CN112110850B - Novel crystal form of levamlodipine besylate - Google Patents
Novel crystal form of levamlodipine besylate Download PDFInfo
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- CN112110850B CN112110850B CN201910536135.2A CN201910536135A CN112110850B CN 112110850 B CN112110850 B CN 112110850B CN 201910536135 A CN201910536135 A CN 201910536135A CN 112110850 B CN112110850 B CN 112110850B
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- besylate
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- 229950008554 levamlodipine Drugs 0.000 title claims abstract description 134
- 239000013078 crystal Substances 0.000 title claims abstract description 125
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- 238000002360 preparation method Methods 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 20
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 56
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- 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 abstract description 7
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- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
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- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
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Images
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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- 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
-
- 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)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a levamlodipine besylate crystal form, and relates to the technical field of crystal form drug molecules. The levorotatory amlodipine besylate crystal form uses Cu-K alpha radiation, and an X-ray diffraction spectrum expressed by 2 theta is 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, and has characteristic peaks; the crystallographic measurement parameters were: monoclinic system with space group P2 1 The method comprises the steps of carrying out a first treatment on the surface of the 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 levamlodipine besylate crystal form.
Background
In recent years, research shows that the medicine crystal forms 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 medicine crystal forms can be changed, so that the research on the medicine crystal forms has important practical values in the medicine and pharmacy. The crystal form drug molecules comprise polymorphism, hydrate, solvate, salt and the like of the drug molecules, not only can the crystallographic parameters of the crystal form drug molecules be clarified through a drug crystallization way, but also the types and the numbers of solvent molecules (such as crystal water molecules) in the crystal form can be determined, and the crystal form drug molecules have very important roles in understanding and grasping the spatial arrangement and physicochemical properties of the drug molecules.
Levamlodipine besylate is white or off-white powder, its chemical name is(s) - (-) -3-ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -1, 4-dihydro-6-methyl-3, 5-pyridine dicarboxylic acid ester benzene sulfonate, molecular formula C 20 H 25 N 2 O 5 Cl·C 6 H 6 O 3 S, molecular weight 567.1, the structure is as follows:
levamlodipine besylate is a calcium influx blocker (i.e., a calcium channel blocker or a calcium ion antagonist) that blocks extracellular calcium ions of cardiac muscle and vascular smooth muscle from entering cells through the calcium ion channels (slow channels) of the cell membrane. Directly dilating vascular smooth muscle, has antihypertensive effect, has long-acting molecular effect, and can be truly taken once a day. Amlodipine besylate has two isomers of levorotatory and dextrorotatory, and the antagonistic activity of calcium ions of the levorotatory body is 1000 times that of the dextrorotatory body and 2 times that of the racemization body. Levamlodipine besylate is a common medicament for treating hypertension at present and is widely applied to clinic due to high curative effect and small side effect. The drug molecules are generally designed for oral administration in solid dosage forms, and in solid forms of the drug, crystalline drug molecules are preferred for their advantages in terms of stability, reproducibility, and operability. 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 atomic space position of the solid preparation can improve the solubility and stability of the existing levamlodipine besylate, and are beneficial to the improvement of the stability and bioavailability of the levamlodipine besylate tablet.
In the current research reports of amlodipine besylate crystal forms, in 2010 danish researchers reported on the journal of international crystallography that three crystal structures of an anhydrous crystal form of amlodipine besylate, amlodipine besylate monohydrate and amlodipine besylate dihydrate (crystal growth & Design,2010, 105279-5290); patent US6828339 discloses three amlodipine besylate crystalline forms.
