CN115745897B - Clozapine recrystallization method - Google Patents
Clozapine recrystallization method Download PDFInfo
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- CN115745897B CN115745897B CN202211394922.6A CN202211394922A CN115745897B CN 115745897 B CN115745897 B CN 115745897B CN 202211394922 A CN202211394922 A CN 202211394922A CN 115745897 B CN115745897 B CN 115745897B
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- clozapine
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- stirring
- eutectic solvent
- feeding
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- 229960004170 clozapine Drugs 0.000 title claims abstract description 39
- QZUDBNBUXVUHMW-UHFFFAOYSA-N clozapine Chemical compound C1CN(C)CCN1C1=NC2=CC(Cl)=CC=C2NC2=CC=CC=C12 QZUDBNBUXVUHMW-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 238000000034 method Methods 0.000 title claims abstract description 25
- 238000001953 recrystallisation Methods 0.000 title description 5
- 239000002904 solvent Substances 0.000 claims abstract description 47
- 230000005496 eutectics Effects 0.000 claims abstract description 27
- 239000013078 crystal Substances 0.000 claims abstract description 20
- 238000002425 crystallisation Methods 0.000 claims abstract description 18
- 230000008025 crystallization Effects 0.000 claims abstract description 18
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 11
- 239000000047 product Substances 0.000 claims abstract description 10
- 239000007788 liquid Substances 0.000 claims abstract description 6
- 238000000926 separation method Methods 0.000 claims abstract description 5
- 238000001035 drying Methods 0.000 claims abstract description 4
- 239000012065 filter cake Substances 0.000 claims abstract description 4
- 238000005406 washing Methods 0.000 claims abstract description 4
- 238000003756 stirring Methods 0.000 claims description 21
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 9
- 239000000725 suspension Substances 0.000 claims description 7
- 239000002002 slurry Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 239000010413 mother solution Substances 0.000 claims description 4
- 239000001763 2-hydroxyethyl(trimethyl)azanium Substances 0.000 claims description 3
- 235000019743 Choline chloride Nutrition 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- SGMZJAMFUVOLNK-UHFFFAOYSA-M choline chloride Chemical group [Cl-].C[N+](C)(C)CCO SGMZJAMFUVOLNK-UHFFFAOYSA-M 0.000 claims description 3
- 229960003178 choline chloride Drugs 0.000 claims description 3
- 238000010907 mechanical stirring Methods 0.000 claims description 3
- 239000012452 mother liquor Substances 0.000 claims description 3
- 239000000243 solution Substances 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 abstract description 4
- 238000005265 energy consumption Methods 0.000 abstract description 3
- 239000000706 filtrate Substances 0.000 abstract 1
- 238000000746 purification Methods 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 230000007547 defect Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- CWXVMYDJJNKKQC-UHFFFAOYSA-N [ClH]1N=CC=CC=C1 Chemical compound [ClH]1N=CC=CC=C1 CWXVMYDJJNKKQC-UHFFFAOYSA-N 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- 206010001497 Agitation Diseases 0.000 description 1
- 206010003805 Autism Diseases 0.000 description 1
- 208000020706 Autistic disease Diseases 0.000 description 1
- 208000020925 Bipolar disease Diseases 0.000 description 1
- 206010012239 Delusion Diseases 0.000 description 1
- 208000004547 Hallucinations Diseases 0.000 description 1
- 208000031555 Treatment-Resistant Schizophrenia Diseases 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 208000028683 bipolar I disease Diseases 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 231100000868 delusion Toxicity 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 208000029252 treatment-refractory schizophrenia Diseases 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to a method for recrystallizing clozapine. The technical proposal is as follows: adding a eutectic solvent and a coarse clozapine product into a crystallization kettle, crystallizing out the clozapine by adopting a method of program feeding and a solvent separating agent, carrying out solid-liquid separation after crystallization is finished, washing a filter cake, and drying to obtain the clozapine crystal. The invention has the advantages of environment-friendly solvent system, recyclable and recyclable eutectic solvent in filtrate, and the like. The method disclosed by the invention has the advantages that an organic solvent is not needed, the post-treatment process is simple, the efficiency is high, the solvent system is environment-friendly, the eutectic solvent can be recycled, the energy consumption of industrial crystallization operation of clozapine is obviously reduced, the quality of clozapine crystal products is effectively improved, and the method is a novel efficient separation and purification method for clozapine.
Description
Technical Field
The invention belongs to the technical field of clozapine production, and particularly relates to a method for recrystallizing clozapine.
Background
Clozapine is a well-known third-generation atypical antipsychotic drug which has a good effect on clinically treating negative and positive symptoms of schizophrenia, and is mainly used for treating schizophrenia and manic depression. Clozapine, an excellent antipsychotic with less side effects, can be administered orally and also treated by intramuscular injection. Clozapine is a first drug approved for treating refractory schizophrenia, has a certain curative effect on controlling symptoms such as agitation behavior, action behavior disturbance and the like of patients, and has a good curative effect on patients with symptoms such as hallucinations, delusions, autism, fear, withdrawal and the like.
However, clozapine is almost insoluble in water, and its low solubility and high permeability are classified as BCS (biopharmaceutical classification system) class II drugs, with low bioavailability. Moreover, because of its almost water-insoluble nature, a large amount of highly toxic organic solvents such as toluene, chloroform, etc. are required in the clozapine synthesis process. When manufacturers at home and abroad carry out recrystallization refining on clozapine, solvents such as isopropanol, ethanol and the like are mostly adopted to dissolve a clozapine crude product, however, the solubility of clozapine in alcohol solvents is still smaller, so that the defects of high solvent consumption, high waste liquid, high solvent recovery rate and the like in the industrial crystallization process are caused.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and aims to provide a clozapine recrystallization method.
In order to achieve the above purpose, the technical scheme adopted by the invention comprises the following specific steps:
adding a eutectic solvent and a coarse clozapine product into a crystallization kettle, wherein the feeding mass ratio of the eutectic solvent to the coarse clozapine product is 100-1000, and stirring for 5-30 min at the constant temperature of 20-100 ℃ to obtain a clozapine crystallization mother solution;
step two, adding a solvent into the chlorzapine crystal mother solution prepared in the step one in a program flow manner to prepare suspension crystal slurry;
and thirdly, leading out the suspension crystal slurry prepared in the second step for solid-liquid separation, washing and drying a filter cake to obtain the clozapine crystal.
The eutectic solvent is prepared by mixing a hydrogen bond donor and a hydrogen bond acceptor, wherein the hydrogen bond donor is choline chloride, the hydrogen bond acceptor is one of glycol, glycerol and urea, the molar ratio of the hydrogen bond acceptor to the hydrogen bond donor in the eutectic solvent is 1 (1-4), and the colorless transparent solution prepared by stirring at 80-100 ℃ for 30-120 min is the eutectic solvent.
The procedure of feeding the solvent-out agent is to add the solvent-out agent in stages, and the solvent-out agent with the mass 0.1-1.0 times of the feeding mass of the eutectic solvent is firstly added continuously, and the feeding time is 10-30 min; stirring at constant temperature for 10-30 min; then continuously adding a solvent-out agent with the mass 1.0-3.0 times of the feeding mass of the eutectic solvent, wherein the feeding time is 60-180 min; continuously adding a solvent out of which the feeding mass is 3.0-6.0 times of that of the eutectic solvent, wherein the feeding time is 30-60 min; then stirring for 10-30 min at constant temperature.
The solvent is water.
The crystallization kettle is a jacket stirring reaction kettle with controllable temperature.
The stirring is mechanical stirring, and the stirring speed is 100 r/min-300 r/min.
By adopting the technical scheme, compared with the prior art, the invention has the following positive effects:
(1) The existing chlorzapine crystallization process mostly adopts organic solvents with relatively high toxicity, such as toluene, chloroform and the like, and the crystallization mode mostly adopts the steps of evaporating, concentrating and cooling crystallization, so that the defects of high energy consumption, large use of toxic organic solvents, large waste liquid and the like are overcome. The method for recrystallizing clozapine adopts the green solvent, namely the eutectic solvent, wherein the solvent system is green and environment-friendly, and the eutectic solvent can be recycled; in addition, evaporation operation is not carried out in the process of chlorazepine recrystallization, and liquid phase is continuously added by virtue of water of a solvent, so that chlorazepine crystals are separated out, and the supersaturation degree required by crystal growth can be conveniently regulated and controlled by changing the adding rate of the solvent, so that the method can obviously reduce the energy consumption of the industrial crystallization operation of the chlorazepine.
(2) The method for recrystallizing the clozapine, disclosed by the invention, avoids the defect that the suspension density of the crystallization mother liquor is continuously increased in the process of evaporative crystallization or cooling crystallization, and the continuous addition of the solvent water continuously increases the volume of a liquid phase, so that the phenomena of crushing and aggregation of crystal products can be greatly reduced, and the concentration of the particle size distribution of the clozapine crystal products is facilitated.
Detailed Description
The invention is further described in connection with the following detailed description, which is not intended to limit the scope of the invention.
Example 1
A method for recrystallizing clozapine comprises the following specific implementation steps:
adding a eutectic solvent and a coarse clozapine product into a crystallization kettle, wherein the feeding mass ratio of the eutectic solvent to the coarse clozapine product is 250-400, and stirring for 30min at a constant temperature of 40 ℃ to obtain a clozapine crystal mother solution;
step two, adding solvent water into the chlorzapine crystal mother liquor prepared in the step one in a program flow manner to prepare suspension crystal slurry;
and thirdly, leading out the suspension crystal slurry prepared in the second step for solid-liquid separation, washing and drying a filter cake to obtain the clozapine crystal.
