WO2022151995A1 - 一种γ-氨基丁酸的新晶型及其制备方法 - Google Patents

一种γ-氨基丁酸的新晶型及其制备方法 Download PDF

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WO2022151995A1
WO2022151995A1 PCT/CN2021/143633 CN2021143633W WO2022151995A1 WO 2022151995 A1 WO2022151995 A1 WO 2022151995A1 CN 2021143633 W CN2021143633 W CN 2021143633W WO 2022151995 A1 WO2022151995 A1 WO 2022151995A1
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crystal form
aminobutyric acid
preparation
concentrated
temperature
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PCT/CN2021/143633
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English (en)
French (fr)
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董海光
杨健民
韩超
王海荣
王珂
穆淑娥
穆惠军
栾贻宏
蒋新
寻克林
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华熙生物科技股份有限公司
华熙生物科技(天津)有限公司
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Publication of WO2022151995A1 publication Critical patent/WO2022151995A1/zh

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    • 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 the technical field of preparation of ⁇ -aminobutyric acid, in particular to a new crystal form of ⁇ -aminobutyric acid and a preparation method thereof.
  • GABA Gamma-aminobutyric acid
  • a sweet taste can adjust the taste of food, and can react with alcohol in the body, so it has the effects of sobering up and deodorizing.
  • drugs that can be used to treat some diseases, such as uremia and CO poisoning contain GABA.
  • the synthesis methods of GABA mainly include chemical synthesis method and biosynthesis method.
  • chemical synthesis of GABA strong acid or strong base and other corrosive solvents are needed, the reaction conditions are severe, the raw materials are toxic, expensive and exist More security risks and other issues.
  • GABA is mainly synthesized by biological methods.
  • Biosynthesis is the main research microbial method. Microbial methods include traditional microbial fermentation methods and emerging microbial transformation methods in recent years.
  • the early fermentation method was mainly based on the fermentation of Escherichia coli to produce GABA.
  • food-safe microorganisms such as yeast, lactic acid bacteria and aspergillus containing glutamate decarboxylase.
  • the microbial transformation method refers to using L-glutamic acid or L-glutamate as a substrate, using the action of lactic acid bacteria decarboxylase to convert L-glutamic acid or L-glutamate into GABA to obtain GABA-containing
  • the transformation liquid can be obtained GABA crystal after further post-processing.
  • the post-processing process of the GABA conversion solution is as follows: the conversion solution is heated to make the protein deteriorate, then activated carbon is added to decolorize, the decolorized conversion solution is evaporated and concentrated to obtain a concentrated solution, and then the concentrated solution is cooled for crystallization, solid-liquid separation, more than 95% Wash with ethanol and vacuum dry to obtain the final GABA crystal.
  • crystallization is carried out by means of three-effect concentration and direct concentration: the temperature of the first effect is controlled at 60-95°C, the temperature of the second effect is 90-115°C, the temperature of the third effect is 50-85°C, and the vacuum degree is controlled at 0.08Mpa-0.1Mpa; When the concentration of the concentrated product reaches 550-600g/L, the concentration is stopped, the concentrated solution is poured into the vacuum concentration crystallizer, the vacuum degree of the vacuum concentration crystallizer is controlled to be 0.08Mpa-0.1Mpa, and the temperature is 60-75°C. When the temperature is 700-900g/L, the heating is stopped, and the crystal is naturally cooled under normal pressure for 1-1.5h to obtain columnar or powdery crystals.
  • the purpose of the present invention is to provide a new crystal form of ⁇ -aminobutyric acid, the crystal form has high crystal purity and better stability.
  • the X-ray powder diffraction pattern of the crystal form is at least 22.3° ⁇ 0.5°, 26.9° ⁇ 0.5°, 29.7° ⁇ 0.5°, 35.4 ⁇ 0.5° at the diffraction angle 2 ⁇ There is a characteristic absorption main peak at °.
  • the X-ray powder diffraction pattern of the crystal form has characteristic absorption peaks at diffraction angles 2 ⁇ of 22.3 ⁇ 0.2°, 26.7 ⁇ 0.2°, 29.6 ⁇ 0.2°, 35.5 ⁇ 0.2°, and 41.0 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form at the diffraction angle 2 ⁇ is 14.6° ⁇ 0.2°, 22.3 ⁇ 0.2°, 26.7 ⁇ 0.2°, 27.2 ⁇ 0.2°, 29.6 ⁇ 0.2°, 35.5 ⁇ 0.2°, 41.0 ⁇
  • the X-ray powder diffraction pattern of the crystal form is at diffraction angles 2 ⁇ of 14.6°, 20.5°, 21.2°, 22.3°, 26.5°, 26.7°, 27.2°, 28.4°, 29.4°, 29.7°, 35.3°, There are characteristic absorption peaks at 40.0°, 41.2°, 42.4°, 42.9°, 44.4°, 46.7°, and 49.6°.
  • the X-ray powder diffraction pattern of the crystal form is at diffraction angles 2 ⁇ of 14.6°, 20.6°, 21.2°, 22.3°, 26.5°, 26.7°, 27.2°, 28.4°, 29.4°, 29.7°, 35.4°, There are characteristic absorption peaks at 40.0°, 41.2°, 42.4°, 42.9°, 44.4°, 46.7°, and 49.8°.
  • the X-ray powder diffraction pattern of the crystal form is at diffraction angles 2 ⁇ of 14.6°, 20.6°, 22.3°, 23.3°, 24.0°, 26.5°, 26.9°, 27.3°, 29.5°, 29.7°, 30.1°, There are characteristic absorption peaks at 32.3°, 33.8°, 35.4°, 35.9°, 38.2°, 41.0°, 41.3°, 42.2°, 42.3°, 43.0°, 44.3°, 46.6°, 46.9°, 47.2°, and 49.8°.
  • the X-ray powder diffraction pattern of the crystal form is at diffraction angles 2 ⁇ of 14.6°, 21.0°, 22.5°, 23.3°, 24.0°, 26.6°, 26.9°, 27.3°, 29.5°, 29.7°, 29.9°, Features at 30.1°, 32.3°, 33.8°, 35.5°, 35.9°, 38.2°, 41.0°, 41.3°, 42.2°, 42.3°, 43.0°, 44.4°, 46.6°, 46.9°, 47.2°, 49.9° absorption peak.
  • the X-ray powder diffraction pattern of the crystal form is at diffraction angles 2 ⁇ of 14.6°, 21.3°, 22.5°, 23.3°, 24.0°, 26.9°, 27.3°, 29.5°, 29.9°, 30.1°, 32.3°, There are characteristic absorption peaks at 33.8°, 35.7°, 38.2°, 40.8°, 42.2°, 42.3°, 43.0°, 44.4°, 46.6°, 46.9°, 47.2°, 49.9°.
  • the X-Ray Powder Diffraction is usually applied to the analysis of crystal structure.
  • X-rays are electromagnetic waves that generate a periodically changing electromagnetic field in the crystal when incident on it. Causes electrons and nuclei in atoms to vibrate, and the vibrations are ignored due to the large mass of the nucleus.
