阅读说明：本技术 结晶于三斜晶系的马来酸左旋氨氯地平共晶药物及其制备方法和应用 (Levamlodipine maleate eutectic drug crystallized in triclinic system and preparation method and application thereof ) 是由 凌云 周亚明 贾瑜 陈珍霞 邓名莉 刘小锋 杨永泰 向睿卿 于 2020-05-17 设计创作，主要内容包括：本发明提供一种结晶于三斜晶系的马来酸左旋氨氯地平共晶药物及其制备方法和应用,该共晶药物化学通式为(C<Sub>20</Sub>H<Sub>26</Sub>ClN<Sub>2</Sub>O<Sub>5</Sub>)·(C<Sub>4</Sub>H<Sub>3</Sub>O<Sub>4</Sub>)·(H<Sub>2</Sub>O)<Sub>n</Sub>,其中：C<Sub>20</Sub>H<Sub>26</Sub>ClN<Sub>2</Sub>O<Sub>5</Sub>是左旋氨氯地平游离碱中伯氨被质子化的分子式；C<Sub>4</Sub>H<Sub>3</Sub>O<Sub>4</Sub>是脱一个质子的(Z)-2-丁烯二酸；0≤n<1；共晶药物分子结晶于三斜晶系,P1手性空间群,晶胞大小：<Image he="51" wi="700" file="DDA0002495160120000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>α＝97.7～97.9°,β＝92.6～93.0°,γ＝109.2～109.6°,<Image he="72" wi="395" file="DDA0002495160120000012.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>本发明提供的共晶药物具有明确的晶型、晶体学参数及确切的原子空间位置,不同于市售的马来酸左旋氨氯地平,其制备方法简单,颗粒晶型明确,易于质量控制和规模生产。(The invention provides a maleic acid levoamlodipine eutectic drug crystallized in a triclinic system and a preparation method and application thereof, wherein the chemical general formula of the eutectic drug is (C) 20 H 26 ClN 2 O 5 )·(C 4 H 3 O 4 )·(H 2 O) n Wherein: c 20 H 26 ClN 2 O 5 Is a molecular formula of protonized primary ammonia in free base of the levamlodipine; c 4 H 3 O 4 Is deprotonated (Z) -2-butenedioic acid; n is more than or equal to 0<1; the eutectic drug molecules are crystallized in a triclinic system, P1 chiral space group, unit cell size: α＝97.7～97.9°,β＝92.6～93.0°，γ＝109.2～109.6°, the eutectic medicine provided by the invention has definite crystal form, crystallographic parameters and definite atom space positions, is different from commercially available levoamlodipine maleate, has a simple preparation method and definite particle crystal form, and is easy for quality control and mass production.)

1. The Levamlodipine maleate eutectic drug crystallized in the triclinic crystal system is characterized in that the chemical general formula of the eutectic drug is (C)₂₀H₂₆ClN₂O₅)·(C₄H₃O₄)·(H₂O)_nWherein: c₂₀H₂₆ClN₂O₅Is a molecular formula of protonized primary ammonia in free base of the levamlodipine; c₄H₃O₄Is deprotonated (Z) -2-butenedioic acid; n is more than or equal to 0<1；

The eutectic drug molecule is crystallized in a triclinic system, P1 chiral space group, unit cell size: α＝97.7～97.9°，β＝92.6～93.0°，γ＝109.2～109.6°，

2. the preparation method of the Levamlodipine maleate eutectic drug crystallized in the triclinic system as claimed in claim 1, which comprises the following steps:

(1) charging levamlodipine free alkali and a salifying reagent into a reaction vessel;

(2) adding a proper amount of prepared solvent into a reaction container, and stirring to fully mix the solvent and the solvent;

(3) and (3) stirring the reaction solution, heating to the target temperature, preserving the temperature for a certain time, cooling, crystallizing, filtering and separating to obtain the product.

3. The preparation method of the Levamlodipine maleate eutectic drug crystallized in the triclinic system as claimed in claim 2, wherein the solvent is one or a mixture of water, ethanol or ethyl acetate.

4. The preparation method of the Levamlodipine maleate eutectic drug crystallized in the triclinic system as claimed in claim 3, wherein the molar ratio of the Levamlodipine free base to the solvent is 1: 50-200.

5. The preparation method of the Levamlodipine maleate eutectic drug crystallized in the triclinic system as claimed in claim 2, wherein the salt forming reagent is (Z) -2-butenedioic acid.

6. The preparation method of the Levamlodipine maleate eutectic drug crystallized in the triclinic system as claimed in claim 5, wherein the molar weight ratio of the Levamlodipine to the salifying reagent is 1: 1-2.

7. The preparation method of the Levamlodipine maleate eutectic drug crystallized in the triclinic crystal system as claimed in claim 2, wherein the target temperature is 50-90 ℃ and the holding time is 2-24 hours.

8. The preparation method of the Levamlodipine maleate eutectic drug crystallized in the triclinic system as claimed in claim 7, wherein the target temperature is 50-70 ℃ and the holding time is 5-24 hours.

9. The preparation method of the Levamlodipine maleate eutectic drug crystallized in the triclinic system as claimed in claim 2, wherein the step (3) further comprises cooling and crystallizing at 5-25 ℃.

10. The use of the Levamlodipine maleate co-crystal drug crystallized in the triclinic system according to claim 1 in the preparation of a drug for treating hypertension.

Technical Field

The invention relates to the technical field of crystal form medicaments, in particular to a maleic acid levorotatory amlodipine eutectic medicament crystallized in a triclinic crystal system and a preparation method and application thereof.

Background

The crystal form drug is preferably selected in patent drugs due to the advantages of stability, reproducibility, bioavailability, operability and the like. The crystal form medicine comprises polymorphism, hydrate, solvate, salt and other types of medicine molecules. The levamlodipine is taken as a chiral resolution structure of the racemic amlodipine and is a levorotatory structure. Research indicates that the blood pressure reducing capacity of the levamlodipine is 1000 times of that of the dextroisomer, and the dextroisomer has higher biological safety risk, so the levamlodipine is the most ideal long-acting blood pressure reducing medicine compared with racemate, is deeply trusted by doctors and patients, and is a common medicine for treating hypertension.

Levamlodipine is a free base compound and needs to be crystallized in a salt forming manner. At present, levoamlodipine salt-forming medicaments sold in China are mainly levoamlodipine besylate and levoamlodipine maleate (the structural formula is shown as follows).

Commercially available levamlodipine maleate, trade name: yanning, produced by Shiyao medicine group, patent CN103058914A discloses a levoamlodipine maleate crystal form and a preparation method thereof, however, the provided so-called crystal form medicine lacks various key parameters (such as space group, crystal system, unit cell, chiral purity and the like) of the crystal form medicine, does not have key contents required by crystal form medicine protection, and does not have molecular structure information required by eutectic medicine. On the other hand, the different crystal forms of the medicine have obvious difference in physicochemical properties, and can directly influence the dissolution and absorption efficiency of the medicine under physiological conditions, thereby influencing the bioavailability, clinical curative effect and the like of the medicine. The existing levamlodipine maleate has poor solubility and low bioavailability and cannot meet the production requirement of large-scale tablets.

Disclosure of Invention

The invention aims to provide a Levamlodipine maleate eutectic drug crystallized in a triclinic crystal system, which is different from commercially available Levamlodipine maleate, and the crystal form drug provided by the invention has clear crystallographic parameters, clear eutectic molecular spatial structure and periodic stacking mode, improves the solubility of Levamlodipine maleate, is potentially beneficial to the quality control of the crystal form drug, is beneficial to the quality evaluation in large-scale tablet application, and ensures the stability of the crystal form drug.

The invention also aims to provide a preparation method and application of the single crystal of the Levamlodipine maleate eutectic drug crystallized in the triclinic crystal system. The method for preparing the crystal form medicine provided by the invention is simple and feasible, and the prepared eutectic medicine has uniform grain diameter, has definite crystallography characteristics, and is potentially suitable for large-scale preparation and tablet application.

To achieve the above objects, according to a first aspect of the present invention, there is provided a Levamlodipine maleate eutectic drug crystallized in a triclinic system, the cocrystal drug crystallized in the triclinic system, P1 chiral space group, unit cell size:

α＝97.7～97.9°，β＝92.6～93.0°，γ＝109.2～109.6°，the chiral absolute configuration is determined by a crystallographic Flack value equal to 0.123 (14). It should be noted that the unit cell number in parentheses is limited by the number of solvent molecules and errors in the number of solvent molecules, test instruments and analytical methods.

The crystallography measurement parameters are obtained by an X-ray single crystal diffraction test method, and the basic process is as follows:

selecting crystal with required size, riveting the crystal on the top of glass wire, and fixing on the tester, testing the X-ray crystal data in Germany Brookd 8 VENTURE model X-ray single crystal diffractometer, using MetalJet liquid gallium alloy target light source, and radiating with Ga-K αDiffraction data was collected in a ω -scan fashion and Lp corrected. Absorption correction employs the SADABS procedure. 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 correcting the structure by a least square method. All parsing is done using the SHELXTL package.

The invention provides a levoamlodipine maleate eutectic medicine crystallized in a triclinic system, which is characterized in that the molecular general formula of the eutectic structure is as follows: (C)₂₀H₂₆ClN₂O₅)·(C₄H₃O₄)·(H₂O)_nWherein: chemical formula C₂₀H₂₆ClN₂O₅Is a molecular formula of the levoamlodipine free base with protonated primary ammonia; chemical formula C₄H₃O₄Is deprotonated (Z) -2-butenedioic acid (commonly known as maleic acid); h₂O is a crystal water molecule, n is not less than 0<1, the molecular structural formula is as follows:

it should be noted that the specific value of n is limited by the type of solvent used in the salt-forming reaction, the temperature conditions, and the subsequent drying conditions of the product, and has a range of variability that does not affect the crystalline form of the co-crystal, which is usually 0 when freshly prepared.

