CN112110850A - Novel crystal form of levamlodipine besylate - Google Patents
Novel crystal form of levamlodipine besylate Download PDFInfo
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- CN112110850A CN112110850A CN201910536135.2A CN201910536135A CN112110850A CN 112110850 A CN112110850 A CN 112110850A CN 201910536135 A CN201910536135 A CN 201910536135A CN 112110850 A CN112110850 A CN 112110850A
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
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- 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 provides a Levamlodipine besylate crystal form, and relates to the technical field of crystal form drug molecules. The Levamlodipine besylate crystal form uses Cu-Kalpha radiation, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at 7.69 +/-0.2 degrees, 11.35 +/-0.2 degrees, 13.45 +/-0.2 degrees, 14.54 +/-0.2 degrees, 16.63 +/-0.2 degrees, 17.32 +/-0.2 degrees, 18.78 +/-0.2 degrees, 22.22 +/-0.2 degrees, 26.07 +/-0.2 degrees, 28.76 +/-0.2 degrees, 29.96 +/-0.2 degrees, 35.80 +/-0.2 degrees and 39.41 +/-0.2 degrees; the crystallography measurement parameters were: monoclinic system, space group P21(ii) a The unit cell parameters are:
26.1230(7)，α＝90.00°，β＝96.496(2)°γ 90.00 °, unit cell volume
Description
Technical Field
The invention relates to the technical field of crystal form drug molecules, in particular to a crystal form of levamlodipine besylate.
Background
In recent years, researches show that the crystal forms of the drugs are different, and the physicochemical properties (density, hardness, solubility, stability, optical property, electrical property and the like), dissolution rate, biological effect and the like of the drug can be changed, so that the research on the crystal forms of the drugs has important practical value in medicine and pharmacology. The crystal form drug molecules comprise polymorphism, hydrate, solvate, salt and the like of the drug molecules, and through the way of drug crystallization, the crystallography parameters of the crystal form drug molecules can be determined, and the types and the number of the solvent molecules (such as crystal water molecules) in the crystal form can be determined, so that the crystal form drug molecules have very important effects on understanding and mastering the spatial arrangement and the physicochemical properties of the drug molecules.
The levoamlodipine besylate is white or white-like powder, the chemical name of the levoamlodipine besylate is(s) - (-) -3-ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chlorphenyl) -1, 4-dihydro-6-methyl-3, 5-pyridine dicarboxylate benzene sulfonate, and the molecular formula is C20H25N2O5Cl·C6H6O3S, molecular weight 567.1, structure shown below:
levamlodipine besylate is a calcium internal flow retardant (namely a calcium channel blocker or a calcium ion antagonist), and can block calcium ions outside cardiac muscle and vascular smooth muscle cells from entering the cells through calcium ion channels (slow channels) of cell membranes. Directly dilate vascular smooth muscle, has the function of anti-hypertension, has long-acting molecules, and can be really taken once a day. The amlodipine besylate has two isomers of levorotation and dextrorotation, and the calcium ion antagonistic activity of the levorotation is 1000 times that of the dextrorotation and 2 times that of a racemate. The levamlodipine besylate is a common medicament for treating hypertension at present due to high curative effect and small side effect, and is widely applied to clinic. The drug molecules are generally designed for oral administration in solid dosage forms, and in the solid form of the drug, the drug molecules in crystal form are preferred due to advantages in terms of stability, reproducibility, operability, and the like. Therefore, the research and development of the molecular crystal form of the medicine have very important value for the medicine. The levamlodipine besylate is used as a solid preparation, and the detailed crystallographic parameters, the definite crystal form, the number of crystal water and the definite atom space position of the levamlodipine besylate can improve the solubility and the stability of the existing levamlodipine besylate, and is beneficial to the improvement of the stability and the bioavailability of the levamlodipine besylate tablets.
In the current research reports of the crystal form of amlodipine besylate, danish researchers report three crystal structures of an anhydrous crystal form of amlodipine besylate, amlodipine besylate monohydrate and amlodipine besylate dihydrate (crystallography growth & Design, 2010, 105279-5290) in an international crystal authority journal in 2010; patent US6828339 discloses three crystalline forms of amlodipine besylate.
