WO2018086053A1 - 一种γ-氨基丁酸半水合物晶体及其制备方法 - Google Patents

一种γ-氨基丁酸半水合物晶体及其制备方法 Download PDF

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WO2018086053A1
WO2018086053A1 PCT/CN2016/105420 CN2016105420W WO2018086053A1 WO 2018086053 A1 WO2018086053 A1 WO 2018086053A1 CN 2016105420 W CN2016105420 W CN 2016105420W WO 2018086053 A1 WO2018086053 A1 WO 2018086053A1
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aminobutyric acid
crystal
acid hemihydrate
product
hours
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PCT/CN2016/105420
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English (en)
French (fr)
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龚俊波
顾钦青
赵凯飞
李江波
侯宝红
尹秋响
王静康
孙怡
杜世超
潘欣
刘中士
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南通励成生物工程有限公司
天津大学
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Priority to JP2018532029A priority Critical patent/JP6667639B2/ja
Priority to PCT/CN2016/105420 priority patent/WO2018086053A1/zh
Priority to US16/062,716 priority patent/US10487044B2/en
Publication of WO2018086053A1 publication Critical patent/WO2018086053A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/38—Separation; Purification; Stabilisation; Use of additives
    • C07C227/40—Separation; Purification
    • C07C227/42—Crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
    • 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 invention relates to a hemihydrate crystal and a preparation method thereof, in particular to a ⁇ -aminobutyric acid hemihydrate crystal and a preparation method thereof.
  • ⁇ -aminobutyric acid chemical name 4-aminobutyric acid, alias: aminobutyric acid, pipecolic acid.
  • the molecular formula C4H9NO2 has a molecular weight of 103.1 and is a white or nearly white crystalline powder. It is a hydrophilic amino acid which is highly soluble in water. The structure is as follows:
  • ⁇ -Aminobutyric acid is a naturally occurring non-proteinogenic amino acid widely distributed in prokaryotic and eukaryotic organisms. In mammals, ⁇ -aminobutyric acid is an inhibitory neurotransmitter, mediates more than 40% of inhibitory nerve signals, has important physiological functions, and has broad application prospects in medicine and food.
  • ⁇ -aminobutyric acid has the functions of lowering blood pressure, preventing seizures, preventing epilepsy, improving sleep, anti-depression, and improving brain cells.
  • ⁇ -aminobutyric acid also has functions such as preventing skin aging, eliminating body odor, improving lipid metabolism, preventing arteriosclerosis and effectively losing weight.
  • gamma-aminobutyric acid can be used in the preparation of food additives, in the development of functional dairy products and baked goods, and in the sports food and beverage industry.
  • the Chinese Ministry of Health approved ⁇ -aminobutyric acid as a new resource food.
  • Patents CN101928736A, CN103509831A, CN104531795A propose the preparation of ⁇ -aminobutyric acid by evaporation concentration and 95% ethanol dissolution crystallization.
  • Patent CN102242161A proposes the preparation of gamma-aminobutyric acid by means of evaporation concentration and cooling crystallization. The products they obtained are all ⁇ -aminobutyric acid anhydrate, and the crystal form of the product is needle-like.
  • the main particle size is small and unevenly distributed, the bulk density is low, and the fluidity is poor; in addition, the anhydrous ⁇ -aminobutyric acid has strong hygroscopicity, and is easily absorbed into the air and aggregated into a block, which is not convenient for further. Used for processing.
  • a ⁇ -aminobutyric acid hemihydrate crystal which has good stability, is not easy to absorb moisture and coalesce, has a large main particle diameter and a uniform distribution, and has high bulk density and good fluidity, and a preparation method thereof.
  • the object of the present invention is to provide a ⁇ -aminobutyric acid hemihydrate crystal and a preparation method thereof, in view of the deficiencies of the prior art.
  • the invention discloses a ⁇ -aminobutyric acid hemihydrate crystal having a molecular formula of C4H9NO2 ⁇ 0.5H2O, and the structural formula is as follows:
  • the X-ray powder diffraction pattern of the crystal is 12.3° ⁇ 0.2°, 24.5° ⁇ 0.2°, 26.5° ⁇ 0.2°, 29.6° ⁇ 0.2°, 31.6° ⁇ 0.2°, 36.0° ⁇ at the diffraction angle 2 ⁇ . Characteristic absorption peaks at 0.2°, 37.5° ⁇ 0.2°, and 39.5° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal is 12.3° ⁇ 0.2°, 17.8° ⁇ 0.2°, 20.6° ⁇ 0.2°, 24.5° ⁇ 0.2°, 25.4° ⁇ 0.2°, 26.5° ⁇ at the diffraction angle 2 ⁇ . 0.2°, 28.5° ⁇ 0.2°, 29.6° ⁇ 0.2°, 31.6° ⁇ 0.2°, 34.6° ⁇ 0.2°, 36.0° ⁇ 0.2°, 37.5° ⁇ 0.2°, 38.4° ⁇ 0.2°, 39.5° ⁇ 0.2° It has a characteristic absorption peak.
  • the crystals have a weight loss percentage of 7.9 to 8.1% at 120 to 180 ° C by TGA thermogravimetric analysis, and the crystals have an endothermic characteristic peak at (225 ⁇ 2) ° C by DSC differential thermal analysis.
  • the invention also discloses a preparation method of ⁇ -aminobutyric acid hemihydrate crystal, which comprises Including the following steps:
  • the crude ⁇ -aminobutyric acid is added to water to prepare a suspension of ⁇ -aminobutyric acid having an initial concentration of 1.2 to 2.0 g/mL;
  • the S1 product is stirred at a constant temperature of 5 to 10 ° C for 6 to 12 hours, and then subjected to filtration and drying to obtain crystals of ⁇ -aminobutyric acid hemihydrate.
  • the S1 product is stirred at a constant temperature of 5 ° C for 12 h in the step S2.
  • the S1 product is stirred at a constant temperature of 5 ° C for 9 h in the step S2.
  • the drying treatment in the step S2 means drying for 8 to 12 hours under the conditions of a temperature of 20 to 35 ° C and a degree of vacuum of 0 to 0.08 MPa.
  • the drying treatment in the step S2 means drying at a temperature of 35 ° C and a vacuum of 0.08 MPa for 12 hours.
  • the drying treatment in the step S2 means drying at a temperature of 35 ° C under normal pressure for 8 hours.
  • the ⁇ -aminobutyric acid hemihydrate is prepared by the present invention because the oxygen on the carboxyl group forms a hydrogen bond interaction with the water molecule, so that the two ⁇ -aminobutyric acid molecules are linked to one water molecule.
  • the invention prepares a solvate by suspension crystallization, which is a solvent-mediated crystal transformation process, which is divided into three steps: dissolution of a metastable crystal form, nucleation of a stable crystal form, and growth of a stable crystal form.
  • thermodynamic basic properties of ⁇ -aminobutyric acid it is found that in the aqueous solution under certain concentration and temperature conditions, the solubility of the raw material ⁇ -aminobutyric acid anhydride is large, which is a metastable crystal form, and the product ⁇ -aminobutyl
  • the acid hemihydrate has a small solubility and is a stable crystal form.
  • the solution suspension crystallizing process is gradually dissolved by a metastable ⁇ -aminobutyric acid anhydrate, and then crystallized to form a stable ⁇ -aminobutyric acid. Hemihydrate.
  • the ⁇ -aminobutyric acid hemihydrate of the invention has good crystal stability, is not easy to absorb moisture, is not easy to coalesce, and is convenient for further processing and use;
  • the ⁇ -aminobutyric acid hemihydrate crystal of the present invention has a large main particle diameter, uniform particle size distribution, high bulk density, and good fluidity;
  • the method for preparing ⁇ -aminobutyric acid hemihydrate crystal of the invention is simple and easy to operate and consume Short time, high efficiency and low energy consumption are conducive to large-scale industrial production.
  • Example 1 is an X-ray powder diffraction pattern of ⁇ -aminobutyric acid hemihydrate crystals in Example 1 of the present invention
  • Example 2 is a TGA thermogravimetric analysis chart and a DSC differential thermal analysis chart of ⁇ -aminobutyric acid hemihydrate crystals in Example 1 of the present invention
  • Figure 3 is a SEM image of ⁇ -aminobutyric acid hemihydrate crystals in Example 1 of the present invention.
  • Figure 4 is a graph showing the particle size distribution curve of ⁇ -aminobutyric acid hemihydrate crystals in Example 1 of the present invention.
  • Figure 5 is a comparison chart of X-ray powder diffraction of ⁇ -aminobutyric acid hemihydrate crystals placed at 30 ° C for 60 days in Example 1 of the present invention.
  • the products in the examples of the present invention all obtained X-ray diffraction data by using a powder X-ray diffractometer of Japanese Science. Using a 1050/70 goniometer, Cu K ⁇ radiation, The scanning speed was 2 degrees/min, and the sample was slightly ground and applied on a horizontal background quartz plate to obtain a thin layer.
  • the particle size distribution curves of the products in the examples of the present invention were all measured by the MASTESIZER laser particle size analyzer of Malvern, UK.
  • the invention discloses a preparation method of ⁇ -aminobutyric acid hemihydrate crystal, which comprises the following steps:
  • the X-ray powder diffraction pattern of the product is 12.3°, 17.7°, 20.6°, 24.5°, 25.5°, 26.4°, 28.6°, 29.7°, 31.7°, 34.6°, 36.0° at diffraction angles 2 ⁇ .
  • the product has a block appearance, a primary particle size of 110 ⁇ m, uniform particle size distribution, and is not easy to absorb moisture and coalesce;
  • the angle of repose is the maximum angle formed by the free slope of the powder accumulation layer and the horizontal plane. When the particles slide on the free slope of the volume layer of the powder pile, the friction between the particles and the friction between the particles is balanced and at rest. It is the easiest way to check the fluidity of a powder. The smaller the angle of repose, the smaller the friction and the better the fluidity.
