WO2015180582A1 - 阿立哌唑半乙醇合物新晶型、其制备方法及用途 - Google Patents

阿立哌唑半乙醇合物新晶型、其制备方法及用途 Download PDF

Info

Publication number
WO2015180582A1
WO2015180582A1 PCT/CN2015/079365 CN2015079365W WO2015180582A1 WO 2015180582 A1 WO2015180582 A1 WO 2015180582A1 CN 2015079365 W CN2015079365 W CN 2015079365W WO 2015180582 A1 WO2015180582 A1 WO 2015180582A1
Authority
WO
WIPO (PCT)
Prior art keywords
aripiprazole
crystal form
hemiethanolate
preparation
temperature
Prior art date
Application number
PCT/CN2015/079365
Other languages
English (en)
French (fr)
Inventor
吴明军
年亦丰
陈伟铭
Original Assignee
上海特化医药科技有限公司
山东特珐曼药业有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 上海特化医药科技有限公司, 山东特珐曼药业有限公司 filed Critical 上海特化医药科技有限公司
Publication of WO2015180582A1 publication Critical patent/WO2015180582A1/zh

Links

Images

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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • 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

Definitions

  • the present invention relates to a novel crystalline form of aripiprazole hemiethanolate and a process for the preparation thereof, and a process for preparing a low-absorbency aripiprazole crystal form I using a novel crystalline form of aripiprazole hemiethanolate.
  • Aripiprazole (OPC-14597) is an antipsychotic drug jointly developed by Otsuka Pharmaceutical Co., Ltd. and Bristol-Myers Squibb, USA. It is clinically used for the treatment of schizophrenia. Its chemical name is 7-[4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)-quinolinone.
  • Aripiprazole is a polymorphic substance that can be obtained by different crystallization solvents and methods.
  • the 4th Japan-Korea Separation Technology Symposium Proceedings (October 6-8, 1996) and WO03/026659 indicate that aripiprazole is recrystallized from ethanol at 80 °C.
  • aripiprazole Form I Drying gives aripiprazole Form I, the wettability data is 0.04% before wetting and 3.28% after wetting; aripiprazole Form I can also be obtained by recrystallization from 20% aqueous ethanol to obtain aripiprazole hydration
  • the material was dried at 80 ° C, and its wettability data was 0.04% before wetting and 1.78% after wetting.
  • the aripiprazole crystal form I prepared by the above two methods has remarkable hygroscopicity, thereby causing the following problems: 1) they are difficult to process because of their moisture absorption, and measures must be taken to ensure that they are not processed and formulated. Contact with moisture.
  • WO 03/026659 describes a low hygroscopic aripiprazole Form B and a process for its preparation, which is obtained by grinding a conventional hydrate by specific grinding conditions to obtain a hydrate A, and then by drying the hydrate A. Conversion to low hygroscopic aripiprazole Form B. Although this process can solve the hygroscopicity problem of aripiprazole, the process is cumbersome, the process is complicated, the repeatability is poor, and a large amount of consumption is required. The power cost is not conducive to large-scale industrial production of products.
  • aripiprazole is a poorly soluble drug which, when formulated into an oral preparation such as a tablet or other solid preparation including a fast-dissolving formulation, has a large influence on its dissolution degree and bioavailability. If mechanical pulverization and/or grinding is used, the average particle size generally can only reach about 100 micrometers, the dissolution rate of the obtained solid preparation is not ideal, and the mechanical pulverization treatment has disadvantages such as dust, pollution environment and large energy consumption.
  • the problem to be solved by the present invention is to provide a process for preparing a low hygroscopic aripiprazole crystal form I.
  • a first object of the present invention is to provide a crystal form of aripiprazole hemiethanolate ⁇ .
  • a second object of the present invention is to provide a process for preparing a crystal form of aripiprazole hemiethanolate ⁇ .
  • a third object of the present invention is to provide a crystalline form of aripiprazole hemiethanolate beta which can be used to prepare a low hygroscopic aripiprazole Form I.
  • the diffraction angle 2 ⁇ of the powder X-ray diffraction spectrum has characteristic peaks at the following values: 17.5° ⁇ 0.2°, 19.7° ⁇ 0.2°, 23.4° ⁇ 0.2°, 24.5° ⁇ 0.2° and 27.9° ⁇ 0.2°.
  • the aripiprazole hemiethanolate beta crystal form has a powder X-ray diffraction spectrum as shown in FIG.
