CN102206864A - Agomelatine monocrystal with agomelatine VI crystal form, agomelatine mixed crystal with the agomelatine VI crystal form and preparation methods - Google Patents
Agomelatine monocrystal with agomelatine VI crystal form, agomelatine mixed crystal with the agomelatine VI crystal form and preparation methods Download PDFInfo
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Abstract
The invention discloses an agomelatine monocrystal with an agomelatine VI crystal form and a preparation method thereof, wherein the agomelatine VI crystal form is a novel crystal form of agomelatine. The invention also provides an agomelatine mixed crystal with the agomelatine VI crystal form and a preparation method thereof. The agomelatine mixed crystal has good effects of treating depression and anxiety. The invention further provided an application of the agomelatine mixed crystal with the agomelatine VI crystal form and an agomelatine II crystal form for preparations of medicines for treating cancers. The beneficial effects of the invention comprise providing an agomelatine monocrystal with agomelatine VI crystal form, an agomelatine mixed crystal with the agomelatine VI crystal form and an agomelatine II crystal form, and their preparation methods, wherein the agomelatine mixed crystal is superior to the agomelatine monocrystal in terms of dissolution rate and bioavailability. In addition, the agomelatine mixed crystal has a long-time stability and is suitable for storage without especial equipment, thus the agomelatine mixed crystal has an important superiority in a pharmacy industry.
Description
Technical field
The present invention relates to the crystal formation preparation of Agomelatine, the single crystal structure of Agomelatine VI crystal formation especially is provided, the mix crystal formation of Agomelatine VI crystal formation with Agomelatine II crystal formation also disclosed simultaneously, and their preparation method and the content assaying method of mixed crystal are provided, have belonged to the chemicals preparing technical field.
Background technology
Agomelatine that the present invention relates to (agomelatine) or N-[2-(7-methoxyl group-1-naphthyl) ethyl] ethanamide, has good pharmacological property, execute new class thymoleptic and the anxiolytic that only refined (Servier) company develops by France, its structure is as follows:
Discover that Agomelatine has dual characteristic, it is the agonist of melatonin energy system acceptor, is again 5-HT
2cThe antagonist of acceptor.Just because of this dual nature, make it in central nervous system, have good activity, of particular concern is it in severe depression, seasonal affective disorder, somnopathy, cardiovascular disorder, digestive system, the activity in the insomnia that jet lag causes and fatigue, limited appetite and the obesity treatment.
European patent EP 0447285 discloses the Preparation method and use of Agomelatine.
In view of the pharmaceutical use of this compound, the form that obtains splendid purity and favorable reproducibility is very important, and this form all demonstrates valuable characteristic at aspects such as stripping and preparations, and temperature, humidity or oxygen etc. are not had particular requirement.
Of equal importance is to obtain having well-defined crystal formation, and reproducibility is good, filter and Agomelatine that easily formation aspect has valuable characteristic.
As everyone knows, most compounds can two or more crystalline states exist, and this is the instinct of material.The molecule that structure is identical crystallizes into different solid forms, is called the polymorphism material.Different crystal has different lattice energies, and it shows the physicals of the good and favorable reproducibility of purity when solid-state thus.
At present, Agomelatine II crystal formation has had bibliographical information, but the mixed crystal of the monocrystalline of Agomelatine VI crystal formation and Agomelatine II crystal formation and VI crystal formation yet there are no bibliographical information.
Summary of the invention
The invention provides a kind of Agomelatine VI crystal formation monocrystalline and preparation method, be the new crystal formation of a kind of Agomelatine.
What the present invention also provided Agomelatine VI crystal formation and Agomelatine VI crystal formation mixes crystal formation and preparation method, has the depressed and anti-burnt disease of treatment and well acts on.
The present invention further provides the purposes of mixed crystal in preparation treatment cancer drug of Agomelatine VI crystal formation and Agomelatine II crystal formation.