  • the vibrating electrons are the source of secondary X-rays with the same wavelength and phase as the incident light.
  • the scattered waves of each electron in the crystal interfere with each other and superimpose each other, which is called diffraction.
  • the direction in which the scattered wave cycles are consistent and mutually reinforcing is called the diffraction direction, resulting in diffraction lines.
  • Copper target, wavelength 0.154056nm
  • the measuring voltage is 40 kV, and the measuring current is 40 mA;
  • Scanning mode step scanning, step size 0.01, dwell time 0.1S for each step;
  • the crystal form has the X-ray powder diffraction pattern shown in FIG. 1 .
  • the crystal form has an endothermic characteristic peak at (248 ⁇ 1)° C. by DSC differential thermal analysis.
  • the temperature of the DSC endothermic characteristic peak is about 248°C, which is about 30°C higher than that of the existing reported crystal form product, indicating that the crystal form has better stability.
  • DSC differential thermal analysis is differential scanning calorimetry (differential scanning calorimetry), under the control of temperature program, a technique to measure the heat flow rate of a sample relative to a reference as a function of temperature or time.
  • the curve recorded by the differential scanning calorimeter is called the DSC curve.
  • W/g or mW/mg that is, the power flowing to each gram of the sample
  • T or time t the abscissa.
  • Thermodynamic and kinetic parameters such as specific heat capacity, heat of reaction, heat of transition, phase diagram, reaction rate, crystallization rate, polymer crystallinity, sample purity, etc. This method has a wide temperature range (-175-725°C), high resolution and less sample consumption. It is suitable for the analysis of inorganic substances, organic compounds and pharmaceuticals.
  • the crystal form has the appearance of a quadrangular prism block, the shape is regular, and the fluidity is better.
  • the melting point of the crystal form is 248 ⁇ 1°C.
  • the present invention also provides a ⁇ -aminobutyric acid raw material, which comprises the above-mentioned ⁇ -aminobutyric acid crystal form.
  • a ⁇ -aminobutyric acid raw material which comprises the above-mentioned ⁇ -aminobutyric acid crystal form.
  • the content of the above-mentioned new crystal form of ⁇ -aminobutyric acid in the raw material is high, and the content is greater than or equal to 99%.
  • the present invention also provides a preparation method of the above-mentioned new ⁇ -aminobutyric acid crystal form, the method comprising:
  • the L-glutamic acid conversion solution is added to the adsorbent for adsorption, and the filtrate is obtained by filtering;
  • the filtrate is concentrated to obtain a concentrate
  • the crystals of ⁇ -aminobutyric acid are added to the concentrated solution for crystallization to obtain the crystal form.
  • the L-glutamic acid conversion solution is heated first, then cooled, and then an adsorbent is added, preferably, the adsorbent is activated carbon;
  • the temperature is raised to 80-85°C, the temperature is lowered to 55-60°C;
  • the cooling rate is 10-15°C/h.
  • the added amount of the adsorbent is 0.5-1% of the total weight of the L-glutamic acid conversion solution.
  • the filtrate is concentrated at 65°C-85°C and a vacuum degree of 0.06-0.1 Mpa, preferably, concentrated to 40-50% of the original volume.
  • ⁇ -aminobutyric acid crystals are added to the concentrated solution to cool down, and then crystallize at 15-24°C;
  • the temperature is naturally lowered at 18-26°C for 1-2h, and then intermittently cooled by an external cold source to reduce the temperature to 30°C; 24°C.
  • the precipitated crystals are washed and dried to obtain the crystal form.
  • the external cold source refers to the artificially added cold source, such as circulating cooling water, frozen water, and the like.
  • the method includes:
  • the L-glutamic acid conversion solution is heated to 80-85°C, maintained for 1-2h, then cooled to 55-60°C, and activated carbon is added for adsorption and filtration to obtain a filtrate;
  • the L-glutamic acid transformation solution described in step (1) is a crude ⁇ -aminobutyric acid solution obtained by L-glutamic acid through a microbial transformation method.
  • step (1) the L-glutamic acid conversion solution is lowered to 55-60°C at a cooling rate of 10-15°C/h.
  • step (1) the amount of activated carbon added is 0.5-1% of the total weight of the L-glutamic acid conversion solution.
  • the filtrate is concentrated at 65°C-85°C and a vacuum degree of 0.06-0.1 Mpa. Preferably, it is concentrated to 40-50% of the original volume.
  • the external cold source refers to the artificially added cold source, such as circulating cooling water, frozen water, and the like.
  • step (5) the obtained crystals are washed with more than 95% ethanol, and the washed crystals are vacuum-dried at a drying temperature of 55-60 ° C, and dried at this temperature for about 2 hours to obtain crystals with a weight loss on drying less than 1%.
  • the crystal form has the appearance of quadrangular prism block, the particle is large, the shape is regular, the impurities are few, the purity is high, and the purity is more than 99%.
  • a new crystal form of ⁇ -aminobutyric acid with higher purity is obtained by adding ⁇ -aminobutyric acid crystals and controlling the crystallization process.
  • the preparation method is simple and feasible, the crystallization process is economical and environmentally friendly, and is suitable for large-scale production.
  • Fig. 1 is the XRD pattern of the crystal form of ⁇ -aminobutyric acid obtained in Example 1 of the present invention.
  • Fig. 2 is a DSC differential thermal analysis diagram of the crystal form of ⁇ -aminobutyric acid obtained in Example 1 of the present invention.
  • Fig. 3 is a morphological diagram of the crystals of ⁇ -aminobutyric acid obtained in Example 1 of the present invention.
  • FIG. 4 is an XRD pattern of the product obtained in Comparative Example 1.
  • FIG. 5 is a DSC differential thermogram of the product obtained in Comparative Example 1.
  • FIG. 6 is a crystal morphology diagram of the product obtained in Comparative Example 1.
  • FIG. 6 is a crystal morphology diagram of the product obtained in Comparative Example 1.
  • the L-glutamic acid transformation solution used is according to the method in the patent 201710760851.X, with Lactobacillus parabrevis HX12-19 as a bacterial classification, through which L-glutamic acid is transformed into the L-glutamic acid obtained.
  • the L-glutamic acid conversion solution was heated to 80-85°C, maintained for 1h, then cooled to 55-60°C at a rate of 10-15°C/h, and then added with 1% activated carbon, adsorbed and filtered to obtain a filtrate ;
  • Cooling and crystallization transfer the concentrated liquid to the cooling tank, start stirring, first cool down naturally at 18-20 °C for 1.5 hours, then drop to 58 °C, and then intermittently pass cooling water of 15 °C for 2 hours, cool down to 30 °C , and finally cool down to 23 °C for 9 minutes under the action of an external cold source, and keep the temperature for crystallization.
  • Drying vacuum-drying the washed crystals at a drying temperature of 58° C. for 2 hours to obtain a ⁇ -aminobutyric acid product S1 with a weight loss on drying less than 1%.