The third aspect of the invention provides a method for preparing a single crystal of a Levamlodipine maleate eutectic drug crystallized in a triclinic system, which is characterized in that the Levamlodipine maleate has the eutectic crystal form described above, and the method for preparing the single crystal product of the eutectic crystal form comprises the following steps:

(1) charging levamlodipine free alkali and a salifying reagent into a reaction vessel;

(2) adding a proper amount of prepared solvent into a reaction container, and stirring to fully mix the solvent and the solvent;

(3) and (3) stirring the reaction solution, heating to the target temperature, preserving the temperature for a certain time, cooling, crystallizing, filtering and separating to obtain the product.

The preparation method provided by the invention is a classical method for preparing eutectic drug single crystals by low-temperature solvothermal method, and comprises the following steps: the free alkali and the salifying reagent are prepared through a closed reaction and nucleation growth under the conditions of proper molar ratio, solvent, temperature and reaction time.

It should be noted that the levamlodipine used herein is all commercially available chemical raw materials, and if used in pharmacy, the raw material drug meeting GMP requirements is used, optimally,using crystals in P2₁2₁2₁The levamlodipine free base is used as a raw material. The solvent used here is any one of commercially available chemical raw materials such as water, ethanol, and ethyl acetate, or a mixed solvent thereof. If the compound is used for pharmacy, the corresponding solvent with the purity meeting the pharmacy requirement is preferably used.

In the step (1), the salt-forming reagent is maleic acid, the amount of the added maleic acid is such that the levamlodipine free base is completely formed into salt, and preferably, in the step (2), the molar ratio of the levamlodipine free base to the maleic acid is 1: 1-2.

In the step (2), the ratio of the levamlodipine free base to the solvent can be determined according to production needs, so as to completely dissolve the levamlodipine free base, and preferably, in the step (2), the molar ratio of the levamlodipine free base to the solvent is 1: 50-200.

In the step (3), the temperature of the reaction solution is raised to the target temperature within a range of 50 to 90 ℃, preferably 50 to 70 ℃, and the time for maintaining the temperature for a certain period of time is not less than 2 hours, and less than this value, the economic benefit of difficult formation of a crystal phase or yield is too low, preferably 5 to 24 hours.

In the step (3), the heat preservation process may be determined according to the conditions of the apparatus in the specific production, and may be performed by a constant temperature heating device to perform closed heat preservation, or may be performed by a heating reflux device, and preferably, performed by a closed reaction apparatus to perform heat preservation.

In the step (3) of preparing the levamlodipine eutectic salt product, cooling is further included, wherein the cooling temperature is generally lower than the holding reaction temperature, and preferably, in the step (3), the temperature is reduced to 5-25 ℃ for crystallization.

In order to obtain the crystalline product, it is preferable that the step (3) further comprises filtering, washing mother liquor (primary crystallization solution), and drying at room temperature.

The filtration may be carried out by any suitable method, and preferably, in the step (3), the filtration is a reduced pressure filtration.

The single crystal of the Levamlodipine maleate eutectic drug crystallized in the triclinic system, prepared by the method, is a flaky colorless transparent crystal with the size of 0.05 multiplied by 0.18 multiplied by 0.25mm in appearance.

The beneficial effects of the invention or the main advantages compared with the prior art are as follows:

(1) the single crystal of the levoamlodipine maleate eutectic medicine provided by the invention is crystallized in a crystal of a triclinic system, P1 chiral space group, has definite crystal form, crystallographic parameters and exact atom space positions, and the commercially available levoamlodipine maleate eutectic crystal form does not have the crystallographic parameters, so that the solubility is improved compared with the levoamlodipine besylate.

(2) The invention provides a maleic acid levamlodipine eutectic drug crystallized in a triclinic system, which has a molecular general formula as follows: (C)₂₀H₂₆ClN₂O₅)·(C₄H₃O₄)·(H₂O)_n. The molecular general formula provided by the invention clearly indicates that primary ammonia in the levamlodipine free base molecule is protonated, and the specific molecular formula is C₂₀H₂₆ClN₂O₅(ii) a Maleic acid, although a typical diacid, has only one acid deprotonated, having the specific formula C₄H₃O₄。

(3) The Levamlodipine maleate eutectic medicine crystallized in the triclinic crystal system has the advantages of simple operation of the single crystal preparation method, regular crystal form of the crystal, uniform grain size, controllable size through cooling rate, wide raw material source of tablet samples, high biocompatibility and suitability for large-scale popularization and application.

Drawings

Fig. 1 is a molecular structure diagram of a crystal of a specific embodiment of a cocrystal drug of levamlodipine maleate crystallized in a triclinic form according to the present invention.

Fig. 2 is a crystal unit cell structure diagram of an embodiment of the cocrystal drug of levamlodipine maleate crystallized in a triclinic crystal form provided by the present invention.

Detailed Description

In order to clarify the levoamlodipine maleate eutectic medicine crystallized in the triclinic crystal form, the single crystal preparation method and the application thereof. In order to clearly understand the technical contents of the present invention, the following examples are given in detail.