  • the differential heat scan showed an absorption peak at about 100.00 ° C and 139.95 ° C (rate of temperature: 10.00 ° C / min);
  • the infrared spectrum (KBr tablet) has a main absorption band (cm -1 ) around the following values: 2948.6, 2823.3, 1673.9, 1627.6, 1446.4, 1378.9, 1170.6, 960.4, and 711.6;
  • the invention also provides a preparation method of the aripiprazole hemiethanolate ⁇ crystal form, the process comprising the following steps:
  • aripiprazole is placed in absolute ethanol, stirred and heated until completely dissolved to obtain aripiprazole ethanol solution;
  • Step (1) The ratio of aripiprazole to absolute ethanol is 1 g: 5 ml to 1 g: 20 ml, preferably 1 g: 8 ml to 1 g: 15 ml.
  • the heating temperature described in the step (1) is usually from 50 ° C to the boiling point of absolute ethanol, and most preferably the boiling point of absolute ethanol.
  • the aripiprazole ethanol solution of the step (1) contains an insoluble matter, it is filtered while hot, and the filtrate is further heated until completely dissolved.
  • Step (1) decolorization of activated carbon may also be added to the solution.
  • the amount of activated carbon is generally 1% to 5% by weight of aripiprazole, and the decolorization process is about 5 to 60 minutes.
  • the activated carbon is filtered while hot, and the filtrate continues. Heat until completely dissolved.
  • Step (2) The aripiprazole ethanol solution is cooled to room temperature or below, preferably from -10 to 25 ° C, most preferably from 0 to 10 ° C.
  • the cooling adopts a natural cooling method or a gradient cooling method; the natural cooling method refers to exposing the reaction device to a natural environment, and the temperature of the aripiprazole ethanol solution is lowered to an ambient temperature, when the ambient temperature is high. At 25 ° C, the temperature of the aripiprazole ethanol solution was further lowered to 25 ° C or below by means of an ice bath or the like.
  • the gradient temperature drop method has a temperature drop of 3 to 15 ° C / hour, preferably 5 to 10 ° C / hour.
  • step (2) After the step (2) reaches the cooling temperature, the stirring is continued for 5 minutes to 5 hours, preferably 0.5 to 3 hours.
  • Step (2) If necessary, the seed crystal of the crystal I may be added to the aripiprazole ethanol solution to induce crystallization; the steps (1) and (2) are a continuous stirring process, and the rotation speed is 5 to 200 rpm. Preferably, it is 50 to 150 rpm; the mechanical agitation may be slurry stirring, anchor stirring, frame stirring or turbine stirring, etc., but not limited to the above.
  • the separation in the step (3) is carried out according to a conventional method in the art, such as filtration, drying, and the like.
  • the drying method in the step (3) is naturally dried at ambient temperature or dried by means of a drying device such as an oven; the drying time is related to the drying mode and the temperature, and the natural drying time at the ambient temperature is 15 to 30 hours, usually we
  • the ambient temperature is from 10 ° C to 30 ° C;
  • the drying temperature by means of a drying apparatus such as an oven is from 10 ° C to 70 ° C, preferably from 30 ° C to 60 ° C, and the drying time is from 3 to 15 hours, preferably from 6 to 10 hours.
  • it can be carried out under normal pressure or under reduced pressure, that is, the value of relative vacuum is between 0 and 95 kPa.
  • the invention also provides the use of the aripiprazole hemiethanolate beta crystal form, which can be used to prepare a low hygroscopic aripiprazole crystal form I, which is: aripiprazole hemiethanolate
  • the ⁇ crystal form is dried at 90 to 110 ° C for 4 to 24 hours, preferably for 6 to 10 hours. When drying, it can be carried out under normal pressure or under reduced pressure, that is, the relative vacuum degree is between 0 and -95 kPa.
  • the diffraction angle 2 ⁇ in the powder X-ray diffraction pattern has characteristic peaks at the following values: 11.1° ⁇ 0.2°, 12.1° ⁇ 0.2°, 14.4° ⁇ 0.2°, 16.7° ⁇ 0.2°, 19.4° ⁇ 0.2°, 20.5 ° ⁇ 0.2° and 22.2° ⁇ 0.2°; as shown in Figure 4;
  • the infrared spectrum (KBr tablet) has the main absorption bands (cm -1 ) around the following values: 2944.8, 2811.7, 1677.8, 1627.6, 1446.4, 1376.9, 1172.5, 960.4 and 779.1;
  • its particle size distribution D (0.5) is 15 ⁇ 30 microns; preferably, the particle size distribution D (0.5) is 15 ⁇ 25 microns;
  • the hygroscopicity data after being kept at a temperature of 60 ° C and placed in a dryer of 100% humidity level for 24 hours, has a wettability of not more than 0.20%, preferably not more than 0.15%.
  • the aripiprazole starting material may be crude, pure, solvate and amorphous aripiprazole, and may also be in various other crystal forms including, but not limited to, aripiprazole crystal forms I, II, C, D, E and F.
  • the method for preparing aripiprazole hemiethanolate ⁇ crystal form and the low hygroscopic aripiprazole crystal form I provided by the present invention is suitable for large-scale industrial production and is environmentally friendly.
  • the room temperature referred to in the present invention means 25 °C.
  • the method of the invention has the advantages of simple process operation, short preparation time, good reproducibility, low energy consumption, small pollution, high safety and easy industrialization and large production;
  • Aripiprazole Form I prepared by the method of the present invention can obtain crystallites having a particle size distribution D (0.5) of 15 to 30 ⁇ m without undergoing a pulverization and/or grinding process;
  • the aripiprazole crystal form I prepared by the method of the invention has a wettability of not more than 0.20% after being placed in a desiccator at a temperature of 60 ° C and a humidity of 100% for 24 hours, so as not to affect the solid oral preparation thereof. Dissolution and bioavailability.
  • Fig. 1 is a powder X-ray diffraction spectrum of the aripiprazole hemiethanolate ⁇ crystal form.
  • Figure 2 is a differential heat scan of the aripiprazole hemiethanolate beta crystal form.
  • Figure 3 is an infrared spectrum of the aripiprazole hemiethanolate beta crystal form.
  • Figure 4 is a powder X-ray diffraction spectrum of the low hygroscopic aripiprazole Form I.
  • Figure 5 is a differential heat scan of the low hygroscopic form of aripiprazole Form I.
  • Figure 6 is an infrared spectrum of the low hygroscopic form of aripiprazole Form I.
  • Figure 7 is a particle size map of the low hygroscopic form of aripiprazole Form I.
  • Stop heating slowly reduce the temperature to 15 ⁇ 25 ° C, filter it, add the filter cake to water (500g), heat to 30 ⁇ 40 ° C, beat for about 1 hour, filter it, filter cake rinsed with water at 70 ⁇ Drying at 80 ° C for 15 hours under normal pressure gave 172 g of a white powder solid.
  • the crude aripiprazole (400 g) was added to ethyl acetate (3600 g), and it was heated under reflux with N 2 to dissolve, and activated carbon (20 g) was added, stirred for 0.5 to 1 h, and the temperature was maintained at 75 to 80 ° C.
  • the activated carbon is filtered, the filter cake is rinsed with ethyl acetate, and the filtrate is concentrated to about half of the original volume, and slowly cooled (about 10 ° C / h) to 0 to 10 ° C, and the temperature is kept stirring for about 2 h, and filtered.
  • the solid was rinsed with ethyl acetate and dried at 60 to 70 ° C for 10 hours to obtain 363 g of aripiprazole having a purity of more than 99%.
  • Example 1 The product of Example 1 was dried under reduced pressure (relative vacuum: -60 kPa) at 90 ° C for 10 hours to obtain aripiprazole Form I 270 g, which was more than 99.5% pure. Humidity: 0.05% before wetting and 0.06% after wetting. The particle size D (0.5) was 19.730 microns.
  • Example 3 The product of Example 3 was dried under reduced pressure (relative vacuum: -40 kPa) at 110 ° C for 4 hours to give aripiprazole Form I 9.2 g, purity greater than 99.5%. Humidity: 0.09% before wetting and 0.14% after wetting. The particle size D (0.5) was 18.474 microns.
  • Example 5 The product of Example 5 was dried at 110 ° C for 6 hours under normal pressure to obtain aripiprazole Form I 8.6 g. Humidity: 0.02% before wetting and 0.08% after wetting.
  • the particle size D (0.5) was 23.151 microns.
  • Example 7 The product of Example 7 was dried at 105 ° C under normal pressure for 8 hours to give aripiprazole Form I 9.2 g. Humidity: 0.07% before wetting and 0.11% after wetting. The particle size D (0.5) was 19.957 microns.
  • Example 9 The product of Example 9 was dried at 90 ° C under normal pressure for 24 hours to give aripiprazole Form I 9.2 g. Humidity: 0.06% before wetting and 0.14% after wetting. The particle size D (0.5) was 16.786 microns.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

