CN104529804A - New crystal form of agomelatine - Google Patents
New crystal form of agomelatine Download PDFInfo
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- CN104529804A CN104529804A CN201410757631.8A CN201410757631A CN104529804A CN 104529804 A CN104529804 A CN 104529804A CN 201410757631 A CN201410757631 A CN 201410757631A CN 104529804 A CN104529804 A CN 104529804A
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- agomelatine
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Abstract
The invention discloses a new crystal form of agomelatine. The X-ray diffraction spectrum (XRPD) of the crystal form has diffraction peaks at 2 theta angles of 11.86 +/-0.2, 17.59 +/- 0.2, 18.39 +/- 0.2, 19.71 +/- 0.2, 20.49 +/- 0.2, 21.87 +/- 0.2, 22.60 +/- 0.2, 22.97 +/- 0.2, 23.97 +/- 0.2, 24.58 +/- 0.2, 25.34 +/- 0.2, 27.12 +/- 0.2, 29.80 +/- 0.2, 30.30 +/- 0.2, 31.30 +/- 0.2, 31.98 +/- 0.2 and 40.55 +/- 0.2. The new crystal form of agomelatine disclosed by the invention is simple to prepare, good in reproducibility and good in fluidity, and the bulk density is greatly improved.
Description
Technical field
The invention belongs to drug crystal forms technical field, new crystal relating to Agomelatine and preparation method thereof, and the drug component comprising agomelatine crystal form.
Background technology
The chemistry of Agomelatine (agomelatine) is called N-[2-(7-methoxy-1-naphthyl) ethyl] ethanamide, this compound has good pharmacological property, is the new class antidepressant and anxiolytic that have French Seville (Servier) company to develop.
This compound is not only melatonin (melatonin, MT) receptor stimulant, is also serotonin (5-HT) 2C receptor antagonist simultaneously.Therefore, it is possible to effectively treat major depression's disease, especially evident in efficacy to major depressive disorder (MMD), in addition, can also improving water flood parameter and retentivity function.
Agomelatine chemical structure is disclosed and as purposes such as antianxiety agent, antidepressive and antipsychotic drugs in patent EP0447285.
The most compounds of current discovery has two kinds or two or more crystal formations, namely different lattice arrangement, and this phenomenon is referred to as polytropism.Same medicine, crystal formation is different, and its bioavailability also may exist difference, and its stability, mobility, compressibility also may be different in addition, and these physico-chemical properties can produce certain impact to the application of medicine.
Give in patent CN101921205A and Agomelatine is heated then cooling crystallization in acid amides and water mixed solvent, filtration drying obtains crystal formation I.Its PXRD characteristic peak collection of illustrative plates is listed in the table below:
The method preparing agomelatine crystal form II with ethanol and water mixed solvent is given in patent CN101041629A.
After giving melting in patent CN1907959A, the mode of Slow cooling prepares the method for crystalline form III.
Cool fast between 50 to 70 DEG C after giving melting in patent CN1907957A, and within about 5 hours, prepare crystalline form IV 70 DEG C of maintenances.
Crystalline form V is obtained by " high energy " mechanical mill in patent CN1907958A.This patent give also another kind of preparation method simultaneously, namely puts after melting to room temperature and adds a small amount of freshly prepd crystalline form V, and cooling is until crystallization completes.
Be cooled to rapidly 0 DEG C, after vacuum filtration after being heated under boiling state by the isopropyl ether solution of Agomelatine in patent CN101429134A, finally obtain crystal formation VI.This patent give also another kind of preparation method, namely under room temperature, high pressure by Agomelatine crystallization 24 hours in ethanol/water (volume ratio 1:1) mixed solvent.
CN101704763 describes Agomelatine and is dissolved in solvent alcohol, acid amides, and adding water after ketone or nitrile obtains crystal formation I.
CN101643432 describes Agomelatine and is dissolved in ethanol and isopropyl ether, and spraying dry obtains crystal form V method.
In above-mentioned preparation method, some is comparatively loaded down with trivial details, some poor reproducibility, some obtained product mobility, poor stability, there is no advantage to next step preparation prescription research.