Among reported results of the research on the levamlodipine besylate crystal form, chinese patent CN102276516a reports a crystal form of levamlodipine besylate; patent CN1355162a mentions that levamlodipine besylate hydrate contains 0-2 water molecules, but only discloses a crystalline form of levamlodipine besylate 2 hydrate; korean patent No. 10-2005-0037498 discloses a crystalline form of levamlodipine besylate dihydrate; patent WO2006043148 mentions that in the process of preparing levamlodipine besylate, a DMF solvent compound of benzenesulfonic acid and levamlodipine-L hemitartrate can obtain levamlodipine besylate salt hydrate containing 1-3 waters in a mixed solution of an organic solvent and water, but discloses only a crystal form compound of 2.5 hydrate of levamlodipine besylate dihydrate and two levamlodipine besylate molecules sharing five crystal waters; the patent KR20120066691A utilizes the prepared levamlodipine besylate crystal form to be placed under certain conditions of temperature and humidity to obtain the levamlodipine besylate crystal form containing 2.5 water. The levamlodipine besylate crystal forms have only common X-ray powder diffraction data or only simple DSC characterization, have no definite main crystallographic parameters and exact atomic space positions, and therefore, bring considerable difficulty for understanding and mastering the spatial arrangement and physicochemical properties of drug molecules. Furthermore, patent CN105111137B provides a crystalline form of levamlodipine besylate containing 1.5 crystal water. The known levamlodipine besylate crystal forms cannot well meet the requirements of pharmaceutical preparations in the aspects of solubility, thermal stability, light stability, dissolution rate, bioavailability and the like, so that more crystal forms need to be developed, more levamlodipine besylate crystal forms are provided for pharmaceutical application, and on the other hand, the levamlodipine besylate crystal forms which are more suitable for industrial production and have high economic benefit are also developed.
Disclosure of Invention
In order to overcome the defects of the prior art, one aim of the invention is to provide a levamlodipine besylate crystal form which has definite crystal form and crystal water number, definite crystallographic main parameters and atomic space position; the invention also aims to provide a preparation method of the levamlodipine besylate crystal form; the invention also aims to provide the application of the levamlodipine besylate crystal form in preparing antihypertensive drugs.
The specific technical scheme of the invention is as follows:
the levo-amlodipine besylate crystal form uses Cu-K alpha radiation, and an X-ray diffraction pattern 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.
Preferably, the levamlodipine besylate crystal form uses Cu-K alpha radiation, and an X-ray diffraction pattern 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 and 35.80 +/-0.2 degrees and 39.41+/-0.2 degrees.
Preferably, the levamlodipine besylate crystal form uses Cu-K alpha radiation, and the characteristic peak accords with an X-ray powder diffraction pattern shown in figure 3.
Preferably, the levamlodipine besylate is in the form of crystal form, formula C 20 H 25 ClN 2 O 5 ·C 6 H 6 O 3 S·H 2 The O, crystallographic measurement parameters were: monoclinic system with space group P2 1 The method comprises the steps of carrying out a first treatment on the surface of the The unit cell parameters are:
α=90.00 °, β= 96.496 (2) °, γ=90.00°, unit cell volume +.>
The preparation method of the levamlodipine besylate crystal form comprises the following steps:
adding levamlodipine besylate into a mixed solution of an organic solvent and purified water, heating, stirring and dissolving the mixture, continuing to perform heat preservation and stirring for reaction T time, filtering, and slowly cooling the filtrate to room temperature; placing the filtrate in a beaker, sealing by a sealing film, punching, 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 volume ratio of the levamlodipine besylate to the mixed solution is 1:80-100, g/ml.
Preferably, the heating dissolution temperature is 40 to 60 ℃.
Preferably, the reaction time T is 0.5 to 1 hour.
In a preferred embodiment, the slow cooling mode of the filtrate is programmed cooling, preferably, the cooling rate is 0.5 ℃/min.
The application of the levamlodipine besylate crystal form serving as an active ingredient in preparing antihypertensive drugs.
A pharmaceutical composition contains the levamlodipine besylate crystal form of the invention and is mixed with other components.
Preferably, the preparation method of the pharmaceutical composition of the invention is as follows: the compounds of the present invention are formulated into useful dosage forms by combining them with a pharmaceutically acceptable solid or liquid carrier, and optionally with a pharmaceutically acceptable excipient, using standard and conventional techniques.
