WO2018076783A1 - 右旋奥拉西坦晶型ii及其制备方法和用途 - Google Patents

右旋奥拉西坦晶型ii及其制备方法和用途 Download PDF

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WO2018076783A1
WO2018076783A1 PCT/CN2017/092220 CN2017092220W WO2018076783A1 WO 2018076783 A1 WO2018076783 A1 WO 2018076783A1 CN 2017092220 W CN2017092220 W CN 2017092220W WO 2018076783 A1 WO2018076783 A1 WO 2018076783A1
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crystal form
solvent
oxiracetam
poor solvent
good solvent
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PCT/CN2017/092220
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French (fr)
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叶雷
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重庆润泽医药有限公司
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Priority to US16/344,338 priority Critical patent/US10793521B2/en
Priority to KR1020197011746A priority patent/KR20190051059A/ko
Priority to EP17863355.8A priority patent/EP3530271A4/en
Priority to JP2019519399A priority patent/JP6957807B2/ja
Publication of WO2018076783A1 publication Critical patent/WO2018076783A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • C07B2200/07—Optical isomers
    • 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

  • Oxiracetam CAS No. 62613-82-5, first synthesized by the Italian company Spiebicem in 1974, a new generation of brain metabolism improving drugs marketed in 1987, which promotes phosphorylcholine and its neighbors.
  • Acetylethanolamine synthesis promotes brain metabolism and stimulates specific central nervous pathways through the blood-brain barrier, improving intelligence and memory.
  • its right-handed body has special biological activity in the field of sedation and anti-epilepsy, and its toxicity is low, and the drug safety range is large, which is expected to become an existing highly toxic anti-epileptic drug. substitute.
  • dextrorotatory oxiracetam In order to effectively develop dextrorotatory oxiracetam into pharmaceutical products, a solid form with easy to manufacture and acceptable chemical and physical stability is required to facilitate its processing and circulation storage.
  • the crystalline solid form is generally superior to the amorphous form in terms of enhancing the purity and stability of the compound.
  • the above-mentioned right-handed oxiracetam crystal form II has a relative peak intensity at a diffraction angle 2 ⁇ of 21.20 ⁇ 0.2° of 100%; a relative peak intensity at a diffraction angle of 2 ⁇ of 20.16 ⁇ 0.2° is greater than 70% and less than 100%; The relative peak intensity of the diffraction angle 2 ⁇ of 17.76 ⁇ 0.2°, 24.17 ⁇ 0.2°, and 25.88 ⁇ 0.2° is not less than 40%.
  • the above-mentioned dextrorotatory oxiracetam crystal form II has a diffraction angle of 2 ⁇ of 10.54 ⁇ 0.2°, 13.76 ⁇ 0.2°, 14.14 ⁇ 0.2°, 16.64 ⁇ 0.2°, 17.76 ⁇ 0.2°, 18.72. ⁇ 0.2°, 20.16 ⁇ 0.2°, 21.20 ⁇ 0.2°, 21.52 ⁇ 0.2°, 23.25 ⁇ 0.2°, 24.17 ⁇ 0.2°, 25.88 ⁇ 0.2°, 27.61 ⁇ 0.2°, 28.57 ⁇ 0.2°, 29.24 ⁇ 0.2°, 31.40 There is a diffraction peak at ⁇ 0.2°.
  • the mixed solvent is a good solvent mixed with a poor solvent, wherein the good solvent is selected from the group consisting of DMF, dimethylacetamide, and positive Propanol or n-butanol, the poor solvent is selected from the group consisting of dichloromethane, acetone, ethyl acetate, tetrahydrofuran, diethyl ether, n-hexane or petroleum ether; when the good solvent is DMF, the poor solvent is dichloromethane, acetone, ethyl acetate Any one of them; when the good solvent is dimethylacetamide, the poor solvent is any one of tetrahydrofuran, acetone, and ethyl acetate; when the good solvent is n-propanol, the poor solvent is tetrahydrofuran, diethyl ether
  • the mixed solvent is a mixture of DMF (N,N-dimethylformamide) and dichloromethane, acetone or ethyl acetate, and the mixed solvent may be mixed with DMF and dichloromethane. It is also possible to mix DMF with acetone and DMF with ethyl acetate.
  • n-propanol is mixed with any one of tetrahydrofuran, diethyl ether and n-hexane, and it can be n-propanol.
  • the mass-to-volume ratio (g/mL) of the above-mentioned dextrorotatory oxiracetam to the mixed solvent is from 1:2 to 1:10.
  • the above filtration is collected and crystallized, it is dried under conditions of 10-40 ° C and a relative humidity of 55-85% for 4-6 hours; preferably 25-40 ° C, and a relative humidity of 65-85%. Dry for 5-6h.
  • the preparation method of the above-mentioned dextrocarbamidine crystal form II adopts the following steps: dissolving dextrorotatory oxiracetam in a mixed solvent, wherein dextrorotatory oxiracetam and a mixed solvent are used.
  • Mass-to-volume ratio (g/mL) is 1:2 ⁇ 1:10, filtered, the filtrate is sealed and sealed, stirred at 100-150r/min for 5 ⁇ 24h, filtered again, and the filtrate is allowed to stand in the desiccator after filtration.
  • the poor solvent is any one of tetrahydrofuran, diethyl ether and n-hexane; when the good solvent is n-butanol, the poor solvent is dichloromethane, diethyl ether and petroleum ether. Any one.
  • the raw material of the present invention may be a commercially available product or may be self-made, and the remaining raw materials or reagents are all commercially available products.
  • filtration is conventional solid-liquid separation methods well known in the art.
  • the present invention provides dextrorotatory oxiracetam Form II (therapeutically effective amount) In the preparation of a medicament for preventing or treating anti-epileptic drugs.
