CN116332832A - Maleic acid levo-amlodipine amorphous crystal form and preparation method thereof - Google Patents
Maleic acid levo-amlodipine amorphous crystal form and preparation method thereof Download PDFInfo
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title claims abstract description 88
- HTIQEAQVCYTUBX-KRWDZBQOSA-N (S)-amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-KRWDZBQOSA-N 0.000 title claims abstract description 87
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 title claims abstract description 87
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 title claims abstract description 84
- 239000011976 maleic acid Substances 0.000 title claims abstract description 84
- 229950008554 levamlodipine Drugs 0.000 title claims abstract description 77
- 239000013078 crystal Substances 0.000 title claims abstract description 57
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 238000010438 heat treatment Methods 0.000 claims abstract description 38
- 238000004321 preservation Methods 0.000 claims abstract description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 57
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 19
- TZNOWAJJWCGILX-HNUXRKMMSA-N (z)-but-2-enedioic acid;3-o-ethyl 5-o-methyl (4s)-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound OC(=O)\C=C/C(O)=O.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC=C1Cl TZNOWAJJWCGILX-HNUXRKMMSA-N 0.000 claims description 15
- 238000001704 evaporation Methods 0.000 claims description 7
- 230000008020 evaporation Effects 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 239000012046 mixed solvent Substances 0.000 claims description 5
- 229940079593 drug Drugs 0.000 abstract description 13
- 239000003814 drug Substances 0.000 abstract description 13
- 239000000243 solution Substances 0.000 description 12
- 238000001816 cooling Methods 0.000 description 9
- 229960000528 amlodipine Drugs 0.000 description 7
- 238000002441 X-ray diffraction Methods 0.000 description 6
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- ZPBWCRDSRKPIDG-UHFFFAOYSA-N amlodipine benzenesulfonate Chemical compound OS(=O)(=O)C1=CC=CC=C1.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl ZPBWCRDSRKPIDG-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229960004005 amlodipine besylate Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010030124 Oedema peripheral Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- OKLAEQBUDFSNDL-UHFFFAOYSA-N calcium;1,4-dihydropyridine Chemical compound [Ca].C1C=CNC=C1 OKLAEQBUDFSNDL-UHFFFAOYSA-N 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940127292 dihydropyridine calcium channel blocker Drugs 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 229940036132 norvasc Drugs 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 238000001144 powder X-ray diffraction data Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 229910052611 pyroxene Inorganic materials 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/13—Dicarboxylic acids
- C07C57/145—Maleic acid
-
- 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
-
- 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 belongs to the technical field of drug crystal forms, and particularly relates to an amorphous crystal form of maleic acid levamlodipine and a preparation method thereof. The invention provides a preparation method of maleic acid levo-amlodipine besylate amorphous crystal form, which comprises the following steps: heating maleic acid levamlodipine to perform heat treatment to obtain the maleic acid levamlodipine amorphous crystal form; the temperature of the heat treatment is 130-180 ℃, and the heat preservation time of the heat treatment is 5-60 min. The amorphous crystal form of the maleic acid levamlodipine is successfully prepared by controlling the temperature and the heat preservation time of the heat treatment within the reasonable range, and the amorphous crystal form of the maleic acid levamlodipine has high stability, and meanwhile, the preparation method provided by the invention has high yield, almost no loss and reduced medication cost.
Description
Technical Field
The invention belongs to the technical field of drug crystal forms, and particularly relates to an amorphous crystal form of maleic acid levamlodipine and a preparation method thereof.
Background
Amlodipine besylate (AmLodipine Besylate) is a third generation 1, 4-dihydropyridine calcium antagonist developed by the american pyroxene company in the 90 s of the 20 th century, and is commercially available under the name of luo-huo-xi (Norvasc), chemical name: 2- [ (2-aminoethoxy) methyl ] -4- (2-chlorophenyl) -3-ethoxyformyl-5-methoxyformyl-6-methyl-1, 4-dihydropyridine benzenesulfonate having the structural formula shown in formula 1:
amlodipine besylate is a long-term calcium channel blocker mainly used for treating cardiovascular diseases such as angina pectoris, hypertension and congestive heart failure, and is a drug for treating hypertension which is consistently recommended by the American FDA committee of cardiac and renal consultants.
In 1987, the study by j.e. arowsmith et al demonstrated that amlodipine has a structure containing two chiral enantiomers, wherein the levorotatory form shows excellent calcium antagonism, about 1000 times that of the dextrorotatory form, and that levamlodipine can alleviate side effects such as acroedema, headache, dizziness, etc. due to racemic amlodipine. Therefore, the adoption of the levamlodipine has great advantages compared with the racemization of the amlodipine. Wherein, the common levamlodipine acid salt is maleic acid levamlodipine, and the structure is shown as formula 2:
chinese patent CN201210545352.6 discloses a crystalline form of levo-amlodipine maleate and a preparation method thereof, which adopts anhydrous ethanol and ethyl acetate as crystallization systems, and the X-ray powder diffraction of the crystallization products has characteristic peaks at diffraction angles of 2θ of 13.1 °, 13.5 °, 15.6 °, 17.5 °, 22.5 °, 23.1 °, 26.4 °, 29.0 °, 30.2 ° and 35.3 °, and the melting point of the crystalline form is 172-176 ℃.
Although both amorphous and crystalline forms belong to the conventional solid state forms of a drug, crystalline forms have lower solubility and bioavailability than amorphous forms. The reason is that: amorphous is in a short-range ordered and long-range unordered state, free energy is higher, and amorphous drugs have higher solubility, however, the defect of amorphous with high free energy is very unstable, and a recrystallization process is easy to occur.
At present, no amorphous crystal form of the maleic acid levamlodipine is reported in the prior art, and no research on the stability of the amorphous crystal form of the maleic acid levamlodipine is available.
Disclosure of Invention
The invention aims to provide the maleic acid levamlodipine amorphous crystal form and the preparation method thereof, and the maleic acid levamlodipine amorphous crystal form provided by the invention has high stability and can improve the drug availability of maleic acid levamlodipine; the preparation method provided by the invention has high yield and effectively reduces the medication cost.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of maleic acid levo-amlodipine besylate amorphous crystal form, which comprises the following steps:
heating maleic acid levamlodipine to perform heat treatment to obtain the maleic acid levamlodipine amorphous crystal form;
the temperature of the heat treatment is 130-180 ℃, and the heat preservation time of the heat treatment is 5-60 min.
Preferably, the heat treatment has a holding time of 5 to 30 minutes.
The invention provides a preparation method of maleic acid levo-amlodipine besylate amorphous crystal form, which comprises the following steps:
dissolving maleic acid levamlodipine in a mixed solvent of lower alcohol and dichloromethane to obtain maleic acid levamlodipine solution; the volume ratio of the lower alcohol to the dichloromethane is 1 (0.9-5);
and removing the solvent from the maleic acid left-handed amlodipine solution to obtain the maleic acid left-handed amlodipine amorphous crystal form, wherein the solvent removal comprises vacuum concentration or heating evaporation.
Preferably, the lower alcohol is methanol and/or ethanol.
Preferably, the ratio of the mass of the maleic acid levamlodipine to the volume of the dichloromethane is 1g (8-15) mL.
Preferably, the ratio of the mass of the maleic acid levamlodipine to the volume of the dichloromethane is 1g to 10mL.
Preferably, the volume ratio of the lower alcohol to the dichloromethane is 1:1.
Preferably, the vacuum degree during vacuum concentration is-0.1 to-0.8 MPa;
the temperature of the heating evaporation is 10-60 ℃.
The invention provides the maleic acid levoamlodipine amorphous crystal form prepared by the preparation method.
The invention provides a preparation method of maleic acid levo-amlodipine besylate amorphous crystal form, which comprises the following steps: heating maleic acid levamlodipine to perform heat treatment to obtain the maleic acid levamlodipine amorphous crystal form; the temperature of the heat treatment is 130-180 ℃, and the heat preservation time of the heat treatment is 5-60 min. The amorphous crystal form of the maleic acid levamlodipine is successfully prepared by controlling the temperature and the heat preservation time of the heat treatment within the reasonable range, and the amorphous crystal form of the maleic acid levamlodipine has high stability, and meanwhile, the preparation method provided by the invention has high yield, almost no loss and reduced medication cost.
The invention provides a preparation method of maleic acid levo-amlodipine besylate amorphous crystal form, which comprises the following steps: dissolving maleic acid levamlodipine in a mixed solvent of lower alcohol and dichloromethane to obtain maleic acid levamlodipine solution; the volume ratio of the lower alcohol to the dichloromethane is 1 (0.9-5); and removing the solvent of the maleic acid levamlodipine solution under a vacuum condition to obtain the maleic acid levamlodipine amorphous crystal form. According to the invention, the maleic acid levamlodipine is dissolved by selecting a specific solvent type, and then recrystallized by vacuumizing to remove the solvent, under the condition of the solvent ratio, the maleic acid levamlodipine amorphous crystal form is successfully prepared, and the maleic acid levamlodipine amorphous crystal form has high stability, and meanwhile, the preparation method provided by the invention has high yield, almost no loss and reduced medication cost.
The invention provides the maleic acid levoamlodipine amorphous crystal form prepared by the preparation method. The maleic acid levamlodipine amorphous crystal form provided by the invention has the characteristic of high stability.
Drawings
Fig. 1 is an XPD spectrum of an amorphous crystalline form of levamlodipine maleate prepared in example 1 of the present invention;
fig. 2 is an XRD spectrum of the crystalline form of levoamlodipine maleate used in example 1 of the present invention.
Detailed Description
The invention provides a preparation method of maleic acid levo-amlodipine besylate amorphous crystal form, which comprises the following steps:
heating maleic acid levamlodipine to perform heat treatment to obtain the maleic acid levamlodipine amorphous crystal form;
the temperature of the heat treatment is 130-180 ℃, and the heat preservation time of the heat treatment is 5-60 min.
In the present invention, all preparation materials/components are commercially available products well known to those skilled in the art unless specified otherwise.
In the invention, the maleic acid levamlodipine is preferably prepared from homemade products.
In the invention, the maleic acid levoamlodipine is a maleic acid levoamlodipine crystal form, and the maleic acid levoamlodipine crystal form has peaks in the following positions in X-ray diffraction: 4.3.+ -. 0.2 °, 8.6.+ -. 0.2 °, 11.6.+ -. 0.2 °, 12.9.+ -. 0.2 °, 13.3.+ -. 0.2 °, 13.9.+ -. 0.2 °, 15.5.+ -. 0.2 °, 18.2.+ -. 0.2 °, 18.9.+ -. 0.2 °, 22.0.+ -. 0.2 °, 22.3.+ -. 0.2 °, 23.0.+ -. 0.2 °, 24.7.+ -. 0.2 °, 25.9.+ -. 0.2 °, 26.1.+ -. 0.2 °, 27.0.+ -. 0.2 ° and 28.9.+ -. 0.2 °.
In the present invention, the relative intensities of the 8.6±0.2° and 28.9±0.2° peaks are independently preferably not less than 10%.
In the present invention, the relative intensities of the 11.6±0.2°, 13.3±0.2°, 13.9±0.2°, 15.5±0.2°, 18.2±0.2°, 18.9±0.2°, 22.0±0.2°, 22.3±0.2°, 23.0±0.2°, 24.7±0.2°, 25.9±0.2°, 26.1±0.2° and 27.0±0.2° peaks are independently preferably not less than 15%.
In the present invention, the relative intensity of the 4.3±0.2° peak is preferably not less than 50%.
In the present invention, the relative intensity of the 12.9±0.2° peak is preferably 100%.
In the present invention, the melting point of the crystalline form of levoamlodipine maleate is preferably 176.1 to 179.0 ℃.
The invention also provides a preparation method of the maleic acid levo-amlodipine besylate crystal form, which comprises the following steps:
and mixing maleic acid levamlodipine, an alcohol solvent and a first solvent for recrystallization to obtain the maleic acid levamlodipine crystal form, wherein the first solvent is water or acetonitrile.
In the present invention, all materials used are commercial products in the art unless otherwise specified.
In the invention, the mass ratio of the maleic acid levamlodipine to the first solvent is preferably 1:3-15, more preferably 1:5-10; the mass ratio of the maleic acid levamlodipine to the alcohol solvent is preferably 1:0.5-8.5, more preferably 3:4-10; the mass ratio of the alcohol solvent to the first solvent is preferably 1.0:2.0-10.0, more preferably 4-10:30.
In the present invention, the alcohol solvent preferably includes one or more of methanol, ethanol, isopropanol and n-butanol.
The specific mode of the mixing is not particularly limited, and modes known to those skilled in the art may be adopted.
In the present invention, the recrystallization is preferably performed under a standing or stirring condition.
In the present invention, the rotation speed of the stirring is preferably 10 to 250 rpm, more preferably 50 to 200 rpm.
In the present invention, the recrystallization temperature is preferably-5 to 40 ℃, and the crystallization time is preferably 0 to 6 hours.
In the present invention, the recrystallization preferably includes the steps of: heating the mixed solution obtained by mixing to reflux, carrying out heat preservation and stirring after dissolving, cooling to carry out first preservation Wen Xijing, cooling to carry out second heat preservation and crystallization, carrying out suction filtration and drying to obtain the levamlodipine maleate crystal form.
In the present invention, the time for the incubation and stirring is preferably 30 minutes.
In the present invention, the temperature of the first protection Wen Xijing is preferably 20-25 ℃, the time is preferably 30min, and the cooling rate for cooling to the temperature of the first protection Wen Xijing is preferably 5-15 ℃/h.
In the invention, the temperature of the second heat preservation crystallization is preferably 0-5 ℃, the time is preferably 2 hours, and the cooling rate for cooling to the temperature of the second heat preservation crystallization is preferably 10-20 ℃/h.
The specific mode of the suction filtration and drying is not particularly limited in the present invention, and modes known to those skilled in the art may be adopted.
In the present invention, the temperature of the heat treatment is particularly preferably 130℃or 180 ℃,
in the present invention, the heat-treatment is preferably carried out for a period of 5 to 30 minutes, particularly preferably 5 minutes or 30 minutes.
In the invention, after the heat treatment, the heat treatment product is cooled to room temperature to obtain the maleic acid levamlodipine amorphous crystal form. The invention has no special requirements on the specific implementation mode of the cooling process.
The invention provides a preparation method of maleic acid levo-amlodipine besylate amorphous crystal form, which comprises the following steps:
dissolving maleic acid levamlodipine in a mixed solvent of lower alcohol and dichloromethane to obtain maleic acid levamlodipine solution; the volume ratio of the lower alcohol to the dichloromethane is 1 (0.9-5);
and removing the solvent of the maleic acid levamlodipine solution to obtain the maleic acid levamlodipine amorphous crystal form, wherein the solvent removal comprises vacuum concentration or heating evaporation.
The invention dissolves maleic acid L-amlodipine in a mixed solvent of lower alcohol and dichloromethane to obtain maleic acid L-amlodipine solution; the volume ratio of the lower alcohol to the dichloromethane is 1 (0.9-5).
In the present invention, the lower alcohol is preferably methanol and/or ethanol, particularly preferably methanol.
In the present invention, the volume ratio of the lower alcohol to methylene chloride is preferably 1:1.
In the present invention, the ratio of the mass of the levamlodipine maleate to the volume of the dichloromethane is preferably 1g (8-15 mL), and particularly preferably 1g:10mL.
In the present invention, the dissolution is preferably performed under room temperature conditions.
In the present invention, the dissolution is preferably performed under stirring.
After the maleic acid levamlodipine solution is obtained, the maleic acid levamlodipine solution is subjected to solvent removal under a vacuum condition, and the maleic acid levamlodipine amorphous crystal form is obtained.
In the present invention, the vacuum concentration is preferably carried out at a vacuum degree of-0.1 to-0.8 MPa.
In the present invention, the temperature of the heating evaporation is preferably 10 to 60 ℃. In the present invention, a specific embodiment of the heating evaporation is rotary evaporation.
The invention provides the maleic acid levoamlodipine amorphous crystal form prepared by the preparation method.
In the invention, the maleic acid levamlodipine amorphous crystal form is an off-white solid.
The technical solutions provided by the present invention are described in detail below with reference to the drawings and examples for further illustrating the present invention, but they should not be construed as limiting the scope of the present invention.
Example 1
Preparation of maleic acid levo-amlodipine crystal form
300g of purified water is added into a 500mL four-neck flask, 30g of maleic acid levamlodipine is added under stirring, 40g of methanol is added, the mixture is heated to reflux, the mixture is stirred for 30 minutes after dissolving, the mixture is stirred at 50 revolutions per minute, the temperature is reduced to 20 ℃ at 5 ℃/h, the mixture is crystallized for 30 minutes under heat preservation, the mixture is crystallized for 2 hours at 10 ℃/h to 0 ℃, the white solid is obtained by suction filtration and drying, and the yield is 95.0%. The melting point is 176.3-176.5 ℃.
Powder X-ray diffraction data are shown in Table 1 and X-ray diffraction pattern is shown in FIG. 2.
TABLE 1X-ray diffraction data for the crystalline form of levoamlodipine maleate prepared in example 1
Adding 30g of maleic acid levamlodipine to a surface dish, heating to 130 ℃, preserving heat for 30 minutes, and cooling to room temperature to obtain an off-white solid which is maleic acid levamlodipine amorphous crystal, wherein the mass is 30g, and the yield is 100%.
The X-ray diffraction pattern of the amorphous crystal form of levamlodipine maleate prepared in the present example is shown in fig. 1, and the corresponding X-ray diffraction peaks are shown in table 3. The test information of the X-ray diffractometer used in the present invention is shown in table 2.
Table 2 test information of X-ray diffractometer
TABLE 3X-ray diffraction peaks
The amorphous crystal form of the levamlodipine maleate prepared by the embodiment has high stability, and can improve the drug availability of the levamlodipine maleate.
Example 2
The preparation method of the maleic acid levo-amlodipine besylate crystal form is the same as in example 1;
adding 30g of maleic acid levamlodipine to a surface dish, heating to 180 ℃, preserving heat for 5 minutes, and cooling to room temperature to obtain an off-white solid which is maleic acid levamlodipine amorphous crystal, wherein the mass is 30g, and the yield is 100%. The X-ray diffraction pattern of the amorphous crystalline form of levamlodipine maleate prepared in this example is the same as that of fig. 1.
The amorphous crystal form of the levamlodipine maleate prepared by the embodiment has high stability, and can improve the drug availability of the levamlodipine maleate.
Example 3
The preparation method of the maleic acid levo-amlodipine besylate crystal form is the same as in example 1;
30g of maleic acid levoamlodipine crystal form, 300mL of methanol and 300mL of dichloromethane are added into a 1000mL four-port bottle, the solution is stirred and quickly decompressed to dryness, and an off-white solid is maleic acid levoamlodipine amorphous crystal form, the mass is 30g, and the yield is 100%. The X-ray diffraction pattern of the amorphous crystalline form of levamlodipine maleate prepared in this example is the same as that of fig. 1.
The amorphous crystal form of the levamlodipine maleate prepared by the embodiment has high stability, and can improve the drug availability of the levamlodipine maleate.
Although the foregoing embodiments have been described in some, but not all embodiments of the invention, other embodiments may be obtained according to the present embodiments without departing from the scope of the invention.
Claims (9)
1. The preparation method of the maleic acid levamlodipine besylate amorphous crystal form comprises the following steps:
heating maleic acid levamlodipine to perform heat treatment to obtain the maleic acid levamlodipine amorphous crystal form;
the temperature of the heat treatment is 130-180 ℃, and the heat preservation time of the heat treatment is 5-60 min.
2. The method according to claim 1, wherein the heat treatment is carried out for a holding time of 5 to 30 minutes.
3. The preparation method of the maleic acid levamlodipine besylate amorphous crystal form comprises the following steps:
dissolving maleic acid levamlodipine in a mixed solvent of lower alcohol and dichloromethane to obtain maleic acid levamlodipine solution; the volume ratio of the lower alcohol to the dichloromethane is 1 (0.9-5);
and removing the solvent of the maleic acid levamlodipine solution to obtain the maleic acid levamlodipine amorphous crystal form, wherein the solvent removal comprises vacuum concentration or heating evaporation.
4. A process according to claim 3, wherein the lower alcohol is methanol and/or ethanol.
5. The process according to claim 3, wherein the ratio of the mass of the levamlodipine maleate to the volume of the dichloromethane is 1g (8-15) mL.
6. The preparation method according to claim 5, wherein the ratio of the mass of the levamlodipine maleate and the volume of the dichloromethane is 1g to 10ml.
7. A process according to claim 3, wherein the volume ratio of lower alcohol to dichloromethane is 1:1.
8. The method according to claim 3, wherein the vacuum concentration is carried out at a vacuum degree of-0.1 to-0.8 MPa;
the temperature of the heating evaporation is 10-60 ℃.
9. The amorphous crystalline form of levamlodipine maleate prepared by the preparation method of any one of claims 1 to 8.
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