OA16621A - Agomelatine hydrobromide hydrate and preparation thereof. - Google Patents
Agomelatine hydrobromide hydrate and preparation thereof. Download PDFInfo
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- OA16621A OA16621A OA1201200380 OA16621A OA 16621 A OA16621 A OA 16621A OA 1201200380 OA1201200380 OA 1201200380 OA 16621 A OA16621 A OA 16621A
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- OAPI
- Prior art keywords
- agomelatine
- hydrochloride hydrate
- préparation
- agomelatine hydrochloride
- hydrate according
- Prior art date
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- YJYPHIXNFHFHND-UHFFFAOYSA-N Agomelatine Chemical compound C1=CC=C(CCNC(C)=O)C2=CC(OC)=CC=C21 YJYPHIXNFHFHND-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 229960002629 agomelatine Drugs 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title abstract description 3
- GVLGAFRNYJVHBC-UHFFFAOYSA-N hydrate;hydrobromide Chemical compound O.Br GVLGAFRNYJVHBC-UHFFFAOYSA-N 0.000 title 1
- ZJVMEXOLMFNQPX-UHFFFAOYSA-N N-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide;hydrochloride Chemical compound Cl.C1=CC=C(CCNC(C)=O)C2=CC(OC)=CC=C21 ZJVMEXOLMFNQPX-UHFFFAOYSA-N 0.000 claims abstract description 35
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 32
- 239000007787 solid Substances 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 5
- KXKVLQRXCPHEJC-UHFFFAOYSA-N Methyl acetate Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 206010002855 Anxiety Diseases 0.000 claims description 2
- 206010057666 Anxiety disease Diseases 0.000 claims description 2
- 208000008787 Cardiovascular Disease Diseases 0.000 claims description 2
- 206010009191 Circadian rhythm sleep disease Diseases 0.000 claims description 2
- 208000005407 Digestive System Disease Diseases 0.000 claims description 2
- 206010016256 Fatigue Diseases 0.000 claims description 2
- 206010022437 Insomnia Diseases 0.000 claims description 2
- 208000001456 Jet Lag Syndrome Diseases 0.000 claims description 2
- 206010034912 Phobia Diseases 0.000 claims description 2
- 206010039775 Seasonal affective disease Diseases 0.000 claims description 2
- 206010040984 Sleep disease Diseases 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- 230000000240 adjuvant Effects 0.000 claims description 2
- 230000036506 anxiety Effects 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-M caproate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 claims description 2
- 230000001193 melatoninergic Effects 0.000 claims description 2
- 201000001552 phobic disease Diseases 0.000 claims description 2
- 230000035882 stress Effects 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims 5
- CATSNJVOTSVZJV-UHFFFAOYSA-N 2-Heptanone Chemical compound CCCCCC(C)=O CATSNJVOTSVZJV-UHFFFAOYSA-N 0.000 claims 1
- 238000002425 crystallisation Methods 0.000 claims 1
- 230000005712 crystallization Effects 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 7
- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 238000000634 powder X-ray diffraction Methods 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 235000011149 sulphuric acid Nutrition 0.000 description 3
- 229960000583 Acetic Acid Drugs 0.000 description 2
- 229960003987 Melatonin Drugs 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N Perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 230000002349 favourable Effects 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 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 2
- 238000005259 measurement Methods 0.000 description 2
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 238000001757 thermogravimetry curve Methods 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N AI2O3 Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 230000036912 Bioavailability Effects 0.000 description 1
- 229910016523 CuKa Inorganic materials 0.000 description 1
- 229960002598 Fumaric acid Drugs 0.000 description 1
- 229940093915 Gynecological Organic acids Drugs 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
- 241000721701 Lynx Species 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 229940116315 Oxalic Acid Drugs 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 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
- 230000035514 bioavailability Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000003247 decreasing Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000002496 gastric Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000001681 protective Effects 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 230000036299 sexual function Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 238000004457 water analysis Methods 0.000 description 1
Abstract
The present invention relates to an agomelatine hydrochloride hydrate of formula I, preparation and use thereof, and to pharmaceutical composition containing it. The agomelatine hydrohalide hydrate obtained through the present method has significant increased solubility than that agomelatine, and therefore is more suitable for manufacturing pharmaceutical formulations. In addition, the product enjoys higher stability and purity. Using the present method, product of high purity can be obtained through a simple process, free of any complicated steps.
