NZ615714B2 - Mixed crystalline form-VIII of agomelatine, its method of preparation, application and pharmaceutical use - Google Patents
Mixed crystalline form-VIII of agomelatine, its method of preparation, application and pharmaceutical use Download PDFInfo
- Publication number
- NZ615714B2 NZ615714B2 NZ615714A NZ61571412A NZ615714B2 NZ 615714 B2 NZ615714 B2 NZ 615714B2 NZ 615714 A NZ615714 A NZ 615714A NZ 61571412 A NZ61571412 A NZ 61571412A NZ 615714 B2 NZ615714 B2 NZ 615714B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- agomelatine
- crystalline form
- preparation
- mixed crystalline
- water
- Prior art date
Links
- 229960002629 agomelatine Drugs 0.000 title claims abstract description 49
- 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 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 238000010586 diagram Methods 0.000 claims description 20
- 238000002441 X-ray diffraction Methods 0.000 claims description 12
- 238000010521 absorption reaction Methods 0.000 claims description 9
- 238000002425 crystallisation Methods 0.000 claims description 9
- 230000005712 crystallization Effects 0.000 claims description 9
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 9
- 239000001632 sodium acetate Substances 0.000 claims description 9
- 235000017281 sodium acetate Nutrition 0.000 claims description 9
- 239000011541 reaction mixture Substances 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 238000007792 addition Methods 0.000 claims description 5
- 230000001193 melatoninergic Effects 0.000 claims description 5
- 208000008787 Cardiovascular Disease Diseases 0.000 claims description 4
- 206010009191 Circadian rhythm sleep disease Diseases 0.000 claims description 4
- 208000005407 Digestive System Disease Diseases 0.000 claims description 4
- 206010016256 Fatigue Diseases 0.000 claims description 4
- 206010022437 Insomnia Diseases 0.000 claims description 4
- 208000001456 Jet Lag Syndrome Diseases 0.000 claims description 4
- 206010039775 Seasonal affective disease Diseases 0.000 claims description 4
- 206010040984 Sleep disease Diseases 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 4
- 230000000240 adjuvant Effects 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 206010002855 Anxiety Diseases 0.000 claims description 3
- 206010057666 Anxiety disease Diseases 0.000 claims description 3
- 230000036506 anxiety Effects 0.000 claims description 3
- 201000001552 phobic disease Diseases 0.000 claims description 3
- 201000000980 schizophrenia Diseases 0.000 claims description 3
- 230000035882 stress Effects 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 238000005259 measurement Methods 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 239000000523 sample Substances 0.000 description 8
- -1 agomelatine compound Chemical class 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 3
- 238000010928 TGA analysis Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 238000002411 thermogravimetry Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000010812 external standard method Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000001757 thermogravimetry curve Methods 0.000 description 2
- 210000003169 Central Nervous System Anatomy 0.000 description 1
- 229910016519 CuK Inorganic materials 0.000 description 1
- 206010012378 Depression Diseases 0.000 description 1
- 102000014630 G protein-coupled serotonin receptor activity proteins Human genes 0.000 description 1
- 108040006927 G protein-coupled serotonin receptor activity proteins Proteins 0.000 description 1
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 230000003042 antagnostic Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000001430 anti-depressive Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000014632 disordered eating Nutrition 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 201000006180 eating disease Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000010813 internal standard method Methods 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory Effects 0.000 description 1
- 230000036299 sexual function Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/08—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
Abstract
Provided herein is a mixed crystal agomelatine (Form-VIII), the preparation method and use thereof and a pharmaceutical composition containing the same, wherein the mixed crystal mainly contains an agomelatine crystal form VI. The mixed crystal is stable and has good reproducibility, and is found through a stability test to be superior to a crystal form VI in terms of stability. Therefore, the Form-VIII of agomelatine has an advantage in terms of preparation. rough a stability test to be superior to a crystal form VI in terms of stability. Therefore, the Form-VIII of agomelatine has an advantage in terms of preparation.
Description
Mixed crystaline form-VIII of agomelatine, its method of preparation,
application and pharmaceutical use
Technical field
The present invention relates to a mixed crystalline form of agomelatine, N-[2-
(7-methoxynaphthyl)ethyl]acetamide, its method of preparation, application
and pharmaceutical composition.
Prior art
Agomelatine, with chemical name N-[2-(7-methoxynaphthyl)ethyl]acetamide
and brand name Valdoxan, has the following chemical structure:
N CH
( Ⅰ )
It has a dual effect, acting not only as an agonist of melatoninergic system
receptors, but also as an antagonist of the 5HT receptor. Its properties mean that
it is active in the central nervous system, especially in the treatment of severe
depression, seasonal affective disorder, sleep disorders, cardiovascular diseases,
digestive system diseases, insomnia and fatigue brought on by jet lag, eating
disorders and obesity. Agomelatine is the first melatoninergic antidepressant, and
is effective in the treatment of depression and the improvement of sleep
parameters, while not affecting sexual function.
The preparation and therapeutic use of agomelatine have been reported in the
European patent EP0447285.
In view of the pharmaceutical value of said compound, it is important to obtain a
highly pure, stable crystalline form with good reproducibility in order for it to be
advantageous in pharmaceutical preparation and stable enough for long-term
storage without having specific requirements in terms of temperature, light,
humidity or oxygen levels.
The Chinese patents CN200510071611.6, CN200610108396.7,
CN200610108394.8, CN200610108395.2, CN200910047329.2,
CN200910245029.5 have made public the various crystalline forms as well as the
preparation methods of agomelatine.
Among these, in CN200910047329.2, the publicly disclosed crystalline form VI
obtained through the process of acetic acid and water recrystallization has
superior solubility over most of the existing publicly disclosed crystalline forms,
thus possessing unique value with regard to its properties in pharmaceutical
formulation. However, when placing crystalline form VI under extreme
conditions (high temperature of 60°C) for 10 days, small amounts of crystal
transition can occur.
Researchers have focused on the search for a crystalline or mixed crystalline form
possessing greater stability without compromising in terms of solubility.
Advantageously, through exploring various preparation processes and
comparisons of stability, the inventor has found a mixed crystalline form which,
when placed under extreme conditions, offers superior stability over crystalline
form VI. Said mixed crystal achieves greater stability without compromising the
excellent solubility of crystalline form VI. It offers great reproducibility and under
extreme conditions, stability in its preparation process, thus greatly increasing the
feasibility of pharmaceutical formulation.
Scope of the Invention
The aim of the present invention is to provide a mixed crystalline form of
agomelatine, form VIII, while also providing a preparation process. When
compared with crystalline form VI, said form VIII offers greater stability under
high temperature. In addition, it exhibits valuable pharmaceutical formulation
properties.
Specifically, the invention provides a mixed crystalline form of agomelatine, its
X-ray diffraction diagram having the following values for Bragg angle 2 θ:
2 θ°
9.493
9.809
.815
11.171
11.879
12.770
13.811
14.939
.315
16.085
17.544
18.491
19.065
19.538
19.774
.801
21.156
21.807
22.499
23.032
23.780
24.610
.419
27.075
31.931
including crystals whose peak diffraction angles are within 2 θ±0.2° of the above.
The invention also provides a mixed crystalline form of agomelatine, its X-ray
diffraction diagram having the following values for interplanar crystal spacing d,
Bragg angle 2 θ and relative intensity:
2 θ° d (Å) Relative intensity
(I%)
9.493 9.3085 12.86
9.809 9.0096 15.62
.815 8.1735 13.10
11.171 7.9141 17.53
11.879 7.4439 64.67
12.770 6.9264 17.90
13.811 6.4065 17.10
14.939 5.9255 12.14
.315 5.7808 10.48
16.085 5.5057 19.89
17.544 5.0510 48.47
18.491 4.7943 66.41
19.065 4.6512 24.02
19.538 4.5398 99.39
19.774 4.4861 100.00
.801 4.2668 50.35
21.156 4.1961 30.66
21.807 4.0722 37.31
22.499 3.9486 22.63
23.032 3.8583 31.18
23.780 3.7387 39.67
24.610 3.6144 21.02
.419 3.5011 30.30
27.075 3.2906 14.67
31.931 2.8004 14.14
including crystals whose peak diffraction angles are within 2 θ±0.2° of the above.
The invention also provides a pharmaceutical composition, including the mixed
crystalline form of agomelatine according to the invention, and pharmaceutically
acceptable adjuvants or excipients.
The invention also provides a use of the mixed crystalline form of agomelatine
according to the invention, in the manufacture of a medicament for treating
diseases of the melatoninergic system.
