WO2022082859A1 - 氨基酸或其衍生物的精制方法及该氨基酸或其衍生物 - Google Patents

氨基酸或其衍生物的精制方法及该氨基酸或其衍生物 Download PDF

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WO2022082859A1
WO2022082859A1 PCT/CN2020/125919 CN2020125919W WO2022082859A1 WO 2022082859 A1 WO2022082859 A1 WO 2022082859A1 CN 2020125919 W CN2020125919 W CN 2020125919W WO 2022082859 A1 WO2022082859 A1 WO 2022082859A1
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crystal
amino acid
acetylcysteine
particle size
derivative
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PCT/CN2020/125919
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English (en)
French (fr)
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朱程军
舒敏
李云
黄蕾
唐鹏
李建华
苏海霞
查丽燕
郭丽萍
刘梦洁
何嘉俊
杨磊
刘莎
吕凡林
梅雪臣
刘珍
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武汉远大弘元股份有限公司
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Priority to EP20958439.0A priority Critical patent/EP4234538A4/en
Publication of WO2022082859A1 publication Critical patent/WO2022082859A1/zh

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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
    • 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

Definitions

  • the present invention relates to the field of medical technology, in particular, to a purification method of an amino acid or a derivative thereof and the amino acid or a derivative thereof.
  • Drug polymorphism is one of the important factors affecting drug quality and clinical efficacy.
  • crystal form is one of the important quality control indicators. Drugs with different crystal forms have different properties. These properties will not only affect the fluidity, compressibility, cohesion and other processing properties of pharmaceutical products, but more importantly, may also cause quality differences in drug dissolution rate, dissolution rate, stability, etc., thereby affecting the biological activity and biological activity of the drug. availability, leading to differences in clinical efficacy.
  • the fluidity of crystals is of great significance to the production of products, the mixing, transport, and storage of different components. If the crystal fluidity is poor, it is difficult to mix the various components in the medicine uniformly, resulting in large differences in the medicine. During the transportation and storage of preparations, crystals with poor fluidity are more likely to reduce the stability and effectiveness of the drug due to the influence of external environmental temperature, humidity, pressure and other factors.
  • the number of repose angles is usually used to characterize the fluidity of powders: when the angle of repose is less than or equal to 30°, the fluidity is excellent; when the angle of repose is 30° to 45°, the fluidity is good; when the angle of repose is greater than 45°, the fluidity is poor .
  • Acetylcysteine (Acetylcysteine), chemical name N-acetyl-L-cysteine, alias Xiaotan Li, Fulu Shi, Tan Yijing, Yikejing, etc., is reduced glutathione ( The precursor of GSH) is a typical amino acid. Its molecular formula: C 5 H 9 NO 3 S, molecular weight: 162.19. The appearance of this product is white crystalline powder, the melting point is 101°C-107°C, it has an odor similar to garlic, sour taste and hygroscopicity. Easily soluble in water and ethanol, insoluble in dichloromethane and ether, the structure is as follows:
  • the disclosed acetylcysteine refining process in patent CN 104844488 B is to dissolve the crude product in water, directly cool for crystallization, collect the crystals by centrifugation, and dry to obtain pure acetylcysteine.
  • the product obtained by this process is slender and pointed, has poor fluidity, is easily broken, and has uneven particle size distribution, many fine crystals, and coalescence during the drying process.
  • the product quality is average and does not meet the requirements of high-end medicinal drugs.
  • the purpose of the present invention is to provide a purification method that can effectively improve the quality of amino acid or its derivative products.
  • Another object of the present invention is to provide an amino acid or a derivative thereof with high sphericity and good fluidity.
  • the present invention provides a method for purifying an amino acid or a derivative thereof, comprising: (1) using the crude product of the amino acid or its derivative to prepare a saturated aqueous solution of the amino acid or its derivative at a preset temperature (2) carrying out the first procedure to cool the saturated aqueous solution to the metastable zone, adding a crystal seed, the sphericity of the crystal seed is not less than 0.6, and maintaining the crystal at a constant temperature to obtain a crystal slurry; (3) carrying out the crystal slurry for The second program is cooled to a second temperature, and the rate of the second program cooling is not higher than 1.0°C/min, and the crystal is incubated at a constant temperature to obtain amino acids or derivatives thereof.
  • the crystal habit and particle size of the drug also have a direct impact on the quality control of the drug.
  • APIs there are a large number of plane contact points on the surface of the long rod-shaped and needle-shaped crystal raw materials, as well as shear force between irregular particles, and their fluidity is poor. It is not uniform, and it is easy to break and agglomerate, which affects the quality of the tableting products in the later stage.
  • the spherical particles have the smallest contact area with each other, and their fluidity is the best, which is suitable for direct compression, and the crystal stability is also high, which can effectively improve the quality of the product.
  • the particle size of the crystal is not uniform, the particle size is small, it is easy to agglomerate, and the fluidity is poor, which is not conducive to the tableting and preparation process, and it is easy to embed impurities, which has a significant impact on the product quality.
  • the particle size distribution of the particles is not uniform and the flow rate of the particles is different during tableting, the size of the particles filled into the die hole is not uniform, or the thickness difference is too large. A slice weight difference overrun will occur.
  • the method can improve the sphericity and particle size uniformity of the amino acid or its derivative product, has excellent flow properties, is suitable for direct compression, and has high crystal stability, which can effectively improve tableting performance. quality of the product.
  • the above method may further include at least one of the following additional technical features:
  • the method according to the embodiment of the present invention adopts a heating method to quickly dissolve the crude product in the solvent, and also facilitates the subsequent use of a two-step step-step procedure to lower the temperature to form spherical crystals.
  • the inventors found that the method of the present invention is suitable for the purification of various substances, especially for the purification of amino acids and related derivatives, and the obtained crystals have high sphericity, uniform particle size, and are not easy to agglomerate.
  • the solvent is water.
  • the solvent raw material is easy to obtain, which is convenient for industrial production, and water is used as the solvent, which effectively avoids the organic residue when using alcohols (such as ethanol) as the solvent.
  • alcohols such as ethanol
  • the higher sphericity avoids the sharp, elongated crystal habit when using alcohol-based solvents.
  • the preset temperature is 40-80°C, preferably, the preset temperature is 50-80°C.
  • the preset temperature is: 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, 51°C , 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, 60°C, 61°C, 62°C, 63°C, 64°C, 65°C, 66°C, 67°C, 68°C °C, 69°C, 70°C, 71°C, 72°C, 73°C, 74°C, 75°C, 76°C, 77°C, 78°C, 79°C, 80°C.
  • the dissolution of the crude product is carried out at the above temperature, and the so
  • the first procedure to cool the solution to be crystallized to the metastable zone is performed under stirring conditions, optionally, the stirring speed is 100-600 r/min, preferably, the The stirring speed is 300-500 r/min, specifically, the stirring speed is: 100 r/min, 200 r/min, 300 r/min, 400 r/min, 500 r/min, 600 r/min.
  • the inventors found that the above-mentioned stirring speed is suitable, which avoids the incomplete crystal habit, the appearance of fine crystals, the uneven particle size distribution, and the agglomeration of crystals when the stirring speed is too fast; The phenomenon of deposition agglomeration and uneven particle size distribution.
  • the metastable region is 25°C to 50°C, preferably, the metastable region is 27°C to 45°C.
  • the metastable zone is: 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C , 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C.
  • the saturated state that is, in the metastable zone, but the crystals have not yet precipitated.
  • the purpose of cooling the saturated solution of amino acid or its derivatives from a higher temperature to a metastable region is to make the solution in a supersaturated state to generate a driving force for the crystallization process without crystal precipitation, which is helpful for the subsequent addition of seed crystals.
  • the region between the solubility equilibrium curve and the super-solubility curve is the metastable region of crystallization, and the temperature range of the metastable region of solutions of different amino acids or their derivatives is a certain temperature range. The difference is related to its physical properties and solubility.
  • the metastable region has a certain dynamic change law, which is closely related to the stirring rate and the cooling rate.
  • the metastable region of the amino acid or its derivative solution is also determined, The purpose of cooling the saturated solution of amino acid or its derivatives from higher temperature to the metastable region is also determined and can be achieved.
  • the cooling rate of the first program is 1.0°C/min ⁇ 6.0°C/min, preferably, the cooling rate of the first program is 1.0°C/min ⁇ 3.0°C/min.
  • the cooling rate of the first program is: 1°C/min, 1.5°C/min, 2°C/min, 2.5°C/min, 3°C/min, 3.5°C/min, 4°C/min min, 4.5°C/min, 5°C/min, 5.5°C/min, 6°C/min.
  • the metastable region is wider, and the crystallization solution can quickly reach the metastable region, so that the operable region of the crystallization temperature is wider, which is conducive to the precipitation of subsequent spherical crystals, and saves the cooling time. Shorten the entire refining time and improve production efficiency.
  • the sphericity of the seed crystal is preferably 0.6 to 0.9, the amount of the seed crystal added is 1% to 15% in terms of the mass percentage of the saturated aqueous solution, and the main particle size of the seed crystal is 10 ⁇ m ⁇ 200 ⁇ m; preferably, the added amount of the seed crystal is 2% ⁇ 6%, and the main particle size of the seed crystal is 50 ⁇ m ⁇ 125 ⁇ m.
  • the crystal seed with the added amount, the main particle size of the crystal seed, and the crystal seed with higher sphericity is conducive to the uniform formation of crystals, and the prepared crystal has a uniform particle size, is not easy to agglomerate, and has high stability, which is conducive to the uniform formation of crystals. Generation of high sphericity crystals.
  • the crude crystal habit sphericity of the amino acid or its derivative is not higher than 0.5.
  • the time for the constant temperature crystal growing is 5-60 min, preferably, the constant temperature crystal growing time is 20-40 min.
  • the crystal growing time according to the embodiment of the present invention gives the crystal sufficient aging time, which is beneficial to crystal precipitation and crystal integrity.
  • the second temperature is 0-25°C, preferably, the second temperature is 5-15°C.
  • the second temperature is: 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C , 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C.
  • the second temperature is lower than the temperature of the metastable region, and the second temperature is low temperature, which is beneficial to the growth of crystals and the improvement of the yield.
  • the cooling rate of the second program is not higher than 1.0°C/min, preferably 0.2-1.0°C/min.
  • the cooling rate of the second program is: 0.1°C/min, 0.2°C/min, 0.3°C/min, 0.4°C/min, 0.5°C/min, 0.6°C/min, 0.7°C /min, 0.8°C/min, 0.9°C/min, 1.0°C/min.
  • the second cooling rate is suitable, so that the crystal slurry slowly reaches the second temperature, which is beneficial to crystal precipitation and crystal growth, and avoids problems such as uneven product particle size and impurity encapsulation due to excessive cooling.
  • the crystal slurry is cooled down to the second temperature by the second procedure, and after the crystal is grown at a constant temperature, it further includes centrifugal filtration and drying of the product; according to the embodiment of the present invention, the centrifugally filtered
  • the rotating speed is 1000-5000 rpm, preferably, the rotating speed of the centrifugal filtration is 3000-4500 rpm.
  • the rotating speed will not destroy the crystals, and the crystals can be quickly filtered, the wet product has less water content, and avoids product agglomeration due to excessive water content in the subsequent drying process.
  • the drying includes at least one selected from drying at 75° C. to 80° C. under atmospheric pressure, drying under reduced pressure, and drying by rotary evaporation.
  • the crystal habit sphericity of the amino acid or its derivative prepared by the method of the present invention is not less than 0.8.
  • the crystals prepared according to the methods of the embodiments of the present invention have high crystal habit sphericity and good fluidity, and are suitable for tableting.
  • the particle size distribution distance of the amino acid or its derivative prepared by the method of the present invention is not higher than 1.1.
  • the crystals prepared according to the method of the embodiment of the present invention have a particle size distribution diameter distance of not higher than 1.1, and have high stability, which can improve the quality of the tablet.
  • the present invention provides an amino acid or a derivative thereof, characterized in that the refined product of the amino acid or its derivative has a crystal habit sphericity of not less than 0.8, and a particle size distribution distance of not more than 0.8. 1.1.
  • the amino acids or derivatives thereof have excellent flow properties, are suitable for direct compression, and have high crystal stability, which can effectively improve the quality of tablet products.
  • the present invention finds that, for the raw material drug, the surface of the long rod-shaped and needle-shaped crystal raw material has a large number of plane contact points, as well as the shear force between irregular particles, and its fluidity is poor.
  • the crystals are filled with
  • the particles in the die holes are not uniform, and are easily broken and agglomerated, which affects the quality of the tableting products in the later stage.
  • the spherical particles have the smallest contact area with each other and have the best fluidity, which is suitable for direct compression, and the crystal stability is also high, which can effectively improve the quality of tablet products.
  • the above-mentioned amino acids or derivatives thereof may further include at least one of the following additional technical features:
  • the amino acid or its derivative includes at least one of the following: acetylcysteine, alanine, arginine, glycine, proline, hydroxyproline, serine, ornithine hydrochloride, arginine hydrochloride, lysine hydrochloride, histidine hydrochloride, preferably acetylcysteine, ornithine hydrochloride, glycine or alanine, more preferably,
  • the amino acid is acetylcysteine.
  • the refining method provided by the present invention can also obtain higher spherical crystal habit and particle size distribution results, and the effect is good. And this method is more superior in refining acetylcysteine, and the refining efficiency is higher.
  • the present invention provides a method for purifying acetylcysteine, the method comprising: using crude acetylcysteine to prepare a saturated aqueous solution of acetylcysteine at 50-80°C; Cool the saturated aqueous solution to a metastable zone of 27°C to 45°C at a rate of 1-3.0°C/min, add seeds, the sphericity of the seeds is not less than 0.6, and keep the crystals at a constant temperature to obtain a crystal slurry; The crystal slurry is cooled to 5-15° C.
  • Fig. 1 is the X-ray diffraction (XRD) contrast pattern of acetylcysteine prepared according to the embodiment of the present invention 1-5 and comparative example 1-3 and raw material;
  • XRD X-ray diffraction
  • Fig. 2 is the X-ray diffraction (XRD) contrast pattern of the ornithine hydrochloride prepared according to the embodiment of the present invention 6 and comparative example 4 and raw material;
  • XRD X-ray diffraction
  • Fig. 3 is the polarized light microscope photograph of acetylcysteine prepared according to the embodiment of the present invention 1;
  • Fig. 4 is the particle size distribution diagram of acetylcysteine prepared according to the embodiment of the present invention 1;
  • Fig. 5 is the polarized light microscope photograph of acetylcysteine prepared according to the embodiment of the present invention 2;
  • Fig. 6 is the particle size distribution diagram of acetylcysteine prepared according to the embodiment of the present invention 2;
  • Example 7 is a polarized light microscope photograph of acetylcysteine prepared according to Example 3 of the present invention.
  • Fig. 8 is the particle size distribution diagram of acetylcysteine prepared according to the embodiment of the present invention 3.
  • Fig. 9 is the polarized light microscope photograph of acetylcysteine prepared according to Example 4 of the present invention.
  • Fig. 10 is the particle size distribution diagram of acetylcysteine prepared according to the embodiment of the present invention 4.
  • Figure 11 is a polarized light microscope photo of acetylcysteine prepared according to Example 5 of the present invention.
  • Figure 12 is a particle size distribution diagram of acetylcysteine prepared according to Example 5 of the present invention.
  • Figure 13 is a polarized light microscope photograph of ornithine hydrochloride prepared according to Example 6 of the present invention.
  • Figure 14 is a particle size distribution diagram of ornithine hydrochloride prepared according to Example 6 of the present invention.
  • Figure 15 is a polarized light microscope photograph of glycine prepared according to Example 7 of the present invention.
  • Figure 16 is a particle size distribution diagram of glycine prepared according to Example 7 of the present invention.
  • Figure 17 is a polarized light microscope photograph of alanine prepared according to Example 8 of the present invention.
  • Figure 18 is a particle size distribution diagram of alanine prepared according to Example 8 of the present invention.
  • Figure 19 is a polarized light microscope photograph of acetylcysteine prepared according to Comparative Example 1 of the present invention.
  • Fig. 20 is the particle size distribution diagram of acetylcysteine prepared according to Comparative Example 1 of the present invention.
  • Figure 21 is a polarized light microscope photograph of acetylcysteine prepared according to Comparative Example 2 of the present invention.
  • Fig. 22 is the particle size distribution diagram of acetylcysteine prepared according to Comparative Example 2 of the present invention.
  • Figure 23 is a polarized light microscope photograph of acetylcysteine prepared according to Comparative Example 3 of the present invention.
  • Figure 24 is the particle size distribution diagram of acetylcysteine prepared according to Comparative Example 3 of the present invention.
  • Figure 25 is a polarized light microscope photograph of ornithine hydrochloride prepared according to Comparative Example 4 of the present invention.
  • 26 is a particle size distribution diagram of ornithine hydrochloride prepared according to Comparative Example 4 of the present invention.
  • first”, “second”, “third” and other similar terms used in this document are for the purpose of distinguishing between description and convenience, and do not imply or expressly differ from each other for any purpose. There are differences in order or importance between them, and it does not mean that the content defined by “first”, “second”, “third” and other similar terms is composed of only one component.
  • the XRD pattern of the acetylcysteine product prepared in this example is shown in Figure 1.
  • the crystal obtained by the new crystallization process in Example 1 is compared with the crystal form in the literature (CrystEngComm, 2013, 15:6498-6505). , the peak position of the obtained product is consistent with the crystal form I, indicating that the acetylcysteine product obtained by the new crystallization process is the pure crystal form I.
  • the microscopic photo of the acetylcysteine product prepared in this example is shown in Figure 3.
  • the crystal habit of the acetylcysteine prepared by the present invention is an ellipsoidal crystal, and the sphericity is 0.865 , the crystal habit is complete, and there is no coalescence.
  • the particle size of the product obtained in this example was measured by a Mastersizer 3000 laser particle size analyzer.
  • the particle size distribution diagram is shown in Figure 4.
  • the particle size distribution is unimodal, and the diameter is 0.914.
