WO2018076784A1 - （r）-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型及其制备方法和用途 - Google Patents

（r）-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型及其制备方法和用途 Download PDF

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WO2018076784A1
WO2018076784A1 PCT/CN2017/092221 CN2017092221W WO2018076784A1 WO 2018076784 A1 WO2018076784 A1 WO 2018076784A1 CN 2017092221 W CN2017092221 W CN 2017092221W WO 2018076784 A1 WO2018076784 A1 WO 2018076784A1
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oxo
hydroxy
pyrrolidineacetamide
crystal
diffraction
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PCT/CN2017/092221
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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 EP17864955.4A priority Critical patent/EP3530650A4/en
Priority to US16/344,340 priority patent/US10556863B1/en
Priority to KR1020197011748A priority patent/KR20190052127A/ko
Priority to JP2019520830A priority patent/JP2019531323A/ja
Publication of WO2018076784A1 publication Critical patent/WO2018076784A1/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

  • the present invention relates to (R)-4-hydroxy-2-oxo-1-pyrrolidinylacetamide, in particular to crystal form of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide, and a preparation method thereof And use.
  • 4-hydroxy-2-oxo-1-pyrrolidone acetamide CAS No. 62613-82-5, first synthesized in 1974 by the Italian company Spiebicem, a new generation of brain metabolism improving drug marketed in 1987, It can promote the synthesis of phosphorylcholine and o-acylethanolamine, promote brain metabolism, stimulate the specific central nervous pathway through the blood-brain barrier, and improve intelligence and memory. Studies have shown that its left-handed body has a better effect in promoting brain mental development.
  • the (R)-4-hydroxy-2-oxo-1-pyrrolidinylacetamide crystal form I of the present invention has a relative peak intensity at a diffraction angle 2 ⁇ of 22.16 ⁇ 0.2° of 100%; and a diffraction angle of 2 ⁇ of 17.54 ⁇
  • the relative peak intensities of 0.2°, 16.66 ⁇ 0.2°, and 30.96 ⁇ 0.2° are not less than 80%.
  • the crystal form I of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide of the invention has a diffraction angle of 2 ⁇ of 16.66 ⁇ 0.2°, 17.54 ⁇ 0.2°, 19.42 ⁇ 0.2°, 21 ⁇ 0.2°, There are diffraction peaks at 22.16 ⁇ 0.2°, 23.46 ⁇ 0.2°, 25.36 ⁇ 0.2°, 26.08 ⁇ 0.2°, and 30.96 ⁇ 0.2°.
  • the (R)-4-hydroxy-2-oxo-1-pyrrolidinylacetamide crystal form I of the invention has a diffraction angle 2 ⁇ of 12.6 ⁇ 0.2°, 16.66 ⁇ 0.2°, 17.54 ⁇ 0.2°, 19.42 ⁇ 0.2°, There are diffraction peaks at 20.68 ⁇ 0.2°, 21 ⁇ 0.2°, 22.16 ⁇ 0.2°, 23.46 ⁇ 0.2°, 25.36 ⁇ 0.2°, 26.08 ⁇ 0.2°, 26.5 ⁇ 0.2°, 30.26 ⁇ 0.2°, and 30.96 ⁇ 0.2°.
  • the crystal form I of the (R)-4-hydroxy-2-oxo-1-pyrrolidinylacetamide of the invention has a diffraction angle 2 ⁇ of 12.6 ⁇ 0.2°, 14.04 ⁇ 0.2°, 15.1 ⁇ 0.2°, 16.66 ⁇ 0.2°, 17.54 ⁇ 0.2°, 19.42 ⁇ 0.2°, 20.68 ⁇ 0.2°, 21 ⁇ 0.2°, 22.16 ⁇ 0.2°, 23.46 ⁇ 0.2°, 25.36 ⁇ 0.2°, 26.08 ⁇ 0.2°, 26.5 ⁇ 0.2°, 30.26 ⁇ 0.2°, There are diffraction peaks at 30.46 ⁇ 0.2°, 30.96 ⁇ 0.2°, and 31.28 ⁇ 0.2°.
  • the (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide crystal form I of the present invention has a powder diffraction pattern as shown in FIG.