The invention also provides a use of the mixed crystalline form of agomelatine
according to the invention, in the manufacture of a medicament for treating sleep
disorders, stress, anxiety, seasonal affective disorder, severe depression,
cardiovascular diseases, digestive system diseases, insomnia and fatigue brought
on by jet lag, schizophrenia, phobias, or depression.
The mixed crystalline form VIII of agomelatine in the present invention may be
used in the treatment of diseases of the melatoninergic system, sleep disorders,
stress, anxiety, seasonal affective disorder, severe depression, cardiovascular
diseases, digestive system diseases, insomnia and fatigue brought on by jet lag,
schizophrenia, phobias, and depression.
The present invention also aims to provide a method of preparation for form VIII
of agomelatine which is simple in its operation and offers good reproducibility.
A further aim of the present invention is to provide a pharmaceutical
composition, which includes the mixed crystalline form VIII of agomelatine of
this invention as well as pharmaceutically acceptable adjuvants or excipients.
The said pharmaceutical composition can be configured to be used in different
application routes, especially when administered either orally or via injection.
According to the nature and severity of the illness, treatment may be
administered via a regulated dosage based on the age and weight of the patient.
The dosage may vary between 0.1mg and 1g per day, being administered once
only or several times.
The following examples of X-ray diffraction diagrams of form VIII of
agomelatine of the present invention use interplanar crystal spacing d, Bragg
angle 2 θ and relative intensity (I%) to show:
2 θ° d (Å) Relative
intensity (I%)
9.493 9.3085 12.86
9.809 9.0096 15.62
.815 8.1735 13.10
11.171 7.9141 17.53
11.879 7.4439 64.67
12.770 6.9264 17.90
13.811 6.4065 17.10
14.939 5.9255 12.14
.315 5.7808 10.48
16.085 5.5057 19.89
17.544 5.0510 48.47
18.491 4.7943 66.41
19.065 4.6512 24.02
19.538 4.5398 99.39
19.774 4.4861 100.00
.801 4.2668 50.35
21.156 4.1961 30.66
21.807 4.0722 37.31
22.499 3.9486 22.63
23.032 3.8583 31.18
23.780 3.7387 39.67
24.610 3.6144 21.02
.419 3.5011 30.30
27.075 3.2906 14.67
31.931 2.8004 14.14
When using X-ray diffraction to measure the crystallization of the present
invention, sometimes owing to the measurement equipment or test conditions, the
measured peaks show slight deviations in measurement; more specifically, for
example there may be a deviation in measurement of the 2 θ value by
approximately ±0.2; even if extremely accurate equipment is used, a deviation of
approximately ±0.1 may be seen. As a result, this deviation must be taken into
consideration when determining each crystalline structure.
XRD test conditions for said form VIII of agomelatine of the present invention:
Instrument model: Bruker D8 ADVANCE X-ray diffractometer
Experiment parameters:
Detector: LynxEye detector
Light source: CuK α 40 kV 40 mA
Monochromator: Ni filter disc
Divergence slit: 1°
DivH.L.Slit: 1.0 mm
Probe: LynxEye probe
Scanning method: θ- θ continuous scanning
Scanning range: 3°~45°
Step length: 0.02°
Scanning speed: 8.0°/min
Scanning time: 5 min
Scanning temperature: Room temperature
Test conditions for DSC change-in-absorption diagram of said form VIII of
agomelatine of the present invention:
Instrument model: NETZSCH DSC 204F1
Experimental conditions:
Crucible type: Standard aluminium crucible (perforated)
Shielding gas: High purity nitrogen 20 ml/min
Sweep gas: High purity nitrogen 60 ml/min
Heating rate: 10°C/min
Temperature range: Room temperature ~140°C
The onset value of the endothermic peak of the DSC change-in-absorption
diagram of the present invention is characterised by: onset value range being 97-
98°C, the endothermic peak area being no lower than 90%, with the preferable
ratio being 95-99%.
When using DSC to measure the crystals of the present invention, sometimes
owing to the measurement equipment or test conditions, the measured peaks show
slight deviations in measurement; more specifically, for example there may be a
deviation in measurement of the onset value by approximately ±1°C, even if
extremely accurate equipment is used, a deviation of approximately ±0.5°C may
be seen. As a result, this deviation must be taken into consideration when
determining each crystalline structure.