  • the particle size distribution is relatively concentrated, and the average particle size D[ 4,3] is 273 ⁇ m.
  • the product obtained in this example is measured by the fixed funnel method, and its angle of repose is 28°, and the fluidity is excellent.
  • the stirring rate is 350 r/min.
  • Cool down to 43°C add 3.48g of ellipsoidal seeds with a main particle size of 80 ⁇ m and a sphericity of 0.803, grow the crystals at a constant temperature for 30min to obtain a crystal slurry, and then start to cool down at a cooling rate of 0.5°C/min, drop to 5°C, and grow the crystals. After 30 min, vacuum filtration and drying to obtain 131.85 g of acetylcysteine crystals.
  • the XRD pattern of the acetylcysteine product prepared in this example is shown in Figure 1, the crystal obtained by the new crystallization process in Example 2 and the two crystals in the literature (CrystEngComm, 2013, 15:6498-6505)
  • the peak position of the obtained product is consistent with the crystal form I, indicating that the acetylcysteine product obtained by the new crystallization process is the pure crystal form I.
  • the microscopic photo of the acetylcysteine product prepared in this example is shown in Figure 5. It can be seen from the figure that the crystal habit of the acetylcysteine prepared by the present invention is an ellipsoidal crystal, and the sphericity is 0.881 , the crystal habit is complete, and there is no coalescence.
  • the particle size of the product obtained in this example was measured by a Mastersizer 3000 laser particle size analyzer.
  • the particle size distribution diagram is shown in Figure 6.
  • the particle size distribution is a unimodal distribution, the diameter distance is 1.021, the particle size distribution is relatively concentrated, and the average particle size D[ 4,3] is 360 ⁇ m.
  • the product obtained in this example is measured by the fixed funnel method, and its angle of repose is 26°, and the fluidity is excellent.
  • the XRD pattern of the acetylcysteine product prepared in this example is shown in Figure 1, the crystal obtained by the new crystallization process in Example 3 and the two crystals in the literature (CrystEngComm, 2013, 15:6498-6505)
  • the peak position of the obtained product is consistent with the crystal form I, indicating that the acetylcysteine product obtained by the new crystallization process is the pure crystal form I.
  • the microscopic photo of the acetylcysteine product prepared in this example is shown in Figure 7.
  • the crystal habit of the acetylcysteine prepared by the present invention is ellipsoid, and the sphericity is 0.875.
  • the crystal habit is complete and there is no coalescence.
  • the particle size of the product obtained in this example was measured by a Mastersizer 3000 laser particle size analyzer.
  • the particle size distribution diagram is shown in Figure 8.
  • the particle size distribution is unimodal, with a diameter distance of 1.060.
  • the particle size distribution is relatively concentrated, and the average particle size is D[4 ,3] is 428 ⁇ m.
  • the product obtained in this example is measured by the fixed funnel method, and its angle of repose is 26°, and the fluidity is excellent.
  • the XRD pattern of the acetylcysteine product prepared in this example is shown in Figure 1.
  • the crystal obtained by the new crystallization process in Example 4 and the two crystals in the literature (CrystEngComm, 2013, 15:6498-6505) The peak position of the obtained product is consistent with the crystal form I, indicating that the acetylcysteine product obtained by the new crystallization process is the pure crystal form I.
  • the microscopic photo of the acetylcysteine product prepared in this example is shown in Figure 9.
  • the crystal habit of the acetylcysteine prepared by the present invention is ellipsoid, and the sphericity is 0.860.
  • the crystal habit is complete and there is no coalescence.
  • the particle size of the product obtained in this example is measured by a Mastersizer 3000 laser particle size analyzer.
  • the particle size distribution diagram is shown in Figure 10.
  • the particle size distribution is unimodal, the diameter is 0.734, and the particle size distribution is relatively concentrated.
  • the average particle size D[4 ,3] is 544 ⁇ m.
  • the product obtained in this example is measured by the fixed funnel method and its angle of repose is 27°, and the fluidity is excellent.
  • the XRD pattern of the acetylcysteine product prepared in this example is shown in Figure 1.
  • the crystal obtained by the new crystallization process in Example 5 and the two crystals in the literature (CrystEngComm, 2013, 15:6498-6505) The peak position of the obtained product is consistent with the crystal form I, indicating that the acetylcysteine product obtained by the new crystallization process is the pure crystal form I.
  • the microscope photo of the acetylcysteine product prepared in this example is shown in Figure 11.
  • the crystal habit of the acetylcysteine prepared by the present invention is ellipsoid, and the sphericity is 0.886.
  • the crystal habit is complete and there is no coalescence.
  • the particle size of the product obtained in this example was measured by a Mastersizer 3000 laser particle size analyzer.
  • the particle size distribution diagram is shown in Figure 12.
  • the particle size distribution is unimodal, with a diameter distance of 0.760.
  • the particle size distribution is relatively concentrated, and the average particle size is D[4 ,3] is 587 ⁇ m.
  • the product obtained in this example is measured by the fixed funnel method to have an angle of repose of 25° and has excellent fluidity.
  • the stirring rate is 400 r/min. /min to cool down to 38°C, add 3.40g of square seed crystals with a main particle size of 100 ⁇ m and a sphericity of 0.674, grow the crystals at a constant temperature for 30min, and then start to cool down at a cooling rate of 0.25°C/min, drop to 5°C, and grow the crystals for 30min.
  • Vacuum filtration and drying gave 82.45 g of ornithine hydrochloride crystals.
  • the microscope photo of the ornithine hydrochloride product prepared in this example is shown in Figure 13.
  • the crystal habit of the ornithine hydrochloride prepared by the present invention is a regular tetragonal shape, and the sphericity is 0.805, the crystal habit is complete, and there is no coalescence.
  • the particle size of the product obtained in this example was measured by a Mastersizer 3000 laser particle size analyzer.
  • the particle size distribution diagram is shown in Figure 14.
  • the particle size distribution is unimodal, with a diameter distance of 0.889.
  • the particle size distribution is relatively concentrated, and the average particle size is D[4 ,3] is 575 ⁇ m.
  • the product obtained in this example has an angle of repose of 30° as measured by the fixed funnel method, and has excellent fluidity.
  • the main particle size is 100 ⁇ m and the ellipsoidal seed crystal with sphericity of 0.830 is kept at constant temperature for 30min, and then starts to cool down at a cooling rate of 0.5°C/min, and then drops to 5°C. .
  • the microscope photo of the glycine product prepared in this example is shown in Figure 15.
  • the crystal habit of the glycine prepared by the present invention is nearly spherical, the sphericity is 0.895, the crystal habit is complete, and there is no coalescence .
  • the particle size of the product obtained in this example was measured by a Mastersizer 3000 laser particle size analyzer.
  • the particle size distribution diagram is shown in Figure 16.
  • the particle size distribution is unimodal, with a diameter distance of 1.074.
  • the particle size distribution is relatively concentrated, and the average particle size D[4 ,3] is 381 ⁇ m.
  • the product obtained in this example is measured by the fixed funnel method, and its angle of repose is 24°, and the fluidity is excellent.
  • the microscope photo of the glycine product prepared in this example is shown in Figure 17.
  • the crystal habit of the glycine prepared by the present invention is ellipsoid, the sphericity is 0.824, the crystal habit is complete, and there is no coalescence .
  • the particle size of the product obtained in this example is measured by a Mastersizer 3000 laser particle size analyzer.
  • the particle size distribution diagram is shown in Figure 18.
  • the particle size distribution is unimodal, with a diameter distance of 0.900.
  • the particle size distribution is relatively concentrated, and the average particle size is D[4 ,3] is 524 ⁇ m.
  • the product obtained in this example is measured by the fixed funnel method, and its angle of repose is 28°, and the fluidity is excellent.
  • the stirring rate is 400 r/min.
  • the ellipsoid seed crystal with a degree of 0.815, the solution temperature was rapidly cooled to 5°C at 2.0°C/min, after the crystallization was completed, vacuum filtration and drying were performed to obtain 75.98g of acetylcysteine crystals, and the obtained crystals were slender spiny crystals habit, and the nodal wall phenomenon occurred.
  • the XRD pattern of the acetylcysteine product prepared in this comparative example is shown in Figure 1.
  • the obtained crystal is compared with the two crystal forms in the literature (CrystEngComm, 2013, 15:6498–6505), and the peak position of the obtained product is the same as The crystal form I is consistent, indicating that the acetylcysteine product obtained by the process of the comparative example 1 is the crystal form I.
  • the microscope photo of the acetylcysteine product prepared in this comparative example is shown in Figure 19. It can be seen from the figure that the acetylcysteine in Comparative Example 1 has uneven particle size distribution, easy agglomeration and fragmentation, etc. question. Through polarized light microscope, it can be observed that the crystal habit of acetylcysteine obtained in Comparative Example 1 is slender and pointed, which is easy to be broken during the crystallization process, the sphericity is too low, which is 0.510, the fluidity is poor, and it is easy to be electrostatically charged.
  • the particle size of the product obtained in this comparative example was measured by a Mastersizer 3000 Malvern particle size analyzer.
  • the particle size distribution diagram is shown in Figure 20. The particle size distribution is too wide, the diameter distance is 1.392, and the average particle size D[4,3] is 754 ⁇ m.
