WO2017206704A1 - Methionine new crystal form ii and preparation method therefor - Google Patents

Methionine new crystal form ii and preparation method therefor Download PDF

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WO2017206704A1
WO2017206704A1 PCT/CN2017/084385 CN2017084385W WO2017206704A1 WO 2017206704 A1 WO2017206704 A1 WO 2017206704A1 CN 2017084385 W CN2017084385 W CN 2017084385W WO 2017206704 A1 WO2017206704 A1 WO 2017206704A1
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methionine
crystal form
crystallization
particles
hours
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PCT/CN2017/084385
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French (fr)
Chinese (zh)
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吴传隆
万霞
刘桢
刘丹
李华萍
金海琴
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宁夏紫光天化蛋氨酸有限责任公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/26—Separation; Purification; Stabilisation; Use of additives
    • C07C319/28—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • 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 new crystalline form of methionine and a preparation method thereof.
  • the chemical formula of DL-Methionine is C 5 H 11 O 2 NS, white flake crystal or crystalline powder with special odor and slightly sweet taste.
  • Also used for amino acid infusion, comprehensive amino acid preparations, can be used as spices according to China's GB2760-86 regulations, it is also an essential animal feed additive, animal feed with methionine can help animals grow quickly in a short time, so that It saves about 40% of the feed. Lack of methionine in livestock and poultry can cause stunting, weight loss, liver and kidney function weakening, muscle atrophy, and skin deterioration.
  • Chinese patent CN104926701 A discloses a purification process of methionine, which uses a macroporous adsorption resin to separate methionine and by-product salts, methionine is adsorbed on a macroporous adsorption resin and then desorbed by a desorbent to recover methionine, a by-product salt substance.
  • the adsorption process it is not adsorbed into the adsorption effluent by the macroporous adsorption resin, and mainly includes the following steps: 1) Resin adsorption: the methionine solution passes through the macroporous adsorption resin layer from top to bottom, and the methionine content in the resin column effluent is greater than When it is equal to 10% (w/w) of the inlet content, the resin adsorption is stopped; the resin adsorbs the effluent as a by-product salt; 2) the resin is desorbed: the adsorbed resin is completed in step 1), and the desorbent is used from top to bottom.
  • the desorbed liquid is subsequently processed according to the existing process flow.
  • the methionine product with purity ⁇ 99% can be obtained, the content of methionine in the by-product salt substance is ⁇ 0.03%, and the yield of resin extraction methionine is ⁇ 98%.
  • Cisoka patent CN104177280 A discloses a methionine production process, step 1: separating the methionine crystallization mother liquor through a continuous chromatographic separation system filled with sodium or potassium type chromatography resin to obtain a methionine solution and an inorganic salt solution; Step 2: methionine solution
  • the reverse osmosis system is used to concentrate the methionine reverse osmosis concentrate, and the obtained methionine reverse osmosis concentrate is returned to the crystallization process; the process is simple, the separation effect is good, the purity of methionine is high, and the concentration cost is low.
  • Chinese Patent No. CN101480385 B discloses the use of methionine for the preparation of a composition for treating or preventing vestibular hair cell disease of the inner ear, the pharmaceutical composition comprising: (a) 50-200 parts by weight of methionine and/or a polypeptide thereof; (b) 400-2000 parts by weight of a pharmaceutically acceptable carrier; and the weight of (a) + (b) is 50-99% by weight based on the total weight of the pharmaceutical composition, the pharmaceutical composition being a solid preparation or A liquid preparation comprising an opacifying agent, a solution, a suspending agent, a syrup, a drop, and the like.
  • the currently produced methionine granule products have poor processing flowability, low bulk density, and increased packaging and transportation costs.
  • Another object of the present invention is to provide a process for preparing the above methionine crystal form II.
  • a methionine crystal form II characterized in that the crystal form has a diffraction angle 2 ⁇ of 22.304 ⁇ 0.2°, 33.757 ⁇ 0.2°, 45.674 ⁇ 0.2°, 28.104 ⁇ 0.2°, 18.615 ⁇ 0.2°, There is a diffraction peak at 42.739 ⁇ 0.2°.
  • the methionine crystal form II of the present invention has a diffraction angle 2 ⁇ of 11.145 ⁇ 0.2°, 16.716 ⁇ 0.2°, 18.615 ⁇ 0.2°, 22.304 ⁇ 0.2°, 25.203 ⁇ 0.2°, 28.104 ⁇ 0.2°, 33.757 ⁇ 0.2°, There are diffraction peaks at 42.739 ⁇ 0.2°, 45.674 ⁇ 0.2°, and 51.812 ⁇ 0.2°.
  • methionine crystal form II is characterized in that it has the following Value and relative intensity percentage I (%) value expressed by -X-ray powder diffraction data,
  • methionine crystal form II is characterized in that it has the following Value and relative intensity percentage I (%) value expressed by -X-ray powder diffraction data,
  • the above methionine crystal form II is characterized in that it has the structure shown in FIG. The X-ray powder diffraction pattern shown.
  • the above-mentioned methionine crystal form II has a melting point peak temperature of 287 ° C, and the crystal form has a DSC/TG pattern as shown in FIG. 2 .
  • the methionine crystal form II of the present invention has the same chemical structure as methionine, and has good quality and excellent processing flowability.