, the invention provides a kind of Agomelatine VI crystal formation monocrystalline, structure iron is as follows:
It is characterized in that characterizing as follows:
-orthorhombic lattice;
-lattice parameter: a=31.4306, b=9.4936, c=17.7282, α=β=γ=90.000 °;
-spacer: Pca2 (1);
Molecule number in the-unit cell: 16;
-unit cell volume: V
Unit cell=5289.91
3
-density: d=1.222g/cm
3
, Agomelatine of the present invention the preparation method of VI crystal formation monocrystalline, it is characterized in that:
The Agomelatine powder dissolution of 0.02mmol in the 0.07mol isopropyl ether, is positioned in the bottle, and bottleneck is with sealing film phonograph seal, an aperture is opened in the centre, room temperature is placed, the crystal of several needle point sizes of 2 weeks back bottle end appearance, and this crystal is the VI crystal formation monocrystalline of Agomelatine.
, the II crystal formation of Agomelatine of the present invention and the mixed crystal type of VI crystal formation, it is characterized in that weight percent is:
The II crystal formation 93%-99% of Agomelatine, the VI crystal formation 7%-1% of Agomelatine.
, above-mentioned II crystal formation and VI crystal formation mixed crystal type, preferred weight percent is:
The VI crystalline form of 5 % of the II crystal formation 95% of Agomelatine, Agomelatine.
Be characterized by:
1) infrared spectrum characterization: 3249cm
-1, 3068 cm
-1, 1640 cm
-1, 1624 cm
-1, 1509 cm
-1, 1432 cm
-1, 1252 cm
-1, 1212 cm
-1, 1028 cm
-1, 827 cm
-1, 834 cm
-1, 759 cm
-1, 700 cm
-1, 609 cm
-1
2) the X-ray powder diffraction characterizes (2 θ value): 9.355,17.288,18.673,19.868,22.210,24.312,25.506.
3) fusing point: 99.83,110.83.
, Agomelatine II crystal formation of the present invention and VI crystal formation the preparation method of mixed crystal type:
The II crystal formation of 93%-99% Agomelatine is mixed with the VI crystal formation of 7%-1% Agomelatine, and 20～80 ℃ of rotation 1h that reduce pressure down make its uniform mixing.
The advantage that obtains mixed crystal is that it allows preparation to have the pharmaceutical preparation of consistent and reproducible composition, and it has fabulous stability as time goes by.
Below test shows pharmacotoxicological effect of the present invention
Test example 1
Pharmacokinetics is measured
Human volunteer is carried out random packet, per 5 volunteers take the tablet of case 6-8, every volunteer was carried out Agomelatine in 0,2,4,6,8,10,12,14,16,18,20,22,24 hour and detect taking the back, write down the maximum plasma concentration (Cmax of this activeconstituents, ng/ml), and Plasma Concentration (AUC, ng.h/ml), Cmax and AUC value of each group see the following form to the area under curve of time.
Above result shows that the technical scheme of claim 3 of the present invention or 4 has and the corresponding to bioequivalence of disclosed case study on implementation, and when the ratio of mixed crystal is the II crystal formation 95% of an Agomelatine best results during with VI crystalline form of 5 %, satisfied the requirement of preparation process, solved the dissolution rate problem of Agomelatine different crystal forms simultaneously, produced a desired effect.
Test example 2
Biological activity test
Adopt HL-60 human leukemia cell line and the strain of Hela human cervical carcinoma cell, go down to posterity, in the animal cell culture case, cultivate with the RPMI-1640 substratum (every milliliter contains 100 microgram Streptomycin sulphates and 100 microgram penicillin respectively) of 10% foetal calf serum.
A. JEG-3: HL-60 human leukemia
Testing method: tetramethyl-azo azoles salt (MTT) method
Test drug: embodiment 3 mixed crystal
Drug level: 2.5 μ g, 5 μ g
Result: cell proliferation inhibition rate 72%, 82%.
B. JEG-3: Hela human cervical carcinoma
Testing method: srb assay
Test drug: embodiment 3 mixed crystal
Drug level: 2.5 μ g, 5 μ g
Result: cell proliferation inhibition rate 62%, 78%.