Description
AGOMELATINE HYDROCHLORIDE HYDRATE AND PREPARATION THEREOF
Technical Field
The présent invention relates to an agomelatine hydrochloride hydrate, préparation and use thereof, and to pharmaceutical composition containing it.
Technical Background
Agomelatine, or N-[2-(7-methoxy-l-naphthyl)ethyl]-acetamide, has the structure of formula II. It is marketed under the trade name of Valdoxan by the French company Servier as a melatonin agonist and antagonist of 5HT2c receptor. It is the first melatonin type anti-depressant, indicated for dépression, improving sleep and sexual function.
In view of its pharmaceutical value, it is important to produce the compound or a complex thereof with better purity, solubility and reproducibility.
Su ni mary of the Invention
The object of the présent invention is to provide an agomelatine hydrochloride hydrate featuring excellent solubility, stability and purity, making it favourable for use in the manufacture of pharmaceutical formulations containing agomelatine.
When the présent inventors attempted to purify agomelatine product, we surprisingly found that agomelatine can form a physically and chemîcally stable agomelatine hydrochloride hydrate when mixed with hydrocholorîc acid (HCl). Said agomelatine hydrochloride hydrate is suitable for the manufacture of pharmaceutical formulations. When other conventional inorganic acids (such as sulphuric acid, phosphoric acid, perchloric acid) or organic acids (such as acetic acid, oxalic acid, tartaric acid, fumaric acid) were used, it was not easy to produce a hydrate or hydrates with unstable physical and chemical properties were obtatned.
The présent invention provides an agomelatine hydrochloride hydrate with the following structure of formula I:
wherein X is Cl.
The présent invention further provides a method for the préparation of said agomelatine hydrochloride hydrate, wherein agomelatine is reacted with HCl in any form to produce the
DUPLICATA agomelatine hydrochloride hydrate. There can be two processes: agomelatine can be dissolved in aqueous organic solvent before HCl gas is bubbled through and the precipitated crystal is rinsed and dried; or agomelatine can be added to a solution containing HCl and then the precipitated crystal is rinsed and dried. The results from repeated experiments show that in the first method, the oversupply of HCl only results in lower yield, while in the second method, it is easier to control the amount of HCl in the solvent. Therefore, the second method is preferred.
Specifically. agomelatine can also be added to an aqueous organic solvent before a solvent containing HCl is added dropwise, and the precipitated crystal is rinsed and dried.
Alternatively. agomelatine îs dissolved in organic solvent before aqueous HCl solution is added dropwise, and the precipitated crystal is rinsed and dried.
The reaction température in the présent invention can be conventional températures for such reactions in the art as long as it is lower than the boiling point of the solvent. In order to increase yield, room température or below is preferred, a température below the room température is more preferred, and 0-20°C îs most preferred.
In the above-mentioned préparation method for said agomelatine hydrochloride hydrate, the organic solvent is not specifically limited so long as it can dissolve the starting materials agomelatine and HCl and meanwhile allows said agomelatine hydrochloride hydrate to be precipitated. Suitable solvent can be used includes ethyl acetate, methyl acetate, n-butyl acetate, acetone, acetonitrile and the like, and ethyl acetate is preferred. Organic solvents with higher polarity such as alcohols (éthanol and methanol etc.), DMF, DMSO are less preferred.
The présent invention is advantageous in that the inventors found that among so many conventional acids, agomelatine can react with HCl to form a stable agomelatine hydrochloride hydrate, the physical propcrties of which, such as stability, solubility, and hygroscopicity, are better than those products of agomelatine with any other conventional acid. The process is also less complicated than if other acid is used.
The agomelatine hydrochloride hydrate produced according to the présent method has significant increased solubility than agomelatine per se, and therefore is more suitable for manufacturing pharmaceutical formulations. The product enjoys higher stability, purity and solubility. In addition, product with high purity can be obtained through a simple process, free of any complicated steps.
Pharmacological tests of the agomelatine hydrochloride hydrate demonstrated that it can be used for the treatment of melatoninergic system disorders, sleep disorders, stress, anxiety, seasonal affective disorder, major dépréssion, cardiovascular diseases, digestive system diseases, insomnia and fatigue caused by jet lag, schizophrenia, phobia or dépréssion disorders.