TGA test conditions of the present invention:
Instrument model NETZSCH TG 209F1
Experimental conditions:
Crucible type: Al O
Sweep gas: N 20 ml/min; shielding gas: N 10 ml/min
Temperature range: Room temperature~300°C
Heating rate: 10°C/min
The method of preparation of form VIII of the present invention involves
dissolving agomelatine compound of formula (II) (Agomelatine-HCl-H O) in
acetic acid, to which sodium acetate is then added, water is then added dropwise
to this reaction mixture and agitated at a temperature of 7-13°C in order to bring
about crystallization, with the crystals then being separated from the solution.
(II)
In the present invention as described, there are no special requirements in terms
of the amount of acetic acid that is to be added as long as a sufficient amount is
used to dissolve the raw materials, while heating can also be suitably applied to
facilitate dissolution.
The molar ratio of agomelatine compound of formula (II) and sodium acetate is
preferably of the order of 1:1-1.5, most optimally 1:1-1.1.
In the preparation method of the present invention as described, the ratio of
volume of acetic acid to water is 1:15-30.
In a preferred embodiment of the preparation method for agomelatine form VIII
in the present invention, when the temperature of the resulting reaction mixture
reaches 12-18°C, and in particular when around 15°C, water is added dropwise in
order to bring about crystallization.
In a further preferred embodiment, when water is added dropwise to the
resulting reaction mixture, agitation is then carried out at a temperature of around
°C. This may be carried out over a period of around 1.5 hours in order to bring
about crystallization.
In another preferred embodiment, following the addition of sodium acetate, the
reaction mixture is heated to 40-80°C, an appropriate, non-fixed, amount of
activated carbon is then added, followed by agitation and filtration; said solution
is then left to cool on its own, and water is added dropwise in order to bring about
crystallization.
The agomelatine form VIII provided by the present invention can be used in
conjunction with pharmaceutically acceptable adjuvants or excipients for
pharmaceutical formulation.
The present invention results in a new form VIII of agomelatine, with greater
stability compared to that of crystalline form VI, thus possessing advantages in
production in terms of stability.
According to the Chinese patent application CN 201010126254.X, agomelatine
compound of formula (II) as previously described may be produced by means of
the following preparation method, where said preparation method involves
reacting agomelatine with various forms of HCl in order to form a hydrate. The
two methods are as follows: Agomelatine is firstly dissolved in a water-containing
organic solvent, after which HCl gas is added, the solid crystals are washed and
then dried; or else agomelatine is added to a solvent containing HCl, and the solid
crystals are then washed and dried. If the first method is used, an overabundance
of HCl may lead to a decrease in yield, while in the second method the amount of
HCl present in the solvent is easily controlled. Therefore the second method is
preferred.
Specifically, agomelatine may be added to a water-containing organic solvent,
followed by the dropwise addition of a solvent containing HCl. The solid crystals
are then washed and then dried.
Likewise, it is also possible to add agomelatine to an organic solvent, followed
by the dropwise addition of an aqueous solution containing HCl. The solid
crystals are then washed and then dried. The full contents of reference documents
either quoted or mentioned in this application have been referenced.
The term 'comprising' as used in this specification and claims means 'consisting
at least in part of'. When interpreting statements in this specification and claims
which include the term 'comprising', other features besides the features prefaced
by this term in each statement can also be present. Related terms such as
'comprise' and 'comprised' are to be interpreted in similar manner.
In this specification where reference has been made to patent specifications,
other external documents, or other sources of information, this is generally for the
purpose of providing a context for discussing the features of the invention.
Unless specifically stated otherwise, reference to such external documents is not
to be construed as an admission that such documents, or such sources of
information, in any jurisdiction, are prior art, or form part of the common general
knowledge in the art.
In the description in this specification reference may be made to subject matter
that is not within the scope of the claims of the current application. That subject
matter should be readily identifiable by a person skilled in the art and may assist
in putting into practice the invention as defined in the claims of this application.
Description of drawings
Figure 1 shows the X-ray diffraction diagram of form VIII in embodiment 1 of
the present invention;
Figure 2 shows the DSC change-in-absorption diagram of form VIII in
embodiment 1 of the present invention;
Figure 3 shows the X-ray diffraction diagram of form VIII in embodiment 2 of
the present invention;
Figure 4 shows the DSC change-in-absorption diagram of form VIII in
embodiment 2 of the present invention;
Figure 5 shows the X-ray diffraction diagram of form VIII in embodiment 3 of
the present invention;
Figure 6 shows the DSC change-in-absorption diagram of form VIII in
embodiment 3 of the present invention;
Figure 7 shows the thermogravimetric analysis TGA curve of the product in
embodiment 5 of the present invention.