Among reported research results of the crystal form of levamlodipine besylate, Chinese patent CN102276516A reports a crystal form of levamlodipine besylate; patent CN1355162A mentions that the water molecules of levamlodipine besylate hydrate can be 0-2, but it only discloses levamlodipine besylate 2 hydrate crystal form; korean patent No. 10-2005-0037498 discloses a crystal form of levamlodipine besylate dihydrate; patent WO2006043148 mentions in the process of preparing levamlodipine besylate, DMF solvent compound of benzenesulfonic acid and levamlodipine-L hemitartrate can obtain levamlodipine besylate hydrate containing 1-3 water in mixed solution of organic solvent and water, but it only discloses levamlodipine besylate dihydrate and 2.5 hydrate crystal form compound of two levamlodipine besylate molecules sharing five crystal waters; the KR20120066691A patent utilizes the prepared Levamlodipine besylate crystal form to be placed under certain conditions of temperature and humidity, and the Levamlodipine besylate crystal form containing 2.5 water is obtained. The crystal forms of the levamlodipine besylate only have common X-ray powder diffraction data or simple DSC representation, and have no definite main crystallographic parameters and definite atom space positions, so that the understanding and mastering of the space arrangement and the physicochemical properties of drug molecules are quite difficult. In addition, patent CN105111137B provides a levamlodipine besylate crystal containing 1.5 crystal waters. The known levamlodipine besylate crystal form cannot well meet the requirements of pharmaceutical preparations in the aspects of solubility, thermal stability, photostability, dissolution rate, bioavailability and the like, so that more crystal forms need to be developed, on one hand, more levamlodipine besylate crystal forms are provided for pharmaceutical application, and on the other hand, levamlodipine besylate crystal forms which are more suitable for industrial production and have high economic benefits are also developed.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide the levamlodipine besylate crystal form which has definite crystal form, crystal water number, definite crystallography main parameters and atom space positions; the invention also provides a preparation method of the levoamlodipine besylate crystal form; the invention also aims to provide application of the levamlodipine besylate crystal form in preparation of antihypertensive drugs.
The specific technical scheme of the invention is as follows:
a levamlodipine besylate crystal form uses Cu-Kalpha radiation, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at 11.35 +/-0.2 degrees, 14.54 +/-0.2 degrees, 16.63 +/-0.2 degrees, 18.78 +/-0.2 degrees, 22.22 +/-0.2 degrees, 26.07 +/-0.2 degrees.
Preferably, the crystal form of levamlodipine besylate has characteristic peaks at 7.69 +/-0.2 °, 11.35 +/-0.2 °, 13.45 +/-0.2 °, 14.54 +/-0.2 °, 16.63 +/-0.2 °, 17.32 +/-0.2 °, 18.78 +/-0.2 °, 22.22 +/-0.2 °, 26.07 +/-0.2 °, 28.76 +/-0.2 °, 29.96 +/-0.2 °, 35.80 +/-0.2 ° and 39.41 +/-0.2 ° in an X-ray diffraction spectrum expressed by 2 theta by using Cu-Kalpha radiation.
Preferably, the crystal form of levamlodipine besylate uses Cu-Ka radiation, and the characteristic peak of the crystal form of levamlodipine besylate accords with an X-ray powder diffraction pattern shown in figure 3.
Preferably, the crystal form of the levamlodipine besylate is of a molecular formula C20H25ClN2O5·C6H6O3S·H2O, the crystallographic measurement parameters are: monoclinic system, space group P21(ii) a The unit cell parameters are:
α is 90.00 °, β is 96.496(2 °), γ is 90.00 °, unit cell volume
The preparation method of the levoamlodipine besylate crystal form comprises the following steps:
adding levamlodipine besylate into a mixed solution of an organic solvent and purified water, heating, stirring, dissolving, continuously keeping the temperature, stirring and reacting for T time, filtering, and slowly cooling the filtrate to room temperature; and putting the filtrate in a beaker, sealing the opening of the beaker by a sealing film, pricking, volatilizing, crystallizing, filtering, and drying under reduced pressure to obtain the levamlodipine besylate crystal form.
In the above reaction, the organic solvent may be selected from any suitable organic solvents. Preferably, the organic solvent is one or two of acetone, tetrahydrofuran, ethanol, methanol, N-dimethylformamide, dimethyl sulfoxide, isopropanol and acetonitrile.
Preferably, the volume ratio of the organic solvent to the purified water is 1:6 to 10.
Preferably, the mass-to-volume ratio of the levamlodipine besylate to the mixed solution is 1: 80-100 g/ml.
Preferably, the heating and dissolving temperature is 40-60 ℃.
Preferably, the reaction time T is 0.5-1 hour.
In a preferable scheme, the slow cooling mode of the filtrate is program cooling, and preferably, the cooling rate is 0.5 ℃/min.
The levamlodipine besylate crystal form is used as an active ingredient for preparing antihypertensive drugs.
The invention relates to a pharmaceutical composition, which contains the crystal form of levamlodipine besylate, and is mixed with other components.
Preferably, the pharmaceutical composition of the present invention is prepared as follows: the compounds of the present invention are combined with pharmaceutically acceptable solid or liquid carriers and optionally with pharmaceutically acceptable excipients using standard and conventional techniques to prepare useful dosage forms.
Preferably, the other components include other active ingredients, fillers, diluents, binders, disintegrants, lubricants, etc., which may be used in combination.
More preferably, the diluent is selected from one or more of starch, sucrose, dextrin, lactose, microcrystalline cellulose, mannitol and sorbitol; the adhesive is selected from one or more of methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium hydroxymethyl cellulose, ethyl cellulose and polyvidone; the disintegrant is selected from one or more of carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, croscarmellose sodium and crospovidone; the lubricant is selected from one or more of magnesium stearate, superfine silica gel powder, talcum powder and sodium dodecyl sulfate.
Preferably, the pharmaceutical composition is tablets, capsules, granules, pills and the like.
The invention has the beneficial effects that:
1. the preparation method of the levamlodipine besylate crystal form is simple, the obtained crystal form is regular, the particle size is uniform, the stability is good, the crystal form and the number of crystal water thereof are clear, the crystallography main parameters and the exact atom space position are clear, and the method is suitable for large-scale popularization and application.
2. The crystal form of the levamlodipine besylate has better photostability, and the dosage form prepared by the crystal form is beneficial to medicine storage and ensures the medicine effect.
3. The levamlodipine besylate crystal form is applied to medicines, so that the dissolution rate is greatly improved, the bioavailability is increased, the drug effect is improved, and the levamlodipine besylate crystal form is suitable for large-scale popularization and application.
Drawings
FIG. 1: crystal form ORTEP diagram of levamlodipine besylate.
FIG. 2: a crystal form stacking diagram of the benzene sulfonic acid levamlodipine.
FIG. 3: a crystal form X-ray powder diffraction pattern of the levamlodipine besylate.
FIG. 4: a crystal form X-ray powder diffraction integral chart of the levamlodipine besylate.
FIG. 5: a differential scanning calorimetry curve (DSC/TGA) graph of the crystal form of the levamlodipine besylate.
Detailed Description
The invention is further illustrated by the following examples. It should be properly understood that: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.
Materials used in the experiment: levamlodipine besylate can be purchased or prepared according to the prior art; all materials used in other experiments, which have not been indicated for their origin and specification, are commercially available, analytically pure or chemically pure.
The optical purity and purity detection of the crystal form of the levamlodipine besylate are both based on the national drug standard (WS)1- (X-019) -2002Z) method.
Example 1
Levamlodipine besylate (5.05g) was added to ethanol/purified water (V)Ethanol:VWater (W)1:8, 450ml), heating to 50 ℃, stirring to dissolve, keeping the temperature, stirring and reacting for 0.5h, filtering, and cooling the filtrate to room temperature at the speed of 0.5 ℃/min; and putting the filtrate in a beaker, sealing the opening of the beaker by a sealing film, pricking holes, volatilizing, crystallizing for 3 days, filtering, and drying at 45 ℃ under reduced pressure to constant weight to obtain the levamlodipine besylate crystal form, wherein the yield is 98.2%, the optical purity is 99.97%, and the purity is 99.92%.
Example 2
Levamlodipine besylate (5.03g) was added to acetone/purified water (V)Acetone (II):VWater (W)1:6, 400ml), heating to 40 ℃, stirring to dissolve, keeping the temperature, stirring and reacting for 1h, filtering, and cooling the filtrate to room temperature at the speed of 0.5 ℃/min; placing the filtrate inSealing the flask with a sealing film, pricking holes, volatilizing, crystallizing for 2 days, filtering, drying at 45 ℃ under reduced pressure to constant weight to obtain the levamlodipine besylate crystal form, wherein the yield is 97.7%, the optical purity is 99.95%, and the purity is 99.82%.
Example 3
Levamlodipine besylate (5.02g) was added to methanol/purified water (V)Methanol:VWater (W)1:7, 450ml), heating to 50 ℃, stirring to dissolve, keeping the temperature, stirring and reacting for 0.5h, filtering, and cooling the filtrate to room temperature at the speed of 0.5 ℃/min; and putting the filtrate in a beaker, sealing the opening of the beaker by a sealing film, pricking holes, volatilizing, crystallizing for 3 days, filtering, and drying at 45 ℃ under reduced pressure to constant weight to obtain the levamlodipine besylate crystal form, wherein the yield is 97.5%, the optical purity is 99.93%, and the purity is 99.84%.
Example 4
Levamlodipine besylate (5.06g) was added to tetrahydrofuran/purified water (V)Tetrahydrofuran (THF):VWater (W)500ml) is heated to 45 ℃, stirred and dissolved, the mixture is kept warm and stirred for reaction for 0.5h, then is filtered, and the filtrate is cooled to the room temperature at the speed of 0.5 ℃/min; and putting the filtrate in a beaker, sealing the opening of the beaker by a sealing film, pricking holes, volatilizing, crystallizing for 3 days, filtering, and drying at 45 ℃ under reduced pressure to constant weight to obtain the levamlodipine besylate crystal form, wherein the yield is 97.2%, the optical purity is 99.95%, and the purity is 99.83%.
Example 5
Levamlodipine besylate (5.02g) was added to isopropanol/purified water (V)Isopropanol (I-propanol):VWater (W)1:9, 450ml), heating to 45 ℃, stirring to dissolve, keeping the temperature, stirring and reacting for 0.5h, filtering, and cooling the filtrate to room temperature at the speed of 0.5 ℃/min; and putting the filtrate in a beaker, sealing the opening of the beaker by a sealing film, pricking holes, volatilizing, crystallizing for 3 days, filtering, and drying at 45 ℃ under reduced pressure to constant weight to obtain the levamlodipine besylate crystal form, wherein the yield is 97.4%, the optical purity is 99.96%, and the purity is 99.85%.
