CN117417289A - Preparation method of nitrendipine flat crystal form - Google Patents
Preparation method of nitrendipine flat crystal form Download PDFInfo
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- CN117417289A CN117417289A CN202311298320.5A CN202311298320A CN117417289A CN 117417289 A CN117417289 A CN 117417289A CN 202311298320 A CN202311298320 A CN 202311298320A CN 117417289 A CN117417289 A CN 117417289A
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- 239000013078 crystal Substances 0.000 title claims abstract description 78
- PVHUJELLJLJGLN-INIZCTEOSA-N (S)-nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-INIZCTEOSA-N 0.000 title claims abstract description 54
- 229960005425 nitrendipine Drugs 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title abstract description 7
- 238000002425 crystallisation Methods 0.000 claims abstract description 67
- 230000008025 crystallization Effects 0.000 claims abstract description 66
- 238000000034 method Methods 0.000 claims abstract description 22
- 238000010438 heat treatment Methods 0.000 claims abstract description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 26
- 238000002844 melting Methods 0.000 claims description 12
- 230000008018 melting Effects 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000002349 favourable effect Effects 0.000 abstract description 3
- 230000035790 physiological processes and functions Effects 0.000 abstract description 2
- 238000011160 research Methods 0.000 abstract description 2
- 230000001737 promoting effect Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 11
- 239000012298 atmosphere Substances 0.000 description 10
- 238000005070 sampling Methods 0.000 description 8
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000003814 drug Substances 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 229940079593 drug Drugs 0.000 description 3
- 239000000155 melt Substances 0.000 description 3
- 230000010287 polarization Effects 0.000 description 3
- 230000000630 rising effect Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 241001648319 Toronia toru Species 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000008094 contradictory effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000011549 crystallization solution Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- 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
Abstract
The invention discloses a preparation method of a nitrendipine crystal form. The method can stably obtain the nitrendipine crystal form II, and has higher yield and purity. The invention also finds that both solution crystallization conditions and heat treatment conditions for melt crystallization affect the yield of form II during melt crystallization. The invention is favorable for promoting the deep research of the properties of the crystal form II, such as physiological functions, bioavailability and the like.
Description
Technical Field
The invention belongs to the field of preparation of pharmaceutical crystal forms, and particularly relates to a preparation method of a nitrendipine crystal form, in particular to a method for stably preparing the nitrendipine crystal form by controlling solution crystallization and melt crystallization conditions.
Background
Among the drugs that have been marketed, most have polymorphism. Different crystal forms of the same medicine have obvious differences in physical and chemical properties such as stability, density, crystal habit, solubility and the like, thereby affecting the pharmaceutical process and the safety and bioavailability in clinical application. Therefore, drug form control is an important link in drug research. Nitrendipine (NTD) belongs to one of 1,4 dihydropyridine derivatives, is a second-generation dihydropyridine calcium ion blocker, and can be used for treating coronary heart disease and hypertension. Because of small side effect, clear antihypertensive effect, and meeting the requirements of clinical requirements, safety, effectiveness, reasonable price, convenient use and the like, the medicine is listed in the Chinese basic medicine catalogue for central vascular system. Nitrendipine exists in three forms, form I (melting point: 158-159 ℃), form II (melting point: 130-131 ℃) and form III (melting point: 124-126 ℃). Form I is a stable form which is crystallized in common solvents to give the form, and form II is currently prepared by melt crystallization (Artur Burger, judith M. Rollinger, peter Bruggeller, J. Pharm. Sci.1997,86, 674-679). However, the melt crystallization conditions reported in the prior art for preparing form II are different from each other, and even if the crystallization conditions are the same, the results are contradictory and have poor reproducibility. For example, miyazaki et al (Tamaki Miyazaki, sumie Yoshioka, yukio Aso, toru Kawanishi, int. J. Pharm.2007,336, 191-195) isothermally crystallize the quenched melt at 60℃for 2 hours to give pure form II, but Bruggeler et al (Artur Burger, judith M. Rollinger, peter Bruggeler, J. Pharm. Sci.1997,86, 674-679) use the same method to give mixed crystals of form I and form II, and Yuan et al give form III (Hengjie Yuan, dawei Chen, lijun Fan. J. Hosp. Pharm.2004,11, 691-693). Due to the lack of a method for stably obtaining the crystal form II, intensive studies on the properties such as physiological functions and bioavailability are limited. Therefore, it is necessary to find a process which can stably produce form II.