  • the obtained ⁇ -aminobutyric acid product was determined by high performance liquid chromatography (HPLC), and the purity of the product was 99.5%.
  • X-ray diffractometer (BRUKER D8) was used to conduct XRD test on the obtained product.
  • the test results showed that the X-ray powder diffraction pattern of the product using CuK ⁇ radiation was at diffraction angles 2 ⁇ of 14.6°, 20.5°, 21.2°, 22.3°, 26.5°, There are characteristic absorption peaks at 26.7°, 27.2°, 28.4°, 29.4°, 29.7°, 35.3°, 40.0°, 41.2°, 42.4°, 42.9°, 44.4°, 46.7°, 49.6°, as shown in Figure 1.
  • DSC Differential scanning calorimetry
  • the morphology of the obtained product was detected with an Olympus optical microscope, and the results are shown in Figure 3.
  • the crystal appearance is a quadrangular prism block, the particles are larger, and the shape is regular.
  • the L-glutamic acid conversion solution is heated to 80-85°C, maintained for 1h, then cooled to 55-60°C at a rate of 10-15°C/h, and then added with 1% activated carbon, adsorbed and filtered to obtain a filtrate;
  • Crystallization control the temperature of crystallization between 65°C-70°C and the vacuum degree of 0.06-0.1Mpa. When the above-mentioned filtrate is evaporated and concentrated to 40-50% of the original volume, more particles appear, and the concentrated solution is obtained.
  • Cooling and crystallization transfer the concentrated liquid to the cooling tank, start stirring, first cool down naturally at 20-25 °C for 2.5 hours, then drop to 50 °C, and then intermittently pass cooling water of 15 °C for 3 hours, cool down to 30 °C , and finally cooled to 20 °C for 6 minutes under the action of an external cold source, and maintained the temperature for crystallization.
  • Drying vacuum drying the washed crystals at a drying temperature of 58° C. for 2 hours to obtain a ⁇ -aminobutyric acid product S2 with a weight loss on drying less than 1%.
  • the obtained product was tested by high performance liquid chromatography (HPLC), and the purity of the product was 99.2%.
  • X-ray diffractometer BRUKER D8 is used to conduct XRD test on the obtained product.
  • the test results show that the X-ray powder diffraction pattern of the product using CuK ⁇ radiation at diffraction angles 2 ⁇ is 14.6°, 20.6°, 21.2°, 22.3°, 26.5°, 26.7°
  • DSC Differential scanning calorimetry
  • the morphology of the obtained product was detected with an Olympus optical microscope, and the crystal was in the form of a quadrangular prism block, with larger particles and regular shape.
  • the L-glutamic acid conversion solution is heated to 80-85°C, maintained for 1h, then cooled to 55-60°C at a rate of 10-15°C/h, and then added with 1% activated carbon, adsorbed and filtered to obtain a filtrate;
  • Crystallization control the temperature of crystallization between 75°C and 80°C and the degree of vacuum at 0.06-0.1Mpa.
  • the above-mentioned filtrate is evaporated and concentrated to 40-50% of the original volume, more particles appear, and a concentrated solution is obtained.
  • Cooling and crystallization transfer the concentrated liquid to a cooling tank, first, start stirring at 18-20 °C to naturally cool down for 2 hours, then drop to 53 °C, then intermittently pass cooling water at 15 °C for 3 hours, and cool down to 30 °C, Finally, the temperature was lowered to 18 °C for 10 min under the action of an external cold source, and the temperature was maintained for crystallization.
  • Drying vacuum drying the washed solid at a drying temperature of 58° C.; ⁇ -aminobutyric acid product S3 with a weight loss on drying less than 1% is obtained in 2 hours.
  • the obtained product was tested by high performance liquid chromatography (HPLC), and the purity of the product was 99.5%.
  • the obtained product was subjected to XRD test with X-ray diffractometer: BRUKER D8.
  • the test results show that the X-ray powder diffraction pattern of the product using CuK ⁇ radiation at diffraction angles 2 ⁇ of 14.6°, 20.6°, 22.3°, 23.3°, 24.0°, 26.5°, 26.9°, 27.3°, 29.5°, 29.7°, 30.1° , 32.3°, 33.8°, 35.4°, 35.9°, 38.2°, 41.0°, 41.3°, 42.2°, 42.3°, 43.0°, 44.3°, 46.6°, 46.9°, 47.2°, 49.8° have characteristic absorption peaks .
  • DSC Differential scanning calorimetry
  • the morphology of the obtained product was detected by an Olympus optical microscope, and the crystal morphology was a quadrangular prism block, the particles were larger, and the shape was regular.
  • the L-glutamic acid conversion solution is heated to 80-85°C, maintained for 1 hour, then cooled to 55-60°C at a rate of 10-15°C/h, and then added with 0.5% activated carbon, adsorbed and filtered to obtain a filtrate;
  • Crystallization Evaporate and concentrate the above-mentioned filtrate to obtain a concentrated solution, control the temperature of crystallization between 80°C and 85°C, and the vacuum degree of 0.06-0.1Mpa. When the above-mentioned filtrate is evaporated and concentrated to 40-50% of the original volume, many particles appear. , to obtain a concentrate.
  • Cooling and crystallization transfer the concentrated liquid to a cooling tank, first, start stirring at 18-20 °C to naturally cool down for 2 hours, then cool down to 55 °C, and then intermittently pass cooling water at 15 °C for about 2.5 hours, cool down to 30 °C, Finally, the temperature was lowered to 17 °C for 8 min under the action of an external cold source, and the temperature was maintained for crystallization.
  • Drying vacuum-drying the washed solid at a drying temperature of 58° C.; ⁇ -aminobutyric acid product S4 with a weight loss on drying less than 1% is obtained in 2 hours.
  • the obtained product was tested by high performance liquid chromatography (HPLC), and the purity of the product was 99.3%.
  • the obtained product was subjected to XRD test with X-ray diffractometer: BRUKER D8.
  • the test results show that the X-ray powder diffraction pattern of the product using CuK ⁇ radiation at diffraction angles 2 ⁇ of 14.6°, 21.0°, 22.5°, 23.3°, 24.0°, 26.6°, 26.9°, 27.3°, 29.5°, 29.7°, 29.9° , 30.1°, 32.3°, 33.8°, 35.5°, 35.9°, 38.2°, 41.0°, 41.3°, 42.2°, 42.3°, 43.0°, 44.4°, 46.6°, 46.9°, 47.2°, 49.9° characteristic absorption peak.
  • DSC Differential scanning calorimetry
  • the morphology of the obtained product was detected by an Olympus optical microscope, and the crystal morphology was a quadrangular prism block, the particles were larger, and the shape was regular.