Example 6
Levamlodipine besylate (5.01g) was added to acetonitrile/purified water (V)Acetonitrile:VWater (W)1:7, 450ml) was heated to 50 cStirring to dissolve, keeping the temperature, stirring and reacting for 0.5h, filtering, and cooling the filtrate to room temperature at the speed of 0.5 ℃/min; and putting the filtrate in a beaker, sealing the opening of the beaker by a sealing film, pricking holes, volatilizing, crystallizing for 4 days, filtering, and drying at 45 ℃ under reduced pressure to constant weight to obtain the levamlodipine besylate crystal form, wherein the yield is 97.8%, the optical purity is 99.95%, and the purity is 99.84%.
Example 7
Levamlodipine besylate (5.02g) was added to DMF/purified water (V)DMF:VWater (W)1:10, 450ml), heating to 60 ℃, stirring to dissolve, keeping the temperature and stirring for reaction for 1 hour, filtering, and cooling the filtrate to room temperature at the speed of 0.5 ℃/min; and putting the filtrate in a beaker, sealing the opening of the beaker by a sealing film, pricking, volatilizing, crystallizing for 5 days, filtering, and drying at 45 ℃ under reduced pressure to constant weight to obtain the levamlodipine besylate crystal form, wherein the yield is 97.6%, the optical purity is 99.92% and the purity is 99.87%.
Example 8
Levamlodipine besylate (5.07g) was added to DMSO/purified water (V)DMSO:VWater (W)500ml) is heated to 55 ℃, stirred and dissolved, the mixture is kept warm and stirred for reaction for 0.5h, then is filtered, and the filtrate is cooled to the room temperature at the speed of 0.5 ℃/min; and putting the filtrate in a beaker, sealing the opening of the beaker by a sealing film, pricking, volatilizing, crystallizing for 5 days, filtering, and drying at 45 ℃ under reduced pressure to constant weight to obtain the levamlodipine besylate crystal form, wherein the yield is 97.7%, the optical purity is 99.95%, and the purity is 99.85%.
Example 9
Levamlodipine besylate (5.03g) was added to ethanol/isopropanol/purified water (V)Ethanol:VIsopropanol (I-propanol):VWater (W)0.5:0.5:6, 400ml), heating to 50 ℃, stirring to dissolve, keeping the temperature, stirring and reacting for 0.5h, filtering, and cooling the filtrate to room temperature at the speed of 0.5 ℃/min; and putting the filtrate in a beaker, sealing the opening of the beaker by a sealing film, pricking holes, volatilizing, crystallizing for 3 days, filtering, and drying at 45 ℃ under reduced pressure to constant weight to obtain the levamlodipine besylate crystal form, wherein the yield is 98.2%, the optical purity is 99.96%, and the purity is 99.87%.
Example 10
L-amlodipine besylateThe dipine (5.04g) was added ethanol/acetone/purified water (V)Ethanol:VAcetone (II):VWater (W)0.5:0.5:7, 450ml) is heated to 50 ℃, stirred and dissolved, the temperature is kept and the stirring reaction is continued for 0.5h, then the filtration is carried out, and the filtrate is cooled to the room temperature at the speed of 0.5 ℃/min; and putting the filtrate in a beaker, sealing the opening of the beaker by a sealing film, pricking holes, volatilizing, crystallizing for 3 days, filtering, and drying at 45 ℃ under reduced pressure to constant weight to obtain the levamlodipine besylate crystal form, wherein the yield is 97.8%, the optical purity is 99.94% and the purity is 99.83%.
Confirmation of crystal form structure of levamlodipine besylate
According to the embodiments 1-10, crystals with the sizes meeting the specification are selected from prepared crystal samples, X-ray crystal form data of the crystals are collected on an instrument of a Japan XtaLAB Synergy model, the temperature is 293(2) K, the voltage is 50kv, the current is 1mA, CuKa radiation is used, data are collected in an omega scanning mode, and Lp correction is carried out. Analyzing the structure by a direct method, finding out all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and refining the structure by a least square method.
The crystallographic data obtained by testing and analyzing the crystal form of the levamlodipine besylate hydrate prepared by the invention are shown in the table 1, wherein the crystallographic parameters are as follows: monoclinic system, space group P21(ii) a The unit cell parameters are:
α is 90.00 °, β is 96.496(2 °), γ is 90.00 °, unit cell volume
The ORTEP diagram (fig. 1) of the crystal form of levamlodipine besylate of the present invention indicates that each molecule of levamlodipine besylate is crystallized with 1 molecule of water, and it can be confirmed that the crystal form is levamlodipine besylate 1 hydrate. The stacking diagram (figure 2) of the Levamlodipine besylate crystal form of the invention shows that the Levamlodipine besylate 1 hydrate crystal form is stacked in a pi-pi way through hydrogen bond actionAnd the like, and crystal water molecules are connected with the levamlodipine besylate molecules through intermolecular hydrogen bonding. The chiral absolute configuration was determined to be levamlodipine besylate from a crystallographic Flack parameter value of 0.05 (3).
