WO2012126385A1 - 阿戈美拉汀的新晶型ⅶ、其制备方法、应用和包含其的药物组合物 - Google Patents

阿戈美拉汀的新晶型ⅶ、其制备方法、应用和包含其的药物组合物 Download PDF

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WO2012126385A1
WO2012126385A1 PCT/CN2012/072816 CN2012072816W WO2012126385A1 WO 2012126385 A1 WO2012126385 A1 WO 2012126385A1 CN 2012072816 W CN2012072816 W CN 2012072816W WO 2012126385 A1 WO2012126385 A1 WO 2012126385A1
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Prior art keywords
agomelatine
preparation
water
crystal form
crystals
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PCT/CN2012/072816
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English (en)
French (fr)
Inventor
黄雨
童玲
朱雪焱
单汉滨
袁哲东
俞雄
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上海医药工业研究院
瑟维尔实验室
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Priority to BR112013024219A priority Critical patent/BR112013024219A2/pt
Priority to PL12760538T priority patent/PL2690087T3/pl
Priority to DK12760538.4T priority patent/DK2690087T3/en
Priority to EP12760538.4A priority patent/EP2690087B1/en
Priority to UAA201312167A priority patent/UA113058C2/uk
Priority to NO12760538A priority patent/NO2690087T3/no
Priority to CA2829687A priority patent/CA2829687C/en
Priority to NZ615707A priority patent/NZ615707B2/en
Priority to KR1020137027637A priority patent/KR20130136544A/ko
Priority to RS20171011A priority patent/RS56444B1/sr
Priority to MDA20130073A priority patent/MD4391C1/ro
Priority to SG2013066543A priority patent/SG193300A1/en
Priority to LTEP12760538.4T priority patent/LT2690087T/lt
Application filed by 上海医药工业研究院, 瑟维尔实验室 filed Critical 上海医药工业研究院
Priority to US14/006,468 priority patent/US9527803B2/en
Priority to MYPI2013701573A priority patent/MY185235A/en
Priority to CN201280013421.7A priority patent/CN103476742B/zh
Priority to MX2013010702A priority patent/MX355552B/es
Priority to JP2014500243A priority patent/JP6203170B2/ja
Priority to MA36225A priority patent/MA34958B1/fr
Priority to AU2012231547A priority patent/AU2012231547B2/en
Priority to MEP-2017-271A priority patent/ME02921B/me
Priority to ES12760538.4T priority patent/ES2650604T3/es
Priority to SI201231112T priority patent/SI2690087T1/sl
Priority to EA201301066A priority patent/EA023297B1/ru
Publication of WO2012126385A1 publication Critical patent/WO2012126385A1/zh
Priority to ZA2013/06760A priority patent/ZA201306760B/en
Priority to HK14106353.2A priority patent/HK1193087A1/zh
Priority to HRP20171831TT priority patent/HRP20171831T1/hr
Priority to CY20171101244T priority patent/CY1119625T1/el

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    • 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
    • C07C233/22—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 an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C07C231/24—Separation; Purification