  • the preparation method of the methionine crystal form II of the invention adopts the following steps:
  • the above methionine neutralization solution is added to the isopropanol solvent, the methionine neutralization solution in the concentration of isopropanol 0.3-1.0 mg / mL, continuously stirring at 55 ° C ⁇ 65 ° C, stirring time 0.5-1.5 hours;
  • the solution is pre-cooled in an environment of -1 ° C - 5 ° C for 1-2 hours; then vacuum crystallization, the cooling medium for crystallization is ethylene glycol, the temperature of the cooling medium is -10 ° C, and the crystallization temperature is 0 ° C to -5 ° C.
  • the stirring rate is 30-60 r/min, the degree of vacuum is 19-30 kPa, and the crystallization time is 3-6 hours.
  • the methionine crystal form II of the invention is white crystal particles, has good light reflectivity, and has large and relatively uniform particles, and has a flat block shape with a length to width ratio of about 2:1, and the particle length is concentrated in the range of 450-550 micrometers, and the single particles.
  • the appearance is a complete and dense crystal with excellent quality.
  • the inventors found that the fluidity and bulk density are closely related to the key peak position and relative peak intensity of the X-ray powder diffraction pattern.
  • the methionine crystal form II of the present invention has a high bulk density of 1-2 g/cm 3 and processing fluidity.
  • the injection angle method (fixed funnel method) is used to determine the angle of repose of the crystal particles, ⁇ ⁇ 40 degrees, which is advantageous for subsequent large-scale industrial production applications.
  • Figure 1 is a crystalline methionine X-ray powder diffraction pattern of the present invention
  • Figure 2 is a differential scanning thermal analysis (DSC) / thermogravimetric analysis (TG) diagram of crystalline methionine of the present invention
  • Figure 3 is a scanning electron micrograph of the crystalline methionine of the present invention at 100 times.
  • the preparation method of methionine crystal form II is carried out as follows:
  • the above methionine neutralization solution is added to the isopropanol solvent, the methionine neutralization solution is at a concentration of 0.5-0.6 mg/mL of isopropanol, and the mixture is continuously stirred and stirred at 60 ° C for 1 hour; Pre-cooling in the environment of 0 ° C -1 ° C for 1.5 hours; vacuum crystallization, the cooling medium for crystallization is ethylene glycol, cooling medium temperature -10 ° C, crystallization temperature -2 ° C, stirring rate 40-45 r / min, vacuum Degree 22-25 kPa, crystallization time 4.5 hours.
  • Example 1 The methionine crystals prepared in Example 1 were subjected to XRD test:
  • the radiation source is a Cu target with a wavelength of 1.54060 nm, a scanning angle of 10 to 70 degrees, a voltage of 30 kV, a current of 20 mA, and a scanning speed of 2.4°/min. Its X-ray powder diffraction pattern is shown in Figure 1.
  • the crystalline methionine has a diffraction angle 2 ⁇ of 11.145 ⁇ 0.2°, 16.716 ⁇ 0.2°, 18.615 ⁇ 0.2°, 22.304 ⁇ 0.2°, 25.203 ⁇ 0.2°, 28.104 ⁇ 0.2°, 33.757 ⁇ 0.2°, 42.739 ⁇ 0.2°, There are diffraction peaks at 45.674 ⁇ 0.2° and 51.812 ⁇ 0.2°.
  • the crystalline methionine of the present invention has a powder X-ray pattern expressed by a crystal plane spacing D, a Bragg angle (2 ⁇ ), a percentage of relative intensity I (%), and an intensity (I value) crystal form, as follows:
  • DSC differential scanning thermal analysis
  • TG thermogravimetric analysis chart
  • the scanning electron micrograph of the methionine crystalline particles at 100 times is shown in Fig. 3.
  • the particles are large and uniform, and have a flat block shape with a length to width ratio of about 2:1.
  • the particle length is concentrated in the range of 450-550 ⁇ m.
  • the individual particles appear as intact and dense crystals.
  • the methionine crystal form II bulk density was determined to be 2 g/cm 3 , and the methionine crystal obtained above was measured for the angle of repose:
  • the angle of repose of the methionine crystal prepared above was measured by an injection method (fixed funnel method). Pour the sample to be tested into the funnel, and gently and evenly fall into the center of the disc to form a cone. When the material falls freely from the oblique edge of the powder along the edge of the disc, the feeding is stopped, and the angle of repose is determined by a protractor. The three angles of repose were measured repeatedly: 36.4, 34.7, and 33.5 degrees, and the crystal particles were excellent in fluidity.
  • the preparation method of methionine crystal form II adopts the following steps:
  • the above methionine neutralization solution is added to the isopropanol solvent, the methionine neutralization solution is at a concentration of 0.9-1.0 mg/mL of isopropanol, and the mixture is continuously stirred and stirred at 65 ° C for 0.5 hour; Pre-cooling for 1 hour in an environment of -1 ° C; vacuum crystallization, crystal cooling medium is ethylene glycol, cooling medium temperature -10 ° C, crystallization temperature -5 ° C, stirring rate 30-35 r / min, vacuum degree 19 - 21 kPa, crystallization time 6 hours.
  • Example 2 It was identified by the method of Example 2 that it was the methionine crystal form II of the present invention, the bulk density was 1.5 g/cm 3 , and the angle of repose ⁇ was 37.1 degrees.
  • the preparation method of methionine crystal form II adopts the following steps:
  • the above methionine neutralization solution is added to the isopropanol solvent, the methionine neutralization solution is at a concentration of 0.3-0.4 mg/mL of isopropanol, and the mixture is continuously stirred and stirred at 55 ° C for 1.5 hours; Pre-cooling for 2 hours in an environment of 4 ° C - 5 ° C; vacuum crystallization, the cooling medium for crystallization is ethylene glycol, cooling medium temperature -10 ° C, crystallization temperature 0 ° C, stirring rate 55-60 r / min, vacuum 28-30 kPa, crystallization time 3 hours.
