shown in Fig. 1.Wherein, θ angle, Prague 2, spacing d and relative intensity are as shown in table 2.
Table 2
Embodiment 6: pharmaceutical composition
The prescription of preparation 1000 tablets of tablets, every sheet 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 the thermostat container of 40 DEG C, place 20 days, studied by the stability of high performance liquid chromatography to these crystal formations.
1. sample purity measures
HPLC chromatographic condition: octadecylsilane chemically bonded silica is weighting agent; 10mM/L phosphate buffered saline buffer (sodium hydroxide regulates pH to 7.0) and acetonitrile volume ratio are that the mixing solutions of 2: 7 is as moving phase; Column temperature is 40 DEG C; Determined 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 by moving phase, respectively get 10 μ L injection liquid chromatographies, record color atlas.
2. samples contg measures
Measuring method reference sample method for detecting purity, measures by 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 than existing crystal formation advantageously, is more suitable for preparation needs in purity and stability.
Claims (5)
1. a preparation method for the crystal formation of Agomelatine, the method comprises:
1) be that the Agomelatine of 1:2 to 1:3 and chloroform reflux are dissolved to described Agomelatine by the ratio of weight/volume, filter gained solution, obtain filtrate, the unit of the ratio of wherein said weight/volume is g/ml;
2) by described filtrate cooling crystallization, then carry out suction filtration, obtain filter cake; And
3) by described filtration cakes torrefaction to constant weight,
In the powder x-ray diffraction spectrogram of the crystal formation of the Agomelatine prepared, θ angle, Prague 2, spacing d and relative intensity are as follows:
Wherein said relative intensity represents with the percentage ratio of the strongest ray.
2. preparation method according to claim 1, wherein, in step 1) in, the ratio of the weight/volume of described Agomelatine and described chloroform is 1:2.5.
3. preparation method according to claim 1, wherein, in step 3) in, described drying is drying under reduced pressure.
4. preparation method according to claim 3, wherein, described drying under reduced pressure carries out at 60 DEG C.
5. preparation method according to claim 1, wherein, in step 2) in, described filter cake chloroform is carried out second time recrystallization, and the amount of chloroform used in described second time recrystallization is the 50-100% of first time recrystallization.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210089529.6A CN103360276B (en) | 2012-03-29 | 2012-03-29 | Crystal form, preparation method and application of agomelatine, as well as medicine composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210089529.6A CN103360276B (en) | 2012-03-29 | 2012-03-29 | Crystal form, preparation method and application of agomelatine, as well as medicine composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103360276A CN103360276A (en) | 2013-10-23 |
| CN103360276B true CN103360276B (en) | 2015-02-18 |
Family
ID=49362632
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210089529.6A Expired - Fee Related CN103360276B (en) | 2012-03-29 | 2012-03-29 | Crystal form, preparation method and application of agomelatine, as well as medicine composition |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103360276B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2012
- 2012-03-29 CN CN201210089529.6A patent/CN103360276B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103360276A (en) | 2013-10-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100448843C (en) | New crystalline form v of agomelatine, a process for its preparation and pharmaceutical compositions containing it | |
| RU2593749C2 (en) | Novel cocrystals of agomelatine, synthesis method thereof and pharmaceutical compositions containing same | |
| TW200936548A (en) | New crystalline form VI of agomelatine, a process for its preparation and pharmaceutical compositions containing it | |
| SG173692A1 (en) | New crystalline form vi of agomelatine, preparation method and application thereof | |
| EP2474522A1 (en) | Agomelatine and pharmaceutical compositions thereof | |
| CN102716493A (en) | Copolymer containing amorphous agomelatine, and preparation method, pharmaceutical composition and application thereof | |
| CN102958911A (en) | Agomelatine hydrochloride hydrate and preparation thereof | |
| DK2690087T3 (en) | NEW CRYSTAL FORM VII OF AGOMELATIN, METHOD OF PREPARING AND USING THEREOF AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME | |
| AU2012231548B2 (en) | Mixed crystal agomelatine (Form-VIII), preparation method and use thereof and pharmaceutical composition containing same | |
| CN102452951B (en) | Agomelatine and pharmaceutical composition thereof | |
| CN102557979B (en) | Agomelatine crystal form, as well as preparation method, application and medicinal composition thereof | |
| CN103360276B (en) | Crystal form, preparation method and application of agomelatine, as well as medicine composition | |
| CN103690499B (en) | Stable crystalline form I agomelatine tablets and preparation method thereof | |
| NZ615714B2 (en) | Mixed crystalline form-VIII of agomelatine, its method of preparation, application and pharmaceutical use | |
| KR101007927B1 (en) | Sibutramine-L-carnitine disulfonate, process for preparing the same, and pharmaceutical composition including the same | |
| NZ615707B2 (en) | New crystalline form vii of agomelatine, preparation method and use thereof and pharmaceutical composition containing same | |
| EP2653159A1 (en) | Bromfenac organic salts and preparation method, composition and use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 100871, Beijing, Haidian District, Cheng Fu Road, No. 298, Zhongguancun Fangzheng building, 5 floor Patentee after: PEKING UNIVERSITY FOUNDER GROUP Co.,Ltd. Patentee after: PKUCARE PHARMACEUTICAL R&D CENTER Patentee after: PKU HEALTHCARE INDUSTRY Group Address before: 100871, Beijing, Haidian District, Cheng Fu Road, No. 298, Zhongguancun Fangzheng building, 5 floor Patentee before: PEKING UNIVERSITY FOUNDER GROUP Co.,Ltd. Patentee before: PKUCARE PHARMACEUTICAL R&D CENTER Patentee before: Pku Healthcare Industry Group Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20221025 Address after: 3007, Hengqin international financial center building, No. 58, Huajin street, Hengqin new area, Zhuhai, Guangdong 519031 Patentee after: New founder holdings development Co.,Ltd. Patentee after: PKUCARE PHARMACEUTICAL R&D CENTER Patentee after: Peking University Medical Management Co.,Ltd. Address before: 100871, Beijing, Haidian District, Cheng Fu Road, No. 298, Zhongguancun Fangzheng building, 5 floor Patentee before: PEKING UNIVERSITY FOUNDER GROUP Co.,Ltd. Patentee before: PKUCARE PHARMACEUTICAL R&D CENTER Patentee before: PKU HEALTHCARE INDUSTRY Group |
|
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150218 |