  • the L-glutamic acid conversion solution is heated to 80-85°C, maintained for 1h, then cooled to 55-60°C at a rate of 10-15°C/h, and then added with 1% activated carbon, adsorbed and filtered to obtain a filtrate;
  • Crystallization Evaporate and concentrate the above-mentioned filtrate to obtain a concentrated solution, control the temperature of crystallization between 70°C and 75°C, and the vacuum degree of 0.06-0.1Mpa. When the above-mentioned filtrate is evaporated and concentrated to 40-50% of the original volume, many particles appear. , to obtain a concentrate.
  • Cooling crystallization transfer the concentrated liquid to a cooling tank, first, start stirring at 18-20 °C to naturally cool down for 2 hours, then cool down to 53 °C, then intermittently pass 15 °C cooling water for about 3 hours, cool down to 30 °C, and finally Under the action of an external cold source, the temperature was lowered to 24 °C for 5 min, and the temperature was maintained for crystallization.
  • Drying vacuum drying the washed solid at a drying temperature of 58° C.; ⁇ -aminobutyric acid product S5 with a weight loss on drying less than 1% is obtained in 2 hours.
  • the obtained product was tested by high performance liquid chromatography (HPLC), and the purity of the product was 99.7%.
  • the obtained product was subjected to XRD test with X-ray diffractometer: BRUKER D8.
  • the test results show that the X-ray powder diffraction pattern of the product using CuK ⁇ radiation at diffraction angles 2 ⁇ of 14.6°, 21.3°, 22.5°, 23.3°, 24.0°, 26.9°, 27.3°, 29.5°, 29.9°, 30.1°, 32.3° , 33.8°, 35.7°, 38.2°, 40.8°, 42.2°, 42.3°, 43.0°, 44.4°, 46.6°, 46.9°, 47.2°, 49.9° have characteristic absorption peaks.
  • DSC Differential scanning calorimetry
  • the morphology of the obtained product was detected with an Olympus optical microscope, and the crystal appearance was a quadrangular prism block, the particles were larger, and the shape was regular.
  • the L-glutamic acid conversion solution is heated to 80-85°C, maintained for 1h, then cooled to 55-60°C at a rate of 10-15°C/h, and then added with 1% activated carbon, adsorbed and filtered to obtain a filtrate;
  • Cooling crystallization transfer the concentrated liquid to the cooling tank, start stirring, first cool down naturally at 18-20 °C for 2 hours, then cool down to 43 °C, and then intermittently pass cooling water at 15 °C for about 2 hours, until the crystal liquid is cooled to 25 °C °C and crystallize at this temperature.
  • the obtained product was tested by high performance liquid chromatography (HPLC), and the purity of the product was 99.7%.
  • X-ray diffractometer BRUKER D8 is used to conduct XRD test on the obtained product, and the XRD pattern is shown in Figure 4.
  • the test results show that the X-ray powder diffraction pattern of the product using CuK ⁇ radiation at diffraction angles 2 ⁇ of 14.5°, 15.8°, 18.9°, 21.2°, 23.5°, 27.6°, 29.73°, 35.49°, 42.21°, 44.35°, 47.31° , 49.77°, and characteristic absorption peaks at 52.77°.
  • DSC Differential scanning calorimetry
  • the morphology of the obtained product was detected with an Olympus optical microscope, as shown in Figure 6, the crystal appearance and shape were not single.