  • Example 2 It was identified by the method of Example 2 that it was the methionine crystal form II of the present invention, the bulk density was 1.0 g/cm 3 , and the angle of repose ⁇ was 35.9 degrees.
  • the preparation method of methionine crystal form II adopts the following steps:
  • the above methionine neutralization solution is added to the isopropanol solvent, the methionine neutralization solution is at a concentration of 0.7-0.8 mg/mL of isopropanol, and the mixture is continuously stirred and stirred for 0.8 hours at 62 ° C; Pre-cooling in the environment of 2 ° C -3 ° C for 1-2 hours; then vacuum crystallization, the cooling medium for crystallization is ethylene glycol, cooling medium temperature -10 ° C, crystallization temperature -1 ° C, stirring rate 50 r / min, vacuum Degree 20-22 kPa, crystallization time 5 hours.
  • Example 2 It was identified by the method of Example 2 that it was the methionine crystal form II of the present invention, the bulk density was 1.3 g/cm 3 , and the angle of repose ⁇ was 34.3 degrees.

Abstract

A methionine new crystal form II, the crystal form II having diffraction peaks at 22.304±0.2°, 33.757±0.2°, 45.674±0.2°, 28.104±0.2°, 18.615±0.2°, and 42.739±0.2° at the diffraction angle 2θ. The methionine crystal form II of the present invention is white crystalline particles having good light reflectivity, the particles being large, relatively uniform, and long, and having a flat block shape with a width ratio of about 2:1, the length of the particles being concentrated within the range of 450-550 microns, the appearance of a single particle being a complete compact crystal, and the quality being excellent. The inventor also finds that the fluidity and the bulk density are related to the key peak position and relative peak intensity of the X-ray powder diffraction spectrum, the methionine crystal form II of the present invention having a large bulk density, reaching 1-2 g/cm3, the processing fluidity thereof being good, the repose angle of the crystalline particles being determined using an injection method (a fixed funnel method), θ≤40 degrees, and being conducive to application in subsequent large-scale industrial production.

Description

一种蛋氨酸新晶型Ⅱ及其制备方法Methionine new crystal form II and preparation method thereof 技术领域Technical field
本发明涉及一种蛋氨酸新晶型及其制备方法。The invention relates to a new crystalline form of methionine and a preparation method thereof.
背景技术Background technique
蛋氨酸(DL-Methionine)化学式为C5H11O2NS，白色薄片状结晶或结晶性粉末，有特殊气味，味微甜。用于营养增补剂，添于燕麦、黑麦、米、玉米、小麦、花生粉、大豆、土豆、菠菜等食品中以改善氨基酸平衡，需要量随胱氨酸摄入量而异，成人男子需要量为1.1g/d。也用于氨基酸输液，综合氨基酸制剂，按我国GB2760-86规定可用作香料，它还是一种必不可少的动物饲料添加剂，加有蛋氨酸的动物饲料可以在短时间内帮助动物快速成长，使其节省大约40％的饲料。畜禽缺乏蛋氨酸,会引起发育不良,体重减轻,肝肾机能减弱,肌肉萎缩，皮毛变质等。The chemical formula of DL-Methionine is C 5 H 11 O 2 NS, white flake crystal or crystalline powder with special odor and slightly sweet taste. Used in nutritional supplements, added to foods such as oatmeal, rye, rice, corn, wheat, peanut meal, soybeans, potatoes, spinach, etc. to improve amino acid balance, the amount varies with cystine intake, adult men need The amount is 1.1 g/d. Also used for amino acid infusion, comprehensive amino acid preparations, can be used as spices according to China's GB2760-86 regulations, it is also an essential animal feed additive, animal feed with methionine can help animals grow quickly in a short time, so that It saves about 40% of the feed. Lack of methionine in livestock and poultry can cause stunting, weight loss, liver and kidney function weakening, muscle atrophy, and skin deterioration.
中国专利CN104926701 A公开了一种蛋氨酸的纯化工艺，采用大孔吸附树脂分离蛋氨酸和副产盐类物质，蛋氨酸被吸附在大孔吸附树脂上然后用解吸剂解吸树脂回收蛋氨酸，副产盐类物质在吸附过程中不被大孔吸附树脂吸附进入吸附流出液中，主要包括以下步骤：1)树脂吸附：蛋氨酸溶液自上而下通过大孔吸附树脂层，当树脂柱流出液中含蛋氨酸含量大于等于进口含量的10％(w/w)时，停止树脂吸附；树脂吸附流出液作为副产盐类物质；2)树脂解吸：步骤1)中完成了吸附的树脂，用解吸剂自上而下通过，解吸树脂，并收集解吸液；3)后续工艺过程：解吸液按照现有工艺流程后续处理。经 过吸附、解吸工艺，可得到纯度≥99％的蛋氨酸产品，副产盐类物质中蛋氨酸含量≤0.03％，树脂提取蛋氨酸收率≥98％。Chinese patent CN104926701 A discloses a purification process of methionine, which uses a macroporous adsorption resin to separate methionine and by-product salts, methionine is adsorbed on a macroporous adsorption resin and then desorbed by a desorbent to recover methionine, a by-product salt substance. During the adsorption process, it is not adsorbed into the adsorption effluent by the macroporous adsorption resin, and mainly includes the following steps: 1) Resin adsorption: the methionine solution passes through the macroporous adsorption resin layer from top to bottom, and the methionine content in the resin column effluent is greater than When it is equal to 10% (w/w) of the inlet content, the resin adsorption is stopped; the resin adsorbs the effluent as a by-product salt; 2) the resin is desorbed: the adsorbed resin is completed in step 1), and the desorbent is used from top to bottom. Passing, desorbing the resin, and collecting the desorbed solution; 3) Subsequent process: the desorbed liquid is subsequently processed according to the existing process flow. By Through the adsorption and desorption process, the methionine product with purity ≥99% can be obtained, the content of methionine in the by-product salt substance is ≤0.03%, and the yield of resin extraction methionine is ≥98%.
