阅读说明：本技术 一种苯磺酸左旋氨氯地平晶型 (Levamlodipine besylate crystal form ) 是由 翟立海 张明明 郭新亮 王亚青 于 2019-03-13 设计创作，主要内容包括：本发明提供了一种苯磺酸左旋氨氯地平晶型,使用Cu-Kα辐射,以2θ表示的X射线衍射谱图在3.37±0.2°,9.52±0.2°,10.08±0.2°,12.63±0.2°,16.34±0.2°,20.22±0.2°,22.70±0.2°,25.04±0.2°,27.00±0.2°,37.60±0.2°有特征峰；晶体学测量参数是：单斜晶系,空间群为P2<Sub>1</Sub>；晶胞参数为：<Image he="38" wi="700" file="DDA0001993143160000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>α＝90.00°,β＝100.1300(10),γ＝90.00°,晶胞体积<Image he="76" wi="399" file="DDA0001993143160000012.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>并提供了相关制备方法和应用。本发明的苯磺酸左旋氨氯地平晶型稳定性好,利用其制备的药物,溶出度高,增加了生物利用度,提高了药效。(The invention provides a levoamlodipine besylate crystal form, which is radiated by Cu-K α, and has characteristic peaks at 3.37 +/-0.2 degrees, 9.52 +/-0.2 degrees, 10.08 +/-0.2 degrees, 12.63 +/-0.2 degrees, 16.34 +/-0.2 degrees, 20.22 +/-0.2 degrees, 22.70 +/-0.2 degrees, 25.04 +/-0.2 degrees, 27.00 +/-0.2 degrees and 37.60 +/-0.2 degrees in an X-ray diffraction spectrogram expressed by 2 theta, wherein the crystallography measurement parameters are monoclinic system, and the space group is P2 degrees 1 (ii) a The unit cell parameters are: α -90.00 deg., β -100.1300 (10), γ -90.00 deg., unit cell volume And provides related preparation method and application. The levamlodipine besylate has good crystal form stability, and a medicine prepared by using the levamlodipine besylate has high dissolution rate, improves the bioavailability and improves the medicine effect.)

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 3.37 +/-0.2 degrees, 9.52 +/-0.2 degrees, 10.08 +/-0.2 degrees, 12.63 +/-0.2 degrees, 16.34 +/-0.2 degrees, 20.22 +/-0.2 degrees, 22.70 +/-0.2 degrees, 25.04 +/-0.2 degrees, 27.00 +/-0.2 degrees, and 37.60 +/-0.2 degrees.

2. The crystalline form of levamlodipine besylate according to claim 1, wherein said crystalline form of levamlodipine besylate has an X-ray diffraction pattern expressed in 2 Θ using Cu-ka radiation having characteristic peaks at 3.37 ± 0.2 °, 6.72 ± 0.2 °, 9.52 ± 0.2 °, 10.08 ± 0.2 °, 12.22 ± 0.2 °, 12.63 ± 0.2 °, 13.44 ± 0.2 °, 14.44 ± 0.2 °, 14.95 ± 0.2 °, 16.34 ± 0.2 °, 16.51 ± 0.2 °, 19.79 ± 0.2 °, 20.22 ± 0.2 °, 21.96 ± 0.2 °, 22.70 ± 0.2 °, 23.60 ± 0.2 °, 25.04 ± 0.2 °, 27.00 ± 0.2 °, 33.95 ± 0.2 °, 37.60 ± 0.2 °.

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: (C)₂₀H₂₅ClN₂O₅)·(C₆H₆O₃S)·(H₂O)_2.5The crystallographic measurement parameters are: monoclinic system, space group P2₁(ii) a The unit cell parameters are:

5. A method for preparing the levoamlodipine besylate crystalline form of any of claims 1-4, comprising the steps of:

(1) adding levamlodipine besylate into a mixed solution of an organic solvent and purified water, and heating for dissolving to obtain a reaction solution;

(2) and (3) carrying out temperature control reaction on the reaction liquid, finishing the reaction, and cooling and crystallizing to obtain the levoamlodipine besylate crystal form.

6. The method for preparing the crystal form of levamlodipine besylate according to claim 5, wherein the organic solvent in step (1) is one or two of ethyl acetate, isopropyl acetate, butyl acetate, ethanol, methanol, acetone, and N, N-dimethylformamide.

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 in the step (1) is 1: 0.5 to 2.5; the mass-volume ratio of the benzene sulfonic acid levamlodipine to the mixed solution is 1: 50-100 g/mL.

8. The method for preparing the crystal form of levamlodipine besylate according to claim 5, wherein the reaction liquid temperature control reaction temperature in the step (2) is that the reaction liquid reaches the reflux reaction temperature.

9. The method for preparing the levoamlodipine besylate crystal form according to claim 5, wherein the temperature-reducing crystallization temperature in the step (2) is 15-20 ℃, the specific temperature-reducing mode is program temperature reduction, and preferably, the temperature-reducing 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.

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 C₂₀H₂₅N₂O_sCl·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 report of amlodipine besylate crystal form research, 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 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; korean patent No. 10-2005-; in the patent WO2006043148, a levamlodipine besylate DMF solvent compound is obtained in the process of preparing the levamlodipine besylate, and a crystal form compound of the levamlodipine besylate dihydrate and two levamlodipine besylate molecules sharing five crystal waters is obtained through further processing; 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 CN 105111137B 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 3.37 +/-0.2 degrees, 9.52 +/-0.2 degrees, 10.08 +/-0.2 degrees, 12.63 +/-0.2 degrees, 16.34 +/-0.2 degrees, 20.22 +/-0.2 degrees, 22.70 +/-0.2 degrees, 25.04 +/-0.2 degrees, 27.00 +/-0.2 degrees and 37.60 +/-0.2 degrees.

Preferably, the levoamlodipine besylate crystal form has characteristic peaks at 3.37 +/-0.2 °, 6.72 +/-0.2 °, 9.52 +/-0.2 °, 10.08 +/-0.2 °, 12.22 +/-0.2 °, 12.63 +/-0.2 °, 13.44 +/-0.2 °, 14.44 +/-0.2 °, 14.95 +/-0.2 °, 16.34 +/-0.2 °, 16.51 +/-0.2 °, 19.79 +/-0.2 °, 20.22 +/-0.2 °, 21.96 +/-0.2 °, 22.70 +/-0.2 °, 23.60 +/-0.2 °, 25.04 +/-0.2 °, 27.00 +/-0.2 °, 33.95 +/-0.2 ° and 37.60 +/-0.2 ° in an X-ray diffraction spectrum expressed by 2 theta under 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 (C)₂₀H₂₅ClN₂O₅)·(C₆H₆O₃5)·(H₂O)_2.5The crystallographic measurement parameters are: monoclinic system, space group P2₁(ii) a The unit cell parameters are: α -90.00 deg., β -100.1300 (10), γ -90.00 deg., unit cell volume

The preparation method of the levoamlodipine besylate crystal form comprises the following steps:

(1) adding levamlodipine besylate into a mixed solution of an organic solvent and purified water, and heating for dissolving to obtain a reaction solution;

(2) and (3) carrying out temperature control reaction on the reaction liquid, finishing the reaction, and cooling and crystallizing to obtain the levamlodipine besylate crystal form.

Preferably, the organic solvent in step (1) is one or two of ethyl acetate, isopropyl acetate, butyl acetate, ethanol, methanol, acetone and N, N-dimethylformamide.

Preferably, the volume ratio of the organic solvent to the purified water in the step (1) is 1: 0.5-2.5.

Preferably, the mass-to-volume ratio of the levamlodipine besylate in the step (1) to the mixed solution is 1: 50-100 g/mL.

Preferably, the heating and dissolving temperature in the step (1) is 40-60 ℃.

Preferably, the reaction liquid temperature in the step (2) is the reaction liquid temperature reaching the reflux reaction temperature.

Preferably, the reaction time in the step (2) is 2-4 hours.

In a preferred scheme, the temperature of the step (2) is reduced to 15-20 ℃, the specific cooling mode 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 levamlodipine besylate crystal form is applied to medicines, greatly improves the dissolution rate, further increases the bioavailability, improves the drug effect, and is suitable for large-scale popularization and application.

Drawings

FIG. 1: crystal form ORTEP diagram of levamlodipine besylate.

FIG. 2: a crystal form hydrogen bond diagram of levamlodipine besylate.

FIG. 3: a crystal form X-ray powder diffraction pattern of the levamlodipine besylate.

FIG. 4: a differential scanning calorimetry curve (DSC/TGA) graph of the crystal form of the levamlodipine besylate.

FIG. 5: comparative example 1 levoamlodipine besylate crystal form X-ray powder diffraction pattern.

FIG. 6: comparative example 1 levoamlodipine besylate crystal form X-ray powder diffraction integral chart.

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.