Table 1 levamlodipine besylate crystal form master crystallographic data
The X-ray powder diffraction test instrument and the test conditions involved in the invention are as follows: x-ray powder diffractometer PANalytical E; Cu-K alpha; a sample stage: a flat plate; the incident light path is BBHD; diffraction light path: PLXCEL; voltage 45kv and current 40 mA; 1/4 of divergent slit; an anti-scatter slit 1; 0.04rad of cable pull slit; step length: 0.5 s; scanning range: 3 to 50 degrees.
According to the above-mentioned crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Ka) are shown in FIG. 3 and Table 2.
Table 2 levamlodipine besylate crystal form PXRD peaks
The invention discloses a crystal form of levamlodipine besylate, which is tested by TGA/DSC thermal analysis under the following conditions: mettler-tolliduo TGA/DSC thermogram (model: TGA/DSC3+), dynamic temperature profile: 30-300 ℃, heating rate: 10 ℃/min, program segment gas N2Flow rate: 50ml/min, crucible: an aluminum crucible of 40. mu.l. As shown in figure 5, the crystal form of levamlodipine besylate has two endothermic peaks respectively at 67.43 ℃ and 213.08 ℃ through TGA/DSC detection, the endothermic peak at 67.43 ℃ is the endothermic peak losing water molecules, the corresponding weight loss is 2.92%, and one water molecule is lost, so the crystal form of levamlodipine besylate isThe result of the levamlodipine besylate hydrate containing one water molecule is consistent with the X single crystal data.
The samples of examples 1-10 all had the same crystallographic parameters, X-ray powder diffraction patterns, and differential scanning calorimetry (DSC/TGA) profile.
The crystal forms of levamlodipine besylate of comparative examples 1-6 were prepared by referring to the existing reported preparation methods of crystal forms of levamlodipine besylate.
Comparative example 1
Levamlodipine besylate (5g) was added to dichloromethane/ethanol (V)Methylene dichloride:VEthanol5:1, 50ml) to obtain a reaction solution; under an ultrasonic field (0.4KW), adding n-heptane dropwise into the reaction solution until crystallization is separated out; and (3) closing the ultrasonic field, standing for 4 hours at the temperature of 20 ℃, filtering, washing a filter cake by using dichloromethane and ethanol respectively, and drying to obtain the levamlodipine besylate anhydrous crystal with the optical purity of 99.74 percent and the purity of 99.68 percent.
Comparative example 2
Levamlodipine besylate (5g) was added to acetone/purified water (V)Acetone (II):VWater (W)1:1, 2.5ml) and stirring to dissolve to obtain a reaction solution; heating the reaction solution to 30 ℃, stirring for reaction for 10min, cooling to room temperature, adding purified water (10ml), cooling to 5 ℃, crystallizing for 24 hours, filtering under reduced pressure, washing the filtrate, washing with cold water, and drying at room temperature to constant weight to obtain the off-white levamlodipine besylate 1.5 hydrate crystal with optical purity of 99.63% and purity of 99.72%.
Comparative example 3
Adding levamlodipine (5g) into purified water (120ml), adding benzenesulfonic acid (1.4g) into the levamlodipine aqueous solution, and uniformly stirring; the mixed solution was heated to 60 ℃ under nitrogen blanket. Stopping stirring after dissolving, cooling to room temperature, and crystallizing overnight; after filtration, the crystal was washed with purified water (20ml), and dried at room temperature to a constant weight to obtain levamlodipine besylate 2 hydrate crystal with an optical purity of 99.54% and a purity of 99.48%.
Comparative example 4
Adding(s) -amlodipine-hemi-L-tartaric acid-DMF solvate (100g) into purified water (550ml), adding isopropanol (100ml), and stirring for 10min to obtain a mixed solution; adding benzenesulfonic acid (32.7g) into purified water (100ml) to obtain benzenesulfonic acid solution; adding the benzenesulfonic acid solution into the mixed solution at room temperature, and stirring for reacting for 10-15 min to obtain a benzenesulfonic acid salt compound; adding purified water (500ml) into the reaction solution, stirring for crystallization, filtering, washing a filter cake with purified water, washing cyclohexane (100ml), and drying at 35-40 ℃ to obtain the white-like levamlodipine besylate 2.5 hydrate crystal with optical purity of 99.25% and purity of 99.52%.
Comparative example 5
The obtained levamlodipine besylate 2.5 hydrate crystal was prepared according to the method of comparative example 4. Adding the Levamlodipine besylate crystals (20g) into purified water (480ml), and uniformly stirring; heating the levamlodipine besylate solution to 60 ℃ under the protection of nitrogen, reacting for 30min, gradually cooling to room temperature, crystallizing for 8-12 h, filtering, and drying to constant weight at room temperature to obtain the white levamlodipine besylate 2 hydrate crystal with optical purity of 99.22% and purity of 99.53%.