提供阿立哌唑半乙醇合物β晶型，其制备方法和用于制备低吸湿性阿立哌唑晶型I的用途。阿立哌唑晶型β和晶型I的制备方法适合工业化生产，对环境友好。

Description

阿立哌唑半乙醇合物新晶型、其制备方法及用途 技术领域
本发明涉及阿立哌唑半乙醇合物的新晶型及其制备方法，以及用阿立哌唑半乙醇合物的新晶型制备低吸湿性阿立哌唑晶型I的方法。
背景技术
阿立哌唑(Aripiprazole，OPC-14597)是由日本大冢(Otsuka)制药公司和美国百时美-施贵宝公司联合开发的抗精神病药物，临床上用于精神分裂症的治疗，其化学名为7-[4-[4-(2，3-二氯苯基)-1-哌嗪基]丁氧基]-3，4-二氢-2(1H)-喹啉酮。
阿立哌唑是一种多晶型物质，通过不同的结晶溶剂和方式可以得到不同的晶型。有关阿立哌唑的晶型，第四届日本-韩国分离技术研讨会论文集(1996年10月6～8日)和WO03/026659中指出，用乙醇重结晶阿立哌唑并在80℃干燥得到阿立哌唑晶型I，其引湿性数据为引湿前0.04％，引湿后3.28％；阿立哌唑晶型I也可以通过用20％乙醇水溶液重结晶得到阿立哌唑水合物并在80℃干燥制得，其引湿性数据为引湿前0.04％，引湿后1.78％。上述2种方法制备的阿立哌唑晶型I具有显著的吸湿性，由此会带来以下问题：1)因其易吸湿使它们难以加工，必须采取措施确保它们在加工和配制过程中不与湿气接触。2)如果与湿气接触，则无水阿立哌唑吸收水转化成含水阿立哌唑，含水阿立哌唑的生物利用度和溶解度均低于无水阿立哌唑；3)每批产品吸收水分的不一致使含量均匀性等质量指标达不到要求；4)研磨可能导致产品吸附在设备上，从而导致成本增加，产率降低；
由于上述晶型所存在的一些缺陷，WO03/026659描述了低吸湿性阿立哌唑晶型B及其制备方法，通过特定的研磨条件研磨常规水合物得到水合物A，再通过干燥水合物A转化成低吸湿性阿立哌唑晶型B。此工艺虽然可以解决阿立哌唑的吸湿性问题，但工艺繁琐，过程复杂，重复性差，需要消耗大量 的动力成本，不利于产品大规模工业化生产。
此外，阿立哌唑是一种难溶性药物，将其做成口服制剂如片剂或其它包括快速溶化配方的固体制剂时，其粒径大小对其溶出度和生物利用度有较大影响。如采用机械粉碎和/或研磨，平均粒径一般只能达到100微米左右，制得的固体制剂的溶出度不理想，且机械粉碎处理存在粉尘多、污染环境和能耗大等缺点。
发明内容
针对现有技术的不足，本发明要解决的问题是提供一种制备低吸湿性阿立哌唑晶型I的方法。
为了解决上述问题，本发明的第一个目的在于提供阿立哌唑半乙醇合物β晶型。
本发明的第二个目的在于提供阿立哌唑半乙醇合物β晶型的制备方法。
本发明的第三个目的在于提供阿立哌唑半乙醇合物β晶型的用途，其可以用于制备低吸湿性阿立哌唑晶型I。
本发明目的是通过如下技术方案实现的：
阿立哌唑半乙醇合物β晶型，其粉末X射线衍射图谱中衍射角2θ在以下值有特征峰：17.5°±0.2°，19.7°±0.2°，23.4°±0.2°，24.5°±0.2°和27.9°±0.2°。
优选的，所述阿立哌唑半乙醇合物β晶型具有如图1所示的粉末X射线衍射光谱。
其差示热量扫描显示约在100.00℃和139.95℃处有吸收峰(升温速率：10.00℃/min)；如图2。
其红外光谱(KBr压片)在以下值左右有主要吸收带(cm-1)：2948.6，2823.3，1673.9，1627.6，1446.4，1378.9，1170.6，960.4，和711.6；如图3。
本发明还提供了所述阿立哌唑半乙醇合物β晶型的制备方法，其过程包括如下步骤：
(1)将阿立哌唑置于无水乙醇中，搅拌加热至完全溶解得到阿立哌唑乙醇溶液；
(2)在搅拌状态下，析出结晶；
(3)分离结晶，结晶经干燥得到阿立哌唑半乙醇合物β晶型。
优选的，
步骤(1)阿立哌唑与无水乙醇的投料比为1g∶5ml～1g∶20ml，优选1g∶8ml～1g∶15ml。
步骤(1)中所述的加热温度通常为50℃至无水乙醇的沸点，最优选为无水乙醇的沸点。
步骤(1)的阿立哌唑乙醇溶液中若含有不溶物，则趁热过滤，滤液继续加热至完全溶解。
步骤(1)视情况需要，也可在溶液中加入活性炭脱色，活性炭的用量一般为阿立哌唑重量的1％～5％，脱色过程约5～60分钟，趁热滤除活性炭，滤液继续加热至完全溶解。
步骤(2)将阿立哌唑乙醇溶液冷却至室温或室温以下，优选-10～25℃，最优选0～10℃。步骤(2)所述冷却采用自然降温法或梯度降温法；所述自然降温法是指将反应装置暴露在自然环境中，使阿立哌唑乙醇溶液的温度降到环境温度，当环境温度高于25℃时，再借助冰浴等冷却方式使阿立哌唑乙醇溶液的温度进一步降至25℃或25℃以下。所述梯度降温法的降温幅度为3～15℃/小时，优选5～10℃/小时。
步骤(2)达到冷却温度后，继续保温搅拌5分钟～5小时，优选0.5～3小时。