Summary of the invention
The present inventor has found the new crystal of the Agomelatine being different from bibliographical information in research process, and this New crystal form of agomelatine product particle is large, good fluidity, and its preparation method is simple, has circulation ratio.
Another object of the present invention is to provide a kind of preparation method of New crystal form of agomelatine.
Another object of the present invention is the composition and use thereof providing a kind of New crystal form of agomelatine.
Object of the present invention can be reached by following measures:
A kind of new crystal of Agomelatine, its X-ray diffracting spectrum (XRPD uses Cu-Ka radiation) is that 11.86 ± 0.2,17.59 ± 0.2,18.39 ± 0.2,19.71 ± 0.2,20.49 ± 0.2,21.87 ± 0.2,22.60 ± 0.2,22.97 ± 0.2,23.97 ± 0.2,24.58 ± 0.2,25.34 ± 0.2,27.12 ± 0.2,29.80 ± 0.2,30.30 ± 0.2,31.30 ± 0.2,31.98 ± 0.2 and 40.55 ± 0.2 places have diffraction peak at 2 θ angles.
Further, the new crystal of this Agomelatine uses Cu-Ka radiation, and it is with the position of diffraction peak (2 θ represent to spend), spacing
the X-ray powder diffraction parameter that the relative intensity (I represents with per-cent %) at peak represents is as following table 1.
The characteristic peak parameter of the X-ray powder diffraction pattern of table 1 New crystal form of agomelatine
Also the crystal of 2 θ angle coincidence loss scopes within ± 0.2 ° at diffractive features peak is comprised.
The new crystal of Agomelatine of the present invention, in its X-ray diffracting spectrum, the relative peak intensities of each diffraction peak does not depart from relative peak intensities more than 20% in collection of illustrative plates shown in accompanying drawing 1.
Further, the X-ray diffracting spectrum (XRPD collection of illustrative plates) of the new crystal of Agomelatine of the present invention is substantially as Fig. 1.
New crystal form of agomelatine even particle size distribution of the present invention, size distribution curve is normal state unimodal distribution, and granularity is large, and main granularity is more than 100 μm.
Because purposes is different, also different to the specification of quality of Agomelatine, especially different to the requirement of bulk density.Such as, when being used as excipient substance or healthcare products prepare tablet or capsule, if bulk density is little, then poor fluidity, causes the content uniformity of the weight difference XOR capsule of tablet to become large, affects quality product.Relative to the agomelatine crystal form of prior art, New crystal form of agomelatine of the present invention has the bulk density significantly improved, and also has good mobility simultaneously.
A kind of preparation method of New crystal form of agomelatine of the present invention is: after being mixed with mixed solvent by Agomelatine, heating for dissolving, then fast cooling crystallization and get final product; Wherein said mixed solvent is alcohol organic solvent and ether organic solvent.
The another kind of preparation method of New crystal form of agomelatine of the present invention is: Agomelatine is placed in crystallization kettle, adds the mixed solvent of alcohols and ether organic solvent, heating for dissolving, then fast cooling crystallization, filters, vacuum-drying.
In preparation method, raw material Agomelatine can be amorphous or crystalline form, and a preferred embodiment of the present invention raw material is agomelatine crystal form II.
In preparation method, alcohol organic solvent is selected from propyl alcohol, Virahol, propyl carbinol, one or more in amylalcohol etc.; Be preferably Virahol or propyl carbinol.
Wherein ether organic solvent is selected from ether, methyl tertiary butyl ether, one or more in isopropyl ether; ; Be preferably methyl tertiary butyl ether.
The consumption of alcohol organic solvent is 2ml ~ 5ml/g Agomelatine, preferred 2ml ~ 3.3ml/g Agomelatine.
The consumption of ether organic solvent is 2ml ~ 10ml/g Agomelatine, preferred 5ml ~ 7ml/g Agomelatine.
Wherein Heating temperature is 35 DEG C ~ 70 DEG C; Preferably at 45 DEG C ~ 60 DEG C.
Recrystallization temperature of wherein lowering the temperature is at 0 DEG C ~-20 DEG C; Preferably at 0 DEG C ~-10 DEG C.