Comparative example 6
Adding levamlodipine (12.11g) into a 94% ethanol (28ml) solution, and uniformly stirring to obtain a levamlodipine solution; adding benzenesulfonic acid (5.15g) into 94% ethanol (35ml), and stirring for dissolving to obtain benzenesulfonic acid solution; adding the levamlodipine solution into a benzenesulfonic acid solution, and stirring and reacting for 2 hours at the temperature of 25 ℃; after the reaction is finished, controlling the temperature to be 20 ℃, adding purified water (370ml) into the reaction solution, and stirring for crystallization for 4 hours; filtering, washing the filter cake with purified water, drying the filter cake for 24 hours at 55 ℃ in vacuum, and placing the obtained dried solid for 24 hours at the temperature of 25 +/-2 ℃ and the humidity of 60 +/-5% to obtain the off-white levamlodipine besylate 2.5 hydrate crystal with the optical purity of 99.92% and the purity of 99.64%.
Heat stability test
The levamlodipine besylate crystals prepared in example 1 and comparative examples 1 to 6 were dissolved in water, stored in the dark at 25 ℃ for 4 weeks, and the dextroisomer and other related substances were detectedContent, according to the national drug Standard (WS)1- (X-019) -2002Z) optical purity and related substance determination. The results are shown in Table 3.
Table 3 stability test results of levamlodipine besylate crystal form solution
As shown in table 3, after being stored in the dark at 25 ℃ for 4 weeks, the levoamlodipine besylate crystal form impurities of the comparative example 6 were significantly increased, and the dextroisomer content was significantly increased; the crystal forms of the levamlodipine besylate disclosed by the invention and the crystal forms of the levamlodipine besylate in the comparative examples 1-5 are not obviously changed and are basically stable after 4-week investigation. The examination found that examples 1 to 10 have similar stability test results.
The levamlodipine besylate crystals prepared in example 1 and comparative examples 1 to 6 were taken, subjected to accelerated testing at 60 ℃ in the dark for 4 weeks, and the contents of dextroisomer and other related substances were measured and observed under the HPLC conditions identical to those used for evaluating the stability in the solution state. The results are shown in Table 4.
Table 4 levamlodipine besylate crystal form solid state accelerated test results at 60 ℃
The solid stability test result shows that the levoamlodipine besylate crystal form impurities of the comparative example 6 are obviously increased, and the content of dextroisomer is obviously increased; the crystal forms of the levamlodipine besylate disclosed by the invention and the crystal forms of the levamlodipine besylate in the comparative examples 1-5 are not obviously changed and are basically stable after 4-week investigation. The examination found that examples 1 to 10 have similar stability test results.
Light stability test
The levoamlodipine besylate crystals prepared in the example 1 and the comparative examples 1 to 6 are respectively taken, and the content of dextroisomer and other related substances is respectively detected at 0, 5 and 10 days under strong light irradiation (4500Lx +/-500 Lx), referring to the national drug standard (WS)1- (X-019) -2002Z) optical purity and related substance determination. The results are shown in Table 5.
Table 5 crystal form photostability test results of levamlodipine besylate
The photostability test result shows that the content of the dextroisomer of the levamlodipine besylate crystal form is not obviously changed compared with the crystal forms of comparative examples 1-6 under the condition of strong light irradiation; compared with other crystal forms, the crystal form of the invention has better light stability, and the dosage form prepared by the crystal form of the invention is beneficial to medicine storage and ensures the medicine effect. The examination found that examples 1 to 10 have similar photostability test results.
Moisture absorption test
The levamlodipine besylate crystals prepared in example 1 and comparative examples 1 to 6 were taken and subjected to water content (karl fischer method, water content%) measurement at 25 ℃ under different humidity conditions (25%, 60%, 75%, 95%). The results are shown in Table 6.
Table 6 crystal form hygroscopicity test results of levamlodipine besylate
| Storage conditions (RH) | 25％ | 60％ | 75％ | 95％ | |
| Storage time | Initial | After 1 week | After 1 week | After 1 week | After 1 week |
| Example 1 | 3.05％ | 3.05％ | 3.06％ | 3.07％ | 3.07％ |
| Comparative example 1 | 0.15％ | 0.14％ | 0.16％ | 0.18％ | 0.19％ |
| Comparative example 2 | 4.62％ | 4.58％ | 4.62％ | 4.63％ | 4.68％ |
| Comparison ofExample 3 | 5.95％ | 5.87％ | 5.97％ | 6.03％ | 6.04％ |
| Comparative example 4 | 7.64％ | 7.58％ | 7.62％ | 7.78％ | 7.82％ |
| Comparative example 5 | 5.92％ | 5.85％ | 5.92％ | 5.96％ | 6.02％ |
| Comparative example 6 | 7.83％ | 7.79％ | 7.83％ | 8.95％ | 10.52％ |
The moisture absorption test results show that the levamlodipine besylate crystal forms prepared in example 1 and comparative examples 1 to 5 show no moisture absorption under various humidity conditions. The crystal form of levamlodipine besylate prepared in comparative example 6 increased from 7.83% to 10.52% after 1 week of storage at 95% RH. Thus, levamlodipine besylate prepared in comparative example 6 exhibits hygroscopicity. The examination shows that the crystal form of the levamlodipine besylate prepared in the examples 2 to 10 has no hygroscopicity as in the example 1.