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 one or more selected from methylcellulose, hydroxypropyl cellulose, hypromellose, sodium hydroxymethyl cellulose, ethylcellulose and povidone; the disintegrating agent is one or more selected from carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, croscarmellose sodium and crospovidone; the lubricant is one or more selected from magnesium stearate, aerosil, talcum powder and sodium dodecyl sulfate.
Preferably, the pharmaceutical composition is a tablet, a capsule, a granule, a pill, etc.
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 definite, the main parameters of crystallography and the exact atomic space positions are definite, and the preparation method is suitable for large-scale popularization and application.
2. The levamlodipine besylate crystal form has better light stability, and the dosage form prepared by the crystal form is beneficial to medicine storage and ensures medicine effect.
3. The levamlodipine besylate crystal form is applied to medicines, and the dissolution rate is greatly improved, so that the bioavailability is increased, the medicine effect is improved, and the invention is suitable for large-scale popularization and application.
Drawings
Fig. 1: the levoamlodipine besylate crystal form ORTEP chart.
Fig. 2: and a pile-up diagram of the levamlodipine besylate crystal form.
Fig. 3: x-ray powder diffraction pattern of levoamlodipine besylate crystal form.
Fig. 4: x-ray powder diffraction integral chart of levoamlodipine besylate crystal form.
Fig. 5: a differential scanning calorimetry (DSC/TGA) profile of the levamlodipine besylate crystalline form.
Detailed Description
The invention is further illustrated by the following examples. It should be correctly understood that: the examples of the present invention are intended to be illustrative of the invention and not limiting thereof, so that simple modifications of the invention based on the method of the invention are within the scope of the invention as claimed.
The materials used in the experiment: levamlodipine besylate can be purchased and can also be prepared by referring to the prior art; the materials used in the other experiments were not of the indicated source and specification, either commercially available analytically pure or chemically pure.
The optical purity and purity detection of the levamlodipine besylate crystal form refer to the national pharmaceutical standards (WS) 1 The method of- (X-019) -2002Z).
Example 1
Levamlodipine besylate (5.05 g) was added to ethanol/purified water (V) Ethanol :V Water and its preparation method =1:8, 450 ml), heating to 50 ℃ and stirring to dissolve, continuing to keep the temperature and stirring to react for 0.5h, filtering, and cooling the filtrate to room temperature at a rate of 0.5 ℃/min; placing the filtrate in a beaker, sealing with a sealing film, punching, volatilizing, crystallizing for 3 days, filtering, and drying under reduced pressure at 45 ℃ to constant weight to obtain the levamlodipine besylate crystal form with the yield of 98.2%, the optical purity of 99.97% and the purity of 99.92%.
Example 2
Levamlodipine besylate (5.03 g) was added to acetone/purified water (V) Acetone (acetone) :V Water and its preparation method =1:6, 400 ml), heating to 40 ℃ and stirring to dissolve, continuing to keep the temperature and stirring to react for 1h, filtering, and cooling the filtrate to room temperature at a rate of 0.5 ℃/min; placing the filtrate in beaker, sealing with sealing film, punching, volatilizing, crystallizing for 2 days, filtering, drying under reduced pressure at 45deg.C to constant weight to obtain levamlodipine besylate crystal form with yield of 977%, optical purity 99.95%, purity 99.82%.
Example 3
Levamlodipine besylate (5.02 g) was added to methanol/purified water (V) Methanol :V Water and its preparation method =1:7, 450 ml), heating to 50 ℃ and stirring to dissolve, continuing to keep the temperature and stirring to react for 0.5h, filtering, and cooling the filtrate to room temperature at a rate of 0.5 ℃/min; placing the filtrate in a beaker, sealing with a sealing film, punching, volatilizing, crystallizing for 3 days, filtering, and drying under reduced pressure at 45 ℃ to constant weight to obtain the levamlodipine besylate crystal form with the yield of 97.5%, the optical purity of 99.93% and the purity of 99.84%.