  • the product obtained in this comparative example was measured by the fixed funnel method to have an angle of repose of 48°, and the fluidity was poor.
  • the XRD pattern of the acetylcysteine product prepared in this comparative example is shown in Figure 1.
  • the obtained crystal is compared with the two crystal forms in the literature (CrystEngComm, 2013, 15:6498–6505), and the peak position of the obtained product is the same as The crystal form I is consistent, indicating that the acetylcysteine product obtained in this comparative example is the crystal form I.
  • the microscope photo of the acetylcysteine product prepared in Comparative Example 2 is shown in Figure 21. As can be seen from the figure, the particle size distribution of the obtained product is uneven and easily broken. Through polarized light microscope, it can be observed that the crystal habit of acetylcysteine obtained in Comparative Example 2 is in the shape of a long rod, which is easily broken during the crystallization process.
  • the particle size of the product obtained in this comparative example was measured by a Mastersizer 3000 Malvern particle size analyzer.
  • the particle size distribution diagram is shown in Figure 22. The particle size distribution is too wide, the diameter distance is 1.642, and the average particle size D[4,3] is 508 ⁇ m.
  • the product obtained in this comparative example has an angle of repose of 50° as measured by the fixed funnel method, and has poor fluidity.
  • the inventors further use organic solvents such as propanol and isopropanol to carry out tests, and the obtained results are close to this comparative example, and will not be repeated here.
  • the long-spiky seed crystals with a degree of 0.413 were incubated at a constant temperature for 30 minutes, and then the temperature was lowered at a cooling rate of 0.25 °C/min to 15 °C.
  • the XRD pattern of the acetylcysteine product prepared in this comparative example is shown in Figure 1.
  • the obtained crystal is compared with the two crystal forms in the literature (CrystEngComm, 2013, 15:6498–6505), and the peak position of the obtained product is the same as The crystal form I is consistent, indicating that the acetylcysteine product obtained in this comparative example is the crystal form I.
  • the microscope photo of the acetylcysteine product prepared in Comparative Example 3 is shown in Figure 23. Through the polarized light microscope picture, it can be observed that the crystal habit of acetylcysteine is cuboid, prone to breakage, and the sphericity is low, which is 0.655 , the liquidity is not good.
  • the particle size of the product obtained in this comparative example was measured by a Mastersizer 3000 Malvern particle size analyzer.
  • the particle size distribution diagram is shown in Figure 24.
  • the particle size distribution is uneven, the diameter distance is 1.004, and the average particle size D[4,3] is 532 ⁇ m.
  • the product obtained in this comparative example was measured by the fixed funnel method to have an angle of repose of 46°, and the fluidity was poor.
  • the microscope photo of the ornithine hydrochloride product prepared by this comparative example is shown in Figure 25. It can be seen from the figure that the crystal habit of the ornithine hydrochloride prepared by the present invention is fine needle-like, and it is very easy to Broken, extremely agglomerated, and very low sphericity of 0.346.
  • the particle size of the product obtained in this example was measured by a Mastersizer 3000 laser particle size analyzer.
  • the particle size distribution diagram is shown in Figure 26.
  • the particle size distribution is uneven, the diameter distance is 1.119, and the average particle size D[4,3] is 377 ⁇ m.
  • the product obtained in this comparative example was measured by the fixed funnel method to have an angle of repose of 54° and poor fluidity.