步骤(2)必要时可向阿立哌唑乙醇溶液中加入所述晶体I的晶种诱导析晶；步骤(1)和(2)是一个连续搅拌的过程，转速为5～200转/分钟，优选50～150转/分钟；机械搅拌可以为浆式搅拌、锚式搅拌、框式搅拌或涡轮式搅拌等，但不仅仅只限于以上几种。
步骤(3)所述分离即按照本领域常规方法进行分离，如过滤、甩干等。
步骤(3)所述干燥的方式为环境温度下自然晾干或借助干燥设备如烘箱进行干燥；干燥时间与干燥方式和温度相关，环境温度下自然晾干的时间为15～30小时，通常我们所述的环境温度为10℃～30℃；借助干燥设备如烘箱进行干燥的温度为10℃～70℃，优选30℃～60℃，干燥时间为3～15小时，优选6～10小时。借助干燥设备干燥时可以在常压下也可在减压下进行，即相对真空度的数值介于0～-95千帕之间。
本发明还提供了所述阿立哌唑半乙醇合物β晶型的用途，其可以用于制备低吸湿性阿立哌唑晶型I，所述方法是：阿立哌唑半乙醇合物β晶型在90～110℃干燥4～24小时，优选6～10小时。干燥时可以在常压下也可在减压下进行，即相对真空度的数值介于0～-95千帕之间。
本发明方法制备的低吸湿性阿立哌唑晶型I，其特征在于：
1)其粉末X射线衍射图谱中衍射角2θ在以下值有特征峰：11.1°±0.2°，12.1°±0.2°，14.4°±0.2°，16.7°±0.2°，19.4°±0.2°，20.5°±0.2°和22.2°±0.2°；如图4；
2)其差示热量扫描显示约在140.47℃处有吸收峰(升温速率：10.00℃/min)；如图5；
3)其红外光谱(KBr压片)在以下值左右有主要吸收带(cm-1)：2944.8，2811.7，1677.8，1627.6，1446.4，1376.9，1172.5，960.4和779.1；如图6；
4)其粒径大小分布D(0.5)为15～30微米；优选地，粒径大小分布D(0.5)为15～25微米；
5)其吸湿性数据，保持在60℃温度且在100％湿度水平的干燥器中放置24小时后，其引湿性不大于0.20％，优选不大于0.15％。
原料阿立哌唑可以是粗品、纯品、溶剂合物和无定形阿立哌唑，还可以是其他各种晶型，包括但不限于阿立哌唑晶型I，II，C，D，E和F。
本发明提供的制备阿立哌唑半乙醇合物β晶型和低吸湿性的阿立哌唑晶型I的方法适应大规模的工业化生产，对环境友好。
本发明所述室温是指25℃。
有益效果
1)本发明方法在于工艺操作简单，制备时间短，重现性好，能耗低，污染小，安全性高，易于工业化大生产；
2)本发明方法制备的阿立哌唑晶型I不需要经过粉粹和/或研磨过程即可得到粒径大小分布D(0.5)为15～30微米的微晶；
3)本发明方法制备的阿立哌唑晶型I在60℃温度且在100％湿度水平的干燥器中放置24小时后，其引湿性不大于0.20％，从而不会影响其固体口服制剂的溶出度和生物利用度。
附图说明
图1是所述阿立哌唑半乙醇合物β晶型的粉末X射线衍射光谱图。
图2是所述阿立哌唑半乙醇合物β晶型的差示热量扫描图。
图3是所述阿立哌唑半乙醇合物β晶型的红外光谱图。
图4是所述低吸湿性的阿立哌唑晶型I的粉末X射线衍射光谱图。
图5是所述低吸湿性的阿立哌唑晶型I的差示热量扫描图。
图6是所述低吸湿性的阿立哌唑晶型I的红外光谱图。
图7是所述低吸湿性的阿立哌唑晶型I的粒径图谱。
具体实施方式
下面将结合实施例对本发明作进一步说明，可以使本领域专业技术人员更全面地理解本发明，但不以任何方式限制本发明。
引湿性数据测定方法：
保持60℃温度且在100％湿度水平的干燥器中放置24小时后，检测引湿前后的水分。
制备例1：阿立哌唑粗品的制备
向装有温度计和机械搅拌的1L三口瓶中，依次加入水(850g)，无水碳酸钾(59g)，N，N-二甲基甲酰胺(124g)，7-(4-氯丁氧基)-3，4-二氢-2(IH)喹喏酮(100g)和1-(2，3-二氯苯基)哌嗪盐酸盐(115g)，在N2保护下，加热至90～100℃反应 15小时。停止加热，缓慢降温至15～25℃，将其过滤，滤饼加入到水(500g)中，加热至30～40℃，打浆1小时左右，将其过滤，滤饼用水淋洗后在70～80℃下常压干燥15小时，得到白色粉末固体172g。
制备例2：阿立哌唑粗品的纯化
将阿立哌唑粗品(400g)加入到乙酸乙酯(3600g)中，在N2保护下，将其加热回流溶清，加入活性炭(20g)，搅拌0.5～1h，温度保持在75～80℃，将活性炭过滤，滤饼用乙酸乙酯淋洗，滤液浓缩至原有体积的一半左右，缓慢梯度降温(约10℃/h)至0～10℃，保持此温度继续搅拌2h左右，过滤，固体用乙酸乙酯淋洗，在60～70℃下干燥10小时，得阿立哌唑363g，纯度大于99％。
实施例1：阿立哌唑半乙醇合物β晶型的制备