The result shows that this mixed crystal has restraining effect to the growth of cancer cells, and its raw material is easy to get, and technology is simple, and is safe, can prepare the medicine for the treatment of cancer.
Mixed crystal form to acquisition like this, pharmaceutical research has shown that it has significant activity in the central nervous system microcirculqtory system of unifying, thus the mixed crystal that can affirm Agomelatine to can be used for treatment nervous, somnopathy, anxiety disorder, severe depression, seasonal affective disorder, cardiovascular disorder, digestive system, it is blind and tired that the time difference causes, schizophrenia, phobia, melancholia, appetite disorder, obesity, blind disease, psychiatric disorder, epilepsy, diabetes, parkinsonism, senile dementia, with the normal or aging relevant various diseases of pathologic, migraine, amnesia, Alzheimer, the brain circulatory diseases.
The mixed crystal of Agomelatine is preferred for treating insomnia and fatigue, appetite disorder and obesity that severe depression, seasonal affective disorder, somnopathy, cardiovascular disorder, the time difference cause.
The invention still further relates to pharmaceutical composition, comprise 95% II crystal formation of Agomelatine and 5% VI crystal formation, also comprise two or more inertia, the vehicle of safety simultaneously as active ingredient.In pharmaceutical composition of the present invention, use be more suitable oral, without digestive tube injection or tablet or coated tablet, particle, Sublingual tablet, capsule, suppository, emulsion, ointment by intranasal administration, be coated with skin glue, injection formulations, oral liquid.
Mixed crystal type with Agomelatine II crystal formation provided by the present invention and VI crystal formation is used for pharmaceutical compositions, is made up of following composition and weight percent:
20% Agomelatine II crystal formation, 1.05% Agomelatine VI crystal formation, 51.95% lactose, 20% starch slurry, 6% cross-linked carboxymethyl cellulose sodium, 1% Magnesium Stearate.
Positively effect of the present invention is: the mixed crystal and the preparation method of monocrystalline, Agomelatine II crystal formation and the VI crystal formation of Agomelatine VI crystal formation are provided, and described mixed crystal is demonstrating aspect stripping and the bioavailability than the better characteristic of single crystal form.In addition, this mixed crystal has the stability of highly significant as time goes by, allows its optimum storage and need not special equipment, and this occupies important advantage in pharmaceutical industry.
Description of drawings:
Fig. 1 is Agomelatine II crystal formation 95% and VI crystalline form of 5 % mixed crystal X-ray powder diffraction;
Fig. 2 is Agomelatine II crystal formation 95% and VI crystalline form of 5 % mixed crystal infrared spectra;
Fig. 3 is Agomelatine II crystal formation 95% and VI crystalline form of 5 % mixed crystal DSC collection of illustrative plates;
Fig. 4 is an Agomelatine mixed crystal content standard graphic representation;
Fig. 5 is that Agomelatine mixed crystal peak area ratio (A6/2) is to the weight percent graphic representation.
Concrete case study on implementation
Following examples are only with helping understand the present invention, and are not to be used for also should not being interpreted as the restriction of by any way listed claim being invented.
Embodiment 1:
The mixed crystal of II crystal formation of Agomelatine (the crystal formation weight percent is 99%) and VI crystal formation (the crystal formation weight percent is 1%):
Take by weighing the II crystal formation of 0.1g Agomelatine VI crystal formation and 9.9g Agomelatine, its mixing is placed in the round-bottomed bottle of 100ml, 20～80 ℃ of rotation 1h that reduce pressure down make its uniform mixing.
The X-ray powder diffraction characterizes (2 θ value): 9.323,17.268,18.671,19.868,22.211,24.314,25.506.
Infrared spectra: 3246cm
-1, 30628 cm
-1, 1638 cm
-1, 1623 cm
-1, 1509 cm
-1, 1432 cm
-1, 1252 cm
-1, 1211 cm
-1, 1024 cm
-1, 827 cm
-1, 833 cm
-1, 755 cm
-1, 700 cm
-1, 605 cm
-1
Fusing point: 99.81 ℃, 110.69 ℃.