  • the inventors tested the flowability of the refined products obtained in the examples and the comparative examples and the crude products used, and the results are shown in Table 3. It can be seen from the results that the prepared amino acid or its derivative of the present invention has excellent flow properties, is suitable for direct compression, and has high crystal stability, which can effectively improve the quality of tablet products.
  • the method of the present invention does not change the crystal form of the product, and the obtained products are all pure crystal forms, which do not affect the bioavailability in vivo.
  • the particle size distribution is concentrated and the distance is small. And through the regulation of the crystallization process, products with different particle size distributions can be obtained to meet the requirements of different particle sizes.

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Abstract

提供了一种氨基酸或其衍生物的精制方法，包括：(1)在预设温度下使用氨基酸或其衍生物的粗品配制氨基酸或其衍生物的饱和水溶液；(2)将所述饱和水溶液进行第一程序降温至介稳区，加入晶种，所述晶种球形度不低于0.6，恒温养晶获得晶浆；(3)将所述晶浆进行第二程序降温至第二温度，所述第二程序降温的速率不高于1.0℃/min，恒温养晶以获得氨基酸或其衍生物。

Description

氨基酸或其衍生物的精制方法及该氨基酸或其衍生物
优先权信息
本申请请求2020年10月22日向中国国家知识产权局提交的、专利申请号为PCT/CN2020/122899的专利申请的优先权和权益，并且通过参照将其全文并入此处。
技术领域
本发明涉及医药技术领域，具体地，涉及氨基酸或其衍生物的精制方法及该氨基酸或其衍生物。
背景技术
药物多晶型现象是影响药品质量与临床疗效的重要因素之一，在药物质量控制中，晶型是其中的一个重要质控指标，不同晶型的药物有着不同的属性差异。这些性质不仅会影响医药产品的流动性、可压缩性、凝聚性能等加工性能，更重要的是还可能引起药物溶出速率、溶出度、稳定性等的质量差异，从而影响药物的生物活性与生物利用度，导致临床疗效的差异。
在制药行业中，晶体的流动性对产品的生产、不同成分的混合、传输、储存等过程，都有着重要的意义。如果晶体流动性较差，很难将药品中的各种成分混合均匀，导致药物的差异性较大。在制剂的运输和贮藏过程中，流动性差的晶体更容易因为外界环境温度、湿度、压力等因素的影响，导致药物的稳定性和有效性降低。目前通常用休止角度数来表征粉体流动性的好坏：当休止角≤30°，流动性优良；当休止角30°～45°，流动性较好；当休止角>45°，流动性差。
乙酰半胱氨酸(Acetylcysteine)，化学名为N-乙酰基-L-半胱氨酸，别名消坦立、富露施、痰易净、易咳净等，为还原型谷胱甘肽(GSH)的前体，是一种比较典型的氨基酸。其分子式：C 5H 9NO 3S，分子量：162.19。本品外观为白色结晶性粉末，熔点为101℃-107℃，有类似蒜的臭气，味酸，有吸湿性。易溶于水和乙醇，不溶于二氯甲烷和乙醚，结构如下：
Figure PCTCN2020125919-appb-000001
专利CN 104844488 B中已公开的乙酰半胱氨酸精制工艺是将粗品加水溶解，直接冷却结晶，离心收集晶体，烘干得到乙酰半胱氨酸纯品。但是此工艺得到的产品呈细长尖状，流动性差，易破碎，且粒度分布不均匀，细晶较多，烘干过程有聚结，产品质量一般，不符合高端药用药物的要求。
目前市面上的氨基酸或其衍生物的制备工艺均较为粗糙，其制备出来的氨基酸或其衍生物均存在呈细长尖状、流动性差且易破碎的状况。随着药品质量的监管日趋严格，以及高端药用药品市场的要求不断提升，研发一种能有效提高氨基酸或其衍生物产品质量的制备工艺实为必要。
发明内容
本发明的目的是提供一种能有效提高氨基酸或其衍生物产品质量的精制方法。
本发明的另一目的是提供一种具有高球形度、良好流动性的氨基酸或其衍生物。
为实现本发明的第一目的，本发明提供一种氨基酸或其衍生物的精制方法，包括：(1)在预设温度下使用氨基酸或其衍生物的粗品配制氨基酸或其衍生物的饱和水溶液；(2)将所述饱和水溶液进行第一程序降温至介稳区，加入晶种，所述晶种球形度不低于0.6，恒温养晶获得晶浆；(3)将所述晶浆进行第二程序降温至第二温度，所述第二程序降温的速率不高于1.0℃/min，恒温养晶以便获得氨基酸或其衍生物。
发明人在研究中发现，对于氨基酸或其衍生物而言，除了药物的晶型以外，药物的晶习和粒度对药物的质量控制也存在直接影响。对于原料药而言，长棒状和针状晶体原料表面有大量的平面接触点，以及不规则粒子间的剪切力，其流动性较差，在压片过程中，晶体填入模孔的颗粒不均匀，且容易破碎、结块，影响后期压片产品的质量。而球形粒子相互间的接触面积最小，其流动性最好，适合直接压片，且晶体的稳定性也较高，能有效提高产品的质量。
另一方面，如果晶体的粒度不均匀，粒度小易团聚，流动性差，也不利于压片和制剂过程，且易包埋杂质，对产品质量有显著影响。具体的，当颗粒的粒度分布不匀，压片时颗粒流速不同，致使填入模孔内的颗粒大小不均匀，或粗细相差太大，下料时由于设备抖动使粗细分层，从而填充时会出现片重差异超限。
根据本发明的实施例，所述方法能提高氨基酸或其衍生物产品的球形度和粒径均匀性，其流动性能优良，适合直接压片，且晶体的稳定性也较高，能有效提高片剂产品的质量。
根据本发明的实施例，上述方法还可进一步包括如下附加技术特征至少之一：
根据本发明实施例的方法采用加热方法使粗品快速溶于溶剂中，同时也便于后续采用两步阶梯程序降温形成球形晶体。发明人发现，本发明的方法适于多种物质的精制，特别适用于氨基酸及相关衍生物的精制，所得晶体球形度高、粒度均匀、不易聚结。
根据本发明的实施例，所述溶剂为水。根据本发明实施例的方法，溶剂原料易得，便于工业化生产，并且采用水为溶剂，有效避免了使用醇类物质(如乙醇)作为溶剂时的有机物残留，同时，使用水为溶剂使晶体的球形度更高，避免了使用醇类溶剂时的尖形细长状晶习。
根据本发明的实施例，所述预设温度为40～80℃，优选所述预设温度为50～80℃。根据本发明实施例的方法，所述预设温度为：40℃、41℃、42℃、43℃、44℃、45℃、 46℃、47℃、48℃、49℃、50℃、51℃、52℃、53℃、54℃、55℃、56℃、57℃、58℃、59℃、60℃、61℃、62℃、63℃、64℃、65℃、66℃、67℃、68℃、69℃、70℃、71℃、72℃、73℃、74℃、75℃、76℃、77℃、78℃、79℃、80℃。在上述温度下进行粗品的溶解，溶解度较大，有利于加快粗品的溶解，并且保证溶解完全，同时，预设温度达到上述温度，有利于后续进行两步阶梯程序降温，利于后续球形度高的晶体生成。
根据本发明的实施例，将待结晶溶液进行第一程序降温至介稳区是在搅拌的条件下进行的，任选地，所述搅拌的速度为100～600r/min，优选地，所述搅拌的速度为300～500r/min，具体地，所述搅拌速度为：100r/min、200r/min、300r/min、400r/min、500r/min、600r/min。发明人发现，上述搅拌速度适宜，避免了搅拌速度过快时晶习不完整、细晶出现、粒度分布不均匀、晶体聚结的情况；同时也避免了搅拌速度过慢时局部过饱和、晶体沉积结块、粒度分布不均匀的现象。
根据本发明的实施例，所述介稳区为25℃～50℃，优选地，所述介稳区为27℃～45℃。根据本发明实施例的方法，所述介稳区为：25℃、26℃、27℃、28℃、29℃、30℃、31℃、32℃、33℃、34℃、35℃、36℃、37℃、38℃、39℃、40℃、41℃、42℃、43℃、44℃、45℃、46℃、47℃、48℃、49℃、50℃，所述温度为晶体达到过饱和状态，即处于介稳区内，但还未析出晶体，在此温度加入球形度不低于0.6的晶种养晶，可以使最终得到的晶体球形度高、粒度分布均匀，而加入球形度低的长尖状晶种，所得晶体球形度很低，为长棒状晶习。
将氨基酸或其衍生物的饱和溶液从较高温度降温至介稳区，其目的是使溶液处于过饱和状态，产生结晶过程的推动力，且没有晶体析出，有助于后续添加晶种操作。对本领域的技术人员而言，可以理解的是，溶解度平衡曲线与超溶解度曲线之间的区域为结晶的介稳区，不同氨基酸或其衍生物的溶液，其介稳区的温度范围是存在一定差异的，具体与其物性以及溶解度相关。同样的，即使对于同一种氨基酸或其衍生物，其介稳区也存在一定的动态变化规律，与搅拌速率、降温速率密切相关。但是，本领域的技术人员可以理解的是，对于任一特定的氨基酸或其衍生物而言，只要精制时的条件是确定的，则该氨基酸或其衍生物溶液的介稳区也是确定的，将氨基酸或其衍生物的饱和溶液从较高温度降温至介稳区的目的也是确定的，且可以实现的。