  • a method for preparing (R)-4-hydroxy-2-oxo-1-pyrrolidinylacetamide crystal form I which comprises the steps of: (R)-4-hydroxy-2-oxo-1-pyrrolidine
  • the acetamide is dissolved in an organic solvent to form a supersaturated solution, which is then crystallized in a low temperature environment of -12 ° C to 21 ° C, filtered, and dried to obtain (R)-4-hydroxy-2-oxo-1-pyrrolidine B.
  • the amide form I; the organic solvent is selected from one or a combination of ethanol, tetrahydrofuran, acetone, methanol, methyl ethyl ketone, isoamyl alcohol, acetonitrile.
  • the above (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide crystal form I is prepared by the following steps:
  • (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide is added in an organic solvent at a concentration of 5 mg/mL to 55 mg/mL, continuously stirred, dissolved at 35 ° C to 90 ° C, filtered, and formed. Saturated solution; the supersaturated solution is sealed and placed in a low temperature environment of -12 ° C ⁇ -21 ° C to cool the crystal, and the separation is separated by filtration.
  • (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide Form I the organic solvent is selected from the group consisting of ethanol, tetrahydrofuran, acetone, methanol, methyl ethyl ketone, isoamyl alcohol, acetonitrile One or several combinations.
  • the above low temperature environment is preferably -15 ° C to -20 ° C; more preferably -17 ° C to -19 ° C.
  • the above (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide crystal form I is prepared by the following steps: 5 mg/mL to 50 mg in an organic solvent. Add (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide to the concentration of mL, stir constantly, dissolve at 45 ° C ⁇ 75 ° C, filter to form a supersaturated solution; seal the supersaturated solution in - The crystal is cooled in a low temperature environment of 17 ° C to -19 ° C, and the crystal is separated by filtration, and dried at 65-75 ° C and a relative humidity of 0-30% for 4-6 hours to obtain (R)-4-hydroxy-2-oxo.
  • Derivative-1-pyrrolidineacetamide Form I the organic solvent is selected from one or a combination of ethanol, tetrahydrofuran, acetone, methanol, methyl ethyl ketone, isoamyl alcohol, acetonitrile.
  • the starting material (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide of the present invention may be a commercially available product or may be self-made, and the remaining raw materials or reagents are commercially available products.
  • the agitation is conventional in a manner well known in the art, and filtration is conventional solid-liquid separation means well known in the art.
  • the invention provides the use of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide Form I (a therapeutically effective amount) for the preparation of a medicament for the prophylaxis or treatment of an anti-epileptic drug.
  • the invention relates to the use of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide crystal form I in the preparation of a medicament for preventing or treating acute epileptic seizures, in particular for preparing an anti-epileptic acute episode drug for preventing or treating epilepsy Application in .
  • the use of the (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide Form I of the present invention for the preparation of a medicament for preventing or treating an epilepticus-sustaining state.
  • the (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide crystal form I of the present invention has special pharmacological activity in stabilizing abnormal brain discharge, sedation, anti-epilepsy, etc., and solubility in water ⁇ 90mg/mL, high bioavailability.
  • a pharmaceutical composition comprising the above (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide Form I and a pharmaceutically acceptable excipient;
  • the composition is any clinically acceptable pharmaceutical dosage form including, but not limited to, oral, rectal, vaginal, nasal, inhalation, topical (including transdermal) or parenteral administration, including tablets. , powder, granules, injections, capsules, pills, sustained release controlled release preparations, freeze-dried powder injections.
  • the present invention provides a crystal form of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide having a diffraction angle of 2 ⁇ of 16.66 ⁇ 0.2°, 17.54 ⁇ 0.2°, 21 ⁇ 0.2°, 22.16 ⁇ 0.2°, 30.96 ⁇ 0.2° have diffraction peaks, and the relative peak intensity at the diffraction angle 2 ⁇ is 22.16 ⁇ 0.2° is 100%; at the diffraction angle 2 ⁇ is 17.54 ⁇ 0.2°, 16.66 ⁇ 0.2°, 30.96 ⁇ 0.2
  • the relative peak intensity of ° is not less than 80%.
  • the (R)-4-hydroxy-2-oxo-1-pyrrolidinylacetamide crystal form I of the invention has special pharmacological activity in stabilizing abnormal brain discharge, sedation and anti-epilepsy.