  • the use of the dextrocarbamidine crystal form II of the invention for the preparation of a medicament for preventing or treating anti-epileptic systemic seizures.
  • a pharmaceutical composition comprising the above-described dextrorotatory oxiracetam Form II and a pharmaceutically acceptable excipient; said composition being any clinically acceptable pharmaceutical dosage form Including, but not limited to, oral, rectal, transvaginal, nasal, inhalation, topical (including transdermal) or parenteral administration, including tablets, powders, granules, injections, capsules, pills , sustained release controlled release preparation, freeze-dried powder injection.
  • the present invention provides a crystal form of dextrorotatory oxiracetam having diffraction peaks at diffraction angles 2 ⁇ of 17.76 ⁇ 0.2°, 20.16 ⁇ 0.2°, 21.20 ⁇ 0.2°, 24.17 ⁇ 0.2°, 25.88 ⁇ 0.2°,
  • the relative peak intensity at a diffraction angle 2 ⁇ of 21.20 ⁇ 0.2° is 100%; the relative peak intensity at a diffraction angle 2 ⁇ of 20.16 ⁇ 0.2° is greater than 70% and less than 100%; and the diffraction angle 2 ⁇ is 17.76 ⁇ 0.2°, 24.17 ⁇
  • the relative peak intensities of 0.2° and 25.88 ⁇ 0.2° are not less than 40%.
  • the dextrocarbamidine crystal form II of the invention can promote the synthesis of phosphorylcholine and o-acylethanolamine, promote brain metabolism, stimulate the specific central nervous system through the blood-brain barrier, and have special effects in the fields of sedation and anti-epilepsy. Biological activity.
  • the crystal form II of dextrorotatory oxime in the present invention is a crystal-containing type, which loses crystal water at 73.5 ⁇ 2° C. and melts and decomposes at 138.0 ⁇ 2° C.
  • the dextrorotatory oxiracetam crystal form II of the invention has a fast dissolution rate in water, a solubility in water ⁇ 100 mg/mL, and high bioavailability.
  • the crystal form of the right-handed oxiracetam of the present invention is placed in a beaker, and the crystal form stability accelerated test is carried out in a constant temperature and humidity chamber at a temperature of 40 ° ⁇ 2 ° C and a relative humidity of 75% ⁇ 5%.
  • the results showed that the crystal form of the dextrorotatory oxiracetam of the present invention did not undergo crystal transformation between 2 and 15 d.
  • the crystal form of dextrorotatory oxiracetam of the invention can be stably existed at room temperature and relative humidity of 0-95%, does not undergo crystal transformation, has good fluidity, high adaptability to preparation process, and is suitable for preparing various drugs.
  • the composition can be formulated into pharmaceutical preparations such as tablets, capsules, pills, sustained release controlled release preparations, freeze-dried powder injections and the like.
  • the preparation method of the invention adopts the raw material which is cheap and easy to obtain, and has the high purity of the right-handed oxiracetam crystal form II, the preparation method is mild, the operation is simple, the introduction of impurities is small, the reproducibility is good, and the production process is easy to control. High safety and suitable for industrial production.
  • Figure 1 is a powder diffraction pattern of dextrocarbamidine crystal form II
  • DSC differential scanning thermal analysis
  • terapéuticaally effective amount means an amount sufficient to effect treatment when administered to a patient in need of treatment.
  • treating means treating a disease, disorder or medical condition of a patient, such as a mammal, especially a human, comprising:
  • Test instrument conditions Normal temperature test was performed using a Bruker D2PHASER powder diffractometer under the following conditions: Cu Ka For the light source, voltage 30kV, current 10mA, test step length 0.014°, scan speed 0.1s/step, scan range 5-40° (2 ⁇ ).
  • the dextrorotatory oxiracetam crystal prepared in Example 1 was tested to have a diffraction angle of 2 ⁇ of 10.54 ⁇ 0.2°, 13.76 ⁇ 0.2°, 14.14 ⁇ 0.2°, 16.64 ⁇ 0.2°, 17.76 ⁇ 0.2°, 18.72 ⁇ 0.2°.
  • the relative peak intensity of the right-handed oxiracetam crystal form II of the present invention at a diffraction angle 2 ⁇ of 21.20 ⁇ 0.2° is 100%; the relative peak intensity at a diffraction angle 2 ⁇ of 20.16 ⁇ 0.2° is greater than 70. % is less than 100%; the relative peak intensity at the diffraction angle 2 ⁇ is 17.76 ⁇ 0.2°, 24.17 ⁇ 0.2°, 25.88 ⁇ 0.2° is not less than 40%.
  • DSC Differential Scanning Thermal Analysis
  • DSC test was carried out using a differential scanning calorimeter (STA 409PC, Netzsch, Germany). The test method was to accurately weigh a certain amount (1 ⁇ 2mg) of the sample in the DSC crucible. Using air as a reference, heating from 20 ° C to 200 ° C, using aluminum crucible in a nitrogen atmosphere, heating at a rate of 10 ° C / min, the sample chamber nitrogen flow rate is 20 mL / min.
  • the differential scanning thermal analysis (DSC) chart of the dextrorotatory oxiracetam crystal form II of the present invention is shown in Fig. 2, which loses crystal water at about 73.5 ° C, and the endothermic transition temperature is about 138.0 ° C.
  • the water content of the right-handed oxiracetam crystal form II of the present invention was 5.56% (theoretical: 5.52%) as measured by the Karl Fischer method, and combined with thermogravimetric analysis characteristics, indicating the right-handed oxiracetam of the present invention.
  • Form II is 1/2 hydrate.
  • dextrocarbamidine crystal form II was prepared according to Examples 3-12.