In addition, different solution crystallization conditions affect the crystal form obtained by crystallization or the crystal habit of the same crystal form such as morphology, size and the like, but little is studied whether the solution crystallization conditions have an effect on the melt crystallization process. For a molecule that needs to be crystallized by melting to prepare a certain crystal form, different crystallization conditions of the solution may affect the quality stability of the crystal form obtained by melting and crystallization and the reliability of the preparation method. Since melt crystallization itself is a relatively difficult process to control, any potential change may affect the crystalline form obtained by crystallization. It is important to pay attention to whether the solution crystallization conditions have an influence on the subsequent melt crystallization or not and to how much.
Disclosure of Invention
In view of the above problems, the present invention aims to provide a method for preparing nitrendipine form ii, by which nitrendipine form ii having high crystal form purity can be stably obtained.
The method for preparing the nitrendipine crystal form II provided by the invention comprises the following steps:
(1) Dissolving nitrendipine in an organic solvent to prepare a solution with a certain concentration;
(2) Placing the dissolved solution at a certain crystallization temperature, and rapidly crystallizing and separating out;
(3) Collecting crystals and drying;
(4) Heating the obtained crystal to a certain temperature at a certain heating rate, melting the crystal at a certain temperature, and then isothermal for a certain time;
(5) And cooling to a certain temperature at a certain cooling rate, performing isothermal crystallization for a certain time to obtain a target crystal, or directly cooling to room temperature at a certain cooling rate and then heating to a certain temperature at a certain rate to obtain the target crystal.
In the step (1) of the method, the nitrendipine is a commercial commodity and can be purchased;
the organic solvent is selected from at least one of the following solvents: isopropyl alcohol, ethyl acetate, acetonitrile, tetrahydrofuran, methanol, acetone, ethanol, N-dimethylformamide, N-dimethylacetamide, preferably isopropyl alcohol;
the concentration of the solution can be 70-500 mg.mL -1 Specifically, it may be 90 to 120 mg.mL -1 More specifically, 117 mg/mL -1 、100mg·mL -1 ；
90-120 mg.ml -1 In the range, the higher the concentration of the crystallization solution is, the more favorable the improvement of the yield of the crystal form II is.
In the step (2) of the method, the crystallization temperature may be 0 to 50 ℃, specifically 10 to 40 ℃, more specifically 40 ℃;
the higher the crystallization temperature is in the range of 10-40 ℃, the more favorable the improvement of the yield of the crystal form II.
The rapid crystallization is carried out after the solution is placed at the corresponding crystallization temperature, a large amount of turbidity can appear in the solution within tens of minutes after a few minutes, and the crystallization is rapid;
in the step (4), the heating rate is 1-100 ℃/min, and can be specifically 5 ℃/min;
the temperature is 165-210 ℃, and can be 165 ℃;
the isothermal duration after melting is 0-3 h, specifically 3min-1h, more specifically 3min;
the cooling rate in the step (5) of the method is 1-100 ℃/min, specifically 1-20 ℃/min, more specifically 10 ℃/min;
the temperature of the isothermal crystallization is 60-80 ℃, and the duration of the isothermal crystallization is 18-24 h.
The heating rate is 1-100 ℃/min, specifically can be 2.5-20 ℃/min, and more specifically can be 5 ℃/min or 2.5 ℃/min.