The présent invention further provides a pharmaceutical composition, comprising an agomelatine hydrochloride hydrate of the invention in associated with pharmaceutically acceptable adjuvants or excipients.
The pharmaceutical composition can be formulated for various routes of administration, especially for oral administration or for injection.
DUPLICATA
The useful dosage can be adjusted depending on the nature and severity of the diseases to be treated, the mode of administration, and âge and weight of the patients. The daily dosage varies from 0.1 mg to l g and may be administrated in a single dose or in several divided doses.
Brief Description ofDrawings
Représentative examples of the présent invention are illustrated with the drawings in order to better convey the objects, features, and advantages of the présent invention.
Fig. I shows the TGA thermogram of the product of Example l in the présent invention.
Fig. 2 shows the X-ray powder diffraction pattern of the product of Example 7 in the présent invention.
I0 Examples
Example 1 g of agomelatine was added to 20 ml of EtOAc, 0.5 g aqueous HCl solution (36%) was added dropwise at IO°C. The mixture was stirred for lh, and then filtered, and the solid was rinsed twice with 2 m! of EtOAc and dried at 40 °C to afford 1 g of white solid (purity: 99.9%; yield: 81.7%).
Elemental analysis for Cl: Calculated: Cl% (11.91 wt%) Found: Cl% (11.88 wt%)
Mp: 88-90°C
Example 2
10 g of agomelatine was added to 100 ml of EtOAc, and 4.6 g of aqueous HCl solution (36%) was added dropwise at 10°C. The mixture was stirred for lh, and then filtered, and the solid was rinsed twice with 10 ml of EtOAc and dried at 40 °C to afford 10.2 g of white solid (purity: 99.8%; yield: 88.7%).
Elemental analysis for Cl:
Calculated: Cl% (11.91 wt%)
Found: Cl% ( 11.86 wt%)
Mp: 88-90°C
Example 3 g of agomelatine was dissolved in 10 ml of EtOAc under stirring, and concentrated H2SO4 was added dropwise at room température. No solid precipitated during the entire process.
Example 4 g of agomelatine was dissolved in 10 ml of EtOAc under stirring, and concentrated H2SO4 was added dropwise at -10°C. No solid precipitated during the entire process.
Example 5
1 g of agomelatine was dissolved in 10 ml of EtOAc under stirring, and glacial acetic acid was added dropwise at -IO°C. No solid precipitated during the entire process.
DUPLICATA
Examplc 6 l g of agomelatine was dissolved in 10 ml of EtOAc under stirring, and fumaric acid was added dropwise al -10°C. No solid precipitated during the entire process.
Examplc 7
100 g of agonielatine was added to 1 L of EtOAc, and 50 g of aqueous HCl solution (36%) was added dropwise at 10 °C. The mixture was stirred for Ih, and then filtered, and the solid was rinsed twice with 100 ml of EtOAc and dried at 40 °C to afford 101 g of white solid (purity: 99.7%; yield: 82.5%).
Elemental analysis for Cl:
Calculated: Cl% (11.91 wt%)
Found: Cl% ( 11.86 wt%)
Mp: 87-89°C
Agomelatine used in the above examples is commercially available or can be prepared according to methods known in the art.
Examplc 8: Pharmaceutical Composition
| Formulation for the préparation of 1000 capsules each containing a dose of 25 mg (agomelatine) | |
| Compound of Example 7 | 30.5 g |
| Lactose (Spherolac 100) | 85.2 g |
| Starch 1500 | 25.5 g |
| CMS-Na | 8.5 g |
| Ac-Di-Sol ® (FMC) | 17g |
| Stearic Acid | 3.4 g |
Détection Methods and Results
1. Purity of Samples
Chromatographie conditions: Cl8 column; mobile phase: 10 mmol/L phosphate buffer (adjusted to pH 7.0 with NaOH): acetonitrile = 2:7 (v/v); column température: 40°C; détection wavelength: 220 nm; internai standard method was used on the products of Examples 1 and 2.
Solutions of the products at 1 mg/mL were prepared with the mobile phase. 10 pL of each solution was injected inio the liquid chromatograph system and chromatograms were recorded. The results of the purity are shown in Examples 1 and 2.