  • the (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide crystal form I of the invention has a fast dissolution rate in water, a solubility in water of ⁇ 90 mg/mL, and high bioavailability.
  • the crystal form I of the (R)-4-hydroxy-2-oxo-1-pyrrolidinylacetamide of the invention has no crystal transformation phenomenon between 30 ° C and 80 ° C, and has high temperature stability, and the invention (R)- Form I of 4-hydroxy-2-oxo-1-pyrrolidineacetamide is used for storage or formulation processing, which requires less processing temperature or storage temperature.
  • the (R)-4-hydroxy-2-oxo-1-pyrrolidinylacetamide crystal form I of the invention has good fluidity, and has good solubility in a conventional solvent (such as water, methanol, DMSO, etc.), and has high adaptability to the preparation process.
  • the preparation method of the invention adopts the raw material which is cheap and easy to obtain, and the obtained (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide crystal form I has high purity, the preparation method is mild, the operation is simple, and the introduction is simple. Less impurities, good reproducibility, easy control of production process, high safety, suitable for industrial production.
  • Figure 1 is a powder diffraction pattern of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide Form I.
  • 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 (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide crystal prepared in Example 1 was tested to have a diffraction angle of 2 ⁇ of 12.6 ⁇ 0.2°, 14.04 ⁇ 0.2°, 15.1 ⁇ 0.2°, and 16.66.
  • the instrument used was an X-ray single crystal diffractometer (Gemini A Ultra, Agilent, USA), launched The Cu Ka ray collects data in an ⁇ /2 ⁇ scan. Data reduction and absorption correction were processed using CrysAlis PRO software. The space group is determined according to the extinction law of the system and verified by the refinement result. The crystal structure was solved by the direct method using the SHELXS-97 program. The results were corrected by the full matrix least squares method. The hydrogen atom coordinates on the carbon were added theoretically, and the hydrogen atom coordinates on the other atoms were calculated according to the electron density map.
  • Table 2 The crystallographic parameters of the (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide crystal form I of the present invention are shown in Table 2 below (Table 2):
  • the (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide crystal form I of the present invention is placed on a single crystal silicon sample stage, which is heated from 30 ° C to 80 ° C at 35, 45, respectively. Powder X-ray diffraction measurement at 55, 65, 75 ° C, the test results show that the (R)-4-hydroxy-2-oxo-1-pyrrolidine acetamide crystal form I of the present invention is between 30 ° C and 80 ° C No crystal change phenomenon occurred, and it was found that the (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide crystal form I of the present invention has high temperature stability.
  • the (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide crystal form I of the present invention is used for storage or formulation processing, which requires low processing temperature or storage condition temperature.
  • the crystal form I of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide prepared by the method described in Example 1 was 180 mg/granule, lactose 90.8 mg/granule, sodium carboxymethyl starch 82 mg/granule.
  • talc powder 7.2mg / granules and 10% polyvinylpyrrolidone amount; to make 1000 tablets of crystal form I (R)-4-hydroxy-2-oxo-1-pyrrolidine acetamide capsules as an example, the specific preparation method Yes: first pass the raw materials through the 80 mesh sieve, weigh the above amount of (R)-4-hydroxy-2-oxo-1-pyrrolidine acetamide crystal form I, lactose, sodium carboxymethyl starch, evenly mixed, plus The soft material is made of 10% PVP ethanol solution, granulated, dried, and granulated. The above amount of talc powder is added to the granules, uniformly mixed, and filled with capsules.
  • the crystal form I of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide prepared by the method described in Example 1 was dissolved in a rare tank according to 60 g, glucose 140 g, 500 ml of water for injection, and the temperature was controlled at 50 ⁇ 58 °C, stir until completely dissolved, the solution is cooled to 25 ° C, decolorized by adding activated carbon to the above prepared solution, and then the activated carbon is removed by filtration, and the pH of the solution is added by adding phosphate buffer. Adjust to 4.0, add water for injection to 5000 ml, potting, and sterilize at 105 ° C for 30 minutes to obtain an injection.