Embodiment 2:
The mixed crystal of II crystal formation of Agomelatine (the crystal formation weight percent is 97%) and VI crystal formation (the crystal formation weight percent is 3%):
Take by weighing the II crystal formation of 0.3g Agomelatine VI crystal formation and 9.7g Agomelatine, its mixing is placed in the round-bottomed bottle of 100ml, 20～80 ℃ of rotation 1h that reduce pressure down make its uniform mixing.
The X-ray powder diffraction characterizes (2 θ value): 9.353,17.268,18.683,19.863,22.110,24.310,25.505.
Infrared spectra: 3247cm
-1, 3063 cm
-1, 1640 cm
-1, 1624 cm
-1, 1509 cm
-1, 1432 cm
-1, 1252 cm
-1, 1212 cm
-1, 1022 cm
-1, 827 cm
-1, 835 cm
-1, 759 cm
-1, 700 cm
-1, 608 cm
-1
Fusing point: 99.73 ℃, 110.03 ℃.
Embodiment 3:
The mixed crystal of II crystal formation of Agomelatine (the crystal formation weight percent is 95%) and VI crystal formation (the crystal formation weight percent is 5%):
Take by weighing the II crystal formation of 0.5g Agomelatine VI crystal formation and 9.5g Agomelatine, its mixing is placed in the round-bottomed bottle of 100ml, 20～80 ℃ of rotation 1h that reduce pressure down make its uniform mixing.
The X-ray powder diffraction characterizes (2 θ value): 9.355,17.288,18.673,19.868,22.210,24.312,25.506.(see figure 1)
Infrared spectra: 3249cm
-1, 3068 cm
-1, 1640 cm
-1, 1624 cm
-1, 1509 cm
-1, 1432 cm
-1, 1252 cm
-1, 1212 cm
-1, 1028 cm
-1, 827 cm
-1, 834 cm
-1, 759 cm
-1, 700 cm
-1, 609 cm
-1(see figure 2)
Fusing point: 99.83 ℃, 110.83 ℃.(see figure 3)
Embodiment 4:
The mixed crystal of II crystal formation of Agomelatine (the crystal formation weight percent is 93%) and VI crystal formation (the crystal formation weight percent is 7%):
Take by weighing the II crystal formation of 0.7g Agomelatine VI crystal formation and 9.3g Agomelatine, its mixing is placed in the round-bottomed bottle of 100ml, 20～80 ℃ of rotation 1h that reduce pressure down make its uniform mixing.
The X-ray powder diffraction characterizes (2 θ value): 9.345,17.298,18.672,19.768,22.211,24.3132,25.516.
Infrared spectra: 3239cm
-1, 3068 cm
-1, 1641 cm
-1, 1642 cm
-1, 1509 cm
-1, 1432 cm
-1, 1252 cm
-1, 1212 cm
-1, 1028 cm
-1, 827 cm
-1, 834 cm
-1, 759 cm
-1, 710 cm
-1, 608 cm
-1
Fusing point: 99.77 ℃, 110.53 ℃.
Embodiment 5:
Pharmaceutical composition: 21.05g Agomelatine II crystal formation and 51.95g lactose, 20g starch slurry, 3g cross-linked carboxymethyl cellulose sodium are progressively increased and mix, and the system softwood is granulated, drying, whole grain adds 3g cross-linked carboxymethyl cellulose sodium and 1g Magnesium Stearate, compressing tablet gets 842, the 25mg/ sheet.
Embodiment 6:
Pharmaceutical composition: 21.05g Agomelatine VI crystal formation and 51.95g lactose, 20g starch slurry, 3g cross-linked carboxymethyl cellulose sodium are progressively increased and mix, and the system softwood is granulated, drying, whole grain adds 3g cross-linked carboxymethyl cellulose sodium and 1g Magnesium Stearate, compressing tablet gets 842, the 25mg/ sheet.
Embodiment 7:
Pharmaceutical composition: 10g embodiment 1 gained mixed crystal and 24.68g lactose, 9.5g starch slurry, 1.42g cross-linked carboxymethyl cellulose sodium are progressively increased and mix, and the system softwood is granulated, drying, whole grain adds 1.43g cross-linked carboxymethyl cellulose sodium and 0.48g Magnesium Stearate, compressing tablet gets 400, the 25mg/ sheet.