Cooling recrystallization temperature is at 0 DEG C ~-10 DEG C, and the crystallization time is 2 ~ 12 hours; Preferably at 4 ~ 6 hours.
Can filter after cooling crystallization and carry out vacuum-drying, wherein vacuum-drying temperature is at 30 DEG C ~ 50 DEG C; Be preferably at 40 DEG C.
The present invention also comprises the pharmaceutical composition containing New crystal form of agomelatine, particularly comprises the composition of New crystal form of agomelatine and pharmaceutical carrier.
Pharmaceutical composition of the present invention is any formulation that can be medicinal.Preferred oral formulation.Particularly preferably be tablet, capsule, granule, oral liquid.Pharmaceutical composition of the present invention, can prepare according to the routine techniques of pharmaceutics, and as by New crystal form of agomelatine and pharmaceutical carrier mixing, by particle processed, tablet, the method such as encapsulated is prepared into oral drug preparation.
Described pharmaceutical carrier comprise be selected from following vehicle one or more: meglumine, N.F,USP MANNITOL, sorbyl alcohol, Sodium Pyrosulfite, sodium bisulfite, Sulfothiorine, cysteine hydrochloride, Thiovanic acid, methionine(Met), vitamins C, EDETATE SODIUM, Ethylenediaminetetraacetic Acid Calcium Salt, the alkali-metal carbonate of monovalence, acetate, phosphoric acid salt or its aqueous solution, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acid, sodium-chlor, Repone K, Sodium.alpha.-hydroxypropionate, Xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, ethanol, Sucralose, citric acid, silicon derivative, cellulose and its derivates, alginate, gelatin, polyvinylpyrrolidone, glycerine, POLYSORBATE 80, agar, calcium carbonate, Calcium hydrogen carbonate, tensio-active agent, polyoxyethylene glycol, cyclodextrin, beta-cyclodextrin, phospholipid material, kaolin, talcum powder, calcium stearate, Magnesium Stearate, essence, Microcrystalline Cellulose, N.F,USP MANNITOL, hydroxypropylcellulose, sodium starch glycolate.
The preparation method of above-mentioned preparation normally those skilled in that art knows conventional method.
The invention still further relates to the purposes of crystal formation in the medicine manufacturing the following illness for the treatment of of above-mentioned Agomelatine: nervous, tired, sleep disordered and anxiety, severe depression, seasonal affective disorder, cardiovascular disorder, digestive system, the insomnia caused by the time difference and fatigue, schizophrenia, panic attack, melancholia, appetite disorder, obesity, insomnia, pain, 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 and cerebral circulation disorder, melatonin dysfunction, sexual dysfunction, immune dysfunction, ovulation suppresses and cancer.
New crystal form of agomelatine preparation of the present invention is simple, and favorable reproducibility, has the bulk density significantly improved, and also has good mobility simultaneously, is suitable for making various specific Agomelatine preparation.
Accompanying drawing explanation
Accompanying drawing 1 is the XRPD collection of illustrative plates of New crystal form of agomelatine;
Accompanying drawing 2 is form under the microscope of New crystal form of agomelatine;
Accompanying drawing 3 is form (× 300) under the scanning electronic microscope of New crystal form of agomelatine;
Accompanying drawing 4 is form (× 500) under the scanning electronic microscope of New crystal form of agomelatine;
Accompanying drawing 5 Agomelatine raw material (crystal form II) grain size distribution (PSD);
Accompanying drawing 6 agomelatine crystal form I grain size distribution (PSD);
Accompanying drawing 7 New crystal form of agomelatine size distribution (PSD).
Embodiment
Further illustrate the present invention below by several specific embodiment, the concrete data related to and operation etc. are not formed to the restriction of application claims protection domain in embodiment.
The preparation of embodiment 1. New crystal form of agomelatine
Take 3.00g Agomelatine (crystal form II, lower same) be placed in crystallization kettle, add 10ml Virahol and 20ml methyl tertiary butyl ether, be heated to 60 DEG C, be stirred to solid to dissolve completely, elimination insolubles, fast cooling to 0 ~-10 DEG C, crystallize out, obtains white powder after filtration, vacuum-drying.