  • Example 2 1 g of dextrorotatory oxiracetam was dissolved in 5 mL of a mixed solvent (DMF 1 mL, ethyl acetate 4 mL), dissolved at 45 ° C, filtered, and the filtrate was capped and stirred at a rate of about 150 r / min for about 12 h. Filtration again, after filtration, the filtrate is allowed to stand in a desiccator to form a crystal, to collect crystals, and the collected crystals are dried at 30 ⁇ 2° C. and a relative humidity of 75-80% for 4-5 hours to obtain crystals.
  • the method of Example 2 was identified as dextrocarbamidine crystal form II.
  • Example 2 1 g of dextrorotatory oxiracetam was dissolved in 6 mL of a mixed solvent (1 mL of n-propanol, 5 mL of diethyl ether), dissolved by heating at 60 ° C, filtered, and the filtrate was sealed and sealed, and stirred at a rate of about 150 r/min for about 5 h. After filtration, the filtrate is filtered in a desiccator to form a crystal in a desiccator to form a crystal. The crystal is collected, and the collected crystal is dried at 40 ⁇ 2° C. and a relative humidity of 65-70% for about 4 hours to obtain crystals.
  • the method of Example 2 was identified as dextrorotatory oxiracetam Form II.
  • Example 2 1 g of dextrorotatory oxiracetam was dissolved in 6 mL of a mixed solvent (1 mL of n-propanol, 5 mL of n-hexane), dissolved by heating at 30 ° C, filtered, and the filtrate was sealed and sealed, and stirred at a rate of about 130 r/min for 5 h. Left and right, filtered again. After filtration, the filtrate is allowed to stand in a desiccator to form a crystal. The crystals are collected, and the collected crystals are dried at 25 ⁇ 2° C. and a relative humidity of 85-95% for about 5 hours to obtain crystals.
  • the method of Example 2 was identified as dextrocarbamidine crystal form II.
  • Example 2 1 g of dextrorotatory oxiracetam was dissolved in 6 mL of a mixed solvent (2 mL of n-propanol, 4 mL of n-hexane), dissolved by heating at 40 ° C, filtered, and the filtrate was sealed and sealed, and stirred at a rate of about 150 r/min for 4 h. Left and right, filtered again. After filtration, the filtrate is allowed to stand in a desiccator to form a crystal, and crystals are collected. The collected crystals are dried at 25 ⁇ 2° C. and a relative humidity of 80-85% for about 5 hours to obtain crystals.
  • the method of Example 2 was identified as dextrocarbamidine crystal form II.
  • Test parameters were as follows: Weighing: Ultra digital microbalance SMS Ultra Balance TM; flow: N 2, 200sccm, system control software: DVS-Intrinsic control software ver.1.0.3.1, data analysis software: Isotherm (ISO) analysis suite.
  • Test 22.4mg of dextrorotatory oxiracetam crystal form II sample, RH 0% for drying, balance the mass to ensure removal of surface adsorption moisture, then place on metal sample tray, test after drying at 0% RH for 2h, constant temperature At 25 ° C, the control relative humidity (RH%) was cyclically varied from 0% to 90% to 0% RH with a 10% gradient. The sample weight was measured as a function of humidity, combined with powder X-ray diffraction characterization to observe humidity versus sample crystals. The effect of the type transition was found to be still the right-handed oxiracetam crystal form II.
  • the crystal form stability accelerated test adopts the provisions of the 2010 Pharmacopoeia Appendix XIXC "Guidelines for the Stability Test of APIs and Pharmaceutical Preparations" in the accelerated test of the drug substance, and the right-handed oxiracetam crystal form II is placed in a beaker and is carried out in a constant temperature and humidity chamber at a temperature of 40 ° ⁇ 2 ° C and a relative humidity of 75% ⁇ 5%.
  • the dextrorotatory oxiracetam crystal form II of the present invention can be stably present at room temperature and relative humidity of 0-95%, and no crystal transformation occurs.
  • the dextrorotatory oxiracetam crystal form II of the present invention is used for preservation or formulation processing, which requires low humidity for processing humidity or storage conditions.
  • the dextrocarbamidine crystal form II prepared by the method described in Example 1 was 180 mg/granule, microcrystalline cellulose 90.8 mg/granule, compressible starch 82 mg/granule, talc powder 7.2 mg/grain and 10% poly
  • the dextrocarbamidine crystal form II prepared by the method described in Example 1 was dissolved in a rare tank according to 60 g, sorbitol 140 g, 500 ml of water for injection, the temperature was controlled at 50 to 58 ° C, stirred until completely dissolved, and dissolved.
  • the liquid was cooled to 25 ° C, decolorized by adding activated carbon to the above prepared solution, and then the activated carbon was removed by filtration, and the pH of the solution was adjusted to 6.0 by adding a phosphate buffer solution, and then water for injection was added to 5000 ml.
  • the mixture was sterilized at 105 ° C for 30 minutes to obtain an injection solution.