The temperature-rising crystallization temperature is 90-129 ℃, specifically can be 102-127 ℃, and more specifically can be 127 ℃;
the operations of the above-described method steps (4) and (5) are carried out in an inert atmosphere, which may be in particular a nitrogen atmosphere.
The invention can see the generation of the crystal form II under a Differential Scanning Calorimeter (DSC) and a thermal polarization microscope.
The invention discovers that the heat treatment condition of the melt crystallization has a great influence on the crystallization yield and purity of the crystal form II, and the concentration and the temperature of the solution crystallization have a certain influence on the yield and the purity of the crystal form II obtained by the subsequent melt crystallization.
The invention provides a melting crystallization method which can stably prepare nitrendipine crystal form II and has higher purity and yield.
Drawings
Fig. 1 is a powder X-ray diffraction chart of crystalline form ii of nitrendipine prepared in example 3 of the present invention.
Fig. 2 is a DSC curve of crystalline form ii of nitrendipine prepared by temperature-rising crystallization in example 5 of the present invention.
Fig. 3 is a DSC curve of crystalline form ii of nitrendipine prepared by isothermal crystallization according to example 9 of the present invention.
Fig. 4 a is a photograph of a nitrendipine crystal form ii prepared in example 5, which is observed under a thermal polarization microscope, and b is a photograph of a nitrendipine crystal form ii prepared in example 5, which is observed under a polarizer.
Detailed Description
The following detailed description of the invention is provided in connection with the accompanying drawings that are presented to illustrate the invention and not to limit the scope thereof. The examples provided below are intended as guidelines for further modifications by one of ordinary skill in the art and are not to be construed as limiting the invention in any way.
The experimental methods in the following examples, unless otherwise specified, are conventional methods, and are carried out according to techniques or conditions described in the literature in the field or according to the product specifications. Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
Example 1
(1) Taking 700mg of nitrendipine, adding 6mL of isopropanol, heating to 75 ℃, fully stirring to dissolve the nitrendipine with the concentration of 117 mg.mL -1 . Rapidly placed at 10 ℃ for crystallization. After crystallization for 10 hours, the crystals were collected and dried in vacuo at 40 ℃.
(2) Sampling about 5mg of the crystals of (1) in N 2 The temperature was raised from 25℃to 165℃at 5℃per minute under an atmosphere (50 mL/min) for 3min, then lowered to 25℃at 10℃per minute, and then raised to 127℃at 5℃per minute. The crystal is nitrendipine flat crystal form II, and the yield is 3.7 percent.
Example 2
(1) Taking 700mg of nitrendipine, adding 6mL of isopropanol, heating to 75 ℃, fully stirring to dissolve the nitrendipine with the concentration of 117 mg.mL -1 . The mixture was rapidly left to crystallize at 32 ℃. After crystallization for 10 hours, the crystals were collected and dried in vacuo at 40 ℃.
(2) Sampling about 5mg of the crystals of (1) in N 2 The temperature was raised from 25℃to 165℃at 5℃per minute under an atmosphere (50 mL/min) for 3min, then lowered to 25℃at 10℃per minute, and then raised to 127℃at 5℃per minute. The crystal is nitrendipine flat crystal form II, and the yield is 39.5%.
Example 3
(1) Taking 700mg of nitrendipine, adding 6mL of isopropanol, heating to 75 ℃, fully stirring to dissolve the nitrendipine, and concentrating117 mg/mL -1 . Rapidly placed at 40 ℃ for crystallization. After crystallization for 10 hours, the crystals were collected and dried in vacuo at 40 ℃.
(2) Sampling about 5mg of the crystals of (1) in N 2 The temperature was raised from 25℃to 165℃at 5℃per minute under an atmosphere (50 mL/min) for 3min, then lowered to 25℃at 10℃per minute, and then raised to 127℃at 5℃per minute. The crystal is nitrendipine flat crystal form II, and the yield is 84.2%.