  • the crystal form obtained in the present invention has an endothermic characteristic peak at (248 ⁇ 1) ° C, while the endothermic characteristic peak of the product of the comparative example is only 220 ° C, which is obviously the stability of the new crystal form of the present invention. higher than that of the comparative example. 4 and 6, it can be seen that the ⁇ -aminobutyric acid product obtained by the method of the comparative example is not single in appearance and shape, and the thermal stability is not as good as that of the high-purity crystal form of the present invention.

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Abstract

本发明公开了一种γ-氨基丁酸的新晶型及其制备方法，该晶型的X射线粉末衍射图在衍射角2θ至少为22.3°±0.5°、26.9°±0.5°、29.7°±0.5°、35.4±0.5°处具有特征吸收峰。本发明通过加入γ-氨基丁酸晶体并控制结晶过程得到一种纯度较高的γ-氨基丁酸的新晶型，该晶型外观为四棱柱块状，形状规则，流动性好，稳定性高，制备方法简单易行，结晶过程经济环保，适合大规模生产。

Description

一种γ-氨基丁酸的新晶型及其制备方法 技术领域
本发明涉及γ-氨基丁酸制备技术领域，具体涉及一种γ-氨基丁酸的新晶型及其制备方法。
背景技术
γ-氨基丁酸(GABA)作为大脑组织重要的抑制性递质，具有镇静安神，降低血压，治疗癫痫和抗衰老的功能。此外，GABA味甜，能够调节食品味道，可以与体内酒精反应，故具有醒酒消臭等作用。在医学上，可用于治疗一些病症，如治疗尿毒症、CO中毒的药物中都含有GABA。
GABA的合成方法主要有化学合成法和生物合成法，在化学法合成GABA的过程中，需要用到强酸或强碱等腐蚀性较强的溶剂，反应条件剧烈，原料毒性大，价格昂贵且存在较多安全隐患等问题。实际工业生产中，主要用生物法合成GABA。生物合成法主要研究的微生物法。微生物法包括传统的微生物发酵法以及最近几年新兴的微生物转化法。早期的发酵法主要是以大肠杆菌(Escherichia coli)发酵生产GABA为主。出于对食品安全性的考虑，后来又逐渐筛选到含有谷氨酸脱羧酶的酵母菌、乳酸菌和曲霉菌等食品安全级微生物来发酵制的GABA。但发酵法生产GABA过程中易污染、可重复性差，周期长等缺点也逐渐被工业生产所淘汰。目前工业生产中主要用微生物转化法进行生产。微生物转化法是指以L-谷氨酸或L-谷氨酸盐为底物，利用乳酸菌脱羧酶的作用，将L-谷氨酸或L-谷氨酸盐转化为GABA，得到含GABA的转化液，该转化液经过进一步的后处理即可得到GABA晶体。一般的，GABA转化液后处理过程是：将转化液升温使蛋白质变质，然后加入活性炭脱色，脱色后的转化液蒸发浓缩得浓缩液，然后将浓缩液降温析晶、固液分离、95％以上乙醇洗涤、真空干燥，得最终的GABA晶体。
专利CN201110151741中，通过三效浓缩与直接浓缩的方式进行结晶：控制一效温度60-95℃，二效温度90-115℃，三效温度50-85℃，控制真空度0.08Mpa-0.1Mpa；在浓缩产品含量达550-600g/L时，停止浓缩，将浓缩液打入真空浓缩结晶罐，控制真空浓缩结晶罐真空度0.08Mpa-0.1Mpa，温度为60-75℃，在浓缩产品含量达700-900g/L时，停止加热，常压下自然降温养晶1-1.5h，得到柱状或粉末状晶体。
专利CN107827766 A中，向溶液中加入添加剂，升温至50-80℃，搅拌使溶液澄清；然后在50-80℃下减压蒸发水分，得到悬浮液，然后对悬浮液进行过滤，得到湿产物，经干燥处理 即得γ-氨基丁酸新晶型产品，得到产品DSC吸热特征峰的温度为220℃。
目前，在现有技术中未见其他类型的γ-氨基丁酸晶型的报道。
发明内容
本发明的目的是提供一种γ-氨基丁酸的新晶型，该晶型结晶纯度高，具有更好的稳定性。
本发明所述的γ-氨基丁酸的新晶型，该晶型X射线粉末衍射图在衍射角2θ至少为22.3°±0.5°、26.9°±0.5°、29.7°±0.5°、35.4±0.5°处具有特征吸收主峰。
进一步的，该晶型的X射线粉末衍射图在衍射角2θ为22.3±0.2°、26.7±0.2°、29.6±0.2°、35.5±0.2°、41.0±0.2°处具有特征吸收峰。
进一步的，该晶型的X射线粉末衍射图在衍射角2θ为14.6°±0.2°、22.3±0.2°、26.7±0.2°、27.2±0.2°、29.6±0.2°、35.5±0.2°、41.0±0.2°、42.4±0.2°、43±0.2°、44.4±0.2°、46.9±0.2°、49.8±0.2°处具有特征吸收峰。
优选的，该晶型的X射线粉末衍射图在衍射角2θ为14.6°、20.5°、21.2°、22.3°、26.5°、26.7°、27.2°、28.4°、29.4°、29.7°、35.3°、40.0°、41.2°、42.4°、42.9°、44.4°、46.7°、49.6°处具有特征吸收峰。
优选的，该晶型的X射线粉末衍射图在衍射角2θ为14.6°、20.6°、21.2°、22.3°、26.5°、26.7°、27.2°、28.4°、29.4°、29.7°、35.4°、40.0°、41.2°、42.4°、42.9°、44.4°、46.7°、49.8°处具有特征吸收峰。
优选的，该晶型的X射线粉末衍射图在衍射角2θ为14.6°、20.6°、22.3°、23.3°、24.0°、26.5°、26.9°、27.3°、29.5°、29.7°、30.1°、32.3°、33.8°、35.4°、35.9°、38.2°、41.0°、41.3°、42.2°、42.3°、43.0°、44.3°、46.6°、46.9°、47.2°、49.8°处具有特征吸收峰。
优选的，该晶型的X射线粉末衍射图在衍射角2θ为14.6°、21.0°、22.5°、23.3°、24.0°、26.6°、26.9°、27.3°、29.5°、29.7°、29.9°、30.1°、32.3°、33.8°、35.5°、35.9°、38.2°、41.0°、41.3°、42.2°、42.3°、43.0°、44.4°、46.6°、46.9°、47.2°、49.9°处具有特征吸收峰。
优选的，该晶型的X射线粉末衍射图在衍射角2θ为14.6°、21.3°、22.5°、23.3°、24.0°、26.9°、27.3°、29.5°、29.9°、30.1°、32.3°、33.8°、35.7°、38.2°、40.8°、42.2°、42.3°、43.0°、44.4°、46.6°、46.9°、47.2°、49.9°处具有特征吸收峰。