  • the crude material ⁇ -aminobutyric acid crude product has an angle of repose of 50°
  • the product ⁇ -aminobutyric acid hemihydrate crystal has an angle of repose of 38°, and the fluidity of the product is good.
  • the ⁇ -aminobutyric acid hemihydrate crystal product was placed in a petri dish and placed in a constant temperature and humidity chamber at 30 ° C for 60 days, and X-ray powder was sampled on the 30th and 60th days, respectively.
  • the diffraction pattern showed that the X-ray powder diffraction pattern did not change significantly, and the crystal remained white powder, indicating that the crystal stability of ⁇ -aminobutyric acid hemihydrate was good.
  • the invention discloses a preparation method of ⁇ -aminobutyric acid hemihydrate crystal, which comprises the following steps:
  • the X-ray powder diffraction pattern of the product is 12.3°, 17.8°, 20.6°, 24.5°, 25.4°, 26.5°, 28.5°, 29.6°, 31.6°, 34.6°, 36.0°, 37.5°, 38.4° at diffraction angles 2 ⁇ . Characteristic absorption peak at 39.5°;
  • thermogravimetric analysis showed that the product had 8.06% water loss at 120-180 °C, and DSC differential thermal analysis showed that the product had an endothermic characteristic peak at 223 °C;
  • the appearance of the product is blocky, the main particle size is 100 ⁇ m, the particle size distribution is uniform; and it is not easy to absorb moisture and coalesce, has high bulk density and good fluidity;
  • the ⁇ -aminobutyric acid hemihydrate crystal product was placed in a petri dish and placed in a constant temperature and humidity chamber at 30 ° C for 60 days.
  • the X-ray powder diffraction pattern was sampled on the 30th and 60th days, respectively.
  • the -ray powder diffraction pattern did not change significantly, and the crystal remained in the form of a white powder, indicating that the crystal stability of the ⁇ -aminobutyric acid hemihydrate was good.
  • the invention discloses a preparation method of ⁇ -aminobutyric acid hemihydrate crystal, which comprises the following steps:
  • the X-ray powder diffraction pattern of the product is 12.1°, 17.6°, 20.4°, 24.4°, 25.3°, 26.4°, 28.3°, 29.5°, 31.5°, 34.6°, 35.9°, 37.3°, 38.3° at diffraction angles 2 ⁇ .
  • Characteristic absorption peak at 39.4°;
  • thermogravimetric analysis showed that the product had 8.02% water loss at 120-180 °C, and DSC differential thermal analysis showed that the product had an endothermic characteristic peak at 225 °C;
  • the appearance of the product is blocky, the main particle size is 120 ⁇ m, the particle size distribution is uniform; and it is not easy to absorb moisture and coalesce, has high bulk density and good fluidity;
  • the ⁇ -aminobutyric acid hemihydrate crystal product was placed in a petri dish and placed in a constant temperature and humidity chamber at 30 ° C for 60 days.
  • the X-ray powder diffraction pattern was sampled on the 30th and 60th days, respectively.
  • the -ray powder diffraction pattern did not change significantly, and the crystal remained in the form of a white powder, indicating that the crystal stability of the ⁇ -aminobutyric acid hemihydrate was good.
  • the invention discloses a preparation method of ⁇ -aminobutyric acid hemihydrate crystal, which comprises the following steps:
  • the X-ray powder diffraction pattern of the product is 12.1°, 17.6°, 20.4°, 24.4°, 25.3°, 26.4°, 28.4°, 29.4°, 31.4°, 34.5°, 35.8°, 37.3°, 38.3° at diffraction angles 2 ⁇ .
  • Characteristic absorption peak at 39.3°;
  • thermogravimetric analysis showed that the product had 8.10% water loss at 120-180 °C, and DSC differential thermal analysis showed that the product had an endothermic characteristic peak at 224 °C;
  • the appearance of the product is blocky, the main particle size is 96 ⁇ m, the particle size distribution is uniform; and it is not easy to absorb moisture and Coalescence, high bulk density and good fluidity;
  • the ⁇ -aminobutyric acid hemihydrate crystal product was placed in a petri dish and placed in a constant temperature and humidity chamber at 30 ° C for 60 days.
  • the X-ray powder diffraction pattern was sampled on the 30th and 60th days, respectively.
  • the -ray powder diffraction pattern did not change significantly, and the crystal remained in the form of a white powder, indicating that the crystal stability of the ⁇ -aminobutyric acid hemihydrate was good.
  • the invention discloses a preparation method of ⁇ -aminobutyric acid hemihydrate crystal, which comprises the following steps:
  • the X-ray powder diffraction pattern of the product is 12.2°, 17.7°, 20.5°, 24.4°, 25.3°, 26.5°, 28.4°, 29.5°, 31.6°, 34.7°, 35.9°, 37.4°, 38.4° at diffraction angles 2 ⁇ .