根据本发明的实施例，所述第一程序降温速率为1.0℃/min～6.0℃/min，优选地，所述第一程序降温速率为1.0℃/min～3.0℃/min。根据本发明实施例的方法，所述第一程序降温速率为：1℃/min、1.5℃/min、2℃/min、2.5℃/min、3℃/min、3.5℃/min、4℃/min、4.5℃/min、5℃/min、5.5℃/min、6℃/min。在所述的快速降温速率下，介稳区更宽，而结晶溶液又能快速到达介稳区，使结晶温度的可操作区域更广，利于后续球形晶体的析出，又节省了降温时间，从而缩短整个精制时间，提高生产效率。
根据本发明的实施例，所述晶种球形度优选为0.6～0.9，以占所述饱和水溶液的质量百分比计，所述晶种加入量为1％～15％，所述晶种主粒度为10μm～200μm；优选地，所述晶种加入量为2％～6％，所述晶种主粒度为50μm～125μm。根据本发明实施例的方 法，所述晶种加入量、晶种主粒度、球形度较高的晶种有利于晶体均匀形成，所制备的晶体粒度均匀，不易聚结，稳定性高，有利于高球形度晶体的产生。
根据本发明的实施例，所述氨基酸或其衍生物的粗品晶习球形度不高于0.5。
根据本发明的实施例，所述恒温养晶的时间为5～60min，优选地，所述恒温养晶的时间为20～40min。根据本发明实施例的养晶时间给予晶体充分的老化时间，利于晶体析出以及晶体完整，所得晶体粒径较大而均匀，有利于后续过滤，减少过滤时间，提高生产效率。
根据本发明的实施例，所述第二温度为0～25℃，优选地，所述第二温度为5～15℃。根据本发明实施例的方法，所述第二温度为：0℃、1℃、2℃、3℃、4℃、5℃、6℃、7℃、8℃、9℃、10℃、11℃、12℃、13℃、14℃、15℃、16℃、17℃、18℃、19℃、20℃、21℃、22℃、23℃、24℃、25℃。所述第二温度低于介稳区温度，所述第二温度为低温，利于晶体的生长以及收率的提升。
根据本发明的实施例，所述第二程序降温的速率不高于1.0℃/min，优选为0.2～1.0℃/min。根据本发明实施例的方法，所述第二程序降温的速率为：0.1℃/min、0.2℃/min、0.3℃/min、0.4℃/min、0.5℃/min、0.6℃/min、0.7℃/min、0.8℃/min、0.9℃/min、1.0℃/min。所述第二降温速率适宜，使晶浆缓慢到达第二温度，利于晶体析出与晶体生长，避免因为降温过快，造成产品粒度不均一以及杂质包裹等问题。
根据本发明的实施例，将所述晶浆进行第二程序降温至第二温度，恒温养晶后，进一步包括将产物进行离心过滤和干燥处理；根据本发明的实施例，所述离心过滤的转速为1000-5000rpm，优选地，所述离心过滤的转速为3000～4500rpm。根据本发明实施例的方法，所述转速不会破坏晶体，可以使晶体快速过滤，湿品含水量更少，避免后续烘干过程因为含水量过高而导致产品结块。
根据本发明的实施例，所述干燥包括选自采用75℃～80℃常压干燥、减压干燥和旋转蒸发干燥至少之一。
根据本发明的实施例，利用本发明的方法所制备的氨基酸或其衍生物的晶习球形度不低于0.8。根据本发明实施例的方法所制备的晶体，其晶习球形度高，流动性好，适合压片。
根据本发明的实施例，利用本发明的方法所制备的氨基酸或其衍生物的粒度分布径距不高于1.1。根据本发明实施例的方法所制备的晶体，其粒度分布径距不高于1.1，稳定性较高，可以提高片剂的质量。
为实现本发明的第二目的，本发明提供一种氨基酸或其衍生物，其特征在于：所述氨基酸或其衍生物的精制品晶习球形度不低于0.8，粒度分布径距不高于1.1。根据本发明的实施例，所述氨基酸或其衍生物流动性能优良，适合直接压片，且晶体的稳定性也较高，能有效提高片剂产品的质量。本发明发现，对于原料药而言，长棒状和针状晶体原料表面有大量的平面接触点，以及不规则粒子间的剪切力，其流动性较差，在压片过程中，晶体填入模孔的颗粒不均匀，且容易破碎、结块，影响后期压片产品的质量。在 胶囊剂、片剂、颗粒剂等的成型或填充时，由于晶体的流动性较差，表面粗糙，容易粘连成块状，导致患者在服用时非常不方便，使制剂的成本增加。而球形粒子相互间的接触面积最小，其流动性最好，适合直接压片，且晶体的稳定性也较高，能有效提高片剂产品的质量。
根据本发明的实施例，上述氨基酸或其衍生物还可进一步包括如下附加技术特征至少之一：
根据本发明的实施例，所述氨基酸或其衍生物包括下列至少之一：乙酰半胱氨酸、丙氨酸、精氨酸、甘氨酸、脯氨酸、羟脯氨酸、丝氨酸、鸟氨酸盐酸盐、精氨酸盐酸盐、赖氨酸盐酸盐、组氨酸盐酸盐，优选为乙酰半胱氨酸、鸟氨酸盐酸盐、甘氨酸或丙氨酸，更优选地，所述氨基酸为乙酰半胱氨酸。发明人在研发过程中发现，对于水中溶解性能与乙酰半胱氨酸接近的其他种类氨基酸，采用本发明提供的精制方法也可以得到较高的球形晶习及粒度分布结果，效果良好。而本方法在精制乙酰半胱氨酸时更具有优越性，精制效率更高。
为实现本发明的第三目的，本发明提供了一种乙酰半胱氨酸精制方法，所述方法包括：在50～80℃下使用乙酰半胱氨酸粗品配制乙酰半胱氨酸饱和水溶液；将所述饱和水溶液以1～3.0℃/min的速率降温至介稳区27℃～45℃，加入晶种，所述晶种球形度不低于0.6，恒温养晶获得晶浆；将所述晶浆以0.2～0.8℃/min的速率降温至5～15℃，恒温养晶以便获得乙酰半胱氨酸。根据本发明的实施例，在加入晶种前，需要以1～3.0℃/min的速率降温至27℃、28℃、29℃、30℃、31℃、32℃、33℃、34℃、35℃、36℃、37℃、38℃、39℃、40℃、41℃、42℃、43℃、44℃、45℃，所述温度为乙酰半胱氨酸晶体达到过饱和状态，即处于乙酰半胱氨酸介稳区内，但还未析出晶体，在此温度加入球形度不低于0.6的晶种养晶，可以使最终得到的晶体球形度高、粒度分布均匀。
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。
附图说明
本发明的上述和/或附加的方面和优点从结合下面附图对实施例的描述中将变得明显和容易理解，其中：
图1为根据本发明实施例1-5和对比例1-3制备的乙酰半胱氨酸以及原料的X射线衍射(XRD)对比图谱；
图2为根据本发明实施例6和对比例4制备的鸟氨酸盐酸盐以及原料的X射线衍射(XRD)对比图谱；
图3为根据本发明实施例1制备的乙酰半胱氨酸的偏光显微镜照片；
图4为根据本发明实施例1制备的乙酰半胱氨酸的粒径分布图；
图5为根据本发明实施例2制备的乙酰半胱氨酸的偏光显微镜照片；
图6为根据本发明实施例2制备的乙酰半胱氨酸的粒径分布图；
图7为根据本发明实施例3制备的乙酰半胱氨酸的偏光显微镜照片；
图8为根据本发明实施例3制备的乙酰半胱氨酸的粒径分布图；
图9为根据本发明实施例4制备的乙酰半胱氨酸的偏光显微镜照片；
图10为根据本发明实施例4制备的乙酰半胱氨酸的粒径分布图；
图11为根据本发明实施例5制备的乙酰半胱氨酸的偏光显微镜照片；
图12为根据本发明实施例5制备的乙酰半胱氨酸的粒径分布图；
图13为根据本发明实施例6制备的鸟氨酸盐酸盐的偏光显微镜照片；
图14为根据本发明实施例6制备的鸟氨酸盐酸盐的粒径分布图；
图15为根据本发明实施例7制备的甘氨酸的偏光显微镜照片；
图16为根据本发明实施例7制备的甘氨酸的粒径分布图；
图17为根据本发明实施例8制备的丙氨酸的偏光显微镜照片；
图18为根据本发明实施例8制备的丙氨酸的粒径分布图；
图19为根据本发明对比例1制备的乙酰半胱氨酸的偏光显微镜照片；
图20为根据本发明对比例1制备的乙酰半胱氨酸的粒径分布图；
图21为根据本发明对比例2制备的乙酰半胱氨酸的偏光显微镜照片；
图22为根据本发明对比例2制备的乙酰半胱氨酸的粒径分布图；
图23为根据本发明对比例3制备的乙酰半胱氨酸的偏光显微镜照片；
图24为根据本发明对比例3制备的乙酰半胱氨酸的粒径分布图；
图25为根据本发明对比例4制备的鸟氨酸盐酸盐的偏光显微镜照片；
图26为根据本发明对比例4制备的鸟氨酸盐酸盐的粒径分布图。
发明详细描述
下面详细描述本发明的实施例，所述实施例的示例在附图中示出。下面通过参考附图描述的实施例是示例性的，旨在用于解释本发明，而不能理解为对本发明的限制。
术语解释
如无特别说明，在本文中所使用的“第一”、“第二”、“第三”等类似术语均为用于描述方便而进行区分的目的，并不以任何目的暗示或者明示互相之间存在顺序或者重要性等差异，同时并不意味着由“第一”、“第二”、“第三”等类似术语所限定的内容仅有一种成分构成。
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品，例如可以采购自Illumina公司。
本发明实施例及对比例所用设备如表1所示。
表1：设备信息
Figure PCTCN2020125919-appb-000002
实施例1
将200.00g乙酰半胱氨酸粗品溶于100.0mL预设温度为75℃的水中搅拌溶解，配制乙酰半胱氨酸的饱和溶液，搅拌速率为300r/min。然后将溶液温度按1.0℃/min降温至45℃，加入5.28g主粒度为50μm的球形度为0.783的椭球状晶种，恒温养晶40min获得晶浆，再按0.3℃/min的降温速度开始降温，降至10℃，养晶30min后离心过滤、干燥得到乙酰半胱氨酸晶体173.98g。
本实施例制备得到的乙酰半胱氨酸产品的XRD图谱如图1所示，利用实施例1中的新结晶工艺得到的晶体与文献(CrystEngComm,2013,15:6498–6505)中晶型对比，所得产品的峰位置与晶型Ⅰ一致，说明通过新结晶工艺得到的乙酰半胱氨酸产品为纯晶型Ⅰ。
本实施例制备得到的乙酰半胱氨酸产品的显微镜照片如图3所示，从图中可以看出，本发明制备得到的乙酰半胱氨酸的晶习为椭球状晶体，球形度为0.865，晶习完整，且无聚结。
本实施例所得产品的粒径由Mastersizer 3000激光粒度仪分析仪测定，粒径分布图如图4所示，粒度分布呈单峰分布，径距为0.914，粒度分布较为集中，平均粒径D[4,3]为273μm。