2. Stability l'est
Some of the product of Example 1 was placed in an incubator at 40°C for 30 days to détermine its stability with HPLC. The results are shown in the following table I.
DUPLICATA
Table l
| Product of Example I | Day 0 | Day 5 | Day 10 | Day 30 |
| AG-HCI-HaO | 99.6% | 99.5% | 99.5% | 99.5% |
AG - Agomelatîne C15H17NO2
3. Water Solubîlity
Using external standard method, the product of Example 1 was tested with HPLC, compared with agomelatîne crystalline form IL The results are shown in the following table 2.
Table 2
| Sample | Agomelatîne content (mg/ml) | ||
| In water | InO.IN HCl | In pH7.0 buffer | |
| AG crystalline form 11 | 0.26 | 0.30 | 0.25 |
| ACrllCI-H2O | 0.30 | 0.40 | 0.30 |
As can be seen, the agomelatîne hydrochloride hydrate of the présent invention has better solubîlity than agomelatîneper se in water, in 0.1N HCl, which is similar to human gastric fluid, or in pH 7.0 buffer. This means the former enjoys the potential of higher bioavailability than the latter.
4. Crystal Water Analysis Calculated water content in CisHnNCL'HCl'HnO is 6.06 wt%.
4.1 Fischer’s Method (Appendix VIH M, Chinese Pharmacopoeia, 2010)
The product ol’ Example I was analyzed according to said Fischer’s method and water content was found to be 6.15 wt%.
The product of Example 7 was analyzed according to said Fischer’s method and water content was found to be 6.10 wt%.
4.2 Thermal Gravity Analysis (Appendix VIII Q, Chinese Pharmacopoeia, 2010)
The product of Example 1 was analyzed according to said TGA method and water loss was found to be 6,67 wt%, meaning crystal water content in the product is 6.67 wt%. Fig 1 shows TGA thermogram.
The measurement condition for TGA method is as follows:
Type of Instrument: NETZSCH TG 209FI
TypeofCrucible: AI2O3
Flushing gas: N2 20 ml/min
Protective gas: N2 10 ml/min
Température range: Room température ~300°C
Heat rate: 10°C/min
5. Crystal Structure Analysis
DUPLICATA
The measurenient condition for the X-ray powder diffraction pattern of the product of Example 7 in the présent invention is as follows:
XRD parameters Instrument
Detector
X-Ray Scanning Mode Monochromalcr DivSlit
IO DivH.L.Slit Scanning Scaning time Scaning speed Scaning temp
Bruker D8 ADVANCE X-Ray Diffractometer Lynx Eye detector
CuKa 40 kV/40 mA
Theta/Theta
Ni-filter l deg.
l.O mm
Continous Scanning from 3° to 45° with 0.027step min
8.07min
Room température
The X-ray powder diffraction pattern of agomelatine hydrochloride hydrate is characterized by Bragg 20 angle. ïnterplanar spacing d and relative intensity (l%) as follows:
Table 3
| 2-Theta | d(A) | I% |
| 9.076 | 9.7360 | 11.24 |
| 13.635 | 6.4887 | 27.62 |
| 14.427 | 6.1345 | 16.38 |
| 16.872 | 5.2507 | 34.17 |
| 18.176 | 4.8767 | 100.00 |
| 21.610 | 4.1089 | 62.25 |
| 22.259 | 3.9905 | 7.94 |
| 22.794 | 3.8981 | 19.22 |
| 23.878 | 3.7235 | 31.32 |
| 24.214 | 3.6726 | 82.40 |
| 25.457 | 3.4960 | 4I.45 |
| 25.714 | 3.4617 | 37.06 |
| 27.430 | 3.2488 | 31.69 |
| 29.207 | 3.0551 | I3.75 |
When the crystal of the présent invention îs measured by X-ray diffraction, there may be measuremenl errors for the recorded peaks sometimes due to the equipment or conditions applied. 20 Specifically, l'or example, the 20 value has sometimes an error of about ± 0.2, and has sometimes an error of about i 0.1 even if very précisé technical equipment is used. Therefore, the measurement error should be taken into account when identifying the structure of each crystal.