  • Characteristic absorption peak at 39.3°;
  • thermogravimetric analysis showed that the product had a water loss of 8.00% at 120-180 °C, and DSC differential thermal analysis showed that the product had an endothermic characteristic peak at 227 °C;
  • the appearance of the product is block-shaped, the main particle size is 106 ⁇ m, the particle size distribution is uniform; and it is not easy to absorb moisture and coalesce, has high bulk density and good fluidity;
  • the ⁇ -aminobutyric acid hemihydrate crystal product was placed in a petri dish and placed in a constant temperature and humidity chamber at 30 ° C for 60 days.
  • the X-ray powder diffraction pattern was sampled on the 30th and 60th days, respectively.
  • the -ray powder diffraction pattern did not change significantly, and the crystal remained in the form of a white powder, indicating that the crystal stability of the ⁇ -aminobutyric acid hemihydrate was good.
  • the invention discloses a preparation method of ⁇ -aminobutyric acid hemihydrate crystal, comprising The following steps:
  • the X-ray powder diffraction pattern of the product is 12.2°, 17.7°, 20.5°, 24.5°, 25.3°, 26.5°, 28.4°, 29.6°, 31.5°, 34.6°, 35.9°, 37.4°, 38.4° at diffraction angles 2 ⁇ .
  • Characteristic absorption peak at 39.4°;
  • thermogravimetric analysis showed that the product had 7.90% water loss at 120-180 °C, and DSC differential thermal analysis showed that the product had an endothermic characteristic peak at 226 °C;
  • the appearance of the product is blocky, the main particle size is 90 ⁇ m, the particle size distribution is uniform; and it is not easy to absorb moisture and coalesce, has high bulk density and good fluidity;
  • the ⁇ -aminobutyric acid hemihydrate crystal product was placed in a petri dish and placed in a constant temperature and humidity chamber at 30 ° C for 60 days.
  • the X-ray powder diffraction pattern was sampled on the 30th and 60th days, respectively.
  • the -ray powder diffraction pattern did not change significantly, and the crystal remained in the form of a white powder, indicating that the crystal stability of the ⁇ -aminobutyric acid hemihydrate was good.
  • the ⁇ -aminobutyric acid hemihydrate is prepared by the present invention because the oxygen on the carboxyl group forms a hydrogen bond interaction with the water molecule, so that the two ⁇ -aminobutyric acid molecules are linked to one water molecule.
  • the invention prepares a solvate by suspension crystallization, which is a solvent-mediated crystal transformation process, which is divided into three steps: dissolution of a metastable crystal form, nucleation of a stable crystal form, and growth of a stable crystal form.
  • thermodynamic basic properties of ⁇ -aminobutyric acid it is found that in the aqueous solution under certain concentration and temperature conditions, the solubility of the raw material ⁇ -aminobutyric acid anhydride is large, which is a metastable crystal form, and the product ⁇ -aminobutyl
  • the acid hemihydrate has a small solubility and is a stable crystal form.
  • the solution suspension crystallizing process is gradually dissolved by a metastable ⁇ -aminobutyric acid anhydrate, and then crystallized to form a stable ⁇ -aminobutyric acid. Hemihydrate.
  • the ⁇ -aminobutyric acid hemihydrate of the present invention has good crystal stability and is not easy to absorb moisture. It is not easy to coalesce and is convenient for further processing and use;
  • the ⁇ -aminobutyric acid hemihydrate crystal of the present invention has a large main particle diameter, uniform particle size distribution, high bulk density, and good fluidity;
  • the method for preparing ⁇ -aminobutyric acid hemihydrate crystal of the invention is simple, easy, short in time, high in efficiency, low in energy consumption, and is favorable for large-scale industrial production.