本实施例所得产品通过固定漏斗法测得其休止角为28°，流动性优良。
实施例2
将150.00g乙酰半胱氨酸粗品溶于预设100.0mL温度为60℃的水中搅拌溶解，配制乙酰半胱氨酸的饱和溶液，搅拌速率为350r/min，然后将溶液温度按1.25℃/min降温至43℃，加入3.48g主粒度为80μm的球形度为0.803的椭球状晶种，恒温养晶30min获得晶浆，再按0.5℃/min的降温速度开始降温，降至5℃，养晶30min后真空过滤、干燥得到乙酰半胱氨酸晶体131.85g。
本实施例制备得到的乙酰半胱氨酸产品的XRD图谱如图1所示，利用实施例2中的新结晶工艺得到的晶体与文献(CrystEngComm,2013,15:6498–6505)中两种晶型对比，所得产品的峰位置与晶型Ⅰ一致，说明通过新结晶工艺得到的乙酰半胱氨酸产品为纯晶型Ⅰ。
本实施例制备得到的乙酰半胱氨酸产品的显微镜照片如图5所示，从图中可以看出，本发明制备得到的乙酰半胱氨酸的晶习为椭球状晶体，球形度为0.881，晶习完整，且无聚结。
本实施例所得产品的粒径由Mastersizer 3000激光粒度仪分析仪测定，粒径分布图如图6所示，粒度分布呈单峰分布，径距为1.021，粒度分布较为集中，平均粒径D[4,3]为360μm。
本实施例所得产品通过固定漏斗法测得其休止角为26°，流动性优良。
实施例3
将100.00g乙酰半胱氨酸粗品溶于100.0mL预设温度为55℃的水中搅拌溶解，配制乙酰半胱氨酸的饱和溶液，搅拌速率为400r/min，然后将溶液温度按2.0℃/min降温至30℃，加入3.01g主粒度为100μm的球形度为0.794的椭球状晶种，恒温养晶40min，再按0.8℃/min的降温速度开始降温，降至5℃，养晶25min后真空过滤、干燥得到乙酰半胱氨酸晶体86.64g。
本实施例制备得到的乙酰半胱氨酸产品的XRD图谱如图1所示，利用实施例3中的新结晶工艺得到的晶体与文献(CrystEngComm,2013,15:6498–6505)中两种晶型对比，所得产品的峰位置与晶型Ⅰ一致，说明通过新结晶工艺得到的乙酰半胱氨酸产品为纯晶型Ⅰ。
本实施例制备得到的乙酰半胱氨酸产品的显微镜照片如图7所示，从图中可以看出，本发明制备得到的乙酰半胱氨酸的晶习为椭球状，球形度为0.875，晶习完整，且无聚结。
本实施例所得产品的粒径由Mastersizer 3000激光粒度分析仪测定，粒径分布图如图8所示，粒度分布呈单峰分布，径距为1.060，粒度分布较为集中，平均粒径D[4,3]为428μm。
本实施例所得产品通过固定漏斗法测得其休止角为26°，流动性优良。
实施例4
将120.21g乙酰半胱氨酸粗品溶于100.0mL预设温度为70℃的水中搅拌溶解，配制乙酰半胱氨酸的饱和溶液，搅拌速率为500r/min，然后将溶液温度按1.5℃/min降温至35℃，加入5.11g主粒度为125μm的球形度为0.751的椭球状晶种，恒温养晶30min，再按0.2℃/min的降温速度开始降温，降至10℃，养晶40min后真空过滤、干燥得到乙酰半胱氨酸晶体105.47g。
本实施例制备得到的乙酰半胱氨酸产品的XRD图谱如图1所示，利用实施例4中的新结晶工艺得到的晶体与文献(CrystEngComm,2013,15:6498–6505)中两种晶型对比，所得产品的峰位置与晶型Ⅰ一致，说明通过新结晶工艺得到的乙酰半胱氨酸产品为纯晶型Ⅰ。
本实施例制备得到的乙酰半胱氨酸产品的显微镜照片如图9所示，从图中可以看出，本发明制备得到的乙酰半胱氨酸的晶习为椭球状，球形度为0.860，晶习完整，且无聚结。
本实施例所得产品的粒径由Mastersizer 3000激光粒度分析仪测定，粒径分布图如图10所示，粒度分布呈单峰分布，径距为0.734，粒度分布较为集中，平均粒径D[4,3]为544μm。
本实施例所得产品通过固定漏斗法测得其休止角为27°，流动性优良。
实施例5
将210.05g乙酰半胱氨酸粗品溶于100.0mL预设温度为80℃的水中搅拌溶解，配制乙酰半胱氨酸的饱和溶液，搅拌速率为350r/min，然后将溶液温度按3.0℃/min降温至50℃，加入6.39g主粒度为75μm的球形度为0.815的椭球状晶种，恒温养晶30min，再按0.25℃/min的降温速度开始降温，降至15℃，养晶30min后真空过滤、干燥得到乙酰半胱氨酸晶体175.28g。
本实施例制备得到的乙酰半胱氨酸产品的XRD图谱如图1所示，利用实施例5中的新结晶工艺得到的晶体与文献(CrystEngComm,2013,15:6498–6505)中两种晶型对比，所得产品的峰位置与晶型Ⅰ一致，说明通过新结晶工艺得到的乙酰半胱氨酸产品为纯晶型Ⅰ。
本实施例制备得到的乙酰半胱氨酸产品的显微镜照片如图11所示，从图中可以看出，本发明制备得到的乙酰半胱氨酸的晶习为椭球状，球形度为0.886，晶习完整，且无聚结。
本实施例所得产品的粒径由Mastersizer 3000激光粒度分析仪测定，粒径分布图如图12所示，粒度分布呈单峰分布，径距为0.760，粒度分布较为集中，平均粒径D[4,3]为587μm。
本实施例所得产品通过固定漏斗法测得其休止角为25°，流动性优良。
进一步的，发明人发现，对于水中溶解性能与乙酰半胱氨酸接近的其他种类氨基酸，采用本发明提供的精制方法依旧可以得到较高的球形晶习及粒度分布结果。进一步使用丙氨酸、精氨酸、甘氨酸、脯氨酸、羟脯氨酸、丝氨酸、鸟氨酸盐酸盐、精氨酸盐酸盐、赖氨酸盐酸盐、组氨酸盐酸盐重复上述试验，所得到的的结果均与实施例1-5的结果类似。由于具体精制过程类似，以下仅选取部分氨基酸精制试验进行详细说明。
实施例6：精制鸟氨酸盐酸盐
将113.03g鸟氨酸盐酸盐粗品溶于150.0mL预设温度为55℃的水中搅拌溶解，配制鸟氨酸盐酸盐的饱和溶液，搅拌速率为400r/min，然后将溶液温度按1.5℃/min降温至38℃，加入3.40g主粒度为100μm的球形度为0.674的方形晶种，恒温养晶30min，再按0.25℃/min的降温速度开始降温，降至5℃，养晶30min后真空过滤、干燥得到鸟氨酸盐酸盐晶体82.45g。
本实施例制备得到的鸟氨酸盐酸盐产品以及原料的XRD图谱如图2所示，利用实施例6中的新结晶工艺得到的晶体与原料的晶型对比，峰位置一致，说明通过新结晶工艺并未改变鸟氨酸盐酸盐晶型。
本实施例制备得到的鸟氨酸盐酸盐产品的显微镜照片如图13所示，从图中可以看出，本发明制备得到的鸟氨酸盐酸盐的晶习为正四方形状，球形度为0.805，晶习完整，且无聚结。
本实施例所得产品的粒径由Mastersizer 3000激光粒度分析仪测定，粒径分布图如图14所示，粒度分布呈单峰分布，径距为0.889，粒度分布较为集中，平均粒径D[4,3]为575μm。
本实施例所得产品通过固定漏斗法测得其休止角为30°，流动性优良。
实施例7：精制甘氨酸
将50.05g甘氨酸粗品溶于100.0mL预设温度为70℃的水中搅拌溶解，配制甘氨酸的饱和溶液，搅拌速率为450r/min，然后将溶液温度按2℃/min降温至43℃，加入1.52g主粒度为100μm的球形度为0.830的椭球状晶种，恒温养晶30min，再按0.5℃/min的降温速度开始降温，降至5℃，养晶30min后真空过滤、干燥得到甘氨酸晶体39.47g。
本实施例制备得到的甘氨酸产品的显微镜照片如图15所示，从图中可以看出，本发明制备得到的甘氨酸的晶习为近球状，球形度为0.895，晶习完整，且无聚结。
本实施例所得产品的粒径由Mastersizer 3000激光粒度分析仪测定，粒径分布图如图16所示，粒度分布呈单峰分布，径距为1.074，粒度分布较为集中，平均粒径D[4,3]为381μm。
本实施例所得产品通过固定漏斗法测得其休止角为24°，流动性优良。
实施例8：精制丙氨酸
将41.06g丙氨酸粗品溶于100.0mL预设温度为65℃的水中搅拌溶解，配制丙氨酸的饱和溶液，搅拌速率为350r/min，然后将溶液温度按2.5℃/min降温至34℃，加入1.63g主粒度为125μm的球形度为0.745的椭球状晶种，恒温养晶30min，再按0.3℃/min的降温速度开始降温，降至5℃，养晶30min后真空过滤、干燥得到甘氨酸晶体31.47g。
本实施例制备得到的甘氨酸产品的显微镜照片如图17所示，从图中可以看出，本发明制备得到的甘氨酸的晶习为椭球状，球形度为0.824，晶习完整，且无聚结。
本实施例所得产品的粒径由Mastersizer 3000激光粒度分析仪测定，粒径分布图如图18所示，粒度分布呈单峰分布，径距为0.900，粒度分布较为集中，平均粒径D[4,3]为524μm。
本实施例所得产品通过固定漏斗法测得其休止角为28°，流动性优良。
对比例1：未采用两步梯度降温
将100.04g乙酰半胱氨酸粗品溶于100.0mL预设温度为60℃的水中搅拌溶解，配制乙酰半胱氨酸的饱和溶液，搅拌速率为400r/min，加入3.5g主粒度为100μm的球形度为0.815的椭球形晶种，将溶液温度以2.0℃/min快速降温至5℃，析晶完成后真空过滤、干燥得到乙酰半胱氨酸晶体75.98g，所得晶体为细长的尖状晶习，且发生了结壁现象。
本对比例制备得到的乙酰半胱氨酸产品的XRD图谱如图1所示，得到的晶体与文献(CrystEngComm,2013,15:6498–6505)中两种晶型对比，所得产品的峰位置与晶型Ⅰ一致，说明对比例1工艺得到的乙酰半胱氨酸产品为晶型Ⅰ。
本对比例制备得到的乙酰半胱氨酸产品的显微镜照片如图19所示，从图中可以看出，对比例1中乙酰半胱氨酸存在产品粒度分布不均匀、易聚结和破碎等问题。通过偏光显微镜可以观察到对比例1得到的乙酰半胱氨酸晶习呈细长尖状，在结晶过程中容易发生破碎，球形度太低，为0.510，流动性差，易带静电。