Details of the embodiments
The following embodiments further describe the present invention but do not
limit the scope thereof.
Embodiment 1:
14g of agomelatine compound of formula (II) is dissolved in 55ml of acetic acid,
to which 4.5g of sodium acetate is then added; the mixture is then heated to 60°C,
after which 0.5g of activated carbon is added. Agitation is carried out for 2 hours
after which the mixture is filtered; at a temperature of 15°C, 1L of water is then
added dropwise. The solution gradually becomes turbid, and at a temperature of
~10°C, agitation is carried out over 1.5 hours, followed by filtration, then washing
and drying the filter cake at 45°C under vacuum until constant weight is achieved,
resulting in 9.6g of white solid;
(Refer to Figure 1 for X-ray diffraction diagram; refer to Figure 2 for DSC
change-in-absorption diagram)
Embodiment 2:
140g of agomelatine compound of formula (II) is dissolved in 490ml of acetic
acid, to which 60g of sodium acetate is then added; the mixture is then heated to
60°C, after which 1.4g of activated carbon is added. Agitation is carried out for 1
hour after which the mixture is filtered; at a temperature of 15°C, 8.8L of water is
then added dropwise. The solution gradually becomes turbid, and at a temperature
of ~10°C, agitation is carried out over 1.5 hours, followed by filtration, then
washing and drying the filter cake at 45°C under vacuum until constant weight is
achieved, resulting in 94g of white solid;
(Refer to Figure 3 for X-ray diffraction diagram; refer to Figure 4 for DSC
change-in-absorption diagram)
Embodiment 3:
66g of agomelatine compound of formula (II) is dissolved in 230ml of acetic
acid, to which 21g of sodium acetate is then added; the mixture is then heated to
60°C, after which 1.3g of activated carbon is added. Agitation is carried out for 1
hour after which the mixture is filtered; at a temperature of 15°C, 6.9L of water is
then added dropwise. The solution gradually becomes turbid, and at a temperature
of ~10°C, agitation is carried out over 1.5 hours, followed by filtration, then
washing and drying the filter cake at 50°C under vacuum until constant weight is
achieved, resulting in 49g of white solid;
(Refer to Figure 5 for X-ray diffraction diagram; refer to Figure 6 for DSC
change-in-absorption diagram)
Embodiment 4:
Agomelatine crystalline forms VI and VIII (obtained through embodiment 2) are
each placed in thermostatic containers at a temperature of 40°C and stored for 20
days, with the stability of these samples being studied using the method of High
Performance Liquid Chromatography.
1. Purity measurement of the sample
Chromatographic conditions: Octadecyl silane chemically bonded silica is used
as packing; a mixed solution of 10 mmol/L phosphate buffer (adjusted to pH 7.0
with sodium hydroxide) and acetonitrile in the ratio 2:7 by volume acts as the
mobile phase; column temperature 40°C; and detection wavelength 220nm. Purity
is measured using an internal standard method.
In the mobile phase, crystalline forms VI and VIII are distributed into 1mg/mL
solutions, 10 μL of each of which are then passed into a liquid chromatograph,
with their chromatograms being recorded.
2. Assay of the Sample
The reference sample purity measurement method was used, with measurements
being made using an external standard method, the results can be seen in Table I.
Table I
Sample name Crystalline form VI Form-VIII
Purity Content Purity Content
Before storage 99.7% 100.1% 99.8% 100.3%
After storage in the 99.6% 99.8% 99.7% 100.1%
thermostatically
controlled containers for
days
3. Measurement of water solubility
The HPLC method was used to determine water solubility, with measurements
being made using an external standard method. The results are shown in Table II.