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Abstract

本发明提供一种右旋奥拉西坦晶型，在衍射角度2θ为17.76±0.2°、20.16±0.2°、21.20±0.2°、24.17±0.2°、25.88±0.2°有衍射峰；该右旋奥拉西坦晶型能促进磷酰胆碱和邻酰乙醇胺合成，促进脑代谢，通过血脑屏障对特异性中枢神经通路有刺激作用，在镇静，抗癫痫等领域有特殊的生物学活性。本发明右旋奥拉西坦晶型为含水晶型，含有0.5个水分子，在73.5±2℃失去结晶水，在138.0±2℃熔融分解。本发明右旋奥拉西坦晶型在室温和相对湿度为0-95％条件下均可稳定存在，不会发生转晶，用于保存或者制剂加工，其对加工湿度或保存条件湿度要求较低。

Description

右旋奥拉西坦晶型II及其制备方法和用途 技术领域
本发明涉及右旋奥拉西坦，具体涉及右旋奥拉西坦的晶型、制备方法和用途。
背景技术
奥拉西坦(Oxiracetam)，CAS号为62613-82-5，由意大利史克比切姆公司于1974年首次合成，1987年上市的新一代脑代谢改善药，可促进磷酰胆碱和邻酰乙醇胺合成，促进脑代谢，通过血脑屏障对特异性中枢神经通路有刺激作用，改善智力和记忆。研究表明，其右旋体(右旋奥拉西坦)在镇静，抗癫痫领域有特殊的生物学活性，并且其毒性低，药物安全范围大，有望成为现有的高毒性抗癫痫类药物的替代品。
Figure PCTCN2017092220-appb-000001
为有效将右旋奥拉西坦开发成药品，需要一种具有易于制造并且可接受的化学和物理稳定性的固态形式，以促进其加工与流通储存。对于增强化合物的纯度和稳定性而言，结晶固体形态一般优于非晶型形态。目前右旋奥拉西坦的制备方法及晶型研究较少，尚未有右旋奥拉西坦的晶型披露。
发明内容
根据本发明的第一方面，本发明提供了一种右旋奥拉西坦晶型，本发明的完整特性如下文所述，但是为了方便起见，将所提供的右旋奥拉西坦晶型称为“晶型II”。
除特殊说明外，本发明所述份数均为重量份，所述百分比均为质量百分比。
本发明的目的是这样实现的：
一种右旋奥拉西坦晶型II，在衍射角度2θ为17.76±0.2°、20.16±0.2°、 21.20±0.2°、24.17±0.2°、25.88±0.2°有衍射峰。
上述右旋奥拉西坦晶型II，在衍射角度2θ为21.20±0.2°处的相对峰强度为100％；在衍射角度2θ为20.16±0.2°的相对峰强度大于70％小于100％；在衍射角度2θ为17.76±0.2°、24.17±0.2°、25.88±0.2°的相对峰强度不小于40％。
根据本发明的一个实施方案，上述右旋奥拉西坦晶型II，在衍射角度2θ为14.14±0.2°、17.76±0.2°、18.72±0.2°、20.16±0.2°、21.20±0.2°、21.52±0.2°、24.17±0.2°、25.88±0.2°有衍射峰。
根据本发明的一个实施方案，上述右旋奥拉西坦晶型II，在衍射角度2θ为10.54±0.2°、13.76±0.2°、14.14±0.2°、16.64±0.2°、17.76±0.2°、18.72±0.2°、20.16±0.2°、21.20±0.2°、21.52±0.2°、23.25±0.2°、24.17±0.2°、25.88±0.2°、27.61±0.2°、28.57±0.2°、29.24±0.2°、31.40±0.2°有衍射峰。
根据本发明的一个实施方案，上述右旋奥拉西坦晶型II为右旋奥拉西坦含水晶型。经差示扫描热分析(DSC)，上述右旋奥拉西坦晶型II在73.5±2℃失去结晶水，在138.0±2℃熔融分解。具体的，上述右旋奥拉西坦晶型II具有如图2所示的差示扫描热分析(DSC)图谱。
根据本发明的第二方面，本发明提供一种右旋奥拉西坦晶型II的制备方法，该方法工艺简单，适合工业化生产。
一种右旋奥拉西坦晶型II的制备方法，采用如下步骤：将右旋奥拉西坦溶于混合溶剂中，过滤，将滤液加盖密封，搅拌；再次过滤，过滤后滤液在干燥器中挥发溶剂形成结晶，收集结晶，干燥既得右旋奥拉西坦晶型II；所述混合溶剂为良溶剂与不良溶剂混合而成，其中良溶剂选自DMF、二甲基乙酰胺、正丙醇或正丁醇，不良溶剂选自二氯甲烷、丙酮、乙酸乙酯、四氢呋喃、乙醚、正己烷或石油醚；当良溶剂为DMF时，不良溶剂为二氯甲烷、丙酮、乙酸乙酯中的任意一种；当良溶剂为二甲基乙酰胺时，不良溶剂为四氢呋喃、丙酮、乙酸乙酯中的任意一种；当良溶剂为正丙醇时，不良溶剂为四氢呋喃、乙醚、正己烷中的任意一种；当良溶剂为正丁醇时，不良溶剂为二氯甲烷、乙醚、石油醚中的任意一种。
上述混合溶剂为DMF(N，N-二甲基甲酰胺)与二氯甲烷、丙酮、乙酸乙酯中的任意一种混合，指的是，混合溶剂可以为DMF与二氯甲烷混合，也可以为DMF与丙酮混合，还可以为DMF与乙酸乙酯混合。同理，正丙醇与四氢呋喃、乙醚、正己烷中的任意一种混合，指的是，可以为正丙醇 与四氢呋喃混合，也可以为正丙醇与乙醚混合，还可以为正丙醇与正己烷混合；二甲基乙酰胺与四氢呋喃、丙酮、乙酸乙酯中的任意一种混合，指的是，二甲基乙酰胺与四氢呋喃混合，也可以为二甲基乙酰胺与丙酮混合，也可以为二甲基乙酰胺与乙酸乙酯混合；正丁醇与二氯甲烷、乙醚、石油醚中的任意一种混合，指的是，正丁醇与二氯甲烷混合，也可以为正丁醇与乙醚混合，还可以为正丁醇与石油醚混合。