Embodiment 8:
Pharmaceutical composition: 10g embodiment 2 gained mixed crystal and 24.68g lactose, 9.5g starch slurry, 1.42g cross-linked carboxymethyl cellulose sodium are progressively increased and mix, and the system softwood is granulated, drying, whole grain adds 1.43g cross-linked carboxymethyl cellulose sodium and 0.48g Magnesium Stearate, compressing tablet gets 400, the 25mg/ sheet.
Embodiment 9:
Pharmaceutical composition: 10g embodiment 3 gained mixed crystal and 24.68g lactose, 9.5g starch slurry, 1.42g cross-linked carboxymethyl cellulose sodium are progressively increased and mix, and the system softwood is granulated, drying, whole grain adds 1.43g cross-linked carboxymethyl cellulose sodium and 0.48g Magnesium Stearate, compressing tablet gets 400, the 25mg/ sheet.
Embodiment 10:
Pharmaceutical composition: 10g embodiment 4 gained mixed crystal and 24.68g lactose, 9.5g starch slurry, 1.42g cross-linked carboxymethyl cellulose sodium are progressively increased and mix, and the system softwood is granulated, drying, whole grain adds 1.43g cross-linked carboxymethyl cellulose sodium and 0.48g Magnesium Stearate, compressing tablet gets 400, the 25mg/ sheet.
Embodiment 11:
The case study on implementation of being announced with patent CA2558782 is embodiment as a comparison
19.23g Agomelatine II crystal formation and 47.62g lactose, 23.04g Mierocrystalline cellulose hydroxyl ethyl ester sodium are progressively increased and mix, and are 30 POVIDONE K 30 BP/USP 30 solution that solvent is prepared 50% concentration with water, as tackiness agent, and the system softwood, drying, whole grain adds 0.23gSiO
2, 2.00g stearic acid and 1.00g Magnesium Stearate, compressing tablet gets 769, the 25mg/ sheet.
Embodiment 12:
Mixed crystal content standard (xrd method)
Select 25.496 place's characteristic peaks of VI crystal formation and 22.225 place's characteristic peaks of II crystal formation for use, two peak angle values differ bigger, and the symmetry at peak is good, and angle value meets and chooses requirement near 20-25.
With two peak intensities ratio is X-coordinate, and percentage composition is an ordinate zou, is figure according to principle of least square method and sees Fig. 4.
Case study on implementation 13:
Mixed crystal content standard (DSC method)
II crystal formation and VI crystal formation fusing point differ bigger, and the fusing point of II crystal formation is 109 ~ 111 ℃, and the fusing point of VI crystal formation is 99-101 ℃, the fusing point difference, and the heat that is absorbed during heat fused is also different, thereby causes the area of absorption peak not wait.Accurately take by weighing the mixed crystal of the different proportionings of equivalent (1% ~ 5%), calculate the peak area ratio of each ratio,, to weight percent (X6/2) mapping, see Fig. 5 with peak area ratio (A6/2) according to principle of least square method:
Claims (6)
1. the VI crystal formation monocrystalline of an Agomelatine, structure iron is as follows:
It is characterized in that characterizing as follows:
-orthorhombic lattice;
-lattice parameter: a=31.4306, b=9.4936, c=17.7282, α=β=γ=90.000 °;
-spacer: Pca2 (1);
Molecule number in the-unit cell: 16;
-unit cell volume: V
Unit cell=5289.91
3
-density: d=1.222g/cm
3
2. prepare the method for the VI crystal formation monocrystalline of claim 1 Agomelatine, it is characterized in that:
The Agomelatine powder dissolution of 0.02mmol in the 0.07mol isopropyl ether, is positioned in the bottle, and bottleneck is with sealing film phonograph seal, and an aperture is opened in the centre, and room temperature is placed, and the crystal of several needle point sizes appears in the 2 back bottle ends in week, promptly gets VI crystal formation monocrystalline.