Example 4
Levamlodipine besylate (5.06 g) was added to tetrahydrofuran/purified water (V Tetrahydrofuran (THF) :V Water and its preparation method =1:8, 500 ml), heating to 45 ℃ and stirring to dissolve, continuing to keep the temperature and stirring to react for 0.5h, filtering, and cooling the filtrate to room temperature at a rate of 0.5 ℃/min; placing the filtrate in a beaker, sealing with a sealing film, punching, volatilizing, crystallizing for 3 days, filtering, and drying under reduced pressure at 45 ℃ to constant weight to obtain the levamlodipine besylate crystal form with the yield of 97.2%, the optical purity of 99.95% and the purity of 99.83%.
Example 5
Levamlodipine besylate (5.02 g) was added to isopropanol/purified water (V Isopropyl alcohol :V Water and its preparation method =1:9, 450 ml), heating to 45 ℃ and stirring to dissolve, continuing to keep the temperature and stirring to react for 0.5h, filtering, and cooling the filtrate to room temperature at a rate of 0.5 ℃/min; placing the filtrate in a beaker, sealing with a sealing film, punching, volatilizing, crystallizing for 3 days, filtering, and drying under reduced pressure at 45 ℃ to constant weight to obtain the levamlodipine besylate crystal form with the yield of 97.4%, the optical purity of 99.96% and the purity of 99.85%.
Example 6
Levamlodipine besylate (5.01 g) was added to acetonitrile/purified water (V) Acetonitrile :V Water and its preparation method =1:7, 450 ml), heating to 50 ℃ and stirring to dissolve, continuing to keep the temperature and stirring to react for 0.5h, filtering, and cooling the filtrate to room temperature at a rate of 0.5 ℃/min; placing the filtrate in beaker, sealing with sealing film, and bindingAnd (3) carrying out hole volatilization, crystallization for 4 days, filtering, and drying under reduced pressure at 45 ℃ 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 (5.02 g) was added to DMF/purified water (V DMF :V Water and its preparation method =1:10, 450 ml), heating to 60 ℃ and stirring to dissolve, continuing to keep the temperature and stirring to react for 1h, filtering, and cooling the filtrate to room temperature at a rate of 0.5 ℃/min; placing the filtrate in a beaker, sealing by a sealing film, punching, volatilizing, crystallizing for 5 days, filtering, and drying under reduced pressure at 45 ℃ to constant weight to obtain the levamlodipine besylate crystal form with the yield of 97.6%, the optical purity of 99.92% and the purity of 99.87%.
Example 8
Levamlodipine besylate (5.07 g) was added to DMSO/purified water (V) DMSO :V Water and its preparation method =1:8, 500 ml), heating to 55 ℃ and stirring to dissolve, continuing to keep the temperature and stirring to react for 0.5h, filtering, and cooling the filtrate to room temperature at a rate of 0.5 ℃/min; placing the filtrate in a beaker, sealing by a sealing film, punching, volatilizing, crystallizing for 5 days, filtering, and drying under reduced pressure at 45 ℃ to constant weight to obtain the levamlodipine besylate crystal form with the yield of 97.7%, the optical purity of 99.95% and the purity of 99.85%.
Example 9
Levamlodipine besylate (5.03 g) was added to ethanol/isopropanol/purified water (V Ethanol :V Isopropyl alcohol :V Water and its preparation method =0.5:0.5:6, 400 ml) heating to 50 ℃ and stirring to dissolve, continuing to keep the temperature and stirring to react for 0.5h, filtering, and cooling the filtrate to room temperature at a speed of 0.5 ℃/min; placing the filtrate in a beaker, sealing by a sealing film, punching, volatilizing, crystallizing for 3 days, filtering, and drying under reduced pressure at 45 ℃ to constant weight to obtain the levamlodipine besylate crystal form with the yield of 98.2%, the optical purity of 99.96% and the purity of 99.87%.