根据本发明的一个实施方案，上述右旋奥拉西坦与混合溶剂的质量体积比(g/mL)为1:2～1:10。
根据本发明的一个实施方案，上述混合溶剂中良溶剂与不良溶剂的体积比为1:1～1:7；优选1:2～1:5。
根据本发明的一个实施方案，上述将滤液加盖密封后，搅拌时间为3～24h，搅拌速度为100～150r/min。
根据本发明的一个实施方案，上述过滤收集结晶后，在10-40℃，相对湿度为55-85％的条件下干燥4-6h；优选25-40℃，相对湿度为65-85％的条件下干燥5-6h。
根据本发明的一个实施方案，上述右旋奥拉西坦晶型II的制备方法，采用如下步骤：将右旋奥拉西坦溶于混合溶剂中，其中右旋奥拉西坦与混合溶剂的质量体积比(g/mL)为1:2～1:10，过滤，将滤液加盖密封，以100～150r/min的速度搅拌5～24h，再次过滤，过滤后滤液在干燥器中静置挥发溶剂形成结晶，收集结晶，将收集的结晶在25-40℃，相对湿度为65-85％的条件下干燥5-6h，既得右旋奥拉西坦晶型II；所述混合溶剂为良溶剂与不良溶剂混合而成，良溶剂与不良溶剂的体积比为1:2～1:5，其中良溶剂选自DMF、二甲基乙酰胺、正丙醇或正丁醇，不良溶剂选自二氯甲烷、丙酮、乙酸乙酯、四氢呋喃、乙醚、正己烷或石油醚；当良溶剂为DMF时，不良溶剂为二氯甲烷、丙酮、乙酸乙酯中的任意一种；当良溶剂为二甲基乙酰胺时，不良溶剂为四氢呋喃、丙酮、乙酸乙酯中的任意一种；当良溶剂为正丙醇时，不良溶剂为四氢呋喃、乙醚、正己烷中的任意一种；当良溶剂为正丁醇时，不良溶剂为二氯甲烷、乙醚、石油醚中的任意一种。
本发明原料右旋奥拉西坦可以为市售产品，也可以自制，其余原料或试剂均为市售产品。本发明晶型的制备过程中，过滤为本领域所熟知的常规固液分离方式。
根据本发明第三方面，本发明提供右旋奥拉西坦晶型II(治疗有效量) 在制备预防或治疗抗癫痫药物中的应用。本发明右旋奥拉西坦晶型II在制备预防或治疗抗癫痫急性发作药物中的应用，尤其是在制备预防或治疗抗癫痫急性大发作药物中的应用。本发明右旋奥拉西坦晶型II在制备预防或治疗抗癫痫全身性发作药物中的应用。本发明右旋奥拉西坦晶型II在制备预防或治疗抗癫痫部分性发作药物中的应用。本发明右旋奥拉西坦晶型II在制备预防或治疗抗癫痫持续状态药物中的应用。本发明所述右旋奥拉西坦晶型II，在稳定大脑异常放电，镇静，抗癫痫等方面有特殊的药理学活性，且在水中溶解度≥100mg/mL，生物利用度高。
根据本发明的第四方面，本发明提供一种药物组合物，包含上述右旋奥拉西坦晶型II和在药学上可接受的辅料；所述组合物为任何临床上可接受的药物剂型，包括(但不限于)经口、经直肠、经阴道、经鼻、吸入、局部(包括经皮)或不经肠投药方式，包括片剂、散剂、颗粒剂、注射剂、胶囊剂、滴丸剂、缓释控释制剂、冻干粉针剂。
有益效果：
本发明提供一种右旋奥拉西坦晶型，该晶型在衍射角度2θ为17.76±0.2°、20.16±0.2°、21.20±0.2°、24.17±0.2°、25.88±0.2°有衍射峰，在衍射角度2θ为21.20±0.2°处的相对峰强度为100％；在衍射角度2θ为20.16±0.2°的相对峰强度大于70％小于100％；在衍射角度2θ为17.76±0.2°、24.17±0.2°、25.88±0.2°的相对峰强度不小于40％。本发明右旋奥拉西坦晶型II能促进磷酰胆碱和邻酰乙醇胺合成，促进脑代谢，通过血脑屏障对特异性中枢神经通路有刺激作用，在镇静，抗癫痫等领域有特殊的生物学活性。本发明右旋奥拉西坦晶型II为含水晶型，在73.5±2℃失去结晶水，在138.0±2℃熔融分解。本发明右旋奥拉西坦晶型II在水中溶解速度快，水中溶解度≥100mg/mL，生物利用度高。将本发明右旋奥拉西坦晶型放于烧杯中，于恒温恒湿箱中，在温度40°±2℃，相对湿度75％±5％的条件下进行晶型稳定性加速试验，实验结果显示，2h-15d间本发明右旋奥拉西坦晶型未发生晶型转变。本发明右旋奥拉西坦晶型在室温和相对湿度为0-95％条件下均可稳定存在，不会发生转晶，且流动性好，制剂工艺适应性高，适合制成多种药物组合物，可制成如片剂、胶囊剂、滴丸剂、缓释控释制剂、冻干粉针剂等药物制剂。本发明所述制备方法采用原料价廉易得、制得的右旋奥拉西坦晶型II纯度高，制备方法条件温和，操作简便，引入杂质少，重现性好，生产过程易于控制，安全性高，适合工业化生产。
附图说明
图1是右旋奥拉西坦晶型II的粉末衍射图；
图2是右旋奥拉西坦晶型II的差示扫描热分析(DSC)图。
定义
当描述本发明的化合物、晶型、应用、组合物和方法时，除非另作说明，否则以下术语具有以下含义。