中国专利CN104177280 A公开了一种蛋氨酸生产工艺，步骤1：将蛋氨酸结晶母液通过填充有钠型或者钾型色谱树脂的连续色谱分离系统分离，得蛋氨酸溶液和无机盐溶液；步骤2：将蛋氨酸溶液采用反渗透系统浓缩得蛋氨酸反渗透浓缩液，将得到的蛋氨酸反渗透浓缩液返回结晶工序；该工艺简单、分离效果好，蛋氨酸纯度高、浓缩成本低等优点。Chinese patent CN104177280 A discloses a methionine production process, step 1: separating the methionine crystallization mother liquor through a continuous chromatographic separation system filled with sodium or potassium type chromatography resin to obtain a methionine solution and an inorganic salt solution; Step 2: methionine solution The reverse osmosis system is used to concentrate the methionine reverse osmosis concentrate, and the obtained methionine reverse osmosis concentrate is returned to the crystallization process; the process is simple, the separation effect is good, the purity of methionine is high, and the concentration cost is low.
中国授权专利CN101480385 B公开了一种蛋氨酸的用途，蛋氨酸在制备治疗或预防内耳前庭毛细胞疾病的组合物中的用途，其药物组合物中含有：(a)50-200重量份蛋氨酸和/或其多肽；(b)400-2000重量份药学上可接受的载体；且(a)+(b)的重量是药物组合物总重量的50-99％，所述的药物组合物是固体制剂或液体制剂，所述的液体制剂包括乳浊剂、溶液剂、悬浮剂、糖浆剂、滴剂等。但目前生产的蛋氨酸颗粒产品，存在着加工流动性能差，堆积密度小、加大了包装运输成本。Chinese Patent No. CN101480385 B discloses the use of methionine for the preparation of a composition for treating or preventing vestibular hair cell disease of the inner ear, the pharmaceutical composition comprising: (a) 50-200 parts by weight of methionine and/or a polypeptide thereof; (b) 400-2000 parts by weight of a pharmaceutically acceptable carrier; and the weight of (a) + (b) is 50-99% by weight based on the total weight of the pharmaceutical composition, the pharmaceutical composition being a solid preparation or A liquid preparation comprising an opacifying agent, a solution, a suspending agent, a syrup, a drop, and the like. However, the currently produced methionine granule products have poor processing flowability, low bulk density, and increased packaging and transportation costs.
发明内容Summary of the invention
本发明的目的在于提供一种加工流动性好的蛋氨酸晶型Ⅱ。It is an object of the present invention to provide a crystalline form II of methionine which is excellent in fluidity.
本发明另一目的在于提供上述蛋氨酸晶型Ⅱ的制备方法。Another object of the present invention is to provide a process for preparing the above methionine crystal form II.
本发明目的通过如下技术方案实现：The object of the present invention is achieved by the following technical solutions:
一种蛋氨酸晶型Ⅱ，其特征在于：所述晶型在衍射角度2θ在22.304±0.2°、33.757±0.2°、45.674±0.2°、28.104±0.2°、18.615±0.2°、 42.739±0.2°处有衍射峰。a methionine crystal form II, characterized in that the crystal form has a diffraction angle 2θ of 22.304±0.2°, 33.757±0.2°, 45.674±0.2°, 28.104±0.2°, 18.615±0.2°, There is a diffraction peak at 42.739±0.2°.
具体地说，本发明蛋氨酸晶型Ⅱ在衍射角度2θ在11.145±0.2°、16.716±0.2°、18.615±0.2°、22.304±0.2°、25.203±0.2°、28.104±0.2°、33.757±0.2°、42.739±0.2°、45.674±0.2°、51.812±0.2°处有衍射峰。Specifically, the methionine crystal form II of the present invention has a diffraction angle 2θ of 11.145±0.2°, 16.716±0.2°, 18.615±0.2°, 22.304±0.2°, 25.203±0.2°, 28.104±0.2°, 33.757±0.2°, There are diffraction peaks at 42.739±0.2°, 45.674±0.2°, and 51.812±0.2°.
进一步地说，上述蛋氨酸晶型Ⅱ，其特征在于：它具有下列
Figure PCTCN2017084385-appb-000001
值和相对强度百分比I(％)值表达的-X射线粉末衍射数据，Further, the above methionine crystal form II is characterized in that it has the following
Figure PCTCN2017084385-appb-000001
Value and relative intensity percentage I (%) value expressed by -X-ray powder diffraction data,
Figure PCTCN2017084385-appb-000002
Figure PCTCN2017084385-appb-000002
更进一步地说，上述蛋氨酸晶型Ⅱ，其特征在于：它具有下列
Figure PCTCN2017084385-appb-000003
Figure PCTCN2017084385-appb-000004
值和相对强度百分比I(％)值表达的-X射线粉末衍射数据，Further, the above methionine crystal form II is characterized in that it has the following
Figure PCTCN2017084385-appb-000003
Figure PCTCN2017084385-appb-000004
Value and relative intensity percentage I (%) value expressed by -X-ray powder diffraction data,
Figure PCTCN2017084385-appb-000005
Figure PCTCN2017084385-appb-000005
更具体地说，上述蛋氨酸晶型Ⅱ，其特征在于：它具有如图1 所示的X-射线粉末衍射图。More specifically, the above methionine crystal form II is characterized in that it has the structure shown in FIG. The X-ray powder diffraction pattern shown.