Dissolution test
The levamlodipine besylate crystals prepared in examples 1 to 10 and comparative examples 1 to 6 were taken and 1000 levamlodipine besylate tablets were prepared according to the formulation ratio of table 7.
TABLE 7 pharmaceutical formulation ratios of levamlodipine besylate crystal forms
Dissolution test
The determination method comprises the following steps: referring to the evaluation method of dissolution consistency of amlodipine besylate tablets in Japanese orange book, a slurry method is adopted, 900ml of buffer solution with pH of 1.2, 4.0 and 6.8 and 900ml of water are respectively used as dissolution media under the condition of keeping out of the sun at 37 ℃, the rotating speed is 50r/min, 5ml of samples are respectively sampled at 5, 10, 15, 20, 30 and 45min, and the samples are timely replenished with liquid, filtered and injected by HPLC (high performance liquid chromatography), which refers to the national drug standard (WS)1- (X-020) -2002Z) and calculating the accumulated dissolution rate at each time point. The results are shown in tables 8 to 11.
TABLE 8 elution amounts of various crystalline levamlodipine besylate tablets in pH 1.2 buffer
TABLE 9 elution amounts of various crystalline levamlodipine besylate tablets in pH 4.0 buffer
TABLE 10 dissolution amounts of various levamlodipine besylate crystal form tablets in pH6.8 buffer
TABLE 11 dissolution of various crystalline levamlodipine besylate tablets in water
The dissolution test adopts a Japanese orange peel book evaluation method, so that the human body correlation is improved, and the rotating speed of 50r/min is closer to the human body gastric motility. The dissolution result shows that the dissolution amount of the levamlodipine besylate crystal form tablet can reach more than 80% in 5min in four dissolution media of buffer solution and water with the pH values of 1.2, 4.0 and 6.8 respectively; in a buffer solution dissolution medium with the pH value of 6.8, which is closer to the human body environment, the dissolution amount of the levamlodipine besylate crystal form tablet reaches 95% in 30min, and the dissolution effect is more remarkable compared with other amlodipine besylate crystal form tablets; the crystal form of the levamlodipine besylate greatly improves the dissolution rate of the drug, thereby increasing the bioavailability and improving the drug effect. Tests show that the levoamlodipine besylate crystal form tablets in examples 1-10 have similar dissolution effects.
Claims (10)
1. The levamlodipine besylate crystal form is characterized in that the levamlodipine besylate crystal form uses Cu-Kalpha radiation, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at 11.35 +/-0.2 degrees, 14.54 +/-0.2 degrees, 16.63 +/-0.2 degrees, 18.78 +/-0.2 degrees, 22.22 +/-0.2 degrees and 26.07 +/-0.2 degrees.
2. The crystalline form of levamlodipine besylate according to claim 1, wherein said crystalline form of levamlodipine besylate has characteristic peaks at 7.69 ± 0.2 °, 11.35 ± 0.2 °, 13.45 ± 0.2 °, 14.54 ± 0.2 °, 16.63 ± 0.2 °, 17.32 ± 0.2 °, 18.78 ± 0.2 °, 22.22 ± 0.2 °, 26.07 ± 0.2 °, 28.76 ± 0.2 °, 29.96 ± 0.2 °, 35.80 ± 0.2 °, 39.41 ± 0.2 ° in an X-ray diffraction pattern expressed in terms of 2 Θ using Cu-ka radiation.
3. The crystalline form of levamlodipine besylate according to claim 1, wherein said crystalline form has an X-ray powder diffraction pattern as shown in figure 3.
4. The crystalline form of levamlodipine besylate according to claim 1, wherein said crystalline form of levamlodipine besylate has the formula: c20H25ClN2O5·C6H6O3S·H2O, the crystallographic measurement parameters are: monoclinic system, space group P21(ii) a The unit cell parameters are:
α is 90.00 °, β is 96.496(2 °), γ is 90.00 °, unit cell volume
5. A method for preparing the levoamlodipine besylate crystalline form of any of claims 1-4, comprising the steps of:
adding levamlodipine besylate into a mixed solution of an organic solvent and purified water, heating, stirring, dissolving, continuously keeping the temperature, stirring and reacting for T time, filtering, and slowly cooling the filtrate to room temperature; and putting the filtrate in a beaker, sealing the opening of the beaker by a sealing film, pricking, volatilizing, crystallizing, filtering, and drying under reduced pressure to obtain the levamlodipine besylate crystal form.
6. The method for preparing the crystal form of levamlodipine besylate according to claim 5, wherein the organic solvent is one or two of acetone, tetrahydrofuran, ethanol, methanol, N-dimethylformamide, dimethyl sulfoxide, isopropanol and acetonitrile.
7. The method for preparing the crystal form of levamlodipine besylate according to claim 5, wherein the volume ratio of the organic solvent to the purified water is 1:6 to 10.
8. The preparation method of the crystal form of the levamlodipine besylate according to claim 5, wherein the mass-to-volume ratio of the levamlodipine besylate to the mixed solution is 1: 80-100 g/ml.
9. The method for preparing the crystal form of levamlodipine besylate according to claim 5, wherein the slow cooling manner of the filtrate is program cooling; preferably, the cooling rate is 0.5 ℃/min.