Definitions

  • Novel crystal form of agomelatine vn preparation method thereof, application and pharmaceutical composition containing the same
  • the present invention relates to a novel crystalline form of agomelatine or ⁇ -[ 2 _( 7 _methoxy-1-naphthalenyl)ethyl acetamide, and a preparation method thereof, application and pharmaceutical composition comprising the same Things. Background technique
  • melatonin has a dual role, not only an agonist of melatonin system receptors, but also an antagonist of 5HT 2C receptors, its properties make it active in the central nervous system, especially in severe depression, seasonal affective disorder, It is active in the treatment of sleep disorders, cardiovascular diseases, digestive diseases, insomnia and fatigue caused by jet lag, appetite disorders and obesity. It is the first melatonin antidepressant that can effectively treat depression, improve sleep parameters and not affect sexual function.
  • Form II is obtained by recrystallization of ethanol and water.
  • Preparation method of crystalline germanium at 110. C Heat the agomelatine until it is completely melted, then slowly cool until crystallization is obtained.
  • Method for preparing Form IV at 110. C heats the agomelatine until it is completely melted, then at 50 and 70. Between C Cooling, and maintaining at 70 Torr for about 5 hours until crystallization is obtained;
  • Preparation method of Form V The so-called "high energy, ⁇ L*9 grinding of agomelatine, crystal form VI by acetic acid and water Crystallized.
  • the type comparison shows valuable properties in terms of formulation, and the preparation method has good reproducibility.
  • the crystalline form of agomelatine of the present invention can be used for treating melatonin system diseases, sleep disorders, nervousness, anxiety disorders, seasonal affective disorders, severe depression, cardiovascular diseases, digestive diseases, and jet lag Insomnia or fatigue, schizophrenia, phobia, depression.
  • Another object of the present invention is to provide a process for preparing a crystal form ⁇ of agomelatine which is easy to reproduce.
  • a further object of the present invention is to provide a pharmaceutical composition comprising the crystalline form W of agomelatine of the present invention together with a pharmaceutically acceptable adjuvant or excipient.
  • compositions can be formulated for use in a variety of routes of administration, particularly for oral administration or injection.
  • the dosage administered can be adjusted depending on the nature and severity of the disease to be treated, the route of administration, and the age and weight of the patient.
  • the dosage can vary from 0.1 mg to 1 g per day and can be administered in one or more divided doses.
  • the crystal form of agomelatine of the present invention is characterized by the following X-ray diffraction pattern, which is expressed by the 2 ⁇ angle of the cloth, the relative spacing of the crystal faces, and the relative intensity:
  • the crystal of the present invention When the crystal of the present invention is measured by X-ray diffraction, there may be a slight measurement error with respect to the measured peak due to the measured instrument or the measurement conditions. Specifically, for example, the measurement error of the 2 ⁇ value is sometimes about ⁇ 0.2. Even when using very sophisticated equipment, an error of about ⁇ 0.1 is sometimes generated. Therefore, this error should be taken into account when determining each crystal structure.
  • Scan range: 3° ⁇ 45°
  • ⁇ type standard aluminum ⁇ (needle piercing)
  • Purge gas high purity nitrogen 20 ml/min; shielding gas: high purity nitrogen 60 ml/min.
  • the preparation method of the crystal form ⁇ of the present invention is to dissolve the agomelatine complex (formula II or hydrazine) in acetic acid, and then add acetate (preferably acetic acid clock or Ammonium acetate), water was added dropwise to the obtained reaction liquid, and the mixture was stirred at 17 to 23 Torr to precipitate crystals, and then the crystals were separated from the liquid phase.
  • acetate preferably acetic acid clock or Ammonium acetate
  • the acetic acid of the present invention has no special requirement for the amount of acetic acid to be added, and is preferably dissolved in the raw material according to the requirements.
  • the molar ratio of the formula II or ⁇ agomelatine complex to the acetate is preferably from 1:1 to 1.5, particularly preferably from 1:1 to 1.1.
  • the acetate salt includes an acetic acid clock and ammonium acetate.
