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Levoamlodipine fumarate eutectic drug as well as preparation method and application thereof

A co-crystal technology of levamlodipine and dipine, which is applied in the field of crystalline drugs, can solve the problems of low stability of levamlodipine and achieve clear X-ray powder diffraction data, uniform and controllable particle size, extended reduction The effect of pressure therapy

Pending Publication Date: 2020-12-04
FUDAN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The purpose of the present invention is to provide a kind of levamlodipine fumarate cocrystal drug in order to solve the problem of low stability of the existing levamlodipine, improve the stability of the existing levamlodipine cocrystal salt, potentially, In large-scale production of tablets, it is conducive to the improvement of tablet drug stability and bioavailability

Method used

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  • Levoamlodipine fumarate eutectic drug as well as preparation method and application thereof
  • Levoamlodipine fumarate eutectic drug as well as preparation method and application thereof
  • Levoamlodipine fumarate eutectic drug as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] The preparation of levamlodipine fumarate co-crystal drug crystal form, the specific steps are as follows:

[0044] 1) Weigh 0.204 g of levoamlodipine free base, add it to 1.8 mL of aqueous solution, heat and stir until fully dissolved;

[0045] 2) Prepare a fumaric acid ethanol solution with a concentration of 0.25M at room temperature, and add 1 mL of fumaric acid ethanol solution dropwise to the solution in step 1) within 30 seconds under stirring at room temperature;

[0046] 3) Transfer the above-mentioned salt-forming reaction solution to a reaction kettle, increase the temperature of the reaction solution to 60°C, keep it warm for 5 hours, and then let it stand and cool to 5°C to obtain a large amount of colorless, transparent, and uniform crystal products;

[0047] 4) Filter the obtained crystalline product under reduced pressure, wash the original crystalline solution, and wash with a water solvent at 5° C. to obtain the product.

[0048] The following specifi...

Embodiment 9

[0052] X-ray single crystal diffraction test

[0053] Taking the eutectic crystal of levamlodipine fumarate prepared in Example 1 as an example, select the crystal whose crystal quality and size meet the requirements of the testing instrument, adopt the Bruker D8 VENTURE of German Bruker Company, use the MetalJet liquid gallium alloy target light source, and test the temperature at 296K, the diffraction data were collected in ω-scan mode and Lp correction was performed. Absorption correction was performed using the SADABS program. The structure is analyzed by the direct method, all non-hydrogen atoms are found by the difference Fourier method, all hydrogen atoms on carbon and nitrogen are obtained by theoretical hydrogenation, and the structure is corrected by the least square method. All parsing processes are completed using the SHELXTL program package.

[0054] In the above measurements, the crystal test can be tested on any X-ray single crystal diffraction instrument, not...

Embodiment 10

[0060] X-ray Powder Polycrystalline Diffraction Test

[0061] The polycrystalline product of levamlodipine fumarate in Example 1 was taken, and it was tested by an Advance D8 X-ray polycrystalline diffractometer from Bruker, Germany. The test parameters were all default standard settings, and the tablet was tested at room temperature. In order to ensure good reproducibility of the test results and avoid strength differences caused by differences in particle crystal plane orientation, the samples to be tested need to be processed by tableting, grinding, 300-mesh sieving, and re-granulation. Copper target Kα1 radiation Irradiation wavelength, scanning angle from 5 to 50°. An example spectrogram for the test is image 3 shown.

[0062] Samples of the polycrystalline products of Examples 2-8 had similar X-ray powder polycrystalline diffraction patterns.

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Abstract

The invention provides a levoamlodipine fumarate eutectic drug; the chemical general formula of the eutectic drug is (C20H25ClN2O5). (C4H4O4) 0.5. (Y) n, wherein Y is a crystal water molecule or an ethanol molecule, and n is more than or equal to 0 and less than or equal to 2. The eutectic drug is crystallized in a monoclinic system and a P21 chiral space group, and the cell size beta is 111.8-112.4 degrees. The levoamlodipine fumarate eutectic drug provided by the invention has definite crystal form, crystallographic parameters and definite atomic space position, and is different from any commercially available levoamlodipine eutectic drug in molecular composition and crystal form. Raw materials are wide and easy to obtain, the preparation method is simple, particle crystal forms are clear, and quality control and large-scale production are easy.

Description

technical field [0001] The invention relates to the technical field of crystalline drugs, in particular to a co-crystal drug of levamlodipine fumarate and a preparation method and application thereof. Background technique [0002] Crystalline drugs are preferred in pharmaceuticals due to their advantages in stability, reproducibility, bