CN112457252A - Metastable crystal form II of carbamazepine and preparation method thereof - Google Patents
Metastable crystal form II of carbamazepine and preparation method thereof Download PDFInfo
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- 239000013078 crystal Substances 0.000 title claims abstract description 121
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 title claims abstract description 99
- 229960000623 carbamazepine Drugs 0.000 title claims abstract description 98
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 238000001816 cooling Methods 0.000 claims abstract description 28
- 238000003756 stirring Methods 0.000 claims abstract description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000002904 solvent Substances 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 11
- 238000001035 drying Methods 0.000 claims abstract description 10
- 230000008569 process Effects 0.000 claims abstract description 7
- 238000001914 filtration Methods 0.000 claims abstract description 6
- 230000009471 action Effects 0.000 claims abstract description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 68
- 239000000377 silicon dioxide Substances 0.000 claims description 35
- 235000012239 silicon dioxide Nutrition 0.000 claims description 30
- 239000002105 nanoparticle Substances 0.000 claims description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 8
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 7
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 3
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 125000001165 hydrophobic group Chemical group 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 abstract description 13
- 230000008025 crystallization Effects 0.000 abstract description 13
- 238000009776 industrial production Methods 0.000 abstract description 2
- 230000009466 transformation Effects 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 28
- 239000000047 product Substances 0.000 description 19
- 239000012065 filter cake Substances 0.000 description 15
- 238000005406 washing Methods 0.000 description 10
- 239000002245 particle Substances 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 7
- 239000002002 slurry Substances 0.000 description 7
- 238000000967 suction filtration Methods 0.000 description 7
- 239000003814 drug Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 239000007787 solid Substances 0.000 description 3
- ZSMRRZONCYIFNB-UHFFFAOYSA-N 6,11-dihydro-5h-benzo[b][1]benzazepine Chemical group C1CC2=CC=CC=C2NC2=CC=CC=C12 ZSMRRZONCYIFNB-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000020925 Bipolar disease Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 150000004683 dihydrates Chemical group 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229960002036 phenytoin Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
- C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of a template agent induced metastable crystal form II of carbamazepine, which comprises the steps of dissolving a stable crystal form III of carbamazepine in an alcohol solvent under the stirring action, adding a template agent after the stable crystal form III of carbamazepine is completely dissolved, cooling and crystallizing under continuous stirring, filtering and drying to obtain a crystal product of the metastable crystal form II of carbamazepine; the invention also provides a metastable crystal form II of carbamazepine, wherein the grain diameter of the crystal product is 200-400 mu m, and the water solubility is 80-110 mg/L. The method has simple process, uses the surface-modified template agent to stably induce the crystallization of the metastable crystal form II, avoids the transformation of the metastable crystal form II to the stable crystal form III, has low operation cost and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of chemical engineering crystallization. More specifically, the invention relates to a metastable crystal form II of carbamazepine and a preparation method thereof.
Background
Carbamazepine (C)15H12N2O, 236.27g/mol, CAS NO:298-46-4), is a drug for the treatment of epilepsy and neuropathic pain, and can be used with other drugs such as phenytoin for the treatment of schizophrenia, or for second-line administration of bipolar disorder. Carbamazepine was first discovered in 1953 by the swiss chemist in watt sinderler and was first marketed in 1962. With medicineAs industrial development and a great deal of researchers have realized that the solid form of the drug largely determines the therapeutic effect of the drug, a great deal of research and development work on the solid form of carbamazepine is carried out, and a plurality of solid forms of carbamazepine, including 5 anhydrous polymorphic structures (crystal form i, crystal form ii, crystal form iii, crystal form iv and crystal form v), 1 dihydrate structure and a plurality of solvate structures, have been developed. Among the 5 anhydrous polymorphic structures, the crystal form III has the most thermodynamically stable structure, and other crystal forms belong to metastable crystal forms, are unstable at normal temperature and are easily converted into the crystal form III. However, the metastable crystal form II of carbamazepine has the highest water solubility, the water solubility is up to 90mg/L at 25 ℃, and the water solubility of the stable crystal form III is only 18mg/L, which means that the metastable crystal form II of carbamazepine has good absorption performance by human body when being used as a final treatment medicament, thereby bringing the best treatment effect. Therefore, a stable and controllable preparation method of the metastable crystal form II crystal product of carbamazepine needs to be developed, and the stable crystal form III is prevented from being converted at normal temperature. However, the existing preparation methods of carbamazepine relate to stable crystal form III, and almost no stable and controllable preparation method of metastable crystal form II is reported.
Chinese patent CN1616433A discloses a carbamazepine drug and a preparation method thereof, the technical scheme adopts multi-step reactions such as condensation, reduction, cyclization, acyl chlorination, bromination, ammoniation, refining and the like, the process is complex, organic solvents are used too much, the purity of the final product is low, impurities are difficult to remove, and a metastable crystal form II of carbamazepine is not formed. Chinese patent CN106117141A discloses a method for synthesizing carbamazepine, which adopts an iminodibenzyl catalytic dehydrogenation mode, then an imino reagent is added, the reaction is carried out to prepare iminoformyl chloride, the carbamazepine is obtained by continuous reaction, the process is also complex, the yield is low, a large amount of toxic solvent is required to be added in the preparation process, the energy consumption is high, the three wastes treatment cost is high, and the prepared carbamazepine crystal form is a stable crystal form III and is not a metastable crystal form II. Chinese patent CN108863933A discloses a method for synthesizing carbamazepine, which comprises using iminodibenzyl and chlorobenzene as raw materials, introducing triphosgene to obtain acid chloride, brominating with bromine to obtain bromide, and ammoniating with ammonia water to obtain a crude product of carbamazepine.
In conclusion, the existing preparation methods for carbamazepine all relate to stable crystal form III, and no stable and controllable preparation method report for metastable crystal form II.
Disclosure of Invention
An object of the present invention is to solve at least the above problems and to provide at least the advantages described later.
The invention also aims to provide a stable and controllable preparation method of the metastable crystal form II of carbamazepine and further provide the metastable crystal form II of carbamazepine, which solves the defect of poor dissolving property of the stable crystal form III of the existing carbamazepine.
In order to achieve these objects and other advantages in accordance with the present invention, there is provided a process for preparing a template-induced metastable crystal form ii of carbamazepine, comprising dissolving stable crystal form iii of carbamazepine in an alcoholic solvent under stirring, adding a template after complete dissolution, cooling for crystallization under continuous stirring, filtering, and drying to obtain a crystal product of metastable crystal form ii of carbamazepine.
Preferably, the mass ratio of the stable crystal form III of carbamazepine to the alcohol solvent is 1-3: 10;
the temperature of the alcohol solvent is 40-60 ℃;
the alcohol solvent is one of methanol, ethanol, n-propanol, isopropanol or n-butanol.
Preferably, the mass ratio of the template to the stable crystal form III of carbamazepine is 1-5: 100.
preferably, the template agent is silica nanoparticles with phenyl hydrophobic groups modified on the surface;
the size of the silicon dioxide nano-particles is 300-800 nm.
Preferably, the cooling rate of the cooling crystallization is 5-15 ℃/min, and the cooling is carried out to 5-25 ℃.
Preferably, in the cooling process, adding ethyl acetate into the mixture at intervals of 20-30 s until the cooling end temperature, wherein the volume ratio of the ethyl acetate added in a single time to the alcohol solvent is 1: 50-80 parts.
Preferably, the washing is carried out by adopting a mixed solution of diethyl ether and methyl isobutyl ketone during the filtration, and the volume ratio of the diethyl ether to the methyl isobutyl ketone is 1: 2-3.
The invention also provides a metastable crystal form II of carbamazepine, which is prepared by a preparation method of inducing the metastable crystal form II of carbamazepine by using a template agent.
The invention also provides a metastable crystal form II of carbamazepine, wherein the grain diameter of a crystal product of the metastable crystal form II of carbamazepine is 200-400 mu m, and the water solubility is 80-110 mg/L.
The invention also provides a metastable crystal form II of carbamazepine, and an x-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 theta of 5.2 +/-0.2, 8.1 +/-0.2, 12.8 +/-0.1, 15.5 +/-0.2, 18.9 +/-0.2, 20.3 +/-0.1 and 24.8 +/-0.1.
The invention at least comprises the following beneficial effects:
based on crystal structure science, the stable crystal form III and the metastable crystal form II of carbamazepine are firstly researched, and the fact that the phenyl-phenyl nonpolar action is mainly used in the metastable crystal form II structure and the polar action is mainly used in the stable crystal form structure is found. The invention uses nano-silica nanoparticles as a template, modifies phenyl groups on the surface of the nano-silica nanoparticles, induces the metastable crystal form II to crystallize through the interaction of the phenyl groups on the surface of the template and the phenyl groups in the carbamazepine molecule, and prepares the carbamazepine metastable crystal form II with uniform particle size, high purity and good solubility. The method has simple process, is characterized in that the preparation and surface modification of the template agent are used for stably inducing the crystallization of the metastable crystal form II, avoiding the transformation of the metastable crystal form II to the stable crystal form III, having low operation cost and being suitable for industrial production. According to the invention, ethyl acetate is added in the crystallization process, so that the quality yield of the metastable crystal form II of carbamazepine can be improved. According to the invention, the water solubility of the metastable crystal form II of carbamazepine can be improved by washing with a mixed solution of diethyl ether and methyl isobutyl ketone during filtration.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention.
Drawings
FIG. 1 is an XRD pattern of a metastable crystalline form II and stable crystalline form III starting material of carbamazepine prepared in example 1 of the present invention;
FIG. 2 is a scanning electron microscope image of silica nanoparticles with phenyl groups modified on the surface by a template used in example 1 of the present invention;
FIG. 3 is a microscopic image of a metastable crystalline form II product of carbamazepine prepared in accordance with example 1 of the present invention and a stable crystalline form III starting material.
Detailed Description
The present invention is further described in detail below with reference to examples so that those skilled in the art can practice the invention with reference to the description.
It is to be noted that the experimental methods described in the following embodiments are all conventional methods unless otherwise specified, and the reagents and materials are commercially available unless otherwise specified.
Example 1
A preparation method of the metastable crystal form II of carbamazepine comprises the following steps:
(1) taking 10g of carbamazepine stable crystal form III with the purity of 95 percent and 100g of ethanol solvent, heating to 40 ℃, and adopting 100rpm
Stirring and dissolving by a paddle to form a uniform solution, wherein the concentration of carbamazepine in the solution is 10%;
(2) taking 0.1g of silicon dioxide nanoparticles with modified phenyl groups on the surfaces, and adding the silicon dioxide nanoparticles into the solution, wherein the mass ratio of the silicon dioxide to the carbamazepine is 1: 100, continuously keeping the stirring speed at 100rpm to uniformly disperse the silicon dioxide nano particles in the solution;
(3) starting cooling crystallization, setting the end point temperature to be 5 ℃, the cooling rate to be 5 ℃/min, and keeping the stirring speed of the paddle to be 100 rpm;
(4) carrying out suction filtration and washing on the crystal slurry to obtain a filter cake, and drying the filter cake at normal temperature for 24 hours to obtain a metastable crystal form II crystal product of carbamazepine;
the product has a main particle size of 200 μm, a purity of 99.5%, a mass yield of 85% and a water solubility of 80 mg/L.
The x-ray powder diffraction pattern of the crystal product of the metastable crystal form II of carbamazepine has characteristic peaks at diffraction angles 2 theta of 5.2 +/-0.2, 8.1 +/-0.2, 12.8 +/-0.1, 15.5 +/-0.2, 18.9 +/-0.2, 20.3 +/-0.1 and 24.8 +/-0.1.
Example 2
A preparation method of the metastable crystal form II of carbamazepine comprises the following steps:
(1) taking 20g of carbamazepine stable crystal form III with the purity of 95 percent and 100g of methanol solvent, heating to 50 ℃, and adopting 200rpm
Stirring and dissolving by a paddle to form a uniform solution, wherein the concentration of carbamazepine in the solution is 20%;
(2) taking 1g of silicon dioxide nanoparticles with modified phenyl groups on the surfaces, and adding the silicon dioxide nanoparticles into the solution, wherein the mass ratio of silicon dioxide to carbamazepine is 5: 100, continuously keeping the stirring speed at 200rpm to uniformly disperse the silicon dioxide nano particles in the solution;
(3) starting cooling crystallization, setting the end point temperature to be 10 ℃, setting the cooling rate to be 10 ℃/min, and keeping the stirring speed of the paddle to be 200 rpm;
(4) carrying out suction filtration and washing on the crystal slurry to obtain a filter cake, and drying the filter cake at normal temperature for 24 hours to obtain a metastable crystal form II crystal product of carbamazepine;
the product has a main particle size of 300 μm, a purity of 99.8%, a mass yield of 83% and a water solubility as high as 90 mg/L.
Example 3
A preparation method of the metastable crystal form II of carbamazepine comprises the following steps:
(1) taking 30g of a stable crystal form III of carbamazepine with the purity of 95% and 100g of an isopropanol solvent, heating to 60 ℃, and stirring and dissolving by adopting a blade at 300rpm to form a uniform solution, wherein the concentration of the carbamazepine in the solution is 30%;
(2) taking 0.6g of silicon dioxide nanoparticles with modified phenyl groups on the surfaces, and adding the silicon dioxide nanoparticles into the solution, wherein the mass ratio of the silicon dioxide to the carbamazepine is 2: 100, continuously keeping the stirring speed at 300rpm to uniformly disperse the silicon dioxide nano particles in the solution;
(3) starting cooling crystallization, setting the end point temperature to be 20 ℃, setting the cooling rate to be 15 ℃/min, and keeping the stirring speed of the blades to be 300 rpm;
(4) carrying out suction filtration and washing on the crystal slurry to obtain a filter cake, and drying the filter cake at normal temperature for 24 hours to obtain a metastable crystal form II crystal product of carbamazepine;
the product has a main particle size of 400 μm, a purity of 99.7%, a mass yield of 82% and a water solubility of up to 100 mg/L.
Example 4
The stable and controllable preparation method of the metastable crystal form II of carbamazepine comprises the following steps:
(1) taking 25g of a stable crystal form III of 95% carbamazepine and 100g of an n-propanol solvent, heating to 55 ℃, and stirring and dissolving by using a blade at 300rpm to form a uniform solution, wherein the concentration of the carbamazepine in the solution is 25%;
(2) taking 0.75g of silicon dioxide nanoparticles with modified phenyl groups on the surfaces, and adding the silicon dioxide nanoparticles into the solution, wherein the mass ratio of the silicon dioxide to the carbamazepine is 3: 100, continuously keeping the stirring speed at 300rpm to uniformly disperse the silicon dioxide nano particles in the solution;
(3) starting cooling crystallization, setting the end point temperature to be 25 ℃, setting the cooling rate to be 15 ℃/min, and keeping the stirring speed of the blades to be 300 rpm;
(4) carrying out suction filtration and washing on the crystal slurry to obtain a filter cake, and drying the filter cake at normal temperature for 24 hours to obtain a metastable crystal form II crystal product of carbamazepine;
the product has a main particle size of 300 μm, a purity of 99.6%, a mass yield of 83%, and a water solubility of 100 mg/L.
Example 5
The stable and controllable preparation method of the metastable crystal form II of carbamazepine comprises the following steps:
(1) taking 15g of the stable crystal form III of the carbamazepine with the purity of 95 percent and 100g of n-butanol solvent, heating to 55 ℃, and stirring and dissolving by adopting a blade at 200rpm to form a uniform solution, wherein the concentration of the carbamazepine in the solution is 15 percent;
(2) taking 0.3g of silicon dioxide nanoparticles with modified phenyl groups on the surfaces, and adding the silicon dioxide nanoparticles into the solution, wherein the mass ratio of the silicon dioxide to the carbamazepine is 2: 100, continuously keeping the stirring speed at 200rpm to uniformly disperse the silicon dioxide nano particles in the solution;
(3) starting cooling crystallization, setting the end point temperature to be 15 ℃, the cooling rate to be 10 ℃/min, and keeping the stirring speed of the paddle to be 200 rpm;
(4) carrying out suction filtration and washing on the crystal slurry to obtain a filter cake, and drying the filter cake at normal temperature for 24 hours to obtain a metastable crystal form II crystal product of carbamazepine;
the product has a main particle size of 200 μm, a purity of 99.8%, a mass yield of 80% and a water solubility of up to 90 mg/L.
Example 6
The stable and controllable preparation method of the metastable crystal form II of carbamazepine comprises the following steps:
(1) taking 15g of the stable crystal form III of the carbamazepine with the purity of 95 percent and 100g of n-propanol solvent, heating to 50 ℃, and stirring and dissolving by adopting a paddle with the speed of 200rpm to form a uniform solution, wherein the concentration of the carbamazepine in the solution is 15 percent;
(2) taking 0.4g of silicon dioxide nanoparticles with modified phenyl groups on the surfaces, and adding the silicon dioxide nanoparticles into the solution, wherein the mass ratio of the silicon dioxide to the carbamazepine is 2: 75, continuously keeping the stirring speed at 200rpm to uniformly disperse the silicon dioxide nano particles in the solution;
(3) starting cooling crystallization, setting the end point temperature to be 20 ℃, the cooling rate to be 10 ℃/min, and keeping the stirring speed of the paddle to be 200 rpm; and (3) cooling and crystallizing, adding ethyl acetate into the mixture at intervals of 20-30 s, cooling to the set end point temperature, wherein the volume of ethyl acetate added once is 1: 50-80 parts;
(4) carrying out suction filtration and washing on the crystal slurry to obtain a filter cake, and drying the filter cake at normal temperature for 24 hours to obtain a metastable crystal form II crystal product of carbamazepine;
the product has a main particle size of 200 μm, a purity of 99.8%, a mass yield of 90% and a water solubility as high as 92 mg/L.
Example 7
The stable and controllable preparation method of the metastable crystal form II of carbamazepine comprises the following steps:
(1) taking 10g of a stable crystal form III of carbamazepine with the purity of 95%, 100g of an ethanol solvent, heating to 45 ℃, and stirring and dissolving by adopting a paddle with the speed of 200rpm to form a uniform solution, wherein the concentration of the carbamazepine in the solution is 10%;
(2) taking 0.5g of silicon dioxide nanoparticles with modified phenyl groups on the surfaces, and adding the silicon dioxide nanoparticles into the solution, wherein the mass ratio of the silicon dioxide to the carbamazepine is 5: 100, continuously keeping the stirring speed at 200rpm to uniformly disperse the silicon dioxide nano particles in the solution;
(3) starting cooling crystallization, setting the end point temperature to be 15 ℃, the cooling rate to be 10 ℃/min, and keeping the stirring speed of the paddle to be 200 rpm;
(4) carrying out suction filtration on the crystal slurry, washing a filter cake by adopting a mixed solution of diethyl ether and methyl isobutyl ketone, wherein the volume ratio of the diethyl ether to the methyl isobutyl ketone is 1: 2-3, obtaining the filter cake after washing, and drying the filter cake at normal temperature for 24 hours to obtain a metastable crystal form II crystal product of carbamazepine;
the product has a main particle size of 300 μm, a purity of 99.8%, a mass yield of 84%, and a water solubility as high as 110 mg/L.