术语“治疗有效量”意指当投与需要治疗的患者时足以实现治疗的量。如本文中所用的术语“治疗”意指治疗例如哺乳动物(尤其人类)的患者的疾病、病症或医学病况，其包括：
(a)预防疾病、病症或医学病况发生，即对患者的预防性治疗；
(b)改善疾病、病症或医学病况，即消除患者的疾病、病症或医学病况或使其消退，包括抵消其它治疗剂的效果。
(c)抑制疾病、病症或医学病况，即减缓或遏止患者的疾病、病症或医学病况的发展；或
(d)减轻患者的疾病、病症或医学病况的症状。
须注意除非内容另外明确规定，否则如本说明书和随附权利要求书中所用，单数形式“一”和“所述”可包括复数个提及物。
具体实施方式
下面通过实施例对本发明进行具体的描述，有必要在此指出的是以下实施例只用于对本发明进行进一步说明，不能理解为对本发明保护范围的限制，该领域的技术人员可以根据上述本发明内容对本发明作出一些非本质的改进和调整。
右旋奥拉西坦晶型II的制备
实施例1
将1g右旋奥拉西坦(重庆润泽医药有限公司)溶解在6mL的混合溶剂中(DMF 2mL，二氯甲烷4mL)溶液中，50℃加热溶解，过滤，将滤液加盖密封，以100～150r/min的速度搅拌15h左右，再次过滤，过滤后滤液在干燥器中静置挥发溶剂形成结晶，收集结晶，将收集的结晶在30±2℃，相对湿度为80-85％的条件下干燥5-6h，得到右旋奥拉西坦晶体。
实施例2
将实施例1得到的右旋奥拉西坦晶体进行粉末衍射实验：
粉末衍射测定(XRPD)：
测试仪器条件：使用Bruker D2PHASER粉末衍射仪进行常温测试，测试条件为：以Cu Ka
Figure PCTCN2017092220-appb-000002
为光源，电压30kV，电流10mA，测试步长0.014°，扫描速度0.1s/step，扫描范围5-40°(2θ)。经检测，实施例1制备的右旋奥拉西坦晶体，在衍射角度2θ为10.54±0.2°、13.76±0.2°、14.14±0.2°、16.64±0.2°、17.76±0.2°、18.72±0.2°、20.16±0.2°、21.20±0.2°、21.52±0.2°、23.25±0.2°、24.17±0.2°、25.88±0.2°、27.61±0.2°、28.57±0.2°、29.24±0.2°、31.40±0.2°有衍射峰，为了方便起见，将该晶体称为“右旋奥拉西坦晶型II”；其粉末衍射图见图1，衍射数据解析如下表1：
表1：晶型II的粉末衍射峰
Figure PCTCN2017092220-appb-000003
Figure PCTCN2017092220-appb-000004
。由表1可知，本发明右旋奥拉西坦晶型II，在衍射角度2θ为21.20±0.2°处的相对峰强度为100％；在衍射角度2θ为20.16±0.2°的相对峰强度大于70％小于100％；在衍射角度2θ为17.76±0.2°、24.17±0.2°、25.88±0.2°的相对峰强度不小于40％。
差示扫描热分析(DSC)图测定：
测试仪器及条件：使用差示扫描量热分析仪(STA 409PC，德国Netzsch公司)进行DSC测试，测试方法为准确称取一定量(1～2mg)的样品于DSC坩埚中，坩埚加盖密封后，以空坩埚作为参比，从20℃加热至200℃，使用铝坩埚在氮气气氛中，以10℃/min速率加热，样品室氮气流量为20mL/min。本发明右旋奥拉西坦晶型II的差示扫描热分析(DSC)图如图2所示，其在73.5℃左右失去结晶水，吸热转变温度在138.0℃左右。用卡尔-费休氏法测得本发明所述右旋奥拉西坦晶型II中的水分为5.56％(理论：5.52％)，结合热重分析特征，表明本发明右旋奥拉西坦晶型II为1/2水合物。
参照实施例1，按照实施例3-12制备右旋奥拉西坦晶型II。
实施例3
将1g右旋奥拉西坦溶解在5mL的混合溶剂中(DMF 1mL，乙酸乙酯4mL)溶液中，45℃加热溶解，过滤，将滤液加盖密封，以150r/min左右的速度搅拌12h左右，再次过滤，过滤后滤液在干燥器中静置挥发溶剂形成结晶，收集结晶，将收集的结晶在30±2℃，相对湿度为75-80％的条件下干燥4-5h，得到晶体，用实施例2的方法鉴定，为右旋奥拉西坦晶型II。
实施例4
将1g右旋奥拉西坦溶解在8mL的混合溶剂中(DMF 1mL，丙酮7mL)溶液中，45℃加热溶解，过滤，将滤液加盖密封，以100r/min左右的速度搅拌20h左右，再次过滤，过滤后滤液在干燥器中静置挥发溶剂形成结晶，收集结晶，将收集的结晶在25±2℃，相对湿度为80-85％的条件下干燥6h左右，得到晶体，用实施例2的方法鉴定，为右旋奥拉西坦晶型II。
实施例5
将500mg右旋奥拉西坦溶解在2mL的混合溶剂中(正丙醇1mL，四氢呋喃1mL)溶液中，50℃加热溶解，过滤，将滤液加盖密封，以120r/min 左右的速度搅拌8h左右，再次过滤，过滤后滤液在干燥器中静置挥发溶剂形成结晶，收集结晶，将收集的结晶在15±2℃，相对湿度为70-75％的条件下干燥10h左右，得到晶体，用实施例2的方法鉴定，为右旋奥拉西坦晶型II。
实施例6