  • the volume fraction ratio of acetic acid to water is 1:10-30.
  • the resulting reaction solution is 19-25. C, especially at about 22. C or 23.
  • crystals were precipitated by dropwise addition of water thereto.
  • crystals are precipitated by dropwise addition of water to the obtained reaction liquid and stirring at about 20 Torr, for example, for about 2 hours.
  • reaction solution is heated to 30 to 50 ° C after the addition of the acetate to obtain a clear solution; the solution is allowed to cool naturally, and crystals are precipitated by dropwise addition of water thereto.
  • the invention obtains a new crystal form ⁇ of agomelatine, has good purity, stable crystal form and good reproducibility, is easy to be enlarged, and has advantages in preparation. It exhibits good stability and excellent solubility compared to the existing crystal form.
  • the above formula II or ⁇ agomelatine complex can be prepared by the following preparation method, which is the combination of agomelatine with various forms of HC1 or HBr
  • the reaction forms a hydrate.
  • the solid precipitated in the solvent is washed and dried. If the first method is used to pass HC1 or HBr too much, the yield is lowered, and the second method is easy to control the amount of HC1 or HBr in the solvent, so the second method is preferred.
  • agomelatine may be added to an aqueous organic solvent, and a solvent containing HC1 or HBr may be added dropwise, and the solid precipitated and washed may be washed and dried.
  • agomelatine may be added to an organic solvent, and an aqueous solution of HC1 or HBr may be added dropwise, and the solid precipitated in the crystal may be washed and dried.
  • Figure 1 is an X-ray diffraction pattern of a crystal form W obtained in Example 1 of the present invention
  • FIG. 2 is a DSC endothermic transition map of the crystal form W obtained in Example 1 of the present invention
  • Figure 3 is a TGA graph of the thermogravimetric analysis of the product of Example 5 of the present invention
  • Figure 4 is a TGA graph of the thermogravimetric analysis of the product of Example 6 of the present invention.
  • Example 1 The invention is further illustrated by the following examples, which are not to be construed as limited.
  • Example 1 The invention is further illustrated by the following examples, which are not to be construed as limited.
  • Example 1 Example 1:
  • the agmelatin complex (7.6 g) was dissolved in AcOH (19 ml) and added to KOAc (3.5 g); heated to 40. C, clear solution; natural cooling, the solution gradually became cloudy, water (250 ml) was added dropwise at 22 ° C, and stirred at ⁇ 20 ° C for 2 hours; filtered, the filter cake was washed with water, 50. Dry under vacuum to constant weight to give a white solid 4.5 g , purity: 99.8%
  • Forms II, ⁇ , VI, W (from Example 3) were placed in an incubator at 40 ° C, placed After 20 days, the stability of these crystal samples was investigated by high performance liquid chromatography.
  • Color transfer conditions using octadecylsilane bonded silica as a filler; a mixed solution of 10 mmol/L phosphate buffer salt (pH adjusted to 7.0 with sodium hydroxide) and acetonitrile volume ratio of 2:7 as mobile phase
  • the column temperature is 40 ⁇ ; the detection wavelength is 220 nm.
  • the purity was determined by an internal standard method.
  • the crystal forms II, m, VI, and W were each placed in a 1 m g /mL solution using a mobile phase, and each was injected into a liquid chromatograph to record a chromatogram.
  • the method of determination uses the stability assessment method in the pharmacopoeia:
  • the new crystal form W of agomelatine of the invention has obvious advantages in preparation process, stability and solubility compared with the current crystal form, and is more conducive to medicine preparation.
  • Example 5 Formula II agomelatine complex
  • C1 content is 11.91wt%
  • Example 5 The product of Example 5 was tested according to the Fisher's method, and the measured crystal water content was 6.15 wt %.
  • Example 5 The product of Example 5 was tested according to the thermal analysis method, and the amount of loss of crystal water was measured to be 6.67 wt%, that is, the original product contained 6.67 wt% of crystal water. See Figure 3 for the TGA curve.
  • Example 6 Formula ⁇ agomelatine complex
  • Example 6 The product of Example 6 was tested according to the Fisher's method, and the measured water content was 5.10 wt % 6.2 Thermogravimetric analysis (Chinese Pharmacopoeia 2 010 version Appendix VIII Q)
  • Example 7 Preparation of a pharmaceutical composition