While embodiments of the invention have been described above, it is not limited to the applications set forth in the description and the embodiments, which are fully applicable to various fields of endeavor for which the invention may be embodied with additional modifications as would be readily apparent to those skilled in the art, and the invention is therefore not limited to the details given herein and to the embodiments shown and described without departing from the generic concept as defined by the claims and their equivalents.
Claims (10)
1. A preparation method of a template agent induced metastable crystal form II of carbamazepine is characterized in that a stable crystal form III of carbamazepine is dissolved in an alcohol solvent under the stirring action, after the stable crystal form III of carbamazepine is completely dissolved, a template agent is added into the stable crystal form III of carbamazepine, the mixture is cooled and crystallized under the continuous stirring, and a crystal product of the metastable crystal form II of carbamazepine is obtained through filtering and drying.
2. The method for preparing the metastable crystal form II of carbamazepine induced by the template agent according to claim 1, wherein the mass ratio of the stable crystal form III of carbamazepine to the alcohol solvent is 1-3: 10;
the temperature of the alcohol solvent is 40-60 ℃;
the alcohol solvent is one of methanol, ethanol, n-propanol, isopropanol or n-butanol.
3. The method for preparing the template-induced metastable crystal form II of carbamazepine according to claim 1, wherein the mass ratio of the template to the stable crystal form III of carbamazepine is 1-5: 100.
4. the method for preparing the template-induced metastable crystal form II of carbamazepine according to claim 1, characterized in that the template is silica nanoparticles with phenyl hydrophobic groups modified on the surface;
the size of the silicon dioxide nano-particles is 300-800 nm.
5. The method for preparing the metastable crystal form II of carbamazepine induced by the template agent according to claim 1, wherein the cooling rate of the cooling crystal is 5-15 ℃/min and the cooling is 5-25 ℃.
6. The method for preparing the template-induced metastable crystal form II of carbamazepine according to claim 1, characterized in that ethyl acetate is added into the mixture at intervals of 20-30 s in the cooling process until the cooling end temperature, and the volume ratio of the single addition of ethyl acetate to the volume of the alcoholic solvent is 1: 50-80 parts.
7. The method for preparing the metastable crystal form II of carbamazepine induced by the template agent according to claim 1, characterized in that the metastable crystal form II of carbamazepine is washed by a mixed solution of diethyl ether and methyl isobutyl ketone during filtration, and the volume ratio of the diethyl ether to the methyl isobutyl ketone is 1: 2-3.
8. A metastable crystal form II of carbamazepine, which is characterized by being prepared by using the preparation method of any one of claims 1 to 7.
9. The metastable crystal form II of carbamazepine is characterized in that the grain diameter of a crystal product of the metastable crystal form II of carbamazepine is 200-400 mu m, and the water solubility is 80-110 mg/L.
10. A metastable crystal form II of carbamazepine is characterized in that an x-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 theta of 5.2 +/-0.2, 8.1 +/-0.2, 12.8 +/-0.1, 15.5 +/-0.2, 18.9 +/-0.2, 20.3 +/-0.1 and 24.8 +/-0.1.
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Non-Patent Citations (2)
| Title |
|---|
| JOSE V. PARAMBIL ET AL.: "Template-induced polymorphic selectivity: the effects of surface chemistry and solute concentration on carbamazepine crystallisation", 《CRYSTENGCOMM》 * |
| WENJU LIU ET AL.: "Investigation into the Cooling Crystallization and Transformations of Carbamazepine Using in Situ FBRM and PVM", 《ORG. PROCESS RES. DEV.》 * |
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