向装有温度计和机械搅拌的反应瓶中，依次加入制备例2产物(300g)和无水乙醇(3000ml)，转速为150转/分钟，N2保护下，将其加热回流溶清，加入活性炭(15g)，继续回流搅拌30分钟，温度保持在75～80℃，将其趁热压滤，滤液加热回流溶清后，梯度降温(5～10℃/小时)至0～10℃，并保持此温度范围内继续搅拌2小时左右，过滤，滤饼用冰的无水乙醇淋洗，将所得固体在30℃常压干燥10小时，得阿立哌唑半乙醇合物β晶型。
实施例2：低吸湿性的阿立哌唑晶型I的制备
将实施例1产物于90℃减压(相对真空度：-60千帕)干燥10小时，得到阿立哌唑晶型I 270g，纯度大于99.5％。引湿性：引湿前0.05％，引湿后0.06％。粒径D(0.5)为19.730微米。
实施例3：阿立哌唑半乙醇合物β晶型的制备
向装有温度计和机械搅拌的反应瓶中，依次加入制备例1产物(10g)和无水乙醇(80ml)，转速为120转/分钟，N2保护下，将其加热回流溶清，加入活性炭(0.1g)，继续回流搅拌1小时，温度保持在75～80℃，将其趁热压滤，滤液加热回流溶清后，梯度降温(3～8℃/小时)至-10～0℃，并保持此温度范围内继续搅拌30分钟左右，过滤，滤饼用冰的无水乙醇淋洗，将所得固体在60℃常压干燥6小时，得阿立哌唑半乙醇合物β晶型。
实施例4：低吸湿性的阿立哌唑晶型I的制备
将实施例3产物于110℃减压(相对真空度：-40千帕)干燥4小时，得到阿立哌唑晶型I 9.2g，纯度大于99.5％。引湿性：引湿前0.09％，引湿后0.14％。粒径D(0.5)为18.474微米。
实施例5：阿立哌唑半乙醇合物β晶型的制备
向装有温度计和机械搅拌的反应瓶中，依次加入制备例1产物(10g)和无水乙醇(150ml)，转速为180转/分钟，N2保护下，将其加热回流溶清，梯度降温(7～12℃/小时)至5～10℃，并保持此温度范围内继续搅拌1小时左右，过滤，滤饼用冰的无水乙醇淋洗，将所得固体在50℃常压干燥8小时，得阿立哌唑半乙醇合物β晶型。
实施例6：低吸湿性的阿立哌唑晶型I的制备
将实施例5产物于110℃常压干燥6小时，得到阿立哌唑晶型I 8.6g。引湿性：引湿前0.02％，引湿后0.08％。粒径D(0.5)为23.151微米。
实施例7：阿立哌唑半乙醇合物β晶型的制备
向装有温度计和机械搅拌的反应瓶中，依次加入制备例2产物(10g)和无水乙醇(80ml)，转速为200转/分钟，N2保护下，将其加热回流溶清，加入活性炭(0.3g)，继续回流搅拌45分钟，温度保持在75～80℃，将其趁热压滤，滤液加热回流溶清后，梯度降温(10～15℃/小时)至0～10℃，并保持此温度范围内继续搅拌3小时左右，过滤，滤饼用冰的无水乙醇淋洗，将所得固体在环境温度下(约10℃)自然晾干30小时，得阿立哌唑半乙醇合物β晶型。
实施例8：低吸湿性的阿立哌唑晶型I的制备
将实施例7产物于105℃常压干燥8小时，得到阿立哌唑晶型I 9.2g。引湿性：引湿前0.07％，引湿后0.11％。粒径D(0.5)为19.957微米。
实施例9：阿立哌唑半乙醇合物β晶型的制备
向装有温度计和机械搅拌的反应瓶中，依次加入制备例2产物(10g)和无水乙醇(100ml)，转速为100转/分钟，N2保护下，将其加热回流溶清，加入活性炭(0.5g)，继续回流搅拌15分钟，温度保持在75～80℃，将其趁热压滤， 滤液加热回流溶清后，梯度降温(5～10℃/小时)至0～10℃，并保持此温度范围内继续搅拌4小时左右，过滤，滤饼用冰的无水乙醇淋洗，将所得固体在环境温度下(约20℃)自然晾干20小时，得阿立哌唑半乙醇合物β晶型。
实施例10：低吸湿性的阿立哌唑晶型I的制备
将实施例9产物于90℃常压干燥24小时，得到阿立哌唑晶型I 9.2g。引湿性：引湿前0.06％，引湿后0.14％。粒径D(0.5)为16.786微米。
实施例11：阿立哌唑半乙醇合物β晶型的制备
向装有温度计和机械搅拌的反应瓶中，依次加入制备例2产物(10g)和无水乙醇(200ml)，转速为50转/分钟，N2保护下，将其加热至50℃，待阿立哌唑完全溶解后，自然降温至环境温度(约20℃)，并保持此温度范围内继续搅拌5分钟左右，过滤，滤饼用冰的无水乙醇淋洗，将所得固体在10℃减压(相对真空度：-60千帕)干燥15小时，得阿立哌唑半乙醇合物β晶型。
实施例12：阿立哌唑半乙醇合物β晶型的制备
向装有温度计和机械搅拌的反应瓶中，依次加入制备例2产物(10g)和无水乙醇(120ml)，转速为5转/分钟，N2保护下，将其加热回流溶清，加入活性炭(0.3g)，继续回流搅拌5分钟，温度保持在75～80℃，将其趁热压滤，滤液加热回流溶清后，自然降温至环境温度(约35℃)，再冰浴冷却至0～10℃，并保持此温度范围内继续搅拌0.5小时左右，过滤，滤饼用冰的无水乙醇淋洗，将所得固体在70℃减压(相对真空度：-60千帕)干燥3小时，得阿立哌唑半乙醇合物β晶型。