上述蛋氨酸晶型Ⅱ的熔点峰值温度为287℃，该晶型具有如图2所示的DSC/TG图谱。The above-mentioned methionine crystal form II has a melting point peak temperature of 287 ° C, and the crystal form has a DSC/TG pattern as shown in FIG. 2 .
本发明所述的蛋氨酸晶型Ⅱ与蛋氨酸化学结构相同，品质好、加工流动性能优异。The methionine crystal form II of the present invention has the same chemical structure as methionine, and has good quality and excellent processing flowability.
本发明蛋氨酸晶型Ⅱ的制备方法，采用如下步骤：The preparation method of the methionine crystal form II of the invention adopts the following steps:
1、在5-(β-甲巯基乙基)乙内酰脲与氢氧化钠溶液反应得到的含甲硫氨酸钠水解液中加入体积百分浓度为15％-37％的盐酸，得到pH值为5.0-6.0的蛋氨酸中和液；1. Adding 15% to 37% by volume of hydrochloric acid to the sodium methionine-containing hydrolyzate obtained by reacting 5-(β-methylmercaptoethyl)hydantoin with sodium hydroxide solution to obtain a pH. a methionine neutralizing solution having a value of 5.0 to 6.0;
2、将上述蛋氨酸中和液加入异丙醇溶剂中、蛋氨酸中和液在异丙醇的浓度0.3-1.0mg/mL，在55℃～65℃下不断搅拌、搅拌时间0.5-1.5小时；将此溶液放入-1℃-5℃环境中进行预冷1-2小时；再进行真空结晶，结晶的冷却介质为乙二醇、冷却介质温度-10℃，结晶温度0℃至-5℃，搅拌速率30-60r/min，真空度19-30kPa，结晶时间3-6小时。2, the above methionine neutralization solution is added to the isopropanol solvent, the methionine neutralization solution in the concentration of isopropanol 0.3-1.0 mg / mL, continuously stirring at 55 ° C ~ 65 ° C, stirring time 0.5-1.5 hours; The solution is pre-cooled in an environment of -1 ° C - 5 ° C for 1-2 hours; then vacuum crystallization, the cooling medium for crystallization is ethylene glycol, the temperature of the cooling medium is -10 ° C, and the crystallization temperature is 0 ° C to -5 ° C. The stirring rate is 30-60 r/min, the degree of vacuum is 19-30 kPa, and the crystallization time is 3-6 hours.
本发明具有如下的有益效果：The invention has the following beneficial effects:
本发明蛋氨酸晶型Ⅱ为白色结晶颗粒、反光性好，其颗粒大、较均匀，呈长、宽比约为2:1的扁平块状，颗粒长度集中在450-550微米范围内，单个颗粒外观为完整致密的晶体、品质优异。同时发明人发现，其流动性、堆积密度与其X-射线粉末衍射图谱的关键峰位、相对峰强很相关，本发明蛋氨酸晶型Ⅱ堆积密度大、达1-2g/cm3，加工流动性好，采用注入法(固定漏斗法)测定结晶颗粒的休止角、θ ≤40度，利于后续规模化工业生产应用。The methionine crystal form II of the invention is white crystal particles, has good light reflectivity, and has large and relatively uniform particles, and has a flat block shape with a length to width ratio of about 2:1, and the particle length is concentrated in the range of 450-550 micrometers, and the single particles. The appearance is a complete and dense crystal with excellent quality. At the same time, the inventors found that the fluidity and bulk density are closely related to the key peak position and relative peak intensity of the X-ray powder diffraction pattern. The methionine crystal form II of the present invention has a high bulk density of 1-2 g/cm 3 and processing fluidity. Well, the injection angle method (fixed funnel method) is used to determine the angle of repose of the crystal particles, θ ≤ 40 degrees, which is advantageous for subsequent large-scale industrial production applications.
附图说明DRAWINGS
图1为本发明结晶型蛋氨酸X射线粉末衍射图；Figure 1 is a crystalline methionine X-ray powder diffraction pattern of the present invention;
图2为本发明结晶型蛋氨酸的差示扫描热分析(DSC)/热重分析(TG)图；Figure 2 is a differential scanning thermal analysis (DSC) / thermogravimetric analysis (TG) diagram of crystalline methionine of the present invention;
图3为本发明结晶型蛋氨酸在100倍下的扫描电镜图。Figure 3 is a scanning electron micrograph of the crystalline methionine of the present invention at 100 times.
具体实施方式detailed description
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。The present invention is specifically described by the following examples, and the following examples are intended to be illustrative of the present invention, and are not to be construed as limiting the scope of the present invention. The content makes some non-essential improvements and adjustments to the invention.
实施例1Example 1
蛋氨酸晶型Ⅱ的制备方法，按如下步骤进行：The preparation method of methionine crystal form II is carried out as follows:
(1)、在5-(β-甲巯基乙基)乙内酰脲与氢氧化钠溶液反应得到的含甲硫氨酸钠水解液中加入体积百分浓度为20％-25％的盐酸，得到pH值为5.5的蛋氨酸中和液；(1) adding hydrochloric acid having a volume concentration of 20% to 25% by adding a sodium methionine-containing hydrolyzate obtained by reacting 5-(β-methylmercaptoethyl)hydantoin with a sodium hydroxide solution, Obtaining a methionine neutralization solution having a pH of 5.5;
(2)、将上述蛋氨酸中和液加入异丙醇溶剂中、蛋氨酸中和液在异丙醇的浓度0.5-0.6mg/mL，在60℃下不断搅拌、搅拌时间1小时；将此溶液放入0℃-1℃环境中进行预冷1.5小时；再进行真空结晶，结晶的冷却介质为乙二醇、冷却介质温度-10℃，结晶温度-2℃，搅拌速率40-45r/min，真空度22-25kPa，结晶时间4.5小时。 (2), the above methionine neutralization solution is added to the isopropanol solvent, the methionine neutralization solution is at a concentration of 0.5-0.6 mg/mL of isopropanol, and the mixture is continuously stirred and stirred at 60 ° C for 1 hour; Pre-cooling in the environment of 0 ° C -1 ° C for 1.5 hours; vacuum crystallization, the cooling medium for crystallization is ethylene glycol, cooling medium temperature -10 ° C, crystallization temperature -2 ° C, stirring rate 40-45 r / min, vacuum Degree 22-25 kPa, crystallization time 4.5 hours.
实施例2Example 2
将实施例1所制得的蛋氨酸晶体，做XRD测试：The methionine crystals prepared in Example 1 were subjected to XRD test:
辐射源为Cu靶，波长为1.54060nm，扫描角度为10°～70°，电压为30kV，电流为20mA，扫描速度为2.4°/min。其X射线粉末衍射图如图1所示。The radiation source is a Cu target with a wavelength of 1.54060 nm, a scanning angle of 10 to 70 degrees, a voltage of 30 kV, a current of 20 mA, and a scanning speed of 2.4°/min. Its X-ray powder diffraction pattern is shown in Figure 1.
所述结晶型蛋氨酸在衍射角度2θ在11.145±0.2°、16.716±0.2°、18.615±0.2°、22.304±0.2°、25.203±0.2°、28.104±0.2°、33.757±0.2°、42.739±0.2°、45.674±0.2°、51.812±0.2°处有衍射峰。The crystalline methionine has a diffraction angle 2θ of 11.145±0.2°, 16.716±0.2°, 18.615±0.2°, 22.304±0.2°, 25.203±0.2°, 28.104±0.2°, 33.757±0.2°, 42.739±0.2°, There are diffraction peaks at 45.674±0.2° and 51.812±0.2°.
本发明的结晶型蛋氨酸，其粉末X射线图以晶面间距D、Bragg角(2θ)、相对强度的百分比I(％)以及强度(I值)晶型表达，如下所示：The crystalline methionine of the present invention has a powder X-ray pattern expressed by a crystal plane spacing D, a Bragg angle (2θ), a percentage of relative intensity I (%), and an intensity (I value) crystal form, as follows:
Figure PCTCN2017084385-appb-000006
Figure PCTCN2017084385-appb-000006
本发明结晶型蛋氨酸的差示扫描热分析(DSC)如图2所示，其吸热转变温度在287℃；其热重分析图(TG)如图2所示，于246℃左 右开始进行第一个反应，287℃进行第二个反应，到381℃时反应结束。The differential scanning thermal analysis (DSC) of the crystalline methionine of the present invention is shown in Figure 2, and its endothermic transition temperature is 287 ° C; its thermogravimetric analysis chart (TG) is shown in Figure 2, at 246 ° C left The first reaction was started from the right, the second reaction was carried out at 287 ° C, and the reaction was completed at 381 ° C.
蛋氨酸结晶型颗粒在100倍下的扫描电镜图如图3所示，其颗粒大、较均匀，呈长、宽比约为2:1的扁平块状，颗粒长度集中在450-550微米范围内，单个颗粒外观为完整致密的晶体。The scanning electron micrograph of the methionine crystalline particles at 100 times is shown in Fig. 3. The particles are large and uniform, and have a flat block shape with a length to width ratio of about 2:1. The particle length is concentrated in the range of 450-550 μm. The individual particles appear as intact and dense crystals.
经测定，上述蛋氨酸晶型Ⅱ堆积密度为2g/cm3；将上述得到的蛋氨酸晶体进行休止角测定：本试验采用注入法(固定漏斗法)测定上述制备的蛋氨酸晶体的休止角。将待测样品倒入漏斗，使其轻轻地、均匀地落入圆盘中心，形成一个圆锥体，当物料从粉体斜边沿圆盘边缘中自由落下时停止加料，用量角器测定休止角，重复测定三次休止角分别为：36.4、34.7、33.5度，该晶体颗粒流动性优异。The methionine crystal form II bulk density was determined to be 2 g/cm 3 , and the methionine crystal obtained above was measured for the angle of repose: In this test, the angle of repose of the methionine crystal prepared above was measured by an injection method (fixed funnel method). Pour the sample to be tested into the funnel, and gently and evenly fall into the center of the disc to form a cone. When the material falls freely from the oblique edge of the powder along the edge of the disc, the feeding is stopped, and the angle of repose is determined by a protractor. The three angles of repose were measured repeatedly: 36.4, 34.7, and 33.5 degrees, and the crystal particles were excellent in fluidity.