  • (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide Form I prepared by the method described in Example 1 According to 200mg / tablet, starch 44mg / tablet, microcrystalline cellulose 50mg / tablet, talc powder 6mg / tablet and 2% hydroxypropyl methylcellulose (K4M model) appropriate amount; to make 1000 tablets (R) -4-
  • the hydroxy-2-oxo-1-pyrrolidinylacetamide crystal form I tablet is taken as an example, and the specific preparation method is as follows: firstly, the original auxiliary material is passed through an 80 mesh sieve, and the above amount of (R)-4-hydroxy-2- is weighed.
  • Oxo-1-pyrrolidine acetamide crystal form I starch, microcrystalline cellulose mixed evenly, add appropriate amount of 2% HPMC aqueous solution to soft material, granulate, dry, granule, add prescription amount of talcum powder to the granules , mix evenly and compress.

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Abstract

一种(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型被公开，该晶型在衍射角度2θ为16.66±0.2°、17.54±0.2°、21±0.2°、22.16±0.2°、30.96±0.2°有衍射峰，该晶型在水中溶解速度快，水中溶解度≥90mg/mL，生物利用度高，且高温稳定性好，适合制成多种药物组合物，可制成多种制剂如片剂、胶囊剂、滴丸剂、缓释控释制剂、冻干粉针剂等。该晶型的制备方法条件温和，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。

Description

(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型及其制备方法和用途 技术领域
本发明涉及(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺，具体涉及(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺的晶型、制备方法和用途。
背景技术
4-羟基-2-氧代-1-吡咯烷乙酰胺，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，其左旋体在促进大脑智力发育方面具有更好的疗效。近年来，有报道显示其右旋体(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺在镇静，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 PCTCN2017092221-appb-000001
(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺
为有效将(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺开发成药品，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(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺的制备方法及晶型研究较少，尚未有(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺的晶型披露。
发明内容
根据本发明的第一方面，本发明提供了一种(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型，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(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型称为“晶型I”。
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(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I，在衍射角度2θ为16.66±0.2°、17.54±0.2°、21±0.2°、22.16±0.2°、30.96±0.2°有衍射峰。
本发明(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I，在衍射角度2θ为22.16±0.2°处的相对峰强度为100％；在衍射角度2θ为17.54±0.2°、16.66±0.2°、30.96±0.2°的相对峰强度不小于80％。
本发明(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I，在衍射角度2θ为16.66±0.2°、17.54±0.2°、19.42±0.2°、21±0.2°、22.16±0.2°、23.46±0.2°、25.36±0.2°、26.08±0.2°、30.96±0.2°处有衍射峰。
本发明(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I，在衍射角度2θ为12.6±0.2°、16.66±0.2°、17.54±0.2°、19.42±0.2°、20.68±0.2°、21±0.2°、22.16±0.2°、23.46±0.2°、25.36±0.2°、26.08±0.2°、26.5±0.2°、30.26±0.2°、30.96±0.2°处有衍射峰。
本发明(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I，在衍射角度2θ为12.6±0.2°、14.04±0.2°、15.1±0.2°、16.66±0.2°、17.54±0.2°、19.42±0.2°、20.68±0.2°、21±0.2°、22.16±0.2°、23.46±0.2°、25.36±0.2°、26.08±0.2°、26.5±0.2°、30.26±0.2°、30.46±0.2°、30.96±0.2°、31.28±0.2°处有衍射峰。
本发明(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I具有如图1所示的粉末衍射图谱。
根据本发明的第二方面，本发明提供一种(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I的制备方法，该方法工艺简单，适合工业化生产。
一种(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I的制备方法，采用如下步骤：将(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺用有机溶剂溶解，形成过饱和溶液，然后在-12℃～-21℃的低温环境中结晶，过滤，干燥，得到(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I；所述有机溶剂选自乙醇、四氢呋喃、丙酮、甲醇、丁酮、异戊醇、乙腈中的一种或几种组合。
根据本发明的一个实施方案，上述(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I的制备方法，采用如下步骤：