Abstract

本发明提供了阿戈美拉汀的新晶型Ⅶ、其制备方法、应用和包含其的药物组合物。该新的晶型纯度好、晶型稳定且重现性好，其制备方法易于放大，在稳定性和溶解度上，更优于现有报道的多数晶型。因此，本发明的晶型Ⅶ在制剂方面具有优势。

Description

阿戈美拉汀的新晶型 vn、 其制备方法、 应用和包含其的药物组合物 技术领域
本发明涉及阿戈美拉汀或 Ν-[2_(7_甲氧基 -1-萘基)乙基】乙酰胺的一种 新晶型， 及其制备方法、 应用和包含其的药物组合物。 背景技术
阿戈美拉汀 (agomelatine),化学名为 N-[2-(7-甲氧基 -1-萘基)乙基】乙酰 胺， 商品名 Valdoxan, 化
Figure imgf000002_0001
它具有双重作用， 不仅是褪黑激素能系统受体的激动剂， 还有拮抗 5HT2C受体的作用， 其性质使其在中枢神经系统具备活性， 尤其在严重抑 郁症、 季节性情感障碍、 睡眠障碍、 心血管疾病、 消化系统疾病、 飞行时 差引起的失眠和疲劳、 食欲紊乱和肥胖症的治疗中具有活性。 它是第一个 褪黑激素类抗抑郁药， 能有效治疗抑郁症， 改善睡眠参数和不影响性功能。
阿戈美拉汀、其制备及其治疗用途在欧洲专利说明书 EP0447285中已 有报道。
鉴于该化合物的药学价值， 获得纯度好、 晶型稳定且重现性好的该化 合物是重要的， 使其在制剂方面具有优势， 并且足够稳定可以长期存储， 且对温度、 光、 湿度或氧气水平没有特定要求。
对于阿戈美拉汀已有多篇文献艮道， 例如在专利 CN200510071611.6、 CN200610108396.7 、 CN200610108394.8 、 CN200610108395.2 、 CN200910047329.2, CN200910245029.5 等公开了阿戈美拉汀的多种晶型 及其制备方法。
其中晶型 II是通过乙醇与水重结晶制得。晶型 ΠΙ的制备方法：在 110。C 加热阿戈美拉汀直至完全熔化， 然后緩慢冷却直至结晶得到。 晶型 IV的制 备方法：在 110。C加热阿戈美拉汀直至完全熔化， 然后在 50和 70。C之间迅 速冷却， 并在 70Ό维持约 5小时直至结晶得到； 晶型 V的制备方法： 对阿 戈美拉汀进行所谓的"高能，， ^L*9磨制得， 晶型 VI通过醋酸和水重结晶所 得。
众所周知， 由于化合物可以呈现出不同的分子排列， 而拥有不同的固 体型态， 即同质多晶型。 在药物中不同的晶型可能会导致药物的在溶出以 及生物利用度的不同， 因此寻找药物中纯度好， 重现性好， 易于生产应用， 溶出及生物利用度优良的晶型， 在药物的开发中显的尤为重要。 发明内容
本发明的目的是提供一种新的阿戈美拉汀的晶型， 即晶型 νπ， 并提供 制备这一晶型的方法， 且该晶型与已上市的药物 (Valdoxan)中的 II晶型比 较， 在制剂方面显示出有价值的特性， 且该制备方法重现性好。
本发明的阿戈美拉汀的晶型 ΥΠ可用于治疗褪黑素能系统疾病、 睡眠障 碍、 紧张、 焦虑症、 季节性情感障碍、 严重抑郁症、 心血管疾病、 消化系 统疾病、 飞行时差引起的失眠或疲劳、 精神分裂症、 恐惧症、 抑郁症。
本发明的另一目的是提供阿戈美拉汀的晶型 νπ的制备方法， 该制备方 法操作筒单， 重现性好。
本发明的又一目的是提供药物组合物， 其包含本发明的阿戈美拉汀的 晶型 W以及可药用辅料或赋形剂。
可配制所述药物组合物以用于各种施用途径， 尤其是用于口服施用或 注射。
可根据待治疗疾病的性质和严重性、 施用途径以及患者的年龄及体重 调节施用剂量。 剂量可在每天 0.1 mg至 l g之间变化， 可以一次或分多次 施用。
本发明的阿戈美拉汀的晶型以下列的 X射线衍射图表征， 其以布拍 2Θ角、 晶面间距^ 相对强度来表示：
Figure imgf000003_0001
13.301 6.6509 11.45
16.145 5.4855 10.60
17.286 5.1258 6.19
17.841 4.9675 100.00
19.359 4.5813 10.83
20.089 4.4164 11.77
23.366 3.8040 29.82
24.944 3.5667 21.60
26.128 3.4078 12.47
用 X射线衍射测定本发明的结晶时， 有时由于测定的仪器或测定的条 件， 对于所测得的峰而言稍有测定误差， 具体来说， 例如， 2Θ值的测定误 差有时为约 ±0.2, 即使使用非常精密的设备时， 有时也会产生约 ±0.1 的误 差。 因此， 在确定每种结晶结构时， 应该将此误差考虑在内。
XRD测试条件：
仪器型号： Bruker D8 ADVANCE X射线衍射仪
实验 ：
检测器： LynxEye检测器
光源： CuKoi 40 kV 40 mA
单色器： M滤片
发散狭缝： 1。
DivH丄 .Slit: 1.0 mm
