阅读说明：本技术 L-门冬氨酸氨氯地平晶型及其制备方法和用途 (L-aspartic acid amlodipine crystal form and preparation method and application thereof ) 是由 蒋玉伟 于 2020-06-12 设计创作，主要内容包括：L-门冬氨酸氨氯地平晶型及其制备方法和用途。本发明公开了一种L-门冬氨酸氨氯地平晶型,其特征在于,所述晶型X-射线衍射使用Cu-Kα辐射,以2θ角度(°)表示的X-射线衍射在以下位置有峰：9.3±0.2°、9.9±0.2°、12.2±0.2°、12.9±0.2°、19.2±0.2°、19.8±0.2°、22.2±0.2°、24.2±0.2°、26.6±0.2°,本发明制备的L-门冬氨酸氨氯地平晶型的质量及稳定性更好,利于长期保存。(An L-aspartic acid amlodipine crystal form, a preparation method and application thereof. The invention discloses an L-aspartic acid amlodipine crystal form, which is characterized in that Cu-Kalpha radiation is used for X-ray diffraction of the crystal form, and X-ray diffraction expressed by 2 theta angle (°) has peaks at the following positions: 9.3 +/-0.2 degrees, 9.9 +/-0.2 degrees, 12.2 +/-0.2 degrees, 12.9 +/-0.2 degrees, 19.2 +/-0.2 degrees, 19.8 +/-0.2 degrees, 22.2 +/-0.2 degrees, 24.2 +/-0.2 degrees and 26.6 +/-0.2 degrees, and the L-aspartic acid amlodipine crystal form prepared by the method has better quality and stability and is beneficial to long-term storage.)

1. A crystalline form of amlodipine L-aspartate, wherein the crystalline form X-ray diffraction uses Cu-ka radiation and the X-ray diffraction in degrees 2 Θ (°) has peaks at the following positions: 9.3 +/-0.2 degrees, 9.9 +/-0.2 degrees, 12.2 +/-0.2 degrees, 12.9 +/-0.2 degrees, 19.2 +/-0.2 degrees, 19.8 +/-0.2 degrees, 22.2 +/-0.2 degrees, 24.2 +/-0.2 degrees and 26.6 +/-0.2 degrees.

2. The amlodipine crystal form of claim 1, wherein the melting point of the crystal form is 145-155 ℃.

3. The crystalline form of amlodipine L-aspartate according to claim 1, characterized in that said crystalline form further has peaks at the following positions: 3.3 +/-0.2 °, 6.6 +/-0.2 °, 13.4 +/-0.2 °, 15.1 +/-0.2 °, 16.1 +/-0.2 °, 17.1 +/-0.2 °, 18.7 +/-0.2 °, 20.5 +/-0.2 °, 21.2 +/-0.2 °, 21.5 +/-0.2 °, 22.9 +/-0.2 °, 25.1 +/-0.2 °, 25.5 +/-0.2 °, 26.1 +/-0.2 °, 26.6 +/-0.2 °, 28.3 +/-0.2 °, 29.0 +/-0.2 °, 31.1 +/-0.2 °, 32.0 +/-0.2 °, 33.5 +/-0.2 ° and 39.1 +/-0.2 °.

4. The crystalline form of amlodipine L-aspartate according to claim 1, characterized in that the X-diffraction pattern of said crystalline form is as shown in figure 1.

5. The method for preparing the crystal form of amlodipine L-aspartate according to claim 1, characterized by comprising the following specific steps: dissolving the L-amlodipine aspartate crude product in a mixed solvent A, stirring and heating the solution to dissolve the L-amlodipine aspartate crude product until the L-amlodipine aspartate crude product is clear, slowly cooling the solution after heat filtration, adding a precooled mixed solvent B into the solution at the flow rate of 1.0-2.0 mL/min when the solution is cooled to 20-30 ℃ until crystals are precipitated, continuously cooling the solution to-5-0 ℃, preserving heat, growing the crystals until the crystals are completely precipitated, and performing suction filtration and drying to obtain the L-amlodipine aspartate crystals.

6. The method for preparing the crystal form of amlodipine aspartate according to claim 5, wherein the mixed solvent A is a mixed solvent of acetonitrile and water, and the volume ratio of the water to the acetonitrile is 0.1-0.3: 1; the mass-volume ratio of the L-aspartic acid amlodipine to the mixed solvent A is 1: 50-100.

7. The method for preparing the amlodipine besylate crystal form according to claim 5, wherein the mixed solvent B is a mixed solvent of acetone and tetrahydrofuran, and the volume ratio of the acetone to the tetrahydrofuran is 1: 0.2-0.5.

8. The method for preparing the amlodipine besylate crystal form according to claim 5, wherein the volume ratio of the mixed solvent A to the mixed solvent B is 1: 0.5-1.

9. The method for preparing the amlodipine besylate crystal form according to claim 5, wherein the cooling rate of the solution after the heat filtration is 2-4 ℃/min.

10. The use of the crystalline form of amlodipine aspartate according to any one of claims 1 to 5, for the preparation of a pharmaceutical combination for the treatment of ischemia and hypertension.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to an L-aspartic acid amlodipine crystal form, and a preparation method and application thereof.