所述X射线粉末衍射(X-Ray Powder Diffraction，XRPD)通常应用于晶体结构的分析。X射线是一种电磁波，入射到晶体时在晶体中产生周期性变化的电磁场。引起原子中的电子和原子核振动，因原子核的质量很大振动忽略不计。振动着的电子是次生X射线的波源，其波长、周相与入射光相同。基于晶体结构的周期性，晶体中各个电子的散射波相互干涉相互叠加，称之为衍射。散射波周相一致相互加强的方向称衍射方向，产生衍射线。
所述X射线粉末衍射所使用的仪器型号为：Bruker D8 Advance测试条件如下：
1.铜靶，波长＝0.154056nm；
2.测量电压40千伏，测量电流40毫安；
3.扫描方式：步进扫描，步长0.01，每一步停留时间0.1S；
4.扫描范围：2θ＝5-90°。
进一步的，所述晶型具有图1所示的X射线粉末衍射图。
进一步的，所述晶型经DSC差热分析在(248±1)℃处具有吸热特征峰。该DSC吸热特征峰的温度为248℃左右，较现有报道的晶型产品提高了30℃左右，说明该晶型具有更好的稳定性。
DSC差热分析即差示扫描量热分析(differential scanning calorimetry)，在温度程序控制下，测量试样相对于参比物的热流速率随温度或时间变化的一种技术。差示扫描量热仪记录到的曲线称DSC曲线，一般以W/g或mW/mg(即流向每克样品的功率)为纵坐标，以温度T或时间t为横坐标，可以测量多种热力学和动力学参数，例如比热容、反应热、转变热、相图、反应速率、结晶速率、高聚物结晶度、样品纯度等。该法使用温度范围宽(-175-725℃)、分辨率高、试样用量少。适用于无机物、有机化合物及药物分析。
进一步的，所述晶型外观为四棱柱块状，形状规则，流动性更好。
进一步的，所述晶型的熔点为248±1℃。
进一步的，本发明还提供了一种γ-氨基丁酸原料，该原料中包含上述γ-氨基丁酸晶型。优选的，该原料中上述γ-氨基丁酸新晶型的含量高，含量大于等于99％。
本发明还提供了上述γ-氨基丁酸新晶型的制备方法，该方法包括：
将L-谷氨酸转化液加入吸附剂吸附，过滤得滤液；
将所述滤液浓缩得到浓缩液；
将γ-氨基丁酸晶体加入到浓缩液中进行析晶得到所述晶型。
进一步的，将L-谷氨酸转化液先升温、然后降温后加入吸附剂，优选的，所述吸附剂为活性炭；
优选的，升温至80-85℃后，再降温至55-60℃；
优选的，降温速度为10-15℃/h。
进一步的，吸附剂的加入量为L-谷氨酸转化液总重量的0.5-1％。
进一步的，将滤液在65℃-85℃、0.06-0.1Mpa的真空度下进行浓缩，优选的，浓缩至原体积的40-50％。
进一步的，向浓缩液中加入其总重量1-5％的γ-氨基丁酸晶体。
进一步的，将γ-氨基丁酸晶体加入到浓缩液后进行降温，然后在15-24℃下进行析晶；
优选的，降温在18-26℃下自然降温1-2h，然后间歇性以外界冷源进行降温使温度降至30℃；优选的，再以0.5-2℃/min的降温速度降至15-24℃。
进一步的，将析出的晶体进行洗涤、干燥得到所述晶型。
进一步的，所述外界冷源指的是人为加入的冷源，例如循环冷却水、冷冻水等。
进一步的，析晶后，使用95％以上的乙醇洗涤，洗涤后的晶体真空干燥得到所述晶型。
进一步的，所述方法包括：
(1)将L-谷氨酸转化液升温至80-85℃，维持1-2h，然后降温至55-60℃，加入活性炭吸附、过滤，得滤液；
(2)将滤液浓缩析晶，至出现较多晶体时停止浓缩；
(3)向浓缩液中加入其总重量1-5％的γ-氨基丁酸晶体；
(4)将浓缩液转移至降温罐，开启搅拌，先在18-26℃下自然降温1-2h，然后间歇性以外界冷源进行降温，使温度在2-3h降至30℃，最后以0.5-2℃/min的降温速度快速降至15-24℃，然后在15-24℃下进行析晶；
(5)固液分离，将所得晶体洗涤、干燥，得γ-氨基丁酸晶型。
进一步的，步骤(1)所述的L-谷氨酸转化液是L-谷氨酸通过微生物转化法得到的γ-氨基丁酸粗品溶液。
进一步的，步骤(1)中，L-谷氨酸转化液以10-15℃/h的降温速度降至55-60℃。
进一步的，步骤(1)中，活性炭的加入量为L-谷氨酸转化液总重量的0.5-1％。
进一步的，步骤(2)中，滤液在65℃-85℃、0.06-0.1Mpa的真空度下进行浓缩。优选的，浓缩至原体积的40-50％。
进一步的，步骤(4)中，所述外界冷源指的是人为加入的冷源，例如循环冷却水、冷冻水等。
进一步的，步骤(5)中，所得晶体用95％以上的乙醇洗涤，洗涤后的晶体真空干燥，干燥温度55-60℃，在此温度下干燥2小时左右即得干燥失重小于1％的晶型，该晶型外观为四棱柱块状，颗粒大，形状规则，杂质少，纯度高，纯度在99％以上。
本发明通过加入γ-氨基丁酸晶体并控制结晶过程得到一种纯度较高的γ-氨基丁酸的新晶型，该晶型外观为四棱柱块状，形状规则，流动性好，稳定性高，制备方法简单易行，结晶过程经济环保，适合大规模生产。
附图说明
图1是本发明实施例1所得γ-氨基丁酸晶型的XRD图。
图2是本发明实施例1所得γ-氨基丁酸晶型的DSC差热分析图。
图3是本发明实施例1所得γ-氨基丁酸晶体形貌图。
图4是对比例1所得产品的XRD图。
图5是对比例1所得产品的DSC差热分析图。
图6是对比例1所得产品的晶体形貌图。
具体实施方式
下面通过具体实施例对本发明进行进一步解释和说明，下述说明仅是示例性的，并不对其内容进行限制。
下述实施例中，所用L-谷氨酸转化液是按照专利201710760851.X中的方法、以副短乳杆菌HX12-19为菌种，经其对L-谷氨酸进行转化得到的L-谷氨酸转化液，该转化液中，γ-氨基丁酸含量为200-500g/L。
下述实施例中，如无特别说明，下述各浓度均为质量百分浓度。
实施例1
1、将L-谷氨酸转化液升温至80-85℃，维持1h，然后以10-15℃/h的速度降温至55-60℃，后添加1％的活性炭，吸附、过滤，得到滤液；
2、结晶：控制温度在70℃-75℃之间，真空度0.06-0.1Mpa，蒸发浓缩上述滤液至原体积的40-50％时，出现较多颗粒，获得浓缩液。
3、向浓缩液中加入总重量2％的γ-氨基丁酸晶体；
4、降温结晶：将浓缩液转移至降温罐，开搅拌，先在18-20℃下自然降温1.5小时，降至58℃，然后间断性通15℃的冷却水降温2小时，降温至30℃，最后在外界冷源的作用下9min降温至23℃,并保持该温度进行析晶。
5、洗涤：将降温结晶后的结晶液固液分离，所得晶体用95％乙醇洗涤。
6、干燥：将洗涤后的晶体进行真空干燥，干燥温度58℃，2小时即得干燥失重小于1％的γ-氨基丁酸产品S1。
采用高效液相色谱(HPLC)法对所得的γ-氨基丁酸产品进行测定，产品的纯度为99.5％。
用X-射线衍射仪(BRUKER D8)对所得产品进行XRD测试，测试结果表明产品使用CuKα 辐射的X射线粉末衍射图在衍射角2θ为14.6°、20.5°、21.2°、22.3°、26.5°、26.7°、27.2°、28.4°、29.4°、29.7°、35.3°、40.0°、41.2°、42.4°、42.9°、44.4°、46.7°、49.6°处有特征吸收峰，如图1所示。
采用差示扫描量热法(DSC)对本实施例中制备的γ-氨基丁酸新晶型产品进行测定。如图2所示，产品在249.0℃具有一个吸热特征峰。
用奥林巴斯光学显微镜对所得产品的形貌进行检测，结果如图3所示，晶体外观为四棱柱块状，颗粒较大，形状规则。
实施例2
1、L-谷氨酸转化液升温至80-85℃，维持1h，然后以10-15℃/h的速度降温至55-60℃，后添加1％的活性炭，吸附、过滤，得到滤液；
2、结晶：控制结晶的温度在65℃-70℃之间，真空度0.06-0.1Mpa，蒸发浓缩上述滤液至原体积的40-50％时，出现较多颗粒，获得浓缩液。
3、向浓缩液中加入总重量3％的γ-氨基丁酸晶体；
4、降温结晶：将浓缩液转移至降温罐，开搅拌，先在20-25℃下自然降温2.5小时，降至50℃，然后间断性通15℃的冷却水降温3小时，降温至30℃，最后在外界冷源的作用下6min降温至20℃，并保持该温度进行析晶。
5、洗涤：将降温结晶后的结晶液固液分离，所得晶体用95％乙醇洗涤。
6、干燥：将洗涤后的晶体进行真空干燥，干燥温度58℃，2小时即得干燥失重小于1％的γ-氨基丁酸产品S2。
采用高效液相色谱(HPLC)法对所得产品进行测试，产品的纯度为99.2％。
用X-射线衍射仪：BRUKER D8对所得产品进行XRD测试，测试结果表明产品使用CuKα辐射的X射线粉末衍射图在衍射角2θ为14.6°、20.6°、21.2°、22.3°、26.5°、26.7°、27.2°、28.4°、29.4°、29.7°、35.4°、40.0°、41.2°、42.4°、42.9°、44.4°、46.7°、49.8°处有特征吸收峰。
采用差示扫描量热法(DSC)对本实施例中制备的γ-氨基丁酸新晶型产品进行测定。产品在248.8℃具有一个吸热特征峰。
用奥林巴斯光学显微镜对所得产品的形貌进行检测，晶体外观为四棱柱块状，颗粒较大，形状规则。
实施例3
1、L-谷氨酸转化液升温至80-85℃，维持1h，然后以10-15℃/h的速度降温至55-60℃，后添加1％的活性炭，吸附、过滤，得到滤液；
2、结晶：控制结晶的温度在75℃-80℃之间，真空度0.06-0.1Mpa，蒸发浓缩上述滤液至原体积的40-50％时，出现较多颗粒，获得浓缩液。
3、向浓缩液中加入总重量3％的γ-氨基丁酸晶体；
4、降温结晶：将浓缩液转移至降温罐，先在18-20℃下开搅拌自然降温2小时，降至53℃，然后间断性通15℃的冷却水降温3小时，降温至30℃，最后在外界冷源的作用下10min降温至18℃，并保持该温度进行析晶。
5、洗涤：将降温结晶后的结晶液固液分离，所得晶体用95％乙醇洗涤。
6、干燥：将洗涤后的固体进行真空干燥，干燥温度58℃；2小时即得干燥失重小于1％的γ-氨基丁酸产品S3。
采用高效液相色谱(HPLC)法对所得产品进行测试，产品的纯度为99.5％。
用X-射线衍射仪：BRUKER D8对所得产品进行XRD测试。测试结果表明产品使用CuKα辐射的X射线粉末衍射图在衍射角2θ为14.6°、20.6°、22.3°、23.3°、24.0°、26.5°、26.9°、27.3°、29.5°、29.7°、30.1°、32.3°、33.8°、35.4°、35.9°、38.2°、41.0°、41.3°、42.2°、42.3°、43.0°、44.3°、46.6°、46.9°、47.2°、49.8°处有特征吸收峰。
采用差示扫描量热法(DSC)对本实施例中制备的γ-氨基丁酸新晶型产品进行测定。产品在247.6℃具有一个吸热特征峰。
用奥林巴斯光学显微镜对所得产品的形貌进行检测，晶体形貌为四棱柱块状，颗粒较大，形状规则。
实施例4
1、L-谷氨酸转化液升温至80-85℃，维持1h，然后以10-15℃/h的速度降温至55-60℃，后添加0.5％的活性炭，吸附、过滤，得到滤液；
2、结晶：蒸发浓缩上述滤液获得浓缩液，控制结晶的温度在80℃-85℃之间，真空度0.06-0.1Mpa，蒸发浓缩上述滤液至原体积的40-50％时，出现较多颗粒，获得浓缩液。
3、向浓缩液中加入总重量5％的γ-氨基丁酸晶体；
4、降温结晶：将浓缩液转移至降温罐，先在18-20℃下开搅拌自然降温2小时，降温至55℃，然后间断性通15℃的冷却水约2.5小时，降温至30℃，最后在外界冷源的作用下8min降温至17℃，并保持该温度进行析晶。
5、洗涤：将降温结晶后的结晶液固液分离，所得晶体用95％乙醇洗涤。
6、干燥：将洗涤后的固体进行真空干燥，干燥温度58℃；2小时即得干燥失重小于1％的γ-氨基丁酸产品S4。
采用高效液相色谱(HPLC)法对所得产品进行测试，产品的纯度为99.3％。
用X-射线衍射仪：BRUKER D8对所得产品进行XRD测试。测试结果表明产品使用CuKα辐射的X射线粉末衍射图在衍射角2θ为14.6°、21.0°、22.5°、23.3°、24.0°、26.6°、26.9°、27.3°、29.5°、29.7°、29.9°、30.1°、32.3°、33.8°、35.5°、35.9°、38.2°、41.0°、41.3°、42.2°、42.3°、43.0°、44.4°、46.6°、46.9°、47.2°、49.9°处有特征吸收峰。
采用差示扫描量热法(DSC)对本实施例中制备的γ-氨基丁酸新晶型产品进行测定。产品在248.5℃具有一个吸热特征峰。
用奥林巴斯光学显微镜对所得产品的形貌进行检测，晶体形貌为四棱柱块状，颗粒较大，形状规则。
实施例5
1、L-谷氨酸转化液升温至80-85℃，维持1h，然后以10-15℃/h的速度降温至55-60℃，后添加1％的活性炭，吸附、过滤，得到滤液；
2、结晶：蒸发浓缩上述滤液获得浓缩液，控制结晶的温度在70℃-75℃之间，真空度0.06-0.1Mpa，蒸发浓缩上述滤液至原体积的40-50％时，出现较多颗粒，获得浓缩液。
3、向浓缩液中加入总重量1％的γ-氨基丁酸晶体；
4、降温结晶：将浓缩液转移至降温罐，先在18-20℃下开搅拌自然降温2小时，降温至53℃，然后间断性通15℃冷却水约3小时，降温至30℃，最后在外界冷源的作用下5min降温至24℃，并保持该温度进行析晶。
5、洗涤：将降温结晶后的结晶液固液分离，所得晶体用95％乙醇洗涤。
6、干燥：将洗涤后的固体进行真空干燥，干燥温度58℃；2小时即得干燥失重小于1％的γ-氨基丁酸产品S5。
采用高效液相色谱(HPLC)法对所得产品进行测试，产品的纯度为99.7％。
用X-射线衍射仪：BRUKER D8对所得产品进行XRD测试。测试结果表明产品使用CuKα辐射的X射线粉末衍射图在衍射角2θ为14.6°、21.3°、22.5°、23.3°、24.0°、26.9°、27.3°、29.5°、29.9°、30.1°、32.3°、33.8°、35.7°、38.2°、40.8°、42.2°、42.3°、43.0°、44.4°、46.6°、46.9°、47.2°、49.9°处有特征吸收峰。
采用差示扫描量热法(DSC)对本实施例中制备的γ-氨基丁酸新晶型产品进行测定。产品在247.9℃具有一个吸热特征峰。
用奥林巴斯光学显微镜对所得产品的形貌进行检测，晶体外观为四棱柱块状，颗粒较大， 形状规则。
对比例1
1、L-谷氨酸转化液升温至80-85℃，维持1h，然后以10-15℃/h的速度降温至55-60℃，后添加1％的活性炭，吸附、过滤，得到滤液；
2、结晶：控制温度在70℃-75℃之间，真空度0.06-0.1Mpa，蒸发浓缩上述滤液至原体积的40-50％时，出现较多颗粒，获得浓缩液。
3、降温结晶：将浓缩液转移至降温罐，开搅拌，先在18-20℃下自然降温2小时，降温至43℃，然后间断性通15℃冷却水约2h，直至结晶液降温至25℃，并在此温度进行析晶。
4、洗涤：将降温结晶后的结晶液固液分离，所得晶体用95％乙醇洗涤。
5、干燥：将洗涤后的固体进行真空干燥，干燥温度58℃；2小时即得干燥失重小于1％的γ-氨基丁酸产品S6。
采用高效液相色谱(HPLC)法对所得产品进行测试，产品的纯度为99.7％。
用X-射线衍射仪：BRUKER D8对所得产品进行XRD测试，XRD图如图4所示。测试结果表明产品使用CuKα辐射的X射线粉末衍射图在衍射角2θ为14.5°，15.8°，18.9°，21.2°，23.5°，27.6°，29.73°，35.49°，42.21°，44.35°，47.31°，49.77°，52.77°处有特征吸收峰。
采用差示扫描量热法(DSC)对本对比例中制备的γ-氨基丁酸新晶型产品进行测定。产品在220.0℃具有一个吸热特征峰。
用奥林巴斯光学显微镜对所得产品的形貌进行检测，如图6所示，晶体外观形状不单一。
上述实施例和对比例制得的γ-氨基丁酸产品的吸热特征峰总结如下表1所示，其中实施例1产品的DSC差热分析图如图2所示，对比例1产品的DSC差热分析图如图5所示：
表1实施例和对比例所得到的晶型的吸热特征峰表
Figure PCTCN2021143633-appb-000001
从上述结果可以看出，本发明所得晶型在(248±1)℃处具有吸热特征峰，而对比例的 产品的吸热特征峰仅为220℃，明显本发明新晶型的稳定性高于对比例的产品。结合图4和6看，对比例方法所得的γ-氨基丁酸产品中晶体外观形状不单一，热稳定性也不如本发明的高纯度的晶型好。

Claims (16)

  1. 一种γ-氨基丁酸晶型，其特征是：该晶型的X射线粉末衍射图在衍射角2θ至少为22.3°±0.5°、26.9°±0.5°、29.7°±0.5°、35.4±0.5°处具有特征吸收峰。
  2. 根据权利要求1所述的γ-氨基丁酸晶型，其特征是：该晶型的X射线粉末衍射图在衍射角2θ为22.3±0.2°、26.7±0.2°、29.6±0.2°、35.5±0.2°、41.0±0.2°处具有特征吸收峰。
  3. 根据权利要求1-2中任一项所述的γ-氨基丁酸晶型，其特征是：该晶型的X射线粉末衍射图在衍射角2θ为14.6°±0.2°、22.3±0.2°、26.7±0.2°、27.2±0.2°、29.6±0.2°、35.5±0.2°、41.0±0.2°、42.4±0.2°、43±0.2°、44.4±0.2°、46.9±0.2°、49.8±0.2°处具有特征吸收峰。
  4. 根据权利要求1-3中任一项所述的γ-氨基丁酸晶型，其特征是：该晶型的X射线粉末衍射图在下述任一2θ衍射角处具有特征吸收峰：
    a).14.6°、20.5°、21.2°、22.3°、26.5°、26.7°、27.2°、28.4°、29.4°、29.7°、35.3°、40.0°、41.2°、42.4°、42.9°、44.4°、46.7°、49.6°；
    b).14.6°、20.6°、21.2°、22.3°、26.5°、26.7°、27.2°、28.4°、29.4°、29.7°、35.4°、40.0°、41.2°、42.4°、42.9°、44.4°、46.7°、49.8°；
    c).14.6°、20.6°、22.3°、23.3°、24.0°、26.5°、26.9°、27.3°、29.5°、29.7°、30.1°、32.3°、33.8°、35.4°、35.9°、38.2°、41.0°、41.3°、42.2°、42.3°、43.0°、44.3°、46.6°、46.9°、47.2°、49.8°；
    d).14.6°、21.0°、22.5°、23.3°、24.0°、26.6°、26.9°、27.3°、29.5°、29.7°、29.9°、30.1°、32.3°、33.8°、35.5°、35.9°、38.2°、41.0°、41.3°、42.2°、42.3°、43.0°、44.4°、46.6°、46.9°、47.2°、49.9°；以及
    e).14.6°、21.3°、22.5°、23.3°、24.0°、26.9°、27.3°、29.5°、29.9°、30.1°、32.3°、33.8°、35.7°、38.2°、40.8°、42.2°、42.3°、43.0°、44.4°、46.6°、46.9°、47.2°、49.9°。
  5. 根据权利要求1-4中任一项所述的γ-氨基丁酸晶型，其特征是：所述晶型具有图1所示的X射线粉末衍射图。
  6. 根据权利要求1-5中任一项所述的γ-氨基丁酸晶型，其特征是：经DSC差热分析在247-249℃处具有吸热特征峰。
  7. 根据权利要求1-6中任一项所述的γ-氨基丁酸晶型，其特征是：所述晶型外观为四棱柱块状。
  8. 一种γ-氨基丁酸原料，其特征是：包含权利要求1-7中任一项所述的γ-氨基丁酸晶型；优选的，所述γ-氨基丁酸晶型的含量大于等于99％。
  9. 一种权利要求1-7中任一项所述的γ-氨基丁酸晶型的制备方法，其特征是包括：
    将L-谷氨酸转化液加入吸附剂吸附，过滤得滤液；
    将所述滤液浓缩得到浓缩液；
    将γ-氨基丁酸晶体加入到浓缩液中进行析晶得到所述晶型。
  10. 根据权利要求9所述的制备方法，其特征是：
    将L-谷氨酸转化液先升温、然后降温后加入吸附剂，优选的，所述吸附剂为活性炭；
    优选的，升温至80-85℃后，再降温至55-60℃；
    优选的，降温速度为10-15℃/h。
  11. 根据权利要求9或10所述的制备方法，其特征是：吸附剂的加入量为L-谷氨酸转化液总重量的0.5-1％。
  12. 根据权利要求9-11中任一项所述的制备方法，其特征是：将滤液在65℃-85℃、0.06-0.1Mpa的真空度下进行浓缩，优选的，浓缩至原体积的40-50％。
  13. 根据权利要求9-12中任一项所述的制备方法，其特征是：
    向浓缩液中加入其总重量1-5％的γ-氨基丁酸晶体。
  14. 根据权利要求9-13中任一项所述的制备方法，其特征是：
    将γ-氨基丁酸晶体加入到浓缩液后进行降温，然后在15-24℃下进行析晶；
    优选的，降温在18-26℃下自然降温1-2h，然后间歇性以外界冷源进行降温使温度降至30℃；优选的，再以0.5-2℃/min的降温速度降至15-24℃。
  15. 根据权利要求9-14中任一项所述的制备方法，其特征是：
    将析出的晶体进行洗涤、干燥得到所述晶型。
  16. 根据权利要求9-15中任一项所述的制备方法，其中，所述方法包括：
    (1)将L-谷氨酸转化液升温至80-85℃，维持1-2h，然后降温至55-60℃，加入活性炭吸附、过滤，得滤液；
    (2)将滤液浓缩析晶，至出现较多晶体时停止浓缩；
    (3)向浓缩液中加入其总重量1-5％的γ-氨基丁酸晶体；
    (4)将浓缩液转移至降温罐，开启搅拌，先在18-26℃下自然降温1-2h，然后间歇性以外界冷源进行降温，使温度在2-3h降至30℃，最后以0.5-2℃/min的降温速度快速降至15-24℃，然后在15-24℃下进行析晶；
    (5)固液分离，将所得晶体洗涤、干燥，得γ-氨基丁酸晶型。
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CN107475151A (zh) * 2017-08-30 2017-12-15 华熙福瑞达生物医药有限公司 一株高产γ‑氨基丁酸的乳酸菌及其应用
CN109735559A (zh) * 2019-03-08 2019-05-10 湖北大学 一种γ-氨基丁酸的生物制备方法
CN109896971A (zh) * 2019-03-26 2019-06-18 华熙生物科技股份有限公司 一种γ-氨基丁酸的制备方法
CN112778150A (zh) * 2021-01-14 2021-05-11 华熙生物科技股份有限公司 一种γ-氨基丁酸的新晶型及其制备方法

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