6. Stability Test of the Agomelatine Hydrochloride Hydrate
The method for stability test as described in Chinese Pharmacopoeia was used in this test.
l) Affecttng factors test (in open container for 10 days): high température (60 °C), photostability under strnng light (4500lx), high humidity (92.5%RH at 25°C)
2) Accelerated test (in closed container for 6 months): at 40 °C, humidity: 75%RH
DUPLICATA
3) Long-tenn test (in closed container for 9 months): at 25°C, humidity: 60%RH The results are shown in the following table 4.
Table 4
| Sample | Water (6.10%) | Cl (11.86%) | Agomelatine hydrochloride hydrate of Example 7 (initial purity: 99.72%) | |
| Affecting factors | High température | 1.00 | 1.75 | 99.51 |
| Slrong light | 5.95 | 11.48 | 99.67 | |
| High humidity | 6.03 | 11.63 | 99.73 | |
| Accelerated test | 6.02 | 11.65 | 99.64 | |
| Long-term test | 6.00 | 11.53 | 99.74 |
Therefore, excepl that water content and Cl content of agomelatine hydrochloride hydrate are 5 decreased under a very severe condition, agomelatine hydrochloride hydrate is stable under other conditions, particularly in accelerated test and long-term test, which is favourable for use in pharmaceutical formulations.
Claims (13)
- Claims:l. An agomelatine hydrochloride hydrate of formula I:wherein X is Cl.5
- 2. An agomelatine hydrochloride hydrate of formula I according to claim l in the form of crystalline form, characterized by Bragg 20 angle, interplanar spacing d and relative intensity as follows:
2-Theta d(Â) Relative Intensity (1%) 9.076 9.7360 11.24 13.635 6.4887 27.62 14.427 6.1345 16.38 16.872 5.2507 34.17 I8.176 4.8767 100.00 21.610 4.1089 62.25 22.259 3.9905 7.94 22.794 3.8981 19.22 23.878 3.7235 31.32 24.214 3.6726 82.40 25.457 3.4960 41.45 25.714 3.4617 37.06 27.430 3.2488 31.69 29.207 3.0551 13.75 and which also încludes crystals whose peak diffraction angles match within an error of ±0.2°. - 3. A method l’or the préparation of the agomelatine hydrochloride hydrate according to claim I or 2, 10 wherein agomelatine is reacted with HCl to produce the agomelatine hydrochloride hydrate.
- 4. The method for the préparation of the agomelatine hydrochloride hydrate according to claim 3, wherein agomelatine is reacted with HCl in an aqueous organic solvent to produce the agomelatine hydrochloride hydrate.
- 5. The method for the préparation of the agomelatine hydrochloride hydrate according to claim 4, I5 wherein agomelatine is dissolved in organic solvent before aqueous HCl solution is added to precipitate the crystal of the product.
- 6. The method for the préparation of the agomelatine hydrochloride hydrate according to claim 5, wherein said aqueous HCl solution is added dropwise.DUPLICATA
- 7. The method l'or the préparation of the agomelatine hydrochloride hydrate according to claim 4, wherein agomelatine is added to an aqueous organic solvent containing HCl to precipitate the crystal of the product.
- 8. The method for the préparation of the agomelatine hydrochloride hydrate according to claim 5 or5 7, which further includes rinsing and dryîng the solid after crystallisation.
- 9. The method for the préparation of the agomelatine hydrochloride hydrate according to claim 5 or 7, wherein lhe reaction température is 0-20°C.
- 10. The method for the préparation of the agomelatine hydrochloride hydrate according to claim 5 or 7, wherein said organic solvent is ethyl acetate, methyl acetate, n-butyl acetate, acetone or10 acetonitrile.
- 11. The method for the préparation of the agomelatine hydrochloride hydrate according to claim 10, wherein said organic solvent is ethyl acetate.
- 12. A pharmaceutical composition, comprising an agomelatine hydrochloride hydrate according to claim l or 2 in assocîated with pharmaceutically acceptable adjuvants or excipients.
- 15 13. Use of an agomelatine hydrochloride hydrate according to claim l or 2 for the treatment of melatoninergic system disorders, sleep disorders, stress, anxiety, seasonal affective disorder, major dépréssion, cardiovascular diseases, digestive system diseases, insomnia and fatigue caused by jet lag, schizophrénie. phobia or dépréssion disorders.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010126263.9 | 2010-03-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| OA16621A true OA16621A (en) | 2015-12-01 |
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