本对比例所得产品的粒径由Mastersizer 3000马尔文粒度仪测定，粒径分布图如图20所示，粒度分布太宽，径距为1.392，平均粒径D[4,3]为754μm。
本对比例所得产品通过固定漏斗法测得其休止角为48°，流动性较差。
对比例2：采用乙醇为溶剂结晶
将80.55g乙酰半胱氨酸粗品溶于100.0mL预设温度为50℃的乙醇溶剂中搅拌溶解，配制乙酰半胱氨酸的饱和溶液，搅拌速率为350r/min，然后将溶液温度按1.0℃/min降温至27℃，加入2.56g主粒度为50μm的球形度为0.796的晶种，恒温养晶30min，再按0.1℃/min的降温速度开始降温，降至10℃，养晶30min后真空过滤、干燥得到乙酰半胱氨酸晶体48.45g，收率偏低。
本对比例制备得到的乙酰半胱氨酸产品的XRD图谱如图1所示，得到的晶体与文献(CrystEngComm,2013,15:6498–6505)中两种晶型对比，所得产品的峰位置与晶型Ⅰ一致，说明本对比例得到的乙酰半胱氨酸产品为晶型Ⅰ。
对比例2制备得到的乙酰半胱氨酸产品的显微镜照片如图21所示，从图中可以看出，得到的产品粒度分布不均匀、易破碎。通过偏光显微镜可以观察到对比例2得到的乙酰半胱氨酸晶习呈长棒状，在结晶过程中容易发生破碎，球形度太低，为0.435，流动性差，易带静电。
本对比例所得产品的粒径由Mastersizer 3000马尔文粒度仪测定，粒径分布图如图 22所示，粒度分布太宽，径距为1.642，平均粒径D[4,3]为508μm。
本对比例所得产品通过固定漏斗法测得其休止角为50°，流动性差。
发明人进一步使用丙醇、异丙醇等有机溶剂进行试验，得到的结果与本对比例接近，此处不再赘述。
对比例3：采用长尖状晶种结晶
将210.00g乙酰半胱氨酸粗品溶于100.0mL温度为80℃的水中，搅拌速率为350r/min，然后将溶液温度按3.0℃/min降温至53℃，加入6.05g主粒度为75μm的球形度为0.413的长尖状晶种，恒温养晶30min，再按0.25℃/min的降温速度开始降温，降至15℃，养晶30min后真空过滤、干燥得到乙酰半胱氨酸晶体158.35g。
本对比例制备得到的乙酰半胱氨酸产品的XRD图谱如图1所示，得到的晶体与文献(CrystEngComm,2013,15:6498–6505)中两种晶型对比，所得产品的峰位置与晶型Ⅰ一致，说明本对比例得到的乙酰半胱氨酸产品为晶型Ⅰ。
对比例3制备得到的乙酰半胱氨酸产品的显微镜照片如图23所示，通过偏光显微镜图片可以观察到乙酰半胱氨酸晶习呈长方体状，容易发生断裂，球形度较低，为0.655，流动性不好。
本对比例所得产品的粒径由Mastersizer 3000马尔文粒度仪测定，粒径分布图如图24所示，粒度分布不均匀，径距为1.004，平均粒径D[4,3]为532μm。
本对比例所得产品通过固定漏斗法测得其休止角为46°，流动性较差。
对比例4：未加晶种结晶
将112.00g鸟氨酸盐酸盐粗品溶于150.0mL温度为60℃的水中，搅拌速率为400r/min，然后将溶液温度按1.5℃/min直接降温至5℃，养晶30min后真空过滤、干燥得到鸟氨酸盐酸盐晶体75.34g。
本实施例制备得到的鸟氨酸盐酸盐产品以及原料的XRD图谱如图2所示，对比例4得到的晶体与原料的晶型对比，峰位置一致，说明通过未加晶种结晶并未改变鸟氨酸盐酸盐晶型。
本对比例制备得到的鸟氨酸盐酸盐产品的显微镜照片如图25所示，从图中可以看出，本发明制备得到的鸟氨酸盐酸盐的晶习为细针状，极易破碎，聚结极其严重，球形度很低为0.346。
本实施例所得产品的粒径由Mastersizer 3000激光粒度分析仪测定，粒径分布图如图26所示，粒度分布不均匀，径距为1.119，平均粒径D[4,3]为377μm。
本对比例所得产品通过固定漏斗法测得其休止角为54°，流动性差。
本发明实施例和对比例的实验参数及晶体参数如表2所示。
表2：实施例和对比例的实验参数及晶体参数
Figure PCTCN2020125919-appb-000003
进一步地，发明人将实施例以及对比例所制得的精制品与所使用的粗品进行流动性检测，结果如表3所示。从结果可以看出，本发明的所制得的氨基酸或其衍生物其流动性能优良，适合直接压片，且晶体的稳定性也较高，能有效提高片剂产品的质量。
表3：实施例及对比例制得的精制品与所使用的粗品流动性检测
样品编号 休止角° 流动性
乙酰半胱氨酸粗品 52 差
实施例1 28 优良
实施例2 26 优良
实施例3 26 优良
实施例4 27 优良
实施例5 25 优良
对比例1 48 差
对比例2 50 差
对比例3 46 差
鸟氨酸盐酸盐粗品 65 差
实施例6 30 优良
对比例4 54 差
甘氨酸粗品 52 差
实施例7 24 优良
丙氨酸粗品 55 差
实施例8 28 优良
当休止角≤30°，流动性优良；当休止角30°～45°，流动性较好；当休止角>45°，流动性差。
综上所述，本发明方法未改变产品晶型，得到的均为纯晶型，不影响体内的生物利用度，晶体产品晶习完整，球形度较高，晶体粒度分布均呈现单峰分布且粒度分布集中，径距小。而且通过结晶过程调控，可以得到不同粒度分布的产品，满足不同粒度大小的要求。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特 征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (17)

  1. 一种氨基酸或其衍生物的精制方法，其特征在于，包括：
    (1)在预设温度下使用氨基酸或其衍生物的粗品配制氨基酸或其衍生物的饱和水溶液；
    (2)将所述饱和水溶液进行第一程序降温至介稳区，加入晶种，所述晶种球形度不低于0.6，恒温养晶获得晶浆；
    (3)将所述晶浆进行第二程序降温至第二温度，所述第二程序降温的速率不高于1.0℃/min，恒温养晶以便获得氨基酸或其衍生物。
  2. 根据权利要求1所述的方法，其特征在于，所述预设温度是40～80℃，优选地，所述预设温度是50～80℃。
  3. 根据权利要求1所述的方法，其特征在于，所述第二温度为0～25℃，优选的，所述第二温度为5～15℃。
  4. 根据权利要求1所述的方法，其特征在于，步骤(2)中，将所述饱和水溶液进行第一程序降温至介稳区是在搅拌的条件下进行的，任选地，所述搅拌的速度为100～600r/min，优选地，所述搅拌的速度为300～500r/min。
  5. 根据权利要求1所述的方法，其特征在于，所述第二程序降温的速率为0.2～1.0℃/min。
  6. 根据权利要求1所述的方法，其特征在于，所述晶种球形度优选为0.6～0.9，以占所述饱和水溶液的质量百分比计，所述晶种加入量为1％～15％，所述晶种主粒度为10μm～200μm；优选地，所述晶种加入量为2％～6％，所述晶种主粒度为50μm～125μm。
  7. 根据权利要求1所述的方法，其特征在于，所述氨基酸或其衍生物的粗品晶习球形度不高于0.5。
  8. 根据权利要求1所述的方法，其特征在于，所述恒温养晶的时间为5～60min，优选地，所述恒温养晶的时间为20～40min。
  9. 根据权利要求1所述的方法，其特征在于，将所述晶浆进行第二程序降温，恒温养晶后，进一步包括将产物进行离心过滤和干燥处理；
    任选地，所述离心过滤的转速为1000-5000rpm，优选地，所述离心过滤的转速为3000～4500rpm；
    任选地，所述干燥包括选自采用75℃～80℃常压干燥、减压干燥和旋转蒸发干燥至少之一。
  10. 根据权利要求1所述的方法，其特征在于，所述介稳区为25℃～50℃，优选地，所述介稳区为27℃～45℃。
  11. 根据权利要求1所述的方法，其特征在于，利用所述方法制备的氨基酸或其衍生物的晶习球形度不低于0.8。
  12. 根据权利要求1所述的方法，其特征在于，利用所述方法制备的氨基酸或其衍生物的粒度分布径距不高于1.1。
  13. 根据权利要求1～12任一所述的氨基酸或其衍生物的精制方法，其特征在于，所述氨基酸或其衍生物包括下列至少之一：乙酰半胱氨酸、丙氨酸、精氨酸、甘氨酸、脯氨酸、羟脯氨酸、丝氨酸、鸟氨酸盐酸盐、精氨酸盐酸盐、赖氨酸盐酸盐、组氨酸盐酸盐；
    优选地，所述氨基酸或其衍生物包括乙酰半胱氨酸、鸟氨酸盐酸盐、甘氨酸或丙氨酸；
    更优选地，所述氨基酸为乙酰半胱氨酸。
  14. 一种氨基酸或其衍生物，其特征在于，所述氨基酸或其衍生物的晶习球形度不低于0.8。
  15. 根据权利要求14所述的氨基酸或其衍生物，其特征在于，所述氨基酸或其衍生物的粒度分布径距不高于1.1。
  16. 根据权利要求14所述的氨基酸或其衍生物，其特征在于，所述氨基酸或其衍生物包括下列至少之一：乙酰半胱氨酸、丙氨酸、精氨酸、甘氨酸、脯氨酸、羟脯氨酸、丝氨酸、鸟氨酸盐酸盐、精氨酸盐酸盐、赖氨酸盐酸盐、组氨酸盐酸盐；
    优选地，所述氨基酸或其衍生物包括乙酰半胱氨酸、鸟氨酸盐酸盐、甘氨酸或丙氨酸；
    更优选地，所述氨基酸为乙酰半胱氨酸。
  17. 一种乙酰半胱氨酸的精制方法，其特征在于，所述方法包括：
    在50～80℃下使用乙酰半胱氨酸粗品配制乙酰半胱氨酸饱和水溶液；
    将所述饱和水溶液以1～3.0℃/min的速率降温至介稳区27℃～45℃，加入晶种，所述晶种球形度不低于0.6，恒温养晶获得晶浆；
    将所述晶浆以0.2～0.8℃/min的速率降温至5～15℃，恒温养晶以便获得精制的乙酰半胱氨酸。
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