探测器： LynxEye探测器
扫描方式： Θ-Θ连续扫描
扫描范围： 3°~45°
步长： 0.02°
扫描速度： 8.0°/min
扫描时间： 5 min
扫描温度： 室温 DSC测试条件：
仪器型号： NETZSCH DSC 204F1
实验糾：
坩埚类型： 标准铝坩埚 (针刺穿孔）
吹扫气： 高纯氮 20 ml/min; 保护气： 高纯氮 60 ml/min。
温度范围： 室温〜 140 "C
升温速率： lO /min
TGA测试 ^
仪器型号 NETZSCH TG 209F1
实验糾
坩埚类型： A1203
吹扫气： N2 20 ml/min; 保护气： N2 10 ml/min
温度范围： 室温〜 300 "C
升温速率： 10"C/miii 本发明晶型 νπ的制备方法， 该方法是将阿戈美拉汀复合物 (式 II或 ΠΙ) 溶于醋酸， 然后向其中加入醋酸盐 (优选醋酸钟或醋酸铵)， 通过向所得到 的反应液中滴加水并在 17-23Ό进行搅拌，使结晶析出，然后将结晶与液相 分离。
Figure imgf000005_0001
( II ) (III) 本发明所述的醋酸， 其加入量无特殊要求， 以能溶解原料为准， 并可 根据需求适当加热助溶。
式 II或 ΠΙ阿戈美拉汀复合物与醋酸盐的摩尔比优选为 1 ： 1-1.5， 特别 优选 1 : 1-1.1。 所述醋酸盐包括醋酸钟、 醋酸铵。 本发明所述制备方法中， 醋酸与水的体积份数比为 1： 10-30。
在本发明晶型 νπ的制备方法的一个优选的实施方案中， 在所得到的反 应液为 19-25。C、 特别是在约 22。C或 23。C时， 通过向其中滴加水使结晶析 出。
在另一个优选的实施方案中， 通过向所得到的反应液中滴加水并在约 20Ό进行搅拌， 例如搅拌约 2小时， 使结晶析出。
在另一个优选的实施方案中， 在加入醋酸盐后将反应液加热至 30-50 °C , 得到澄清的溶液； 使该溶液自然冷却， 通过向其中滴加水使结晶 析出。
本发明得到了一种新的阿戈美拉汀的晶型 νπ， 纯度好、 晶型稳定且重 现性好， 易于放大制备， 在制剂方面具有优势。 与现有晶型相比， 表现出 良好的稳定性和优良的溶解度。
根据中国专利申请 CN 201010126254.X和 CN 201010126263.9, 上述 式 II或 ΠΙ阿戈美拉汀复合物可通过以下的制备方法来制备， 该方法是将阿 戈美拉汀与各种形式的 HC1或 HBr反应形成水合物。 具体步骤为两种： 先将阿戈美拉汀溶解于含水有机溶剂， 然后通入 HC1或 HBr气体， 再将 结晶析出的固体洗涤、 干燥； 或者将阿戈美拉汀加入到含有 HC1或 HBr 的溶剂中，再将结晶析出的固体洗涤、干燥。如果使用第一种方法通入 HC1 或 HBr过多反而会造成收率降低， 而第二种方法对于溶剂中 HC1或 HBr 的量则容易控制， 所以优选第二种方法。
其中， 也可以将阿戈美拉汀加入到含水有机溶剂中， 再滴加含 HC1或 HBr的溶剂， 再将结晶析出的固体洗涤、 干燥。
同样也可以将阿戈美拉汀加入到有机溶剂中， 再滴加 HC1或 HBr水 溶液， 再将结晶析出的固体洗涤、 干燥。
所引用或提及的参考文献的全部内容引入本申请作为参考。 附图说明
图 1是本发明实施例 1所得晶型 W的 X射线衍射图谱；
图 2是本发明实施例 1所得晶型 W的 DSC吸热转变图谱； 图 3为本发明实施例 5产物进行热重分析的 TGA曲线图； 图 4为本发明实施例 6产物进行热重分析的 TGA曲线图。 具体实施方式
下面通过实施例的方式进一步说明本发明， 但并不因此将本发明 P艮制 在所述的实施例范围之中。 实施例 1:
将式 ΠΙ阿戈美拉汀复合物 (7.6 g)溶于 AcOH (19 ml)溶液中， 加入 KOAc (3.5 g); 加热至 40。C， 得澄清溶液； 自然冷却， 溶液逐渐变浑浊， 于 22°C， 滴加水 (250 ml)， 并在〜 20°C搅拌 2小时； 过滤， 用水洗涤滤饼， 50。C下真空干燥至恒重， 得到白色固体 4.5 g， 纯度： 99.8%
熔点： 98-100 °C 实施例 2:
将式 II阿戈美拉汀复合物 (2 g)溶于 AcOH (5 ml), 加入 NH4OAc (0.57 g); 加热至 40。C， 得澄清溶液； 自然冷却， 溶液逐渐变浑浊， 于 22°C , 滴 加水 (150 ml), 并在〜 20°C搅拌 2小时； 过滤， 用水洗涤滤饼， 50°C下真空 干燥至恒重， 得到白色固体 1.4 g， 纯度： 99.7%
熔点： 98-100。C 实施例 3:
将式 ΠΙ阿戈美拉汀复合物 (40 g)溶于 AcOH (130 ml)溶液中， 加入 NH4OAc(10g); 加热至 40。C， 得澄清溶液； 自然冷却， 溶液逐渐变浑浊， 于 23。C， 滴加水 (2.6 L), 并在〜 20。C搅拌 2小时； 过滤， 用水洗涤滤饼， 50。C下真空干燥至恒重， 得到白色固体 25 g， 纯度： 99.8%