10. Use of the crystal form of levamlodipine besylate according to any of claims 1-4 as an active ingredient for the preparation of an antihypertensive medicament.
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Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1355162A (en) * | 2001-11-22 | 2002-06-26 | 张喜田 | Levo-amlodipine salt able to generate hydrate and its hydrate and preparation |
| US6608206B1 (en) * | 2002-10-30 | 2003-08-19 | Council Of Scientific & Industrial Research | Process for making S(-) Amlodipine salts |
| WO2005049571A1 (en) * | 2003-11-20 | 2005-06-02 | Council Of Scientific And Industrial Research | Process for preparation of chiral amlodipine salts |
| WO2006043148A1 (en) * | 2004-10-20 | 2006-04-27 | Emcure Pharmaceuticals Limited | Process for producing enantiomer of amlodipine in high optical purity |
| WO2008060093A1 (en) * | 2006-11-14 | 2008-05-22 | Cj Cheiljedang Corporation | Crystalline s-(-)-amlodipine maleic acid salt anhydride and preparation method thereof |
| KR20090129079A (en) * | 2008-06-12 | 2009-12-16 | 에이치 엘 지노믹스(주) | Process for preparing optically pure s-(-)-amlodipine benzensulfonate |
| CN102276516A (en) * | 2011-08-19 | 2011-12-14 | 海南锦瑞制药股份有限公司 | Levamlodipine besylate crystals, preparation method thereof and brand-new medicinal composition containing crystals |
| KR20120066691A (en) * | 2010-09-15 | 2012-06-25 | 대화제약 주식회사 | A manufacturing method of esamlodipine besilate and its hydrate |
| CN102659672A (en) * | 2012-05-07 | 2012-09-12 | 山东新华制药股份有限公司 | Preparation method of high-purity levamlodipine besylate |
| CN104592099A (en) * | 2014-12-30 | 2015-05-06 | 山东鲁抗医药股份有限公司 | Refining method for improving optical purity of levoamlodipine besylate |
| CN105111137A (en) * | 2015-08-21 | 2015-12-02 | 薛传校 | Levamlodipine besylate crystal and preparation method and application thereof |
-
2019
- 2019-06-20 CN CN201910536135.2A patent/CN112110850B/en active Active
Patent Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1355162A (en) * | 2001-11-22 | 2002-06-26 | 张喜田 | Levo-amlodipine salt able to generate hydrate and its hydrate and preparation |
| US6608206B1 (en) * | 2002-10-30 | 2003-08-19 | Council Of Scientific & Industrial Research | Process for making S(-) Amlodipine salts |
| WO2005049571A1 (en) * | 2003-11-20 | 2005-06-02 | Council Of Scientific And Industrial Research | Process for preparation of chiral amlodipine salts |
| CN1882543A (en) * | 2003-11-20 | 2006-12-20 | 科学与工业研究委员会 | Process for preparation of chiral amlodipine salts |
| WO2006043148A1 (en) * | 2004-10-20 | 2006-04-27 | Emcure Pharmaceuticals Limited | Process for producing enantiomer of amlodipine in high optical purity |
| WO2008060093A1 (en) * | 2006-11-14 | 2008-05-22 | Cj Cheiljedang Corporation | Crystalline s-(-)-amlodipine maleic acid salt anhydride and preparation method thereof |
| KR20090129079A (en) * | 2008-06-12 | 2009-12-16 | 에이치 엘 지노믹스(주) | Process for preparing optically pure s-(-)-amlodipine benzensulfonate |
| KR20120066691A (en) * | 2010-09-15 | 2012-06-25 | 대화제약 주식회사 | A manufacturing method of esamlodipine besilate and its hydrate |
| CN102276516A (en) * | 2011-08-19 | 2011-12-14 | 海南锦瑞制药股份有限公司 | Levamlodipine besylate crystals, preparation method thereof and brand-new medicinal composition containing crystals |
| CN102659672A (en) * | 2012-05-07 | 2012-09-12 | 山东新华制药股份有限公司 | Preparation method of high-purity levamlodipine besylate |
| CN104592099A (en) * | 2014-12-30 | 2015-05-06 | 山东鲁抗医药股份有限公司 | Refining method for improving optical purity of levoamlodipine besylate |
| CN105111137A (en) * | 2015-08-21 | 2015-12-02 | 薛传校 | Levamlodipine besylate crystal and preparation method and application thereof |
Non-Patent Citations (4)
| Title |
|---|
| ICH指导委员会著: "《药品注册的国际技术要求》", 30 September 2000, 北京：人民卫生出版社 * |
| 伍丽萍等: "(S)-(-)-氨氯地平苯磺酸盐二水合物的制备", 《中国医药工业杂志》 * |
| 傅超美: "《中药药剂学 第2版》", 31 August 2018, 北京：中国医药科技出版社 * |
| 国家食品药品监督管理局执业药师资格认证中心组织编写: "《国家执业药师资格考试应试指南 药学专业知识2》", 31 January 2014, 北京：中国医药科技出版社 * |
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