The preparation of embodiment 2. New crystal form of agomelatine
Take 3.00g Agomelatine and be placed in crystallization kettle, add 8ml Virahol and 16ml methyl tertiary butyl ether, be heated to 45 DEG C, be stirred to solid to dissolve completely, elimination insolubles, fast cooling to 0 ~-10 DEG C, crystallize out, obtains white powder after filtration, vacuum-drying.
The preparation of embodiment 3. New crystal form of agomelatine
Take 3.00g Agomelatine and be placed in crystallization kettle, add 10ml propyl carbinol and 20ml methyl tertiary butyl ether, be heated to 40 DEG C, be stirred to solid to dissolve completely, elimination insolubles, fast cooling to 0 ~-10 DEG C, crystallize out, obtains white powder after filtration, vacuum-drying.
The preparation of embodiment 4 agomelatine crystal form I
Prepare agomelatine crystal form I according to Chinese patent CN101921205, the X-ray powder diffraction pattern of this sample is consistent with diffraction angle in patent and relative intensity.
Embodiment 5
The size distribution of New crystal form of agomelatine sample and raw material in agomelatine crystal form I, embodiment 3 in embodiment 4 is contrasted
By Malvern ParticleSizer, in dispersion agent water, the stirring velocity of 2000rpm is adopted to carry out the size distribution contrast of obtained sample.Its result is respectively accompanying drawing 5,6 and 7, the result obtained is arranged in table 1.
Table 1 each sample size-grade distribution D10, D50 and D90 compare
| Sample | D10(μm) | D50(μm) | D90(μm) |
| Raw material (crystal form II) | 25.10 | 89.30 | 341.92 |
| Crystalline form I | 6.54 | 18.07 | 41.14 |
| New crystal | 116.7 | 219.2 | 371.2 |
Embodiment 6
The slope of repose of agomelatine crystal form I in New crystal form of agomelatine sample, raw material (crystal form II) and embodiment 4 in embodiment 3 and bulk density are contrasted
Fixed funnel method measures slope of repose.Be fixed on certain altitude H by funnel, powder is placed in funnel, and it is in heaps to be that nature flows down, and to hopper outlet is just removed in the top of cone, measures the radius r of circular cone bottom surface, calculates slope of repose.Slope of repose=arc tg (H/r).Measuring result arranges in table 2.
Table 2
| Sample | Slope of repose (°) | Bulk density (g/ml) |
| Raw material (crystal form II) | 45.31 | 0.411 |
| Crystalline form I | 39.20 | 0.166 |
| New crystal | 21.50 | 0.644 |
Result shows, crystal formation of the present invention has less slope of repose, higher bulk density relative to Agomelatine (crystal form II, crystal formation I), illustrates that the mobility of crystal formation of the present invention is higher.
Claims (10)
1. a new crystal for Agomelatine, is characterized in that its X-ray diffracting spectrum (XRPD) is that 11.86 ± 0.2,17.59 ± 0.2,18.39 ± 0.2,19.71 ± 0.2,20.49 ± 0.2,21.87 ± 0.2,22.60 ± 0.2,22.97 ± 0.2,23.97 ± 0.2,24.58 ± 0.2,25.34 ± 0.2,27.12 ± 0.2,29.80 ± 0.2,30.30 ± 0.2,31.30 ± 0.2,31.98 ± 0.2 and 40.55 ± 0.2 places have diffraction peak at 2 θ angles.
2. the new crystal of Agomelatine according to claim 1, is characterized in that its X-ray diffracting spectrum (XRPD) characteristic peak parameter is as follows:
Also the crystal of 2 θ angle coincidence loss scopes within ± 0.2 ° at diffractive features peak is comprised.
3. the new crystal of Agomelatine according to claim 1 and 2, in its X-ray diffracting spectrum, the relative peak intensities of each diffraction peak does not depart from relative peak intensities more than 20% in collection of illustrative plates shown in accompanying drawing 1.
4. the new crystal of Agomelatine according to claim 1 and 2, its X-ray diffracting spectrum is substantially as Fig. 1.