Claims (10)

  1. 阿立哌唑半乙醇合物β晶型，其特征在于，其粉末X射线衍射图谱中衍射角2θ在以下值具有特征峰：17.5°±0.2°，19.7°±0.2°，23.4°±0.2°，24.5°±0.2°和27.9°±0.2°；优选的，具有如图1所示的粉末X射线衍射光谱图谱。
  2. 如权利要求1所述的阿立哌唑半乙醇合物β晶型，其特征在于：其差示热量扫描显示约在100.00℃和139.95℃处有吸收峰。
  3. 如权利要求1所述的阿立哌唑半乙醇合物β晶型，其特征在于：其红外光谱在以下值具有主要吸收带：2948.6，2823.3，1673.9，1627.6，1446.4，1378.9，1170.6，960.4，和711.6cm-1。
  4. 权利要求1-3中任一项所述阿立哌唑半乙醇合物β晶型的制备方法，其特征在于，包括以下步骤：
    (1)将阿立哌唑置于无水乙醇中，搅拌加热至完全溶解得到阿立哌唑乙醇溶液；
    (2)在搅拌状态下，析出结晶；
    (3)分离结晶，结晶经干燥得到阿立哌唑半乙醇合物β晶型。
  5. 如权利要求4所述制备方法，其特征在于：步骤(1)中所述阿立哌唑与无水乙醇投料比为1g∶5ml～1g∶20ml，优选1g∶8ml～1g∶15ml；所述的加热温度为50℃至无水乙醇的沸点，优选为无水乙醇的沸点。
  6. 如权利要求4所述制备方法，其特征在于：步骤(2)将阿立哌唑乙醇溶液冷却至室温或室温以下，优选-10～25℃，最优选0～10℃；所述冷却采用自然降温法或梯度降温法；所述梯度降温法的降温幅度为3～15℃/小时，优选5～10℃/小时。
  7. 如权利要求4所述制备方法，其特征在于：步骤(1)和(2)是一个连续搅拌的过程，所述搅拌的转速为5～200转/分钟，优选50～150转/分钟。
  8. 如权利要求4所述制备方法，其特征在于：步骤(3)所述干燥为环境温度下自然晾干或借助干燥设备进行干燥；借助干燥设备进行干燥的温度为10℃～70℃，优选30℃～60℃。
  9. 权利要求1-3中任一项所述阿立哌唑半乙醇合物β晶型的用途，其特征在于：用于制备低吸湿性阿立哌唑晶型I。
  10. 如权利要求9所述的用途，其特征在于：阿立哌唑半乙醇合物β晶型制备低吸湿性阿立哌唑晶型I的方法为，阿立哌唑半乙醇合物β晶型在90～110℃干燥4～24小时，优选6～10小时。
PCT/CN2015/079365 2014-05-30 2015-05-20 阿立哌唑半乙醇合物新晶型、其制备方法及用途 WO2015180582A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410238468.4 2014-05-30
CN201410238468.4A CN105085397B (zh) 2014-05-30 2014-05-30 阿立哌唑半乙醇合物新晶型、其制备方法及用途