在有机溶剂中以5mg/mL-55mg/mL的浓度加入(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺，不断搅拌，35℃～90℃加热溶解，过滤，形成过饱和溶液；将过饱和溶液密封放置在-12℃～-21℃的低温环境中冷却结晶，过滤分离出结 晶，干燥，得到(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I；所述有机溶剂选自乙醇、四氢呋喃、丙酮、甲醇、丁酮、异戊醇、乙腈中的一种或几种组合。
根据本发明的一个实施方案，上述低温环境优选-15℃～-20℃；更优选-17℃～-19℃。
根据本发明的一个实施方案，上述(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I的制备方法，采用如下步骤：在有机溶剂中以5mg/mL-50mg/mL的浓度加入(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺，不断搅拌，45℃～75℃加热溶解，过滤，形成过饱和溶液；将过饱和溶液密封放置在-17℃～-19℃的低温环境中冷却结晶，过滤分离出结晶，在65-75℃、相对湿度为0-30％条件下干燥4-6h，得到(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I；所述有机溶剂选自乙醇、四氢呋喃、丙酮、甲醇、丁酮、异戊醇、乙腈中的一种或几种组合。
本发明原料(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺可以为市售产品，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，搅拌为为本领域所熟知的常规方式，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(R)-4-羟基-2-氧-1-吡咯烷乙酰胺晶型I(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(R)-4-羟基-2-氧-1-吡咯烷乙酰胺晶型I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(R)-4-羟基-2-氧-1-吡咯烷乙酰胺晶型I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(R)-4-羟基-2-氧-1-吡咯烷乙酰胺晶型I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(R)-4-羟基-2-氧-1-吡咯烷乙酰胺晶型I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(R)-4-羟基-2-氧-1-吡咯烷乙酰胺晶型I，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≥90mg/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(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I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(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型，该晶型在衍射角度2θ为16.66±0.2°、17.54±0.2°、21±0.2°、22.16±0.2°、30.96±0.2°有衍射峰，且在衍射角度2θ为22.16±0.2°处的相对峰强度为100％；在衍射角度2θ为17.54±0.2°、16.66±0.2°、30.96±0.2°的相对峰强度不小于80％。本发明(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I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。本发明(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I在水中溶解速度快，水中溶解度≥90mg/mL，生物利用度高。本发明(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I在30℃-80℃之间未出现转晶现象，高温稳定性好，将本发明(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I用于保存或者制剂加工，其对加工温度或保存条件温度要求较低。本发明(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I流动性好，且在常规溶剂(如水、甲醇、DMSO等)中溶解性好，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(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I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(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I的粉末衍射图。
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。
(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I的制备
实施例1
将30mg的(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺(重庆润泽医药有限公司)溶解在2mL异戊醇中，50℃加热，过滤，得过饱和溶液，将此溶液密封放置在-19℃环境下冷却析晶24小时，过滤分离，在温度为70℃、相对湿度为20％条件下干燥5h左右，得到晶体。
实施例2
将实施例1得到的(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶体进行晶体学测定。
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 PCTCN2017092221-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(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶体，在衍射角度2θ为12.6±0.2°、14.04±0.2°、15.1±0.2°、16.66±0.2°、17.54±0.2°、19.42±0.2°、20.68±0.2°、21±0.2°、22.16±0.2°、23.46±0.2°、25.36±0.2°、26.08±0.2°、26.5±0.2°、30.26±0.2°、30.46±0.2°、30.96±0.2°、31.28±0.2°处有衍射峰，为了方便起见，将该晶体称为“(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I”，其粉末衍射图见图1，衍射数据解析如下表1：
表1：晶型I的粉末衍射峰
Figure PCTCN2017092221-appb-000003
Figure PCTCN2017092221-appb-000004
由上表1可知，本发明(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I，在衍射角度2θ为22.16±0.2°处的相对峰强度为100％；在衍射角度2θ为17.54±0.2°、16.66±0.2°、30.96±0.2°的相对峰强度不小于80％。
单晶X-射线衍射法(SXRD)测定：
使用仪器是X-射线单晶衍射仪(Gemini A Ultra,美国Agilent公司)，发射
Figure PCTCN2017092221-appb-000005
的Cu Ka射线，以ω/2θ扫描方式收集数据。数据的还原 和吸收校正使用CrysAlis PRO软件处理。空间群根据系统的消光规律确定，并由精修结果验证。晶体结构使用SHELXS-97程序，由直接法解出，以全矩阵最小二乘法修正结果，碳上的氢原子坐标按理论计算加入，其他原子上的氢原子坐标根据电子密度图计算加入。本发明(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I的晶体学参数如下表2(Table2)所示：
Table 2.Crystal data and structure refinement for exp_9533.
Figure PCTCN2017092221-appb-000006
Figure PCTCN2017092221-appb-000007
*R1＝Σ||Fo|-|Fc||/Σ|Fo|,wR2＝[Σw(Fo 2-Fc 2)2/Σw(Fo 2)2]1/2,w＝[σ2(Fo)2+(0.1(max(0,Fo 2)+2Fc 2)/3)2]-1
由上表2可知，本发明(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I为单斜晶系Monoclinic,P21，其中a＝6.7856(2)A alpha＝90deg.；b＝12.6010(4)A beta＝102.471(4)deg.；c＝8.6586(3)A gamma＝90deg.
参照实施例1，按照实施例3-10制备(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I。
实施例3
将30mg的(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺溶解在4mL乙腈中，55℃加热，过滤，得过饱和溶液，将此溶液密封放置在-17℃环境下冷却析晶3小时，过滤分离，在65℃、相对湿度为30％条件下干燥4h左右，得到无色沙粒状晶体，用实施例2的方法鉴定，为(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I。
实施例4
将60mg的(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺溶解在10mL乙醇中，40℃加热，过滤，得过饱和溶液，将此溶液密封放置在-20℃环境下24小时冷却析晶，过滤分离，在75℃、相对湿度为10％条件下干燥6h左右，得到无色沙粒状晶体，用实施例2的方法鉴定，为(R)-4-羟基-2-氧代-1-吡 咯烷乙酰胺晶型I。
实施例5
将60mg(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺溶解在2mL异戊醇中，75℃加热，过滤，得过饱和溶液，将此溶液密封放置在-12℃环境下冷却析晶36小时，过滤分离，在50℃、相对湿度为30％条件下干燥5h左右，得到无色沙粒状晶体，用实施例2的方法鉴定，为(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I。
实施例6
将(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺30mg溶解在4mL异戊醇中，65℃加热，过滤，得过饱和溶液，将此溶液密封放置在-21℃环境下冷却析晶36小时，过滤分离，在75℃、相对湿度为40％条件下干燥3h左右，得到无色沙粒状晶体，用实施例2的方法鉴定，为(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I。
实施例7
将100mg的(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺溶解在2mL四氢呋喃中，45℃加热，过滤，得过饱和溶液，将此溶液密封放置在-18℃环境下冷却析晶36小时，过滤分离，在70℃、相对湿度为15％条件下干燥8h左右，得到无色沙粒状晶体，用实施例2的方法鉴定，为(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I。
实施例8
将80mg的(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺溶解在2mL丙酮中，45℃加热，过滤，得过饱和溶液，将此溶液密封放置在-19℃环境下冷却析晶36小时，过滤分离，在75℃、相对湿度为20％条件下干燥6h左右，得到无色沙粒状晶体，用实施例2的方法鉴定，为(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I。
实施例9
将330mg的(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺溶解在6mL甲醇中，45℃加热，过滤，得过饱和溶液，将此溶液密封放置在-19℃环境下冷却析晶36小时，过滤分离，在75℃、相对湿度为25％条件下干燥6h左右，得到无色沙粒状晶体，用实施例2的方法鉴定，为(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I。
实施例10
将30mg的(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺溶解在5mL丁酮中，40℃加热，过滤，得过饱和溶液，将此溶液密封放置在-19℃环境下冷却析晶48小时，过滤分离，在65℃、相对湿度为15％条件下干燥5h左右，得到无色沙粒状晶体，用实施例2的方法鉴定，为(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I。
(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I的性能测定实验
实施例11
将本发明(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I放置于单晶硅样品台上，将其由30℃加热到80℃，分别在35，45，55，65，75℃进行粉末X-射线衍射测定，试验结果显示，本发明(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I在30℃-80℃之间未出现转晶现象，可见本发明(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I高温稳定性好。将本发明(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I用于保存或者制剂加工，其对加工温度或保存条件温度要求较低。
含(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I组合物的制备
实施例12
实施例1所述方法制得的(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I按照180mg/粒、乳糖90.8mg/粒、羧甲基淀粉钠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(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺胶囊剂为例，具体制备方法是：先将原辅料过80目筛，称取上述量的(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I、乳糖、羧甲基淀粉钠混合均匀，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13
实施例1所述方法制得的(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I按照60g，葡萄糖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4.0，再加入注射用水至5000ml，灌封，在105℃灭菌30分钟，得到注射液。
实施例14：
实施例1所述方法制得的(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I按 照200mg/片、淀粉44mg/片、微晶纤维素50mg/片、滑石粉6mg/片和2％羟丙基甲基纤维素(K4M型号)适量；以制成1000片(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I片剂为例，具体制备方法是：先将原辅料过80目筛，称取上述量的(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I、淀粉、微晶纤维素混合均匀，加适量2％HPMC水溶液制软材，制粒，烘干，整粒，向颗粒中加入处方量的滑石粉，混合均匀，压片。

Claims (13)

  1. 一种(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I，在衍射角度2θ为16.66±0.2°、17.54±0.2°、21±0.2°、22.16±0.2°、30.96±0.2°有衍射峰。
  2. 一种(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I，其特征在于：所述(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I，在衍射角度2θ为16.66±0.2°、17.54±0.2°、19.42±0.2°、21±0.2°、22.16±0.2°、23.46±0.2°、25.36±0.2°、26.08±0.2°、30.96±0.2°处有衍射峰。
  3. 如权利要求1或2所述(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I，其特征在于：在衍射角度2θ为22.16±0.2°处的相对峰强度为100％；在衍射角度2θ为17.54±0.2°、16.66±0.2°、30.96±0.2°的相对峰强度不小于80％。
  4. 一种(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I，其特征在于：所述(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I，在衍射角度2θ为12.6±0.2°、16.66±0.2°、17.54±0.2°、19.42±0.2°、20.68±0.2°、21±0.2°、22.16±0.2°、23.46±0.2°、25.36±0.2°、26.08±0.2°、26.5±0.2°、30.26±0.2°、30.96±0.2°处有衍射峰。
  5. 一种(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I，其特征在于：所述(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I，在衍射角度2θ为12.6±0.2°、14.04±0.2°、15.1±0.2°、16.66±0.2°、17.54±0.2°、19.42±0.2°、20.68±0.2°、21±0.2°、22.16±0.2°、23.46±0.2°、25.36±0.2°、26.08±0.2°、26.5±0.2°、30.26±0.2°、30.46±0.2°、30.96±0.2°、31.28±0.2°处有衍射峰。
  6. 一种(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I，其特征在于：所述晶型I具有如图1所示的粉末衍射图谱。
  7. 如权利要求1-6任一项所述(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I的制备方法，采用如下步骤：将(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺用有机溶剂溶解，形成过饱和溶液，然后在-12℃～-21℃的低温环境中结晶，过滤，干燥，得到(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I；所述有机溶剂选自乙醇、四氢呋喃、丙酮、甲醇、丁酮、异戊醇、乙腈中的一种或几种组合。
  8. 如权利要求7所述方法，其特征在于，采用如下步骤：在有机溶剂中以10mg/mL-55mg/mL的浓度加入(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺，不断搅拌，35℃～90℃加热溶解，过滤，形成过饱和溶液；将过饱和溶液密封放置在-12℃～-21℃的低温环境中冷却结晶，过滤分离出结晶，干燥，得到(R)-4- 羟基-2-氧代-1-吡咯烷乙酰胺晶型I；所述有机溶剂选自乙醇、四氢呋喃、丙酮、甲醇、丁酮、异戊醇、乙腈中的一种或几种组合。
  9. 如权利要求7或8所述方法，其特征在于：所述低温环境为-17℃～-19℃。
  10. 如权利要求1-6任一项所述(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I在制备预防或治疗抗癫痫药物中的应用。
  11. 一种药物组合物，包含权利要求1-6任一项所述(R)-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型I和在药学上可接受的辅料。
  12. 如权利要求11所述的药物组合物，其特征在于：所述组合物为任何临床上可接受的药物剂型。
  13. 如权利要求11或12所述的药物组合物，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。
PCT/CN2017/092221 2016-10-24 2017-07-07 （r）-4-羟基-2-氧代-1-吡咯烷乙酰胺晶型及其制备方法和用途 WO2018076784A1 (zh)

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