Table II
Sample name Crystalline form VI Form-VIII
Solubility (mg/ml) 0.336 0.335
4. Determination of crystalline stability
Measured using the pharmacopoeia stability assessment method:
1) Influencing factor testing (exposed for 10 days): High temperature (60°C),
illumination (4500 lx), high humidity (92.5%RH, 25°C)
2) Accelerated testing (hermetically sealed for 6 months): Temperature 30°C,
humidity 65%RH
3) Long term testing (hermetically sealed for 12 months): Temperature 25°C,
humidity 60%RH
Table III
Sample name Crystalline form VI Form VIII
Influencing High x* √*
factor temperature
Illumination √ √
High √ √
humidity
Accelerated testing √ √
Long term testing (6 months) √ √
Long term testing (9 months) √ √
Long term testing (12 months) x √
*: √- stable; ×- unstable
As can be seen from the test results, form VIII of agomelatine of the present
invention clearly offers greater stability under high temperature and comparable
solubility when compared with crystalline form VI. Its preparation method offers
good reproducibility. In addition, it exhibits valuable pharmaceutical formulation
properties.
. Study into the preparation and stability of pharmaceutical compositions
(crystalline form, purity and content)
1000 capsules prescribed (dosage: 25mg)
Form VIII 25 mg
Lactose 71.2 mg
Magnesium stearate 1.3 mg
Stearic acid 1.3 mg
Starch (Starch 1500) 19.5 mg
Sodium carboxymethyl starch (CMS- 6.5 mg
Subjected to the pharmacopoeia stability assessment method and undergoing
influencing factor testing (10 day exposure): High temperature (60°C),
illumination (4500 lx), high humidity (92.5%RH, 25°C); Accelerated testing
(hermetically sealed for 6 months): temperature 30°C, humidity 65%RH; Long
term testing (hermetically sealed for 12 months): temperature 25°C, humidity
60%RH. The assessment results demonstrate that under the above conditions
neither the crystalline form, purity nor content of the product underwent any
changes.
Consequently, the test results of the pharmaceutical ingredients and capsules of
this product show that form VIII has a great potential in pharmaceutical
production.
Embodiment 5: Agomelatine compound of formula (II)
10g of agomelatine is added to a 100ml solution of ethyl acetate. At a
temperature of 10°C, 4.6g of an aqueous solution of HCl (36%) is slowly added
dropwise. Agitation is then carried out for 1 hour, followed by filtration and the
resulting solid is washed twice in 10ml of ethyl acetate, then dried at a
temperature of 40°C to obtain 10.2g of form II white solid; purity: 99.8%, yield:
88.7%.
Cl elemental analysis:
Theoretically calculated value: Cl content 11.91 wt %
Measured value: Cl content 11.86 wt %
Determination of crystal water content of agomelatine compound of formula (II):
The calculated theoretical crystal water content of C H NO •HCl•H O is 6.06 wt
17 2 2
.1 The Fischer method (Chinese Pharmacopoeia 2010 edition, appendix VIII M)
The product resulting from embodiment 5 was measured according to the Fischer
method as mentioned above, and the crystal water content recorded was: 6.15 wt
.2 Thermogravimetric analysis (Chinese Pharmacopoeia 2010 edition, appendix
VIII Q)
The product resulting from embodiment 5 was measured according to
thermogravimetric analysis as mentioned above, and the loss of crystal water
recorded was: 6.67 wt %, i.e. the crystal water content of the original product was
6.67 wt %. For TGA curve, please refer to Figure 7.
Claims (16)
1. Mixed crystalline form of agomelatine, its X-ray diffraction diagram having the following values for Bragg angle 2 θ: 2 θ° 9.493 9.809 10.815 11.171 11.879 12.770 13.811 14.939 15.315 16.085 17.544 18.491 19.065 19.538 19.774 20.801 21.156 21.807 22.499 23.032 23.780 24.610 25.419 27.075 31.931 including crystals whose peak diffraction angles are within 2 θ±0.2° of the above.
2. Mixed crystalline form of agomelatine, its X-ray diffraction diagram having the following values for interplanar crystal spacing d, Bragg angle 2 θ and relative intensity: 2 θ° d (Å) Relative intensity (I%) 9.493 9.3085 12.86 9.809 9.0096 15.62 10.815 8.1735 13.10 11.171 7.9141 17.53 11.879 7.4439 64.67 12.770 6.9264 17.90 13.811 6.4065 17.10 14.939 5.9255 12.14 15.315 5.7808 10.48 16.085 5.5057 19.89 17.544 5.0510 48.47 18.491 4.7943 66.41 19.065 4.6512 24.02 19.538 4.5398 99.39 19.774 4.4861 100.00 20.801 4.2668 50.35 21.156 4.1961 30.66 21.807 4.0722 37.31 22.499 3.9486 22.63 23.032 3.8583 31.18 23.780 3.7387 39.67 24.610 3.6144 21.02 25.419 3.5011 30.30 27.075 3.2906 14.67 31.931 2.8004 14.14 including crystals whose peak diffraction angles are within 2 θ±0.2° of the above.