熔点： 98-100 °C 实施例 4:
将晶型 II、 ΠΙ、 VI、 W (得自实施例 3)分别放入 40 °C的恒温箱中， 放 置 20天， 通过高效液相色谱法对这些晶型样品的稳定性进行研究。
1、 样品纯度测定
色傳条件： 用十八烷基硅烷键合硅胶为填充剂； 以 10 mmol/L磷酸緩 冲盐 (用氢氧化钠调节 pH至 7.0)和乙腈体积比为 2: 7的混合溶液作为流动 相； 柱温为 40Ό; 检测波长为 220 nm。 通过内标法测定纯度。
用流动相分别将晶型 II、 m、 VI、 W配置成 1 mg/mL 的溶液， 各取 10 注入液相色谱仪， 记录色谱图。
2、 样品含量测定
方法参考样品纯度测定的方法，用外标法进行测定，结果见表一：
Figure imgf000008_0001
3、 水溶性测定
方法采用 HPLC方法， 用外标法进行测定。 结果如下表二:
Figure imgf000008_0002
4、 晶型稳定性测定
测定方法采用药典中稳定性考核方法：
1 ) 影响因素实验 (敞口 10天)： 高温 (60。C)， 光照 (45001x)， 高湿 (92.5%RH, 25°C) 加速实验 (密闭 6个月）： 温度为 40°C , 湿度为 75%RH
3 ) 长期实验 (密闭 12个月）： 温度为 25°C， 湿度为 60%RH 表三
Figure imgf000009_0001
根据测试结果看到， 本发明的阿戈美拉汀的新晶型 W在制备工艺、 稳 定性和溶解度与目前的晶型相比均存在明显的优势， 更利于成药。
5 药物组合物的稳定性研究 (晶型、 纯度和含量）
本品 (得自实施例 7)按照药典稳定性考核研究方法，经过影响因素实验 (敞口 10天)： 高温 (40"€)， 光照 (45001χ)， 高湿 (92.5%RH， 25"€)； 加速实 验 (密闭 6个月）： 温度为 40"€， 湿度为 75%RH; 长期实验 (密闭 8个月）： 温度为 25C 湿度为 60%RH， 考核结果显示在上述条件下本品的晶型、 纯度和含量均未发生改变。
因此，本品的原料药和胶嚢的各项试验结果显示形式 -νπ具有优良的成 药前景。 实施例 5: 式 II阿戈美拉汀复合物
将 10 g阿戈美拉汀加入到 100 ml乙酸乙酯溶液中， 10"€条件下逐滴 加入 HC1 (36%)水溶液 4.6 g,搅拌 1个小时；过滤， 固体用乙酸乙酯 10 ml 洗涤两次， 40 下干燥得到式 II的白色固体 10.2 g; 纯度： 99.8%, 收率： 88.7%。
C1元素分析：
理 十算值： C1含量为 11.91wt %
实测值： C1含量为 11.86 wt % 式 II阿戈美拉汀复合物结晶水含量测定：
根据计算得 Ci5H17N02 HC1 H20中结晶水的理论含量为 6.06 wt %。
5.1 费休氏法（《中国药典》 2010版 附录 VIII M)
取实施例 5产物按照所述费休氏法测试， 实测结晶水含量： 6.15 wt %
5.2 热重分析（《中国药典》 2010版 附录 VIII Q)
取实施例 5产物按照所述热分析法测试， 测得结晶水损失量 6.67 wt %, 即原产物中含有结晶水 6.67 wt %。 TGA曲线请参见图 3。 实施例 6: 式 ΠΙ阿戈美拉汀复合物
将 100 g阿戈美拉汀搅摔溶解于 800 ml乙酸乙酯中， 低温下逐滴加入 HBr水溶液 (8.32 g， 40%), 搅拌 1个小时； 过滤， 固体用乙酸乙酯 100 ml 洗涤两次，在 40 X下干燥得到白色固体 120 g;纯度： 99.9%,收率： 85.3%。 分析结果 (C15H17N02 · HBr · H20 )
计算值： Br%(23.35%)
实测值： Br%(23.29%) 式 m阿戈美拉汀复合物结晶水含量测定：
根据计算得 Ci5H17N02 HBr ·Η20中结晶水的理论含量为 5.26 wt %。 6.1 费休氏法（《中国药典》 2010版 附录 VIII M)
取实施例 6产物按照所述费休氏法测试， 实测结晶水含量： 5.10 wt % 6.2 热重分析（《中国药典》 2010版 附录 VIII Q)
取实施例 6产物按照所述热分析法测试， 测得结晶水损失量 5.70 wt %, 即原产物中含有结晶水 5.70 wt %。 TGA曲线请参见图 4。 实施例 7: 药物组合物的制备
1000粒胶嚢处方 (剂量： 25 mg)
晶型 νπ 25 g
乳糖 (Spherolac 100) 88.9 g
硬脂酸镁 1 7 g
淀粉 (Starch 1500) 25.5 g
羧甲基淀粉钠 (CMS-Na) 8.5 g
Ac-Di-Sol ® (FMC) 17 g
硬脂酸 3.4 g