3. the mixed crystal of the II crystal formation of an Agomelatine and VI crystal formation is characterized in that weight percent is:
The II crystal formation 93%-99% of Agomelatine, the VI crystal formation 7%-1% of Agomelatine.
4. the mixed crystal type of described II crystal formation of claim 3 and VI crystal formation is characterised in that weight percent is:
The VI crystalline form of 5 % of the II crystal formation 95% of Agomelatine, Agomelatine;
1) infrared spectrum characterization: 3249cm
-1, 3068 cm
-1, 1640 cm
-1, 1624 cm
-1, 1509 cm
-1, 1432 cm
-1, 1252 cm
-1, 1212 cm
-1, 1028 cm
-1, 827 cm
-1, 834 cm
-1, 759 cm
-1, 700 cm
-1, 609 cm
-1
2) the X-ray powder diffraction characterizes (2 θ value): 9.355,17.288,18.673,19.868,22.210,24.312,25.506;
3) fusing point: 99.83,110.83.
5. the preparation method of the mixed crystal type of claim 3 or 4 described Agomelatine II crystal formations and VI crystal formation:
The II crystal formation of 93%-99% Agomelatine is mixed with the VI crystal formation of 7%-1% Agomelatine, and 20～80 ℃ of rotation 1h that reduce pressure down make its uniform mixing promptly.
6. the Agomelatine mixed crystal of claim 3 is preparing the purposes for the treatment of in the cancer drug.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102503886A (en) * | 2011-10-11 | 2012-06-20 | 中山大学 | Agomelatine-isonicotine eutectic crystal and compound and preparation method thereof |
| EP2556824A1 (en) | 2011-08-10 | 2013-02-13 | Les Laboratoires Servier | Solid pharmaceutical composition for buccal administration of agomelatine |
| WO2014122405A1 (en) | 2013-02-08 | 2014-08-14 | Les Laboratoires Servier | Solid pharmaceutical composition for oral delivery of agomelatine |
| CN105777572A (en) * | 2014-12-26 | 2016-07-20 | 辽宁药联制药有限公司 | Preparation method of agomelatine mixed crystal and application thereof in tablets |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5225442A (en) * | 1990-02-27 | 1993-07-06 | Adir Et Compagnie | Compounds having a naphthalene structure |
| CN101429134A (en) * | 2007-11-09 | 2009-05-13 | 瑟维尔实验室 | New crystalline form VI of agomelatine, method of preparation and pharmaceutical compositions thereof |
-
2011
- 2011-04-13 CN CN201110091682A patent/CN102206864B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5225442A (en) * | 1990-02-27 | 1993-07-06 | Adir Et Compagnie | Compounds having a naphthalene structure |
| CN101429134A (en) * | 2007-11-09 | 2009-05-13 | 瑟维尔实验室 | New crystalline form VI of agomelatine, method of preparation and pharmaceutical compositions thereof |
Non-Patent Citations (1)
| Title |
|---|
| 《J.Med.Chem.》 19921231 S.Yous et al Novel naphthalenic ligands with high affinity for the melatonin receptor 第35卷, * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2556824A1 (en) | 2011-08-10 | 2013-02-13 | Les Laboratoires Servier | Solid pharmaceutical composition for buccal administration of agomelatine |
| WO2013021139A1 (en) | 2011-08-10 | 2013-02-14 | Les Laboratoires Servier | Solid pharmaceutical composition for orally delivering agomelatine |
| CN102503886A (en) * | 2011-10-11 | 2012-06-20 | 中山大学 | Agomelatine-isonicotine eutectic crystal and compound and preparation method thereof |
| WO2014122405A1 (en) | 2013-02-08 | 2014-08-14 | Les Laboratoires Servier | Solid pharmaceutical composition for oral delivery of agomelatine |
| CN105777572A (en) * | 2014-12-26 | 2016-07-20 | 辽宁药联制药有限公司 | Preparation method of agomelatine mixed crystal and application thereof in tablets |
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|---|---|
| CN102206864B (en) | 2012-10-03 |
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