Abstract

本发明公开了一种γ-氨基丁酸半水合物晶体，该晶体的分子式为C4H9NO2·0.5H2O，本发明还公开了一种γ-氨基丁酸半水合物晶体制备方法，先将γ-氨基丁酸粗品加入水中，配成初始浓度为1.2～2.0g/mL的γ-氨基丁酸悬浮液；再将悬浮液在5～10℃下恒温搅拌6～12小时，然后进行过滤、干燥处理，即得γ-氨基丁酸半水合物晶体。本发明的γ-氨基丁酸半水合物晶体稳定性能好，不易吸湿，不易聚结，方便进一步地加工使用；晶体主粒径大且粒度分布均匀、堆密度高、流动性好，纯度≥99％；本发明制备γ-氨基丁酸半水合物晶体的方法简单易行、耗时短、效率高、耗能低，有利于大规模工业化生产。

Description

一种γ-氨基丁酸半水合物晶体及其制备方法 技术领域
本发明涉及一种半水合物晶体及其制备方法，尤其涉及一种γ-氨基丁酸半水合物晶体及其制备方法。
背景技术
γ-氨基丁酸，化学名称4-氨基丁酸，别名：氨酪酸、哌啶酸。分子式C4H9NO2，分子量103.1，性状为白色或近白色结晶性粉末，是一种亲水性氨基酸，在水中极易溶。结构式如下：
Figure PCTCN2016105420-appb-000001
γ-氨基丁酸是一种天然存在的非蛋白组成氨基酸，广泛分布于原核和真核生物中。在哺乳动物体内γ-氨基丁酸是一种抑制性神经递质，介导40％以上的抑制性神经信号，具有重要的生理功能，在医药和食品中具有广泛的应用前景。
在医药研究和应用中，γ-氨基丁酸具有降血压、抗惊厥、预防癫痫、改善睡眠、抗抑郁、改善脑细胞等机能。最新的研究表明，γ-氨基丁酸还具有防止皮肤老化、消除体臭、改善脂质代谢、防止动脉硬化和高效减肥等功能。在食品工业中，γ-氨基丁酸可用于制备食品添加剂、开发功能性乳制品和烘焙食品，还可以应用于运动食品和饮料行业。2009年9月27日，中国***批准γ-氨基丁酸为新资源食品。
专利CN101928736A、CN103509831A、CN104531795A提出了通过蒸发浓缩和95％乙醇溶析结晶的方式来制备γ-氨基丁酸。专利CN102242161A提出了通过蒸发浓缩和冷却结晶的方式来制备γ-氨基丁酸。它们得到的产品均为γ-氨基丁酸无水物，产品晶型呈针状 或片状，主粒径偏小且分布不均匀，堆密度低，流动性差；此外，无水γ-氨基丁酸的吸湿性强，暴露于空气中极易吸水聚结成块，不便于进一步地加工使用。
因此，有必要发明一种稳定性好、不易吸湿和聚结、主粒径大且分布均匀、堆密度高、流动性好的γ-氨基丁酸半水合物晶体及其制备方法。
发明内容
本发明的目的是针对现有技术的不足，提供一种γ-氨基丁酸半水合物晶体及其制备方法。
本发明是通过以下技术方案实现的：
本发明公开了一种γ-氨基丁酸半水合物晶体，该晶体的分子式为C4H9NO2·0.5H2O，结构式如下：
Figure PCTCN2016105420-appb-000002
进一步地，所述晶体的X射线粉末衍射图在衍射角2θ为12.3°±0.2°、24.5°±0.2°、26.5°±0.2°、29.6°±0.2°、31.6°±0.2°、36.0°±0.2°、37.5°±0.2°、39.5°±0.2°处具有特征吸收峰。
进一步地，所述晶体的X射线粉末衍射图在衍射角2θ为12.3°±0.2°、17.8°±0.2°、20.6°±0.2°、24.5°±0.2°、25.4°±0.2°、26.5°±0.2°、28.5°±0.2°、29.6°±0.2°、31.6°±0.2°、34.6°±0.2°、36.0°±0.2°、37.5°±0.2°、38.4°±0.2°、39.5°±0.2°处具有特征吸收峰。
进一步地，所述晶体经TGA热重分析在120～180℃处具有7.9～8.1％的失重百分比，所述晶体经DSC差热分析在(225±2)℃处具有吸热特征峰。
本发明还公开了一种γ-氨基丁酸半水合物晶体的制备方法，包 括如下步骤：
S1.将γ-氨基丁酸粗品加入水中，配成初始浓度为1.2～2.0g/mL的γ-氨基丁酸悬浮液；
S2.将S1产品在5～10℃下恒温搅拌6～12小时，然后进行过滤、干燥处理，即得γ-氨基丁酸半水合物晶体。
优选地，所述步骤S2中将S1产品在5℃下恒温搅拌12h。
优选地，所述步骤S2中将S1产品在5℃下恒温搅拌9h。
优选地，所述步骤S2中干燥处理是指在温度为20～35℃，真空度为0～0.08MPa的条件下干燥8～12小时。
优选地，所述步骤S2中干燥处理是指在温度为35℃，真空度为0.08MPa的条件下干燥12小时。
优选地，所述步骤S2中干燥处理是指在温度为35℃，常压条件下干燥8小时。