Publications (1)

Publication Number Publication Date
WO2015180582A1 true WO2015180582A1 (zh) 2015-12-03

Family

ID=54566824

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/079365 WO2015180582A1 (zh) 2014-05-30 2015-05-20 阿立哌唑半乙醇合物新晶型、其制备方法及用途

Country Status (2)

Country Link
CN (1) CN105085397B (zh)
WO (1) WO2015180582A1 (zh)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1676517A (zh) * 2004-04-02 2005-10-05 北京德众万全药物技术开发有限公司 阿立哌唑的晶型
WO2006053780A1 (en) * 2004-11-18 2006-05-26 Synthon B.V. Crystalline aripiprazole solvates
CN1914174A (zh) * 2003-12-16 2007-02-14 特瓦制药工业有限公司 阿立哌唑晶形的制备方法
CN101370780A (zh) * 2005-01-27 2009-02-18 桑多斯股份公司 有机化合物
CN103172563A (zh) * 2011-12-26 2013-06-26 北京京卫燕康药物研究所有限公司 小粒径的晶型i阿立哌唑的工业化制备

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1679517A (zh) * 2005-01-07 2005-10-12 山东轻工业学院 肠溶型水性药物薄膜包衣材料及其制备方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1914174A (zh) * 2003-12-16 2007-02-14 特瓦制药工业有限公司 阿立哌唑晶形的制备方法
CN1676517A (zh) * 2004-04-02 2005-10-05 北京德众万全药物技术开发有限公司 阿立哌唑的晶型
WO2006053780A1 (en) * 2004-11-18 2006-05-26 Synthon B.V. Crystalline aripiprazole solvates
CN101370780A (zh) * 2005-01-27 2009-02-18 桑多斯股份公司 有机化合物
CN103172563A (zh) * 2011-12-26 2013-06-26 北京京卫燕康药物研究所有限公司 小粒径的晶型i阿立哌唑的工业化制备

Also Published As

Publication number Publication date
CN105085397B (zh) 2018-02-09
CN105085397A (zh) 2015-11-25

Similar Documents

Publication Publication Date Title
WO2015165320A1 (zh) 瑞戈非尼盐及其晶型、制备方法
KR20150036336A (ko) 타이로신 키나제 억제제 다이말리에이트의 결정형 아이 및 그의 제조 방법
CN106256824B (zh) 一种高纯度德拉沙星葡甲胺盐的制备方法
CN102311382B (zh) 罗氟司特的晶态及其制备方法
CN105859615B (zh) 一种地喹氯铵的制备方法和中间体
CN104072416B (zh) 一种制备阿立哌唑结晶b的方法
WO2015180582A1 (zh) 阿立哌唑半乙醇合物新晶型、其制备方法及用途
CN104030963A (zh) 一种巴多昔芬醋酸盐晶型a的制备方法
CN103787924A (zh) 抗肿瘤药物Belinostat的一种新纯化方法
CN101353325B (zh) 稳定型盐酸伊伐布雷定结晶及其制备方法
CN104817557B (zh) 一种盐酸莫西沙星的稳定晶型及其制备方法
WO2010108417A1 (zh) 阿昔洛韦2/3水合物的制备方法
CN102372672B (zh) 低吸湿性阿立哌唑晶体iv、制备方法及其应用
CN107663210A (zh) 一种新的制备无水他达拉非晶型i的方法
CN106580888A (zh) 一种异维a酸微粒的制备方法
CN102321141B (zh) 一种17α-乙酰氧基-11β-（4-N,N-二甲氨基苯基）-19-去甲孕甾-4，9-二烯-3,20-二酮的无定形物及其制备方法
CN104529864A (zh) 一种醋酸巴多昔芬晶型a的制备方法
CN103102316A (zh) ZD1839Form 1晶型的制备方法
KR101088988B1 (ko) 퀴놀린카르복실산 유도체 용매화물의 결정
JP6023770B2 (ja) アリピプラゾール無水物ｂ形結晶の製造方法
CN104211693A (zh) 一种利伐沙班新晶型及其制备方法与用途
JP2021535218A (ja) Ｄｐｐ−ｉｖ阻害剤の血糖降下薬の新しい結晶形およびその調製方法
CN103059023B (zh) 一种制备更昔洛韦晶型ⅱ的方法
CN104230799A (zh) 制备阿立哌唑晶型的方法
WO2016034150A1 (zh) 博舒替尼及其结晶的制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15799724

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15799724

Country of ref document: EP

Kind code of ref document: A1