5. the preparation method of the New crystal form of agomelatine described in claim 1 or 2, after it is characterized in that Agomelatine to mix with mixed solvent, heating for dissolving, then fast cooling crystallization and get final product; Wherein said mixed solvent is alcohol organic solvent and ether organic solvent.
6. preparation method according to claim 5, is characterized in that one or more that described alcohol organic solvent is selected from propyl alcohol, Virahol, propyl carbinol and amylalcohol; Described ether organic solvent is selected from one or more in ether, methyl tertiary butyl ether or isopropyl ether.
7. the preparation method according to claim 5 or 6, is characterized in that the consumption of alcohol organic solvent is 2ml ~ 5ml/g Agomelatine, and the consumption of described ether organic solvent is 2ml ~ 10ml/g Agomelatine.
8. the preparation method according to claim 5 or 6, is characterized in that the temperature of heating for dissolving is 35 DEG C ~ 70 DEG C; Cooling recrystallization temperature is at 0 DEG C ~-20 DEG C; Cooling crystallization after filter and through vacuum-drying, wherein vacuum-drying temperature is 30 DEG C ~ 50 DEG C.
9. a pharmaceutical composition, it comprises New crystal form of agomelatine according to claim 1 and pharmaceutical carrier.
10. the application of New crystal form of agomelatine according to claim 1 in the following disease medicament of preparation treatment: nervous, tired, sleep disordered and anxiety, severe depression, seasonal affective disorder, cardiovascular disorder, digestive system, the insomnia caused by the time difference and fatigue, schizophrenia, panic attack, melancholia, appetite disorder, obesity, insomnia, pain, 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 and cerebral circulation disorder, melatonin dysfunction, sexual dysfunction, immune dysfunction, ovulation suppresses or cancer.
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| US20100076088A1 (en) * | 2005-03-08 | 2010-03-25 | Les Laboratoires Servier | Crystalline form IV of agomelatine, a process for its preparation and pharmaceutical compositions containing it |
| CN101723844A (en) * | 2009-11-21 | 2010-06-09 | 浙江华海药业股份有限公司 | Agomelatine crystal form B, preparation method thereof and medicinal composition containing same |
| CN101781225A (en) * | 2009-11-21 | 2010-07-21 | 浙江华海药业股份有限公司 | Preparation method of agomelatine crystal form A |
| WO2011054917A1 (en) * | 2009-11-09 | 2011-05-12 | Ratiopharm Gmbh | Process for the production of polymorph form i of agomelatine |
| CN102690209A (en) * | 2011-03-23 | 2012-09-26 | 上海医药工业研究院 | Mixed crystal of agomelatine (form-VIII), preparation method and application thereof and pharmaceutical composition containing the same |
| CN103804212A (en) * | 2013-10-31 | 2014-05-21 | 四川奥邦药业有限公司 | Method for preparing high-yield and high-purity agomelatine crystal I |
-
2014
- 2014-12-11 CN CN201410757631.8A patent/CN104529804A/en active Pending
Patent Citations (6)
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| US20100076088A1 (en) * | 2005-03-08 | 2010-03-25 | Les Laboratoires Servier | Crystalline form IV of agomelatine, a process for its preparation and pharmaceutical compositions containing it |
| WO2011054917A1 (en) * | 2009-11-09 | 2011-05-12 | Ratiopharm Gmbh | Process for the production of polymorph form i of agomelatine |
| CN101723844A (en) * | 2009-11-21 | 2010-06-09 | 浙江华海药业股份有限公司 | Agomelatine crystal form B, preparation method thereof and medicinal composition containing same |
| CN101781225A (en) * | 2009-11-21 | 2010-07-21 | 浙江华海药业股份有限公司 | Preparation method of agomelatine crystal form A |
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| CN103804212A (en) * | 2013-10-31 | 2014-05-21 | 四川奥邦药业有限公司 | Method for preparing high-yield and high-purity agomelatine crystal I |
Non-Patent Citations (2)
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| 孙莉莉 等: "阿戈美拉汀的多晶型研究", 《华西药学杂志》, vol. 27, no. 5, 15 October 2012 (2012-10-15), pages 533 - 536 * |
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Application publication date: 20150422 |