Claims

权利要求
1. 阿戈美拉汀的晶型， 其以用布拉格 2Θ角表示的以下 X射线衍射图 表征：
Figure imgf000012_0001
并且其还包括峰衍射角在上述 2Θ±0.2°的误差内匹配的晶体。
2. 阿戈美拉汀的晶型， 其以用布拉格 2Θ角、 晶面间距 d和相对强度 表示的以下 X射线衍射图表征：
Figure imgf000012_0002
并且其还包括峰衍射角在上述 2Θ±0.2°的误差内匹配的晶体。
3.如权利要求 1或 2所述的阿戈美拉汀的晶型的制备方法， 将式 II或 ΠΙ阿戈美拉汀复合物溶于醋酸， 然后向其中加入醋酸盐， 通过向所得到的 反应液中滴加水并在 17-23°C进行搅拌，使结晶析出，然后将结晶与液相分 离
Figure imgf000013_0001
( II ) (III ) 。
4.如权利要求 3所述的制备方法， 其中， 式 II或 ΠΙ阿戈美拉汀复合物 与醋酸盐的摩尔比为 1： 1-1.5， 优选 1： 1-1.1。
5.如权利要求 3或 4所述的制备方法， 其中， 醋酸与水的体积份数比 为 1： 10-30。
6.如权利要求 3-5中任意一项所述的制备方法， 其中， 所述醋酸盐是 醋酸钟或者醋酸铵。
7.如权利要求 3-6中任意一项所述的制备方法， 其中， 在所得到的反 应液为 19-25。 ( 、 特别是在 22或 23。C时， 通过向其中滴加水使结晶析出。
8.如权利要求 3-7中任意一项所述的制备方法， 其中， 通过向所得到 的反应液中滴加水并在 20。C进行搅拌， 使结晶析出。
9.如权利要求 3-8中任意一项所述的制备方法， 其中， 在加入醋酸盐 后将反应液加热至 30-50 C，得到澄清的溶液； 使该溶液自然冷却，通过向 其中滴加水使结晶析出。
10. 药物组合物， 其包含如权利要求 1或 2所述的阿戈美拉汀的晶型 以及可药用辅料或赋形剂。
11. 用于制备药物的如权利要求 10所述的药物组合物， 所述药物用于 治疗褪黑素能系统疾病。
12. 用于制备药物的如权利要求 10所述的药物组合物， 所述药物用于 治疗睡眠障碍、 紧张、 焦虑症、 季节性情感障碍、 严重抑郁症、 心血管疾 病、 消化系统疾病、 飞行时差引起的失眠或疲劳、 精神分裂症、 恐惧症或 抑郁症。
13.如权利要求 1或 2所述的阿戈美拉汀的晶型在制备药物中的应用， 所述药物用于治疗褪黑素能系统疾病。
14.如权利要求 1或 2所述的阿戈美拉汀的晶型在制备药物中的应用， 所述药物用于治疗睡眠障碍、 紧张、 焦虑症、 季节性情感障碍、 严重抑郁 症、 心血管疾病、 消化系统疾病、 飞行时差引起的失眠或疲劳、 精神分裂 症、 恐惧症或抑郁症。
PCT/CN2012/072816 2011-03-23 2012-03-22 阿戈美拉汀的新晶型ⅶ、其制备方法、应用和包含其的药物组合物 WO2012126385A1 (zh)

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EP3075724A1 (en) 2015-03-31 2016-10-05 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Solid form of agomelatine