本发明制备得到γ-氨基丁酸半水合物，是由于羧基上的氧和水分子形成氢键相互作用，使得两个γ-氨基丁酸分子和一个水分子连接。本发明通过悬浮结晶法来制备溶剂化物，是一种溶剂介导转晶过程，分为三个步骤：介稳晶型的溶解、稳定晶型的成核和稳定晶型的生长。通过对γ-氨基丁酸热力学基础特性研究发现，在一定的浓度和温度条件下的水溶液中，原料γ-氨基丁酸无水物的溶解度大，是介稳晶型，而产品γ-氨基丁酸半水合物的溶解度小，是稳定晶型，从热力学角度讲，溶液悬浮转晶过程是由介稳态的γ-氨基丁酸无水物逐渐溶解，然后结晶生成稳定态的γ-氨基丁酸半水合物。
本发明的有益效果是：
(1)本发明的γ-氨基丁酸半水合物晶体稳定性能好，不易吸湿，不易聚结，方便进一步地加工使用；
(2)本发明的γ-氨基丁酸半水合物晶体主粒径大且粒度分布均匀、堆密度高、流动性好；
(3)本发明制备的γ-氨基丁酸半水合物晶体的纯度≥99％；
(4)本发明制备γ-氨基丁酸半水合物晶体的方法简单易行、耗 时短、效率高、耗能低，有利于大规模工业化生产。
附图说明
为了更清楚地说明本发明的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其它附图。
图1是本发明实施例1中γ-氨基丁酸半水合物晶体的X射线粉末衍射图；
图2是本发明实施例1中γ-氨基丁酸半水合物晶体的TGA热重分析图和DSC差热分析图；
图3是本发明实施例1中γ-氨基丁酸半水合物晶体的SEM图；
图4是本发明实施例1中γ-氨基丁酸半水合物晶体的粒度分布曲线；
图5是本发明实施例1中γ-氨基丁酸半水合物晶体在30℃下放置60天的X射线粉末衍射对比图。
具体实施方式
下面将结合本发明中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明的一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动的前提下所获得的所有其他实施例，都属于本发明保护的范围。
本发明实施例中产品均采用日本理学的粉末X-射线衍射仪获得X-射线衍射数据。采用1050/70型的测角仪，CuKα辐射，
Figure PCTCN2016105420-appb-000003
扫描速度为2度/分钟，将样品在水平背景石英板上轻微研磨并且涂抹，从而得到薄层。
本发明实施例中产品的粒度分布曲线均采用英国马尔文公司的MASTESIZER激光粒度分析仪测得。
实施例1
本发明公开了一种γ-氨基丁酸半水合物晶体的制备方法，包括如下步骤：
S1.将120gγ-氨基丁酸粗品加入100mL水中得到γ-氨基丁酸悬浮液；
S2.将S1产品在5℃下恒温搅拌9小时，然后过滤得到滤饼，将滤饼在35℃、常压条件下干燥8小时至恒重，得到γ-氨基丁酸半水合物晶体产品，采用高效液相色谱法(HPLC)检测产品的纯度为99.2％。
如图1所示、产品的X射线粉末衍射图在衍射角2θ为12.3°、17.7°、20.6°、24.5°、25.5°、26.4°、28.6°、29.7°、31.7°、34.6°、36.0°、37.3°、38.4°、39.5°处有特征吸收峰；
如图2所示，TGA热重分析表明产品在120～180℃处有7.94％的失水量，DSC差热分析表明产品在225℃具有吸热特征峰；
如图3-4所示，产品外观为块状，主粒径110μm、粒度分布均匀；且不易吸湿和聚结；
堆密度测试：原料γ-氨基丁酸粗品的堆密度为0.65g/mL，产品γ-氨基丁酸半水合物晶体的堆密度为0.85g/mL，可见产品的堆密度较高。
流动性测试：休止角是粉体堆积层的自由斜面与水平面形成的最大角，是粒子在粉体堆体积层的自由斜面上滑动时所受重力和粒子间摩擦力达到平衡而处于静止状态下测得，是检验粉体流动性的好坏的最简便的方法。休止角越小，摩擦力越小，流动性越好。原料γ-氨基丁酸粗品的休止角为50°，产品γ-氨基丁酸半水合物晶体的休止角为38°，可见产品的流动性好。
如图5所示，将γ-氨基丁酸半水合物晶体产品置于培养皿中，在30℃的恒温恒湿箱中放置60天，分别于第30天和第60天取样测试X射线粉末衍射图，对比发现X-射线粉末衍射图谱未发生明显变化，晶体保持白色粉末状，说明γ-氨基丁酸半水合物晶体稳定性好。
实施例2
本发明公开了一种γ-氨基丁酸半水合物晶体的制备方法，包括如下步骤：
S1.将200gγ-氨基丁酸粗品加入100mL水中得到γ-氨基丁酸悬浮液；
S2.将S1产品在5℃下恒温搅拌12小时，然后过滤得到滤饼，将滤饼在35℃、0.08MPa真空度条件下干燥12小时至恒重，得到γ-氨基丁酸半水合物晶体产品，采用高效液相色谱法(HPLC)检测产品的纯度为99.6％。
产品的X射线粉末衍射图在衍射角2θ为12.3°、17.8°、20.6°、24.5°、25.4°、26.5°、28.5°、29.6°、31.6°、34.6°、36.0°、37.5°、38.4°、39.5°处有特征吸收峰；