Background

Amlodipine is a new generation calcium ion antagonist, effectively overcomes the defects of unstable blood pressure reduction and large adverse reaction of a second generation calcium ion antagonist diltiazem and nifedipine, is clinically used for treating hypertension and stable angina pectoris, has the characteristics of obvious curative effect, stable effect, long drug effect time, small side effect and the like, is convenient to take, only needs to be taken once every day, has good tolerance of patients, is recognized as a safe and effective drug by the American FDA, is accepted by vast hypertension patients, and becomes a preferred drug for treating hypertension. The amlodipine salt comprises amlodipine besylate, amlodipine maleate, amlodipine mesylate, L-amlodipine aspartate, amlodipine nicotinate, amlodipine camsylate and the like, and the invention patent with the application number of CN201910065643.7 reports the crystal form of the L-amlodipine aspartate, but reports that the crystal form has poor stability and is not beneficial to preparing corresponding pharmaceutical preparations.

Disclosure of Invention

In order to solve the defects of the prior art, the invention aims to provide the L-aspartic acid amlodipine crystal form which has better quality and stability and is beneficial to long-term storage and the preparation method thereof.

In order to achieve the above object, the present invention adopts the following technical solutions:

a crystalline form of amlodipine L-aspartate, characterized in that the crystalline form X-ray diffraction uses Cu-ka radiation and the X-ray diffraction in degrees 2 Θ (°) has peaks at the following positions: 9.3 +/-0.2 degrees, 9.9 +/-0.2 degrees, 12.2 +/-0.2 degrees, 12.9 +/-0.2 degrees, 19.2 +/-0.2 degrees, 19.8 +/-0.2 degrees, 22.2 +/-0.2 degrees, 24.2 +/-0.2 degrees and 26.6 +/-0.2 degrees.

Preferably, the melting point of the crystal form is 145-155 ℃.

Still preferably, the aforementioned crystalline form further has peaks at the following positions: 3.3 +/-0.2 °, 6.6 +/-0.2 °, 13.4 +/-0.2 °, 15.1 +/-0.2 °, 16.1 +/-0.2 °, 17.1 +/-0.2 °, 18.7 +/-0.2 °, 20.5 +/-0.2 °, 21.2 +/-0.2 °, 21.5 +/-0.2 °, 22.9 +/-0.2 °, 25.1 +/-0.2 °, 25.5 +/-0.2 °, 26.1 +/-0.2 °, 26.6 +/-0.2 °, 28.3 +/-0.2 °, 29.0 +/-0.2 °, 31.1 +/-0.2 °, 32.0 +/-0.2 °, 33.5 +/-0.2 ° and 39.1 +/-0.2 °.

More preferably, the X-ray diffraction pattern of the aforementioned crystalline form is shown in figure 1.

Dissolving an L-amlodipine aspartate crude product in a mixed solvent A, stirring and heating the solution to dissolve the L-amlodipine aspartate crude product to be clear, slowly cooling after heat filtration, adding a precooled mixed solvent B into the solution at the flow rate of 1.0-2.0 mL/min when the solution is cooled to 20-30 ℃ until crystals are precipitated, continuously cooling to-5-0 ℃, preserving heat, growing crystals until the crystals are completely precipitated, and performing suction filtration and drying to obtain the L-amlodipine aspartate crystals.

Preferably, the mixed solvent A is a mixed solvent of acetonitrile and water, and the volume ratio of the water to the acetonitrile is 0.1-0.3: 1; the mass-volume ratio of the L-aspartic acid amlodipine to the mixed solvent A is 1: 50-100.

Still preferably, the mixed solvent B is a mixed solvent of acetone and tetrahydrofuran, and the volume ratio of acetone to tetrahydrofuran is 1: 0.2-0.5.

More preferably, the volume ratio of the mixed solvent A to the mixed solvent B is 1: 0.5-1.

Further preferably, the cooling rate of the solution after heat filtration is 2-4 ℃/min.

The application of the L-aspartic acid amlodipine crystal form in preparing a medicinal composition for treating ischemia and hypertension.

The invention has the advantages that: the L-aspartic acid amlodipine crystal form prepared by the invention has better quality and stability, is beneficial to long-term storage, and simultaneously, the dissolution of a corresponding preparation prepared by the crystal form is matched with the activity and the preference of the original grinding agent.

Drawings

FIG. 1 is an X-ray diffraction pattern of a crystalline form of amlodipine aspartate according to a first embodiment of the present invention;

FIG. 2 is a DSC diagram of a crystal form of amlodipine aspartate in the first embodiment of the present invention;

FIG. 3 is an IR spectrum of a crystalline form of amlodipine L-aspartate in the first embodiment of the present invention;

FIG. 4 is a detection spectrum of related substances after the crystal form of amlodipine aspartate is stabilized for a long time in the invention;

fig. 5 is a graph comparing the dissolution curves of the amlodipine besylate crystal form preparation tablet and the original preparation tablet of the invention.

Detailed Description

The invention is described in detail below with reference to the figures and the embodiments.