实施例3Example 3
蛋氨酸晶型Ⅱ的制备方法，采用如下步骤：The preparation method of methionine crystal form II adopts the following steps:
(1)、在5-(β-甲巯基乙基)乙内酰脲与氢氧化钠溶液反应得到的含甲硫氨酸钠水解液中加入体积百分浓度为15％-18％的盐酸，得到pH值为6.0的蛋氨酸中和液；(1) adding hydrochloric acid having a volume percentage of 15% to 18% by adding a sodium methionine hydrolyzate obtained by reacting 5-(β-methylmercaptoethyl) hydantoin with a sodium hydroxide solution, Obtaining a methionine neutralization solution having a pH of 6.0;
(2)、将上述蛋氨酸中和液加入异丙醇溶剂中、蛋氨酸中和液在异丙醇的浓度0.9-1.0mg/mL，在65℃下不断搅拌、搅拌时间0.5小时；将此溶液放入-1℃环境中进行预冷1小时；再进行真空结晶，结晶的冷却介质为乙二醇、冷却介质温度-10℃，结晶温度-5℃，搅拌速率30-35r/min，真空度19-21kPa，结晶时间6小时。 (2), the above methionine neutralization solution is added to the isopropanol solvent, the methionine neutralization solution is at a concentration of 0.9-1.0 mg/mL of isopropanol, and the mixture is continuously stirred and stirred at 65 ° C for 0.5 hour; Pre-cooling for 1 hour in an environment of -1 ° C; vacuum crystallization, crystal cooling medium is ethylene glycol, cooling medium temperature -10 ° C, crystallization temperature -5 ° C, stirring rate 30-35 r / min, vacuum degree 19 - 21 kPa, crystallization time 6 hours.
用实施例2的方法鉴定，为本发明蛋氨酸晶型Ⅱ，堆积密度为1.5g/cm3，休止角θ为37.1度。It was identified by the method of Example 2 that it was the methionine crystal form II of the present invention, the bulk density was 1.5 g/cm 3 , and the angle of repose θ was 37.1 degrees.
实施例4Example 4
蛋氨酸晶型Ⅱ的制备方法，采用如下步骤：The preparation method of methionine crystal form II adopts the following steps:
(1)、在5-(β-甲巯基乙基)乙内酰脲与氢氧化钠溶液反应得到的含甲硫氨酸钠水解液中加入体积百分浓度为35％-37％的盐酸，得到pH值为5.0的蛋氨酸中和液；(1) adding hydrochloric acid having a volume concentration of 35% to 37% in a hydrolyzate containing sodium methionine obtained by reacting 5-(β-methylmercaptoethyl) hydantoin with a sodium hydroxide solution, Obtaining a methionine neutralization solution having a pH of 5.0;
(2)、将上述蛋氨酸中和液加入异丙醇溶剂中、蛋氨酸中和液在异丙醇的浓度0.3-0.4mg/mL，在55℃下不断搅拌、搅拌时间1.5小时；将此溶液放入4℃-5℃环境中进行预冷2小时；再进行真空结晶，结晶的冷却介质为乙二醇、冷却介质温度-10℃，结晶温度0℃，搅拌速率55-60r/min，真空度28-30kPa，结晶时间3小时。(2), the above methionine neutralization solution is added to the isopropanol solvent, the methionine neutralization solution is at a concentration of 0.3-0.4 mg/mL of isopropanol, and the mixture is continuously stirred and stirred at 55 ° C for 1.5 hours; Pre-cooling for 2 hours in an environment of 4 ° C - 5 ° C; vacuum crystallization, the cooling medium for crystallization is ethylene glycol, cooling medium temperature -10 ° C, crystallization temperature 0 ° C, stirring rate 55-60 r / min, vacuum 28-30 kPa, crystallization time 3 hours.
用实施例2的方法鉴定，为本发明蛋氨酸晶型Ⅱ，堆积密度为1.0g/cm3，休止角θ为35.9度。It was identified by the method of Example 2 that it was the methionine crystal form II of the present invention, the bulk density was 1.0 g/cm 3 , and the angle of repose θ was 35.9 degrees.
实施例5Example 5
蛋氨酸晶型Ⅱ的制备方法，采用如下步骤：The preparation method of methionine crystal form II adopts the following steps:
(1)、在5-(β-甲巯基乙基)乙内酰脲与氢氧化钠溶液反应得到的含甲硫氨酸钠水解液中加入体积百分浓度为28％-32％的盐酸，得到pH值为5..5的蛋氨酸中和液； (1) adding hydrochloric acid having a volume percentage of 28% to 32% by adding a sodium methionine-containing hydrolyzate obtained by reacting 5-(β-methylmercaptoethyl)hydantoin with a sodium hydroxide solution, Obtaining a methionine neutralization solution having a pH of 5..5;
(2)、将上述蛋氨酸中和液加入异丙醇溶剂中、蛋氨酸中和液在异丙醇的浓度0.7-0.8mg/mL，在62℃下不断搅拌、搅拌时间0.8小时；将此溶液放入2℃-3℃环境中进行预冷1-2小时；再进行真空结晶，结晶的冷却介质为乙二醇、冷却介质温度-10℃，结晶温度-1℃，搅拌速率50r/min，真空度20-22kPa，结晶时间5小时。(2), the above methionine neutralization solution is added to the isopropanol solvent, the methionine neutralization solution is at a concentration of 0.7-0.8 mg/mL of isopropanol, and the mixture is continuously stirred and stirred for 0.8 hours at 62 ° C; Pre-cooling in the environment of 2 ° C -3 ° C for 1-2 hours; then vacuum crystallization, the cooling medium for crystallization is ethylene glycol, cooling medium temperature -10 ° C, crystallization temperature -1 ° C, stirring rate 50 r / min, vacuum Degree 20-22 kPa, crystallization time 5 hours.