The eutectic solvent is choline chloride and glycerol, the molar ratio is 1:2, and the colorless transparent solution prepared by stirring at 80 ℃ for 60min is the eutectic solvent.
The procedure of feeding the solvent-out agent is to add the solvent-out agent in stages, and the solvent-out agent with the mass 0.5-1.0 times of the feeding mass of the eutectic solvent is firstly added continuously, and the feeding time is 30min; stirring at constant temperature for 30min; then continuously adding a solvent out of which the feeding mass is 2.0-3.0 times of that of the eutectic solvent, wherein the feeding time is 120min; continuously adding a solvent which is 4.0 to 5.0 times of the feeding mass of the eutectic solvent, wherein the feeding time is 60 minutes; then stirring for 30min at constant temperature.
The crystallization kettle is a jacket stirring reaction kettle with controllable temperature.
The stirring is mechanical stirring, and the stirring speed is 200r/min.
Claims (3)
1. The method for recrystallizing clozapine is characterized by comprising the following steps of:
adding a eutectic solvent and a coarse clozapine product into a crystallization kettle, wherein the feeding mass ratio of the eutectic solvent to the coarse clozapine product is 250-400, and stirring for 30min at a constant temperature of 40 ℃ to obtain a clozapine crystal mother solution;
step two, adding solvent water into the chlorzapine crystal mother liquor prepared in the step one in a program flow manner to prepare suspension crystal slurry;
step three, leading out the suspension crystal slurry prepared in the step two for solid-liquid separation, washing and drying a filter cake to obtain a clozapine crystal,
the eutectic solvent is choline chloride and glycerol, the mol ratio is 1:2, the colorless transparent solution prepared by stirring for 60min at 80 ℃ is the eutectic solvent,
the procedure of feeding the solvent-out agent is to add the solvent-out agent in stages, and the solvent-out agent with the mass 0.5-1.0 times of the feeding mass of the eutectic solvent is firstly added continuously, and the feeding time is 30min; stirring at constant temperature for 30min; then continuously adding a solvent out of which the feeding mass is 2.0-3.0 times of that of the eutectic solvent, wherein the feeding time is 120min; continuously adding a solvent which is 4.0 to 5.0 times of the feeding mass of the eutectic solvent, wherein the feeding time is 60 minutes; then stirring for 30min at constant temperature.
2. The method for recrystallizing clozapine according to claim 1, wherein the crystallization kettle is a temperature-controllable jacketed stirring reaction kettle.
3. The method for recrystallizing clozapine according to claim 1, wherein the stirring is mechanical stirring with a stirring speed of 200r/min.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211394922.6A CN115745897B (en) | 2022-11-09 | 2022-11-09 | Clozapine recrystallization method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211394922.6A CN115745897B (en) | 2022-11-09 | 2022-11-09 | Clozapine recrystallization method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115745897A CN115745897A (en) | 2023-03-07 |
| CN115745897B true CN115745897B (en) | 2024-03-22 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211394922.6A Active CN115745897B (en) | 2022-11-09 | 2022-11-09 | Clozapine recrystallization method |
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| Country | Link |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109381433A (en) * | 2018-09-18 | 2019-02-26 | 浙江工业大学 | A method of preparing the polymer microsphere of load indissoluble flavonoids drug using eutectic solvent |
| CN114149374A (en) * | 2021-12-22 | 2022-03-08 | 齐鲁工业大学 | Preparation method of highly-dispersed clozapine bulk drug crystal particles |
| CN115160239A (en) * | 2022-07-08 | 2022-10-11 | 山东省分析测试中心 | Preparation method of clozapine fine powder |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX2019003010A (en) * | 2016-09-17 | 2019-11-28 | Intas Pharmaceuticals Ltd | Extended release pharmaceutical composition of clozapine. |
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2022
- 2022-11-09 CN CN202211394922.6A patent/CN115745897B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109381433A (en) * | 2018-09-18 | 2019-02-26 | 浙江工业大学 | A method of preparing the polymer microsphere of load indissoluble flavonoids drug using eutectic solvent |
| CN114149374A (en) * | 2021-12-22 | 2022-03-08 | 齐鲁工业大学 | Preparation method of highly-dispersed clozapine bulk drug crystal particles |
| CN115160239A (en) * | 2022-07-08 | 2022-10-11 | 山东省分析测试中心 | Preparation method of clozapine fine powder |
Non-Patent Citations (2)
| Title |
|---|
| "Enhancement of clozapine solubility in three aqueous choline chloridebased deep eutectic solvents: Experimental and COSMO-RS prediction";Chunrong Li等;《Journal of Molecular Liquids》;第359卷;第1-15页 * |
| "氯氮平的固液相平衡及结晶工艺研究";弓祎;《中国优秀硕士学位论文全文数据库 工程科技I辑》(第5期);第22-23, 69页 * |
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| CN115745897A (en) | 2023-03-07 |
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