Fig. 1 is a powder X-ray diffraction pattern of the prepared nitrendipine crystal form ii.
Example 4
(1) 450mg of nitrendipine is taken, 5mL of isopropanol is added, the temperature is raised to 75 ℃, and the mixture is fully stirred to dissolve the nitrendipine with the concentration of 90 mg.mL -1 . Rapidly placed at 40 ℃ for crystallization. After crystallization for 10 hours, the crystals were collected and dried in vacuo at 40 ℃.
(2) Sampling about 5mg of the crystals of (1) in N 2 The temperature was raised from 25℃to 165℃at 5℃per minute under an atmosphere (50 mL/min) for 3min, then lowered to 25℃at 10℃per minute, and then raised to 127℃at 5℃per minute. The crystal is nitrendipine flat crystal form II, and the yield is 17.6%.
Example 5
(1) 600mg of nitrendipine is taken, 6mL of isopropanol is added, the temperature is raised to 75 ℃, and the mixture is fully stirred to dissolve the nitrendipine with the concentration of 100 mg.mL -1 . Rapidly placed at 40 ℃ for crystallization. After crystallization for 10 hours, the crystals were collected and dried in vacuo at 40 ℃.
(2) Sampling about 5mg of the crystals of (1) in N 2 The temperature was raised from 25℃to 165℃at 5℃per minute under an atmosphere (50 mL/min) for 3min, then lowered to 25℃at 10℃per minute, and then raised to 127℃at 5℃per minute. The crystal is nitrendipine flat crystal form II, and the yield is 64.4%.
Fig. 2 is a DSC curve of nitrendipine form ii prepared by temperature-rising crystallization.
Example 6
(1) 600mg of nitrendipine is taken, 6mL of isopropanol is added, the temperature is raised to 75 ℃, and the mixture is fully stirred to dissolve the nitrendipine with the concentration of 100 mg.mL -1 . Rapidly placed at 40 ℃ for crystallization. After crystallization for 10 hours, the crystals were collected and dried in vacuo at 40 ℃.
(2) About 5mg of1) Middle crystal sample preparation in N 2 The temperature was raised from 25℃to 175℃at 5℃per minute under an atmosphere (50 mL/min) for 1 hour, then lowered to 25℃at 10℃per minute, and then raised to 127℃at 5℃per minute. The crystalline form II was nitrendipine and the yield was 34.7%.
Example 7
(1) 600mg of nitrendipine is taken, 6mL of isopropanol is added, the temperature is raised to 75 ℃, and the mixture is fully stirred to dissolve the nitrendipine with the concentration of 100 mg.mL -1 . Rapidly placed at 40 ℃ for crystallization. After crystallization for 10 hours, the crystals were collected and dried in vacuo at 40 ℃.
(2) Sampling about 5mg of the crystals of (1) in N 2 The temperature was raised from 25℃to 165℃at 5℃per minute under an atmosphere (50 mL/min) for 3min, then cooled to 25℃at 20℃per minute, and then raised to 127℃at 5℃per minute. The crystal is nitrendipine flat crystal form II, and the yield is 13.7%.
Example 8
(1) 600mg of nitrendipine is taken, 6mL of isopropanol is added, the temperature is raised to 75 ℃, and the mixture is fully stirred to dissolve the nitrendipine with the concentration of 100 mg.mL -1 . Rapidly placed at 40 ℃ for crystallization. After crystallization for 10 hours, the crystals were collected and dried in vacuo at 40 ℃.
(2) Sampling about 5mg of the crystals of (1) in N 2 The temperature was raised from 25℃to 165℃at 5℃per minute under an atmosphere (50 mL/min) for 3min, then lowered to 25℃at 10℃per minute and raised to 127℃at 2.5℃per minute. The crystal is nitrendipine flat crystal form II, and the yield is 100%.