用实施例2的方法鉴定，为本发明蛋氨酸晶型Ⅱ，堆积密度为1.3g/cm3，休止角θ为34.3度。 It was identified by the method of Example 2 that it was the methionine crystal form II of the present invention, the bulk density was 1.3 g/cm 3 , and the angle of repose θ was 34.3 degrees.

Claims (7)

  1. 一种蛋氨酸晶型Ⅱ，其特征在于：所述晶型Ⅱ在衍射角度2θ在22.304±0.2°、33.757±0.2°、45.674±0.2°、28.104±0.2°、18.615±0.2°、42.739±0.2°处有衍射峰。A methionine crystal form II, characterized in that the crystal form II has a diffraction angle 2θ of 22.304±0.2°, 33.757±0.2°, 45.674±0.2°, 28.104±0.2°, 18.615±0.2°, 42.739±0.2°. There are diffraction peaks.
  2. 如权利要求1所述蛋氨酸晶型Ⅱ，其特征在于：所述晶型在衍射角度2θ在11.145±0.2°、16.716±0.2°、18.615±0.2°、22.304±0.2°、25.203±0.2°、28.104±0.2°、33.757±0.2°、42.739±0.2°、45.674±0.2°、51.812±0.2°处有衍射峰。The methionine crystal form II according to claim 1, wherein the crystal form is at a diffraction angle of 2θ of 11.145±0.2°, 16.716±0.2°, 18.615±0.2°, 22.304±0.2°, 25.203±0.2°, 28.104. There are diffraction peaks at ±0.2°, 33.757±0.2°, 42.739±0.2°, 45.674±0.2°, and 51.812±0.2°.
  3. 如权利要求1或2所述蛋氨酸晶型Ⅱ，其特征在于：它具有如图1所示的X-射线粉末衍射图。The methionine crystal form II according to claim 1 or 2, which has an X-ray powder diffraction pattern as shown in Fig. 1.
  4. 如权利要求1所述的蛋氨酸晶型Ⅱ，其特征在于：它具有下列
    Figure PCTCN2017084385-appb-100001
    值和相对强度百分比I(％)值表达的-X射线粉末衍射数据，    The methionine crystal form II according to claim 1, which has the following
    Figure PCTCN2017084385-appb-100001
    Value and relative intensity percentage I (%) value expressed by -X-ray powder diffraction data,
    Figure PCTCN2017084385-appb-100002
    Figure PCTCN2017084385-appb-100002
  5. 如权利要求1、2、3或4所述的蛋氨酸晶型Ⅱ，其特征在于：它具有下列
    Figure PCTCN2017084385-appb-100003
    值和相对强度百分比I(％)值表达的-X射线粉末衍射数据：    The methionine crystal form II according to claim 1, 2, 3 or 4, characterized in that it has the following
    Figure PCTCN2017084385-appb-100003
    Value and relative intensity percentage I (%) value expressed by -X-ray powder diffraction data:
    Figure PCTCN2017084385-appb-100004
    Figure PCTCN2017084385-appb-100004
    Figure PCTCN2017084385-appb-100005
    Figure PCTCN2017084385-appb-100005
  6. 如权利要求1或2所述蛋氨酸晶型Ⅱ，其特征在于：它具有如图2所示的DSC/TG图谱，其熔点峰值温度为287℃。The methionine crystal form II according to claim 1 or 2, which has a DSC/TG pattern as shown in Fig. 2, and has a melting point peak temperature of 287 °C.
  7. 如权利要求1-6任一项所述蛋氨酸晶型Ⅱ的制备方法，其特征在于，采用如下步骤：The method for preparing methionine crystal form II according to any one of claims 1 to 6, wherein the following steps are employed:
    (1)、在5-(β-甲巯基乙基)乙内酰脲与氢氧化钠溶液反应得到的含甲硫氨酸钠水解液中加入体积百分浓度约为15％-37％的盐酸，得到pH值为5.0-6.0的蛋氨酸中和液；(1) adding a concentration of about 15% to 37% hydrochloric acid to the sodium methionine-containing hydrolyzate obtained by reacting 5-(β-methylmercaptoethyl)hydantoin with sodium hydroxide solution. , obtaining a methionine neutralization solution having a pH of 5.0-6.0;
    (2)、将上述蛋氨酸中和液加入异丙醇溶剂中、蛋氨酸中和液在异丙醇的浓度0.3-1.0mg/mL，在55℃～65℃下不断搅拌、搅拌时间0.5-1.5小时左右；将此溶液放入-1℃-5℃环境中进行预冷1-2小时；再进行真空结晶，结晶的冷却介质为乙二醇、冷却介质温度-10℃，结晶温度0℃至-5℃，搅拌速率30-60r/min，真空度19-30kPa，结晶时间3-6小时。 (2), the above methionine neutralization solution is added to the isopropanol solvent, the concentration of the methionine neutralization solution in the isopropanol is 0.3-1.0 mg/mL, and the stirring is continued at 55 ° C to 65 ° C for 0.5-1.5 hours. Left and right; this solution is placed in an environment of -1 ° C - 5 ° C for pre-cooling for 1-2 hours; then vacuum crystallization, the cooling medium for the crystal is ethylene glycol, the temperature of the cooling medium is -10 ° C, and the crystallization temperature is 0 ° C to - 5 ° C, stirring rate 30-60r / min, vacuum 19-30kPa, crystallization time 3-6 hours.
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CN101602700A (en) * 2008-06-09 2009-12-16 住友化学株式会社 Produce the method for methionine(Met)
CN106008297A (en) * 2016-06-03 2016-10-12 宁夏紫光天化蛋氨酸有限责任公司 Novel methionine crystal form II and preparation method thereof

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