TGA热重分析表明产品在120～180℃处有8.06％的失水量，DSC差热分析表明产品在223℃具有吸热特征峰；
产品外观为块状，主粒径100μm、粒度分布均匀；且不易吸湿和聚结、堆密度高、流动性好；
将γ-氨基丁酸半水合物晶体产品置于培养皿中，在30℃的恒温恒湿箱中放置60天，分别于第30天和第60天取样测试X射线粉末衍射图，对比发现X-射线粉末衍射图谱未发生明显变化，晶体保持白色粉末状，说明γ-氨基丁酸半水合物晶体稳定性好。
实施例3
本发明公开了一种γ-氨基丁酸半水合物晶体的制备方法，包括如下步骤：
S1.将135gγ-氨基丁酸粗品加入100mL水中得到γ-氨基丁酸悬浮液；
S2.将S1产品在6℃下恒温搅拌8小时，然后过滤得到滤饼，将滤饼在25℃、0.05MPa真空度条件下干燥11小时至恒重，得到γ- 氨基丁酸半水合物晶体产品，采用高效液相色谱法(HPLC)检测产品的纯度为99.1％。
产品的X射线粉末衍射图在衍射角2θ为12.1°、17.6°、20.4°、24.4°、25.3°、26.4°、28.3°、29.5°、31.5°、34.6°、35.9°、37.3°、38.3°、39.4°处有特征吸收峰；
TGA热重分析表明产品在120～180℃处有8.02％的失水量，DSC差热分析表明产品在225℃具有吸热特征峰；
产品外观为块状，主粒径120μm、粒度分布均匀；且不易吸湿和聚结、堆密度高、流动性好；
将γ-氨基丁酸半水合物晶体产品置于培养皿中，在30℃的恒温恒湿箱中放置60天，分别于第30天和第60天取样测试X射线粉末衍射图，对比发现X-射线粉末衍射图谱未发生明显变化，晶体保持白色粉末状，说明γ-氨基丁酸半水合物晶体稳定性好。
实施例4
本发明公开了一种γ-氨基丁酸半水合物晶体的制备方法，包括如下步骤：
S1.将200gγ-氨基丁酸粗品加入100mL水中得到γ-氨基丁酸悬浮液；
S2.将S1产品在10℃下恒温搅拌10小时，然后过滤得到滤饼，将滤饼在30℃、0.07MPa真空度条件下干燥12小时至恒重，得到γ-氨基丁酸半水合物晶体产品，采用高效液相色谱法(HPLC)检测产品的纯度为99.5％。
产品的X射线粉末衍射图在衍射角2θ为12.1°、17.6°、20.4°、24.4°、25.3°、26.4°、28.4°、29.4°、31.4°、34.5°、35.8°、37.3°、38.3°、39.3°处有特征吸收峰；
TGA热重分析表明产品在120～180℃处有8.10％的失水量，DSC差热分析表明产品在224℃具有吸热特征峰；
产品外观为块状，主粒径96μm、粒度分布均匀；且不易吸湿和 聚结、堆密度高、流动性好；
将γ-氨基丁酸半水合物晶体产品置于培养皿中，在30℃的恒温恒湿箱中放置60天，分别于第30天和第60天取样测试X射线粉末衍射图，对比发现X-射线粉末衍射图谱未发生明显变化，晶体保持白色粉末状，说明γ-氨基丁酸半水合物晶体稳定性好。
实施例5
本发明公开了一种γ-氨基丁酸半水合物晶体的制备方法，包括如下步骤：
S1.将150gγ-氨基丁酸粗品加入100mL水中得到γ-氨基丁酸悬浮液；
S2.将S1产品在8℃下恒温搅拌8小时，然后过滤得到滤饼，将滤饼在35℃、常压条件下干燥8小时至恒重，得到γ-氨基丁酸半水合物晶体产品，采用高效液相色谱法(HPLC)检测产品的纯度为99.4％。
产品的X射线粉末衍射图在衍射角2θ为12.2°、17.7°、20.5°、24.4°、25.3°、26.5°、28.4°、29.5°、31.6°、34.7°、35.9°、37.4°、38.4°、39.3°处有特征吸收峰；
TGA热重分析表明产品在120～180℃处有8.00％的失水量，DSC差热分析表明产品在227℃具有吸热特征峰；
产品外观为块状，主粒径106μm、粒度分布均匀；且不易吸湿和聚结、堆密度高、流动性好；
将γ-氨基丁酸半水合物晶体产品置于培养皿中，在30℃的恒温恒湿箱中放置60天，分别于第30天和第60天取样测试X射线粉末衍射图，对比发现X-射线粉末衍射图谱未发生明显变化，晶体保持白色粉末状，说明γ-氨基丁酸半水合物晶体稳定性好。
实施例6
本发明公开了一种γ-氨基丁酸半水合物晶体的制备方法，包括 如下步骤：
S1.将120gγ-氨基丁酸粗品加入100mL水中得到γ-氨基丁酸悬浮液；
S2.将S1产品在10℃下恒温搅拌6小时，然后过滤得到滤饼，将滤饼在20℃、0.05MPa真空度条件下干燥9小时至恒重，得到γ-氨基丁酸半水合物晶体产品，采用高效液相色谱法(HPLC)检测产品的纯度为99.2％。