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PH12012000132A1 (en) * 2011-06-09 2014-10-20 Servier Lab New co-crystals of agomelatine, a process for their preparation and pharmaceutical compositions containing them
JP6595990B2 (ja) * 2013-07-29 2019-10-23 レ ラボラトワール セルヴィエ アゴメラチンとスルホン酸との新規な複合体、これらの製造方法及びこれらを含有する医薬組成物
KR101470794B1 (ko) 2014-06-30 2014-12-08 순천향대학교 산학협력단 아고멜라틴 공결정의 제조 방법 및 이를 포함하는 조성물
EP3466413A1 (en) 2017-10-09 2019-04-10 KRKA, d.d., Novo mesto Pharmaceutical composition containing agomelatine and process for the preparation thereof
EP3466923A1 (en) 2017-10-09 2019-04-10 KRKA, d.d., Novo mesto Process for the preparation of agomelatine in crystalline form

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0447285A1 (fr) 1990-02-27 1991-09-18 Adir Et Compagnie Nouveaux dérivés à structure naphtalénique, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
CN1907957A (zh) * 2005-08-03 2007-02-07 瑟维尔实验室 阿戈美拉汀的新晶形ⅳ、它的制备方法和包含它的药物组合物
CN101585779A (zh) * 2009-03-10 2009-11-25 上海医药工业研究院 阿戈美拉汀的新晶型ⅵ及其制备方法和应用
CN101704763A (zh) * 2009-11-25 2010-05-12 天津泰普药品科技发展有限公司 阿戈美拉汀i型晶体的制备方法
CN101781225A (zh) * 2009-11-21 2010-07-21 浙江华海药业股份有限公司 一种阿戈美拉汀晶形a制备方法
CN101792400A (zh) * 2010-03-16 2010-08-04 华东师范大学 一种阿戈美拉汀的合成方法
CN101921205A (zh) * 2010-08-30 2010-12-22 江苏恩华药业股份有限公司 阿戈美拉汀ⅰ晶型的制备方法

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2866335B1 (fr) * 2004-02-13 2006-05-26 Servier Lab Nouveau procede de synthese de l'agomelatine
US7498466B2 (en) * 2004-02-13 2009-03-03 Les Laboratoires Servier Process for the synthesis and crystalline form of agomelatine
FR2889521B1 (fr) * 2005-08-03 2007-12-28 Servier Lab Nouvelle forme cristalline iii de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent
US7358395B2 (en) * 2005-08-03 2008-04-15 Les Laboratories Servier Crystalline form V of agomelatine, a process for its preparation and pharmaceutical compositions containing it
FR2889523B1 (fr) * 2005-08-03 2007-12-28 Servier Lab Nouvelle forme cristalline v de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent
EP2319827A1 (en) * 2009-11-09 2011-05-11 Ratiopharm GmbH Process for the production of polymorph form I of agomelatine
CN101781226B (zh) * 2009-12-23 2012-03-28 天津泰普药品科技发展有限公司 阿戈美拉汀及其药物组合物
CN102452951B (zh) * 2010-10-25 2014-02-19 天津泰普药品科技发展有限公司 阿戈美拉汀及其药物组合物

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0447285A1 (fr) 1990-02-27 1991-09-18 Adir Et Compagnie Nouveaux dérivés à structure naphtalénique, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
CN1907957A (zh) * 2005-08-03 2007-02-07 瑟维尔实验室 阿戈美拉汀的新晶形ⅳ、它的制备方法和包含它的药物组合物
CN101585779A (zh) * 2009-03-10 2009-11-25 上海医药工业研究院 阿戈美拉汀的新晶型ⅵ及其制备方法和应用
CN101781225A (zh) * 2009-11-21 2010-07-21 浙江华海药业股份有限公司 一种阿戈美拉汀晶形a制备方法
CN101704763A (zh) * 2009-11-25 2010-05-12 天津泰普药品科技发展有限公司 阿戈美拉汀i型晶体的制备方法
CN101792400A (zh) * 2010-03-16 2010-08-04 华东师范大学 一种阿戈美拉汀的合成方法
CN101921205A (zh) * 2010-08-30 2010-12-22 江苏恩华药业股份有限公司 阿戈美拉汀ⅰ晶型的制备方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"Chinese Pharmacopoeia", 2010
See also references of EP2690087A1
TINANT, B. ET AL.: "N-[2-(7-Methoxy-1-naphthyl)ethyl]-acetamide, a potent melatonin analog", ACTA CRYST, vol. C50, 1994, pages 907 - 910, XP055123493 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3075724A1 (en) 2015-03-31 2016-10-05 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Solid form of agomelatine

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