Example 9
(1) 600mg of nitrendipine is taken, 6mL of isopropanol is added, the temperature is raised to 75 ℃, and the mixture is fully stirred to dissolve the nitrendipine with the concentration of 100 mg.mL -1 . Rapidly placed at 40 ℃ for crystallization. After crystallization for 10 hours, the crystals were collected and dried in vacuo at 40 ℃.
(2) Sampling about 5mg of the crystals of (1) in N 2 Heating from 25 ℃ to 165 ℃ at 5 ℃/min for 3min under the atmosphere (50 mL/min), cooling to 60 ℃ at 10 ℃/min, and carrying out isothermal treatment for 22h, wherein the crystal is nitrendipine crystal form II, and the yield is 100%.
Fig. 3 is a DSC curve of crystalline form ii of nitrendipine prepared by isothermal crystallization.
As can be seen by comparing fig. 2 and 3: FIG. 2 is a DSC curve of the temperature-rising crystallization, which occurs during the temperature rising process, so that a crystallization peak of the crystal form II occurs at 102-127 ℃, if the temperature rising is continued again, the crystal form II obtained during the temperature rising crystallization is melted, a melting peak occurs on the curve, and the yield can be calculated to be 64.4% according to the theoretical enthalpy value of the crystal form II. FIG. 3 is a temperature-rising DSC curve after completion of isothermal crystallization, and since the crystallization process thereof occurs at isothermal time, no crystallization peak appears on the DSC curve, and only the melting peak of form II generated by isothermal crystallization appears, the yield can be calculated to be 100%.
Fig. 4 a is a photograph of a nitrendipine crystal form ii prepared in example 5, which is observed under a thermal polarization microscope, and b is a photograph of a nitrendipine crystal form ii prepared in example 5, which is observed under a polarizer. As is clear from fig. 4, the crystallization of form ii did occur during the temperature rise, and it was observed that form ii was a long rod-like crystal, and exhibited a birefringence phenomenon under polarized light.
The present invention is described in detail above. It will be apparent to those skilled in the art that the present invention can be practiced in a wide range of equivalent parameters, concentrations, and conditions without departing from the spirit and scope of the invention and without undue experimentation. While the invention has been described with respect to specific embodiments, it will be appreciated that the invention may be further modified. In general, this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains.
Claims (6)
1. A process for preparing nitrendipine form ii comprising the steps of:
(1) Dissolving nitrendipine in an organic solvent to prepare a solution with a certain concentration;
(2) Placing the dissolved solution at a certain crystallization temperature, and rapidly crystallizing and separating out;
(3) Collecting crystals and drying;
(4) Heating the obtained crystal to a certain temperature at a certain heating rate, melting the crystal at a certain temperature, and then isothermal for a certain time;
(5) And cooling to a certain temperature at a certain cooling rate, performing isothermal crystallization for a certain time to obtain a target crystal, or directly cooling to room temperature at a certain cooling rate and then heating to a certain temperature at a certain rate to obtain the target crystal.
2. The method according to claim 1, characterized in that: in the step (1), the organic solvent is at least one selected from the following solvents: isopropanol, ethyl acetate, acetonitrile, tetrahydrofuran, methanol, acetone, ethanol, N-dimethylformamide, N-dimethylacetamide;
the concentration of the solution is 70-500 mg.mL -1 。
3. The method according to claim 1 or 2, characterized in that: in the step (2), the crystallization temperature is 0-50 ℃.
4. The method according to claim 1 or 2, characterized in that: in the step (4), the heating rate is 1-100 ℃/min;
the temperature is 165-210 ℃;
the isothermal time length after melting is 0-3 h.
5. The method according to claim 1 or 2, characterized in that: in the step (5), the cooling rate is 1-100 ℃/min;
the isothermal crystallization temperature is 60-80 ℃, and the isothermal time is 18-24 h.
6. The method according to claim 1 or 2, characterized in that: in the step (5), the heating rate is 1-100 ℃/min; the temperature rise crystallization temperature is 90-129 ℃.
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