产品的X射线粉末衍射图在衍射角2θ为12.2°、17.7°、20.5°、24.5°、25.3°、26.5°、28.4°、29.6°、31.5°、34.6°、35.9°、37.4°、38.4°、39.4°处有特征吸收峰；
TGA热重分析表明产品在120～180℃处有7.90％的失水量，DSC差热分析表明产品在226℃具有吸热特征峰；
产品外观为块状，主粒径90μm、粒度分布均匀；且不易吸湿和聚结、堆密度高、流动性好；
将γ-氨基丁酸半水合物晶体产品置于培养皿中，在30℃的恒温恒湿箱中放置60天，分别于第30天和第60天取样测试X射线粉末衍射图，对比发现X-射线粉末衍射图谱未发生明显变化，晶体保持白色粉末状，说明γ-氨基丁酸半水合物晶体稳定性好。
本发明制备得到γ-氨基丁酸半水合物，是由于羧基上的氧和水分子形成氢键相互作用，使得两个γ-氨基丁酸分子和一个水分子连接。本发明通过悬浮结晶法来制备溶剂化物，是一种溶剂介导转晶过程，分为三个步骤：介稳晶型的溶解、稳定晶型的成核和稳定晶型的生长。通过对γ-氨基丁酸热力学基础特性研究发现，在一定的浓度和温度条件下的水溶液中，原料γ-氨基丁酸无水物的溶解度大，是介稳晶型，而产品γ-氨基丁酸半水合物的溶解度小，是稳定晶型，从热力学角度讲，溶液悬浮转晶过程是由介稳态的γ-氨基丁酸无水物逐渐溶解，然后结晶生成稳定态的γ-氨基丁酸半水合物。
本发明的有益效果是：
(1)本发明的γ-氨基丁酸半水合物晶体稳定性能好，不易吸湿， 不易聚结，方便进一步地加工使用；
(2)本发明的γ-氨基丁酸半水合物晶体主粒径大且粒度分布均匀、堆密度高、流动性好；
(3)本发明制备的γ-氨基丁酸半水合物晶体的纯度≥99％；
(4)本发明制备γ-氨基丁酸半水合物晶体的方法简单易行、耗时短、效率高、耗能低，有利于大规模工业化生产。
以上所述是本发明的优选实施方式，应该指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也视为本发明的保护范围。

Claims (10)

  1. 一种γ-氨基丁酸半水合物晶体，其特征在于，该晶体的分子式为C4H9NO2·0.5H2O，结构式如下：
    Figure PCTCN2016105420-appb-100001
  2. 根据权利要求1所述的一种γ-氨基丁酸半水合物晶体，其特征在于，所述晶体的X射线粉末衍射图在衍射角2θ为12.3°±0.2°、24.5°±0.2°、26.5°±0.2°、29.6°±0.2°、31.6°±0.2°、36.0°±0.2°、37.5°±0.2°、39.5°±0.2°处具有特征吸收峰。
  3. 根据权利要求1或2所述的一种γ-氨基丁酸半水合物晶体，其特征在于，所述晶体的X射线粉末衍射图在衍射角2θ为12.3°±0.2°、17.8°±0.2°、20.6°±0.2°、24.5°±0.2°、25.4°±0.2°、26.5°±0.2°、28.5°±0.2°、29.6°±0.2°、31.6°±0.2°、34.6°±0.2°、36.0°±0.2°、37.5°±0.2°、38.4°±0.2°、39.5°±0.2°处具有特征吸收峰。
  4. 根据权利要求3所述的一种γ-氨基丁酸半水合物晶体，其特征在于，所述晶体经TGA热重分析在120～180℃处具有7.9～8.1％的失重百分比，所述晶体经DSC差热分析在(225±2)℃处具有吸热特征峰。
  5. 一种γ-氨基丁酸半水合物晶体的制备方法，其特征在于，包括如下步骤：
    S1.将γ-氨基丁酸粗品加入水中，配成初始浓度为1.2～2.0g/mL的γ-氨基丁酸悬浮液；
    S2.将S1产品在5～10℃下恒温搅拌6～12小时，然后进行过滤、干燥处理，即得γ-氨基丁酸半水合物晶体。
  6. 根据权利要求5所述的一种γ-氨基丁酸半水合物晶体的制备方法，其特征在于，所述步骤S2中将S1产品在5℃下恒温搅拌12h。
  7. 根据权利要求5所述的一种γ-氨基丁酸半水合物晶体的制备方法，其特征在于，所述步骤S2中将S1产品在5℃下恒温搅拌9h。
  8. 根据权利要求6或7所述的一种γ-氨基丁酸半水合物晶体的制备方法，其特征在于，所述步骤S2中干燥处理是指在温度为20～35℃，真空度为0～0.08MPa的条件下干燥8～12小时。
  9. 根据权利要求8所述的一种γ-氨基丁酸半水合物晶体的制备方法，其特征在于，所述步骤S2中干燥处理是指在温度为35℃，真空度为0.08MPa的条件下干燥12小时。
  10. 根据权利要求8所述的一种γ-氨基丁酸半水合物晶体的制备方法，其特征在于，所述步骤S2中干燥处理是指在温度为35℃，常压条件下干燥8小时。
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