Example 10
Levamlodipine besylate (5.04 g) was added to ethanol/acetone/purified water (V Ethanol :V Acetone (acetone) :V Water and its preparation method Mixed solution of =0.5:0.5:7, 450 ml) was heated to 50 ℃ and stirredStirring and dissolving, continuing to perform heat preservation and stirring reaction for 0.5h, filtering, and cooling the filtrate to room temperature at a speed of 0.5 ℃/min; placing the filtrate in a beaker, sealing with a sealing film, punching, volatilizing, crystallizing for 3 days, filtering, and drying under reduced pressure at 45 ℃ to constant weight to obtain the levamlodipine besylate crystal form with the yield of 97.8%, the optical purity of 99.94% and the purity of 99.83%.
Confirmation of crystal structure of levoamlodipine besylate
For the above examples 1 to 10, crystals conforming to the specification size were selected from the prepared crystal samples, X-ray crystal form data thereof were collected on a model XtaLAB Synergy instrument of japan, temperature 293 (2) K, voltage 50kv, current 1mA, data were collected by CuKa radiation in an ω -scanning manner and Lp correction was performed. Analyzing the structure by a direct method, finding all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and finishing the structure by a least square method.
The crystallographic data obtained by testing and analyzing the levamlodipine besylate hydrate crystal form prepared by the invention are shown in the table 1, wherein the crystallographic parameters are as follows: monoclinic system with space group P2 1 The method comprises the steps of carrying out a first treatment on the surface of the The unit cell parameters are:
α=90.00 °, β= 96.496 (2) °, γ=90.00°, unit cell volume +.>
The ORTEP diagram (figure 1) of the levamlodipine besylate crystal form shows that each levamlodipine besylate molecule and 1 water molecule are crystallized, and the crystal form can be confirmed to be the levamlodipine besylate 1 hydrate. The stacking diagram (figure 2) of the levamlodipine besylate crystal form shows that the levamlodipine besylate 1 hydrate crystal form forms a stacking structure through interaction of hydrogen bond action, pi-pi stacking and the like, and crystal water molecules are connected with levamlodipine besylate molecules through intermolecular hydrogen bond action. Chiral absolute configurationLevamlodipine besylate was determined from a crystallographic Flack parameter value of 0.05 (3).
TABLE 1 Levamlodipine besylate Crystal form primary crystallographic data
The X-ray powder diffraction test instrument and test conditions related in the invention: an X-ray powder diffractometer, PANalytical E; cu-K alpha; sample stage: a flat plate; the incident light path is BBHD; diffraction light path: PLXCEL; voltage 45kv and current 40mA; 1/4 of the divergent slit; an anti-scattering slit 1; a cable pull slit of 0.04rad; step size: 0.5s; scanning range: 3-50 deg.
According to the above-mentioned crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-K alpha) are shown in FIG. 3 and Table 2.
TABLE 2 Levamlodipine besylate crystalline form PXRD peak
The TGA/DSC thermal analysis test conditions for the levamlodipine besylate crystal form are as follows: mertrer-tolidol TGA/DSC thermogram (model: TGA/DSC 3+), dynamic temperature profile: 30-300 ℃, heating rate: 10 ℃/min, procedure gas N 2 Flow rate: 50ml/min, crucible: 40 μl of aluminum crucible. As shown in figure 5, the crystal form of the levamlodipine besylate has two endothermic peaks which are 67.43 ℃ and 213.08 ℃ respectively 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 that the crystal form of the levamlodipine besylate is the levamlodipine besylate hydrate containing one water molecule, and the result is consistent with the X single crystal data.
The samples of examples 1-10 all have the same crystallographic parameters, X-ray powder diffraction pattern and differential scanning calorimetry (DSC/TGA) pattern.
The comparative examples 1 to 6 were prepared by referring to the preparation methods of the levamlodipine besylate crystal forms reported in the prior art.
Comparative example 1
Levamlodipine besylate (5 g) was added to dichloromethane/ethanol (V) Dichloromethane (dichloromethane) :V Ethanol =5:1, 50 ml) to obtain a reaction solution; dripping n-heptane into the reaction liquid under the ultrasonic field (0.4 KW) until crystallization is separated out; closing an ultrasonic field, standing for 4 hours at 20 ℃, filtering, washing a filter cake with dichloromethane and ethanol respectively, and drying to obtain the levamlodipine besylate anhydrous crystal with the optical purity of 99.74% and the purity of 99.68%.
Comparative example 2
Levamlodipine besylate (5 g) was added to acetone/purified water (V Acetone (acetone) :V Water and its preparation method =1:1, 2.5 ml) to obtain a reaction solution by stirring and dissolving; the reaction solution is heated to 30 ℃, stirred and reacted for 10min, cooled to room temperature, purified water (10 ml) is added, cooled to 5 ℃, crystallized for 24 h, reduced pressure filtered, washed by filtrate, washed by cold water, dried to constant weight at room temperature, and white-like benzene sulfonic acid levamlodipine 1.5 hydrate crystal with optical purity of 99.63% and purity of 99.72% is obtained.
Comparative example 3
Adding levamlodipine (5 g) into purified water (120 ml), adding benzenesulfonic acid (1.4 g) into the levamlodipine aqueous solution, and stirring and mixing uniformly; the mixed solution was heated to 60 ℃ under nitrogen. Stopping stirring after dissolution, cooling to room temperature, and crystallizing overnight; after filtration, the mixture was washed with purified water (20 ml), and dried at room temperature to a constant weight, to obtain levamlodipine besylate 2 hydrate crystals having an optical purity of 99.54% and a purity of 99.48%.
Comparative example 4
Adding(s) -amlodipine-semi-L-tartaric acid-DMF solvate (100 g) into purified water (550 ml), adding isopropanol (100 ml), and stirring for 10min to obtain a mixed solution; benzenesulfonic acid (32.7 g) was added to purified water (100 ml) to obtain a 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 benzenesulfonate compound; purified water (500 ml) is added into the reaction solution, stirred for crystallization, filtered, and filter cake is washed by the purified water, and after washing by cyclohexane (100 ml), the mixture is dried at 35-40 ℃ to obtain white-like benzene sulfonic acid levamlodipine 2.5 hydrate crystals with optical purity of 99.25% and purity of 99.52%.
Comparative example 5
The levamlodipine besylate 2.5 hydrate crystals were prepared according to the method of comparative example 4. Adding levamlodipine besylate crystals (20 g) into purified water (480 ml), and stirring and uniformly mixing; under the protection of nitrogen, heating the levamlodipine besylate solution to 60 ℃ for reaction for 30min, gradually cooling to room temperature for crystallization for 8-12 h, filtering, and drying to constant weight at room temperature to obtain white-like levamlodipine besylate 2 hydrate crystals with optical purity of 99.22% and purity of 99.53%.
Comparative example 6
Adding levamlodipine (12.11 g) into a 94% ethanol (28 ml) solution, and stirring and uniformly mixing to obtain a levamlodipine solution; benzenesulfonic acid (5.15 g) was added to a 94% ethanol (35 ml) solution, and the mixture was dissolved with stirring to obtain a benzenesulfonic acid solution; adding the levamlodipine solution into the benzenesulfonic acid solution, and stirring and reacting for 2 hours at 25 ℃; after the reaction, the temperature is controlled at 20 ℃, purified water (370 ml) is added into the reaction solution, and the mixture is stirred and crystallized for 4 hours; filtering, washing a filter cake with purified water, and vacuum drying the filter cake at 55 ℃ for 24 hours, wherein the obtained dry solid is placed for 24 hours under the conditions of the temperature of 25+/-2 ℃ and the humidity of 60+/-5%, so that the white-like benzene sulfonic acid levamlodipine 2.5 hydrate crystal is obtained, the optical purity is 99.92%, and the purity is 99.64%.
Thermal stability test
Dissolving levamlodipine besylate crystals prepared in example 1 and comparative examples 1-6 in water, respectively, and storing at 25deg.C in dark for 4 weeks to detect the content of dextroisomer and other related substances, and referring to national pharmaceutical standards (WS) 1 - (X-019) -2002Z) optical purity and related substances. The results are shown in Table 3.
TABLE 3 stability test results of Levamlodipine besylate in solution
As shown in table 3, the levamlodipine besylate crystal form impurity of comparative example 6 was significantly increased and the content of dextroisomer was significantly increased after storage in the dark at 25 ℃ for 4 weeks; the levamlodipine besylate crystal form of the invention has insignificant change and is basically stable after 4 weeks of investigation with the levamlodipine besylate crystal form of the comparative examples 1-5. Examples 1 to 10 were examined to find similar stability test results.
The levamlodipine besylate crystals prepared in example 1 and comparative examples 1 to 6 were subjected to accelerated test at 60℃in the dark for 4 weeks, and the content of dextroisomer and other related substances was detected, and observed under the same HPLC conditions as those for evaluating the stability in the solution state. The results are shown in Table 4.
TABLE 4 results of accelerated test of levamlodipine besylate in solid state at 60℃
Solid stability test results show that the levamlodipine besylate crystal form impurity of the comparative example 6 is obviously increased, and the content of the dextroisomer is obviously increased; the levamlodipine besylate crystal form of the invention has insignificant change and is basically stable after 4 weeks of investigation with the levamlodipine besylate crystal form of the comparative examples 1-5. Examples 1 to 10 were examined to find similar stability test results.
Light stability test
Taking the benzene sulfonic acid L-ammonia chloride prepared in the example 1 and the comparative examples 1-6 respectivelyHorizon crystals, which are used for detecting the content of dextroisomer and other related substances on days 0, 5 and 10 under strong light irradiation (4500 Lx+/-500 Lx), refer to the national pharmaceutical standards (WS) 1 - (X-019) -2002Z) optical purity and related substances. The results are shown in Table 5.
TABLE 5 light stability test results for levamlodipine besylate crystalline form
The photo stability test result shows that under the condition of strong light irradiation, the content change of the dextroisomer of the levamlodipine besylate crystal form of the invention is not obvious compared with the crystal forms of comparative examples 1-6; 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 medicine effect. Examples 1 to 10 were examined and found to have similar light stability test results.
Hygroscopicity test
The levamlodipine besylate crystals prepared in example 1 and comparative examples 1 to 6 were respectively taken and subjected to measurement of water content (karl fischer method, water%) under different humidity conditions (25%, 60%, 75%, 95%) at 25 ℃. The results are shown in Table 6.
TABLE 6 results of test of hygroscopicity of the levamlodipine besylate crystalline form
| Storage condition (RH) | 25％ | 60％ | 75％ | 95％ | |
| Storage time | Initial initiation | 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％ |
| Comparative example 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 hygroscopicity test results show that the levamlodipine besylate crystal form prepared in example 1 and comparative examples 1 to 5 shows non hygroscopicity under various humidity conditions. The levamlodipine besylate crystalline form 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 crystalline form of levoamlodipine besylate prepared in examples 2 to 10 was found to exhibit non-hygroscopicity as in example 1.
Dissolution test
The levamlodipine besylate crystals prepared in examples 1 to 10 and comparative examples 1 to 6 were taken respectively, and 1000 tablets of levamlodipine besylate were prepared respectively according to the formulation ratio of table 7.
Table 7 pharmaceutical formulation ratio of levamlodipine besylate crystalline form
Dissolution test
The measuring method comprises the following steps: referring to the evaluation method of dissolution consistency of amlodipine besylate tablets in Japanese orange paper, a slurry method is adopted, buffer solution with pH of 1.2,4.0,6.8 and 900ml of water are respectively used as dissolution media under the dark condition of 37 ℃, the rotation speed is 50r/min, 5ml is respectively sampled at 5, 10, 15, 20, 30 and 45min, and the liquid is timely supplemented, filtered, injected by HPLC, and the method is referred to the national pharmaceutical standards (WS 1 - (X-020) -2002Z) content measurement method, and calculating the cumulative dissolution rate at each time point. The results are shown in tables 8 to 11.
TABLE 8 dissolution of different Levamlodipine besylate crystalline form tablets in pH 1.2 buffer
TABLE 9 dissolution of different Levamlodipine besylate crystalline form tablets in pH 4.0 buffer
TABLE 10 dissolution of different Levamlodipine besylate crystalline form tablets in pH6.8 buffer
TABLE 11 dissolution of different Levamlodipine besylate crystalline form tablets in Water
The dissolution test adopts a Japanese orange paper evaluation method, so that the correlation of human bodies is improved, and the rotating speed of 50r/min is closer to the gastric motility of human bodies. The dissolution results show that the levamlodipine besylate crystal form tablet can be dissolved for more than 80% in four dissolution media of buffer solution with pH of 1.2,4.0,6.8 and water respectively in 5 min; in a buffer solution dissolution medium with the pH of 6.8 which is closer to the human body environment, the dissolution amount of the levamlodipine besylate crystal form tablet for 30min reaches 95%, and compared with other amlodipine besylate crystal form tablets, the invention has outstanding dissolution effect; the levamlodipine besylate crystal form of the invention greatly improves the dissolution rate of the medicine, thereby improving the bioavailability and the medicine effect. The test shows that the levamlodipine besylate crystal form tablets of examples 1 to 10 have similar dissolution effect.
Claims (9)
1. The levoamlodipine besylate crystal form is characterized in that the levoamlodipine besylate crystal form uses Cu-K alpha radiation and has an X-ray powder diffraction pattern shown in figure 3.
2. The crystalline form of levamlodipine besylate according to claim 1 wherein the molecular formula of the crystalline form of levamlodipine besylate is: c (C) 20 H 25 ClN 2 O 5 ·C 6 H 6 O 3 S · H 2 The O, crystallographic measurement parameters were: monoclinic system with space group P2 1 The method comprises the steps of carrying out a first treatment on the surface of the The unit cell parameters are: a= 14.5011 (3) a, b= 7.8082 (2) a, c= 26.1230 (7) a，α= 90.00°，β= 96.496(2) °，γUnit cell volume v= 2938.85 (13) a=90.00° 3 。
3. A process for preparing the crystalline form of levoamlodipine besylate according to any one of claims 1-2, characterized in that the preparation process comprises the steps of:
adding levamlodipine besylate into a mixed solution of an organic solvent and purified water, heating, stirring, dissolving, continuing to perform heat preservation, stirring, reacting for 0.5-1 hour, filtering, and slowly cooling the filtrate to room temperature; placing the filtrate in a beaker, sealing by a sealing film, punching, volatilizing, crystallizing, filtering, and drying under reduced pressure to obtain the levamlodipine besylate crystal form.
4. The method for preparing the levamlodipine besylate crystal form according to claim 3 wherein the organic solvent is one or two of acetone, tetrahydrofuran, ethanol, methanol, N-dimethylformamide, dimethyl sulfoxide, isopropanol and acetonitrile.
5. The method for preparing the levamlodipine besylate crystal form according to claim 3 wherein the volume ratio of the organic solvent to the purified water is 1: 6-10.
6. The preparation method of the levamlodipine besylate crystal form according to claim 3, wherein the mass-volume ratio of the levamlodipine besylate to the mixed solution is 1:80-100, g/ml.
7. The method for preparing the levamlodipine besylate crystal form according to claim 3 wherein the slow cooling mode of the filtrate is programmed cooling.
8. The method for preparing the levamlodipine besylate crystal form according to claim 7 wherein the programmed cooling rate is 0.5 ℃/min.
9. Use of the crystalline form of levoamlodipine besylate according to any one of claims 1-2 as an active ingredient for the preparation of antihypertensive drugs.
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