3. The mixed crystalline form of agomelatine according to claim 1 or 2, characterised by: its DSC change-in-absorption diagram, the onset value range being 97-98°C, the endothermic peak area being no lower than 90%, with the preferable ratio being 95-99%.
4. The preparation method for the mixed crystalline form of agomelatine according to any of claims 1-3, wherein agomelatine compounds of formula (II) are dissolved in acetic acid, to which sodium acetate is then added, followed by the dropwise addition of water to this reaction mixture, which is then agitated at a temperature of 7-13°C in order to bring about crystallization, with the crystals then being separated from the solution
5. The preparation method according to claim 4, wherein the molar ratio of agomelatine compounds of formula (II) and sodium acetate is of the order of 1 : 1-1.5, most optimally 1 : 1-1.1.
6. The preparation method according to claim 4 or 5, wherein the ratio of volume of acetic acid to water is 1:15-30.
7. The preparation method according to any of claims 4-6, wherein when the temperature of the resulting reaction mixture reaches 12-18°C, and in particular when 15°C, water is added dropwise in order to bring about crystallization.
8. The preparation method according to any of claims 4-7, wherein water is added dropwise to the resulting reaction mixture which is then agitated at a temperature of 10°C in order to bring about crystallization.
9. The preparation method according to any of claims 4-8, wherein following the addition of the sodium acetate, the reaction mixture is heated to 40-80°C; the said solution is then left to cool on its own, and water is added dropwise in order to bring about crystallization.
10. A pharmaceutical composition, including the mixed crystalline form of agomelatine according to any of claims 1-3 and pharmaceutically acceptable adjuvants or excipients.
11. A use of the mixed crystalline form of agomelatine according to any of claims 1-3 in the manufacture of a medicament for treating diseases of the melatoninergic system.
12. A use of the mixed crystalline form of agomelatine according to any of claims 1-3 in the manufacture of a medicament for treating sleep disorders, stress, anxiety, seasonal affective disorder, severe depression, cardiovascular diseases, digestive system diseases, insomnia and fatigue brought on by jet lag, schizophrenia, phobias, or depression.
13. The mixed crystalline form of agomelatine according to claim 1 or claim 2, substantially as herein described with reference to any example thereof.
14. The preparation method according to claim 4, substantially as herein described with reference to any example thereof.
15. The pharmaceutical composition according to claim 10, substantially as herein described with reference to any example thereof.
16. The use according to claim 11 or claim 12, substantially as herein described with reference to any example thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2011100706340A CN102690209A (en) | 2011-03-23 | 2011-03-23 | Mixed crystal of agomelatine (form-VIII), preparation method and application thereof and pharmaceutical composition containing the same |
CN201110070634.0 | 2011-03-23 | ||
PCT/CN2012/072818 WO2012126386A1 (en) | 2011-03-23 | 2012-03-22 | Mixed crystal agomelatine (form-viii), preparation method and use thereof and pharmaceutical composition containing same |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ615714A NZ615714A (en) | 2016-03-31 |
NZ615714B2 true NZ615714B2 (en) | 2016-07-01 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
DK2547649T3 (en) | Agomelatine Hydrochloride Hydrate and its Preparation | |
WO2010102554A1 (en) | New crystalline form vi of agomelatine, preparation method and application thereof | |
EP2690087B1 (en) | New crystal form vii of agomelatine, preparation method and use thereof and pharmaceutical composition containing same | |
EP2690088B1 (en) | Mixed crystal agomelatine (form-viii), preparation method and use thereof and pharmaceutical composition containing same | |
NZ615714B2 (en) | Mixed crystalline form-VIII of agomelatine, its method of preparation, application and pharmaceutical use | |
EA022066B1 (en) | Agomelatine hydrobromide hydrate and preparation thereof | |
NZ615707B2 (en) | New crystalline form vii of agomelatine, preparation method and use thereof and pharmaceutical composition containing same | |
CN103360276B (en) | Crystal form, preparation method and application of agomelatine, as well as medicine composition |