将1g右旋奥拉西坦溶解在6mL的混合溶剂中(正丙醇1mL，乙醚5mL)溶液中，60℃加热溶解，过滤，将滤液加盖密封，以150r/min左右的速度搅拌5h左右，再次过滤，过滤后滤液在干燥器中静置挥发溶剂形成结晶，收集结晶，将收集的结晶在40±2℃，相对湿度为65-70％的条件下干燥4h左右，得到晶体，用实施例2的方法鉴定，为右旋奥拉西坦晶型II。
实施例7
将1g右旋奥拉西坦溶解在6mL的混合溶剂中(正丙醇1mL，正己烷5mL)溶液中，30℃加热溶解，过滤，将滤液加盖密封，以130r/min左右的速度搅拌5h左右，再次过滤，过滤后滤液在干燥器中静置挥发溶剂形成结晶，收集结晶，将收集的结晶在25±2℃，相对湿度为85-95％的条件下干燥5h左右，得到晶体，用实施例2的方法鉴定，为右旋奥拉西坦晶型II。
实施例8
将1g右旋奥拉西坦溶解在10mL的混合溶剂中(正丁醇2mL，二氯甲烷8mL)溶液中，40℃加热溶解，过滤，将滤液加盖密封，以150r/min左右的速度搅拌5h左右，再次过滤，过滤后滤液在干燥器中静置挥发溶剂形成结晶，收集结晶，将收集的结晶在35±2℃，相对湿度为80-85％的条件下干燥6h左右，得到晶体，用实施例2的方法鉴定，为右旋奥拉西坦晶型II。
实施例9
将1g右旋奥拉西坦溶解在8mL的混合溶剂中(二甲基乙酰胺2mL，四氢呋喃6mL)溶液中，30℃加热溶解，过滤，将滤液加盖密封，以200r/min左右的速度搅拌5h左右，再次过滤，过滤后滤液在干燥器中静置挥发溶剂形成结晶，收集结晶，将收集的结晶在30±2℃，相对湿度为80-85％的条件下干燥5h左右，得到晶体，用实施例2的方法鉴定，为右旋奥拉西坦晶型II。
实施例10
将1g右旋奥拉西坦溶解在7mL的混合溶剂中(二甲基乙酰胺2mL， 丙酮5mL)溶液中，30℃加热溶解，过滤，将滤液加盖密封，以200r/min左右的速度搅拌5h左右，再次过滤，过滤后滤液在干燥器中静置挥发溶剂形成结晶，收集结晶，将收集的结晶在35±2℃，相对湿度为75-80％的条件下干燥5h左右，得到晶体，用实施例2的方法鉴定，为右旋奥拉西坦晶型II。
实施例11
将1g右旋奥拉西坦溶解在10mL的混合溶剂中(二甲基乙酰胺2mL，乙酸乙酯8mL)溶液中，30℃加热溶解，过滤，将滤液加盖密封，以130r/min左右的速度搅拌5h左右，再次过滤，过滤后滤液在干燥器中静置挥发溶剂形成结晶，收集结晶，将收集的结晶在35±2℃，相对湿度为75-80％的条件下干燥5h左右，得到晶体，用实施例2的方法鉴定，为右旋奥拉西坦晶型II。
实施例12
将1g右旋奥拉西坦溶解在6mL的混合溶剂中(正丙醇2mL，正己烷4mL)溶液中，40℃加热溶解，过滤，将滤液加盖密封，以150r/min左右的速度搅拌4h左右，再次过滤，过滤后滤液在干燥器中静置挥发溶剂形成结晶，收集结晶，将收集的结晶在25±2℃，相对湿度为80-85％的条件下干燥5h左右，得到晶体，用实施例2的方法鉴定，为右旋奥拉西坦晶型II。
右旋奥拉西坦晶型II的性能测定实验
实施例13动态水分吸附分析(DVS)试验
试验参数如下：称重：Ultra数字化微天平SMS Ultra BalanceTM；流速：N2、200sccm，系统控制软件：DVS-Intrinsic control software ver.1.0.3.1，数据分析软件：Isotherm(ISO)analysis suite。
测试右旋奥拉西坦晶型II样品22.4mg，RH＝0％进行干燥，平衡质量以确保除去表面吸附水分，然后置于金属样品托盘上，在0％RH干燥2h后进行测试，温度恒定在25℃，控制相对湿度(RH％)以10％的梯度由0％-90％-0％RH循环变化，测量样品重量随湿度的变化，结合粉末X-射线衍射表征以观察湿度对样品晶型转变的影响，结果发现仍为右旋奥拉西坦晶型II。
实施例14加速实验
晶型稳定性加速试验采用2010年药典附录XIXC“原料药与药物制剂稳定性试验指导原则”中有关原料药加速试验的规定，将右旋奥拉西坦晶型 II放于烧杯中，于恒温恒湿箱中，在温度40°±2℃，相对湿度75％±5％的条件下进行。
实验结果：2h后，发现右旋奥拉西坦晶型II无变化；10d后右旋奥拉西坦晶型II无变化；15d后右旋奥拉西坦晶型II仍然无变化。
由此可见，本发明右旋奥拉西坦晶型II在室温和相对湿度为0-95％条件下均可稳定存在，不会发生转晶。将本发明右旋奥拉西坦晶型II用于保存或者制剂加工，其对加工湿度或保存条件湿度要求较低。
含右旋奥拉西坦晶型II组合物的制备
实施例15
实施例1所述方法制得的右旋奥拉西坦晶型II按照180mg/粒、微晶纤维素90.8mg/粒、可压性淀粉82mg/粒、滑石粉7.2mg/粒和10％聚乙烯吡咯烷酮适量；以制成1000粒I晶型右旋奥拉西坦胶囊剂为例，具体制备方法是：先将原辅料过80目筛，称取上述量的右旋奥拉西坦晶型II、微晶纤维素、可压性淀粉混合均匀，加10％PVP乙醇溶液制软材，制粒，烘干，整粒，向颗粒中加入上述量的滑石粉，混合均匀，充填胶囊。
实施例16
实施例1所述方法制得的右旋奥拉西坦晶型II按照60g，山梨醇140g，500ml注射用水溶解于稀配罐中，温度控制在50～58℃，搅拌直至完全溶解，将溶解液冷却到25℃，向上述配好的溶解液中加入活性炭脱色，再将其中的活性炭过滤除去，加入磷酸盐缓冲液将该溶解液的pH值调节为6.0，再加入注射用水至5000ml，灌封，在105℃灭菌30分钟，得到注射液。

Claims (14)

  1. 一种右旋奥拉西坦晶型II，在衍射角度2θ为17.76±0.2°、20.16±0.2°、21.20±0.2°、24.17±0.2°、25.88±0.2°有衍射峰。
  2. 如权利要求1所述的右旋奥拉西坦晶型II，其特征在于：所述右旋奥拉西坦晶型II在衍射角度2θ为21.20±0.2°处的相对峰强度为100％；在衍射角度2θ为20.16±0.2°的相对峰强度大于70％小于100％；在衍射角度2θ为17.76±0.2°、24.17±0.2°、25.88±0.2°的相对峰强度不小于40％。
  3. 如权利要求1所述的右旋奥拉西坦晶型II，其特征在于：所述右旋奥拉西坦晶型II，在衍射角度2θ为14.14±0.2°、17.76±0.2°、18.72±0.2°、20.16±0.2°、21.20±0.2°、21.52±0.2°、24.17±0.2°、25.88±0.2°有衍射峰。
  4. 如权利要求1所述的右旋奥拉西坦晶型II，其特征在于：所述右旋奥拉西坦晶型II，在衍射角度2θ为10.54±0.2°、13.76±0.2°、14.14±0.2°、16.64±0.2°、17.76±0.2°、18.72±0.2°、20.16±0.2°、21.20±0.2°、21.52±0.2°、23.25±0.2°、24.17±0.2°、25.88±0.2°、27.61±0.2°、28.57±0.2°、29.24±0.2°、31.40±0.2°有衍射峰。
  5. 如权利要求1所述的右旋奥拉西坦晶型II，其特征在于：所述右旋奥拉西坦晶型II在138.0±2℃熔融分解。
  6. 如权利要求1所述的右旋奥拉西坦晶型II，其特征在于：所述右旋奥拉西坦晶型II具有如图2所示的差示扫描热分析(DSC)图谱。
  7. 如权利要求1-6任一项所述右旋奥拉西坦晶型II的制备方法，采用如下步骤：将右旋奥拉西坦溶于混合溶剂中，过滤，将滤液加盖密封，搅拌；再次过滤，过滤后滤液在干燥器中挥发溶剂形成结晶，收集结晶，干燥既得右旋奥拉西坦晶型II；所述混合溶剂为良溶剂与不良溶剂混合而成，其中良溶剂选自DMF、二甲基乙酰胺、正丙醇或正丁醇，不良溶剂选自二氯甲烷、丙酮、乙酸乙酯、四氢呋喃、乙醚、正己烷或石油醚；当良溶剂为DMF时，不良溶剂为二氯甲烷、丙酮、乙酸乙酯中的任意一种；当良溶剂为二甲基乙酰胺时，不良溶剂为四氢呋喃、丙酮、乙酸乙酯中的任意一种；当良溶剂为正丙醇时，不良溶剂为四氢呋喃、乙醚、正己烷中的任意一种；当良溶剂为正丁醇时，不良溶剂为二氯甲烷、乙醚、石油醚中的任意一种。
  8. 如权利要求7所述的方法，其特征在于：所述右旋奥拉西坦与混合溶剂的质量体积比为1:2～1:10，以g/mL计；所述混合溶液中良溶剂与不良溶剂的体积比为1:1～1:7。
  9. 如权利要求7或8所述的方法，其特征在于：将滤液加盖密封后，搅拌时间为3～24h，搅拌速度为100～150r/min。
  10. 如权利要求7或8所述的方法，其特征在于：过滤收集结晶后，在10-40℃，相对湿度为55-85％的条件下干燥4-10h。
  11. 如权利要求7所述的方法，其特征在于，采用如下步骤：将右旋奥拉西坦溶于混合溶剂中，其中右旋奥拉西坦与混合溶剂的质量体积比为1:2～1:10，以g/mL计，过滤，将滤液加盖密封，以100～150r/min的速度搅拌5～24h，再次过滤，过滤后滤液在干燥器中静置挥发溶剂形成结晶，收集结晶，将收集的结晶在25-40℃，相对湿度为65-85％的条件下干燥5-6h，既得右旋奥拉西坦晶型II；所述混合溶剂为良溶剂与不良溶剂混合而成，良溶剂与不良溶剂的体积比为1:2～1:5，其中良溶剂选自DMF、二甲基乙酰胺、正丙醇或正丁醇，不良溶剂选自二氯甲烷、丙酮、乙酸乙酯、四氢呋喃、乙醚、正己烷或石油醚；当良溶剂为DMF时，不良溶剂为二氯甲烷、丙酮、乙酸乙酯中的任意一种；当良溶剂为二甲基乙酰胺时，不良溶剂为四氢呋喃、丙酮、乙酸乙酯中的任意一种；当良溶剂为正丙醇时，不良溶剂为四氢呋喃、乙醚、正己烷中的任意一种；当良溶剂为正丁醇时，不良溶剂为二氯甲烷、乙醚、石油醚中的任意一种。
  12. 如权利要求1-6任一项所述右旋奥拉西坦晶型II在制备抗癫痫药物中的应用。
  13. 一种药物组合物，包含如权利要求1-6任一项所述右旋奥拉西坦晶型II和在药学上可接受的辅料。
  14. 如权利要求13所述组合物，其特征在于：所述组合物为片剂、散剂、颗粒剂、注射剂、胶囊剂、滴丸剂、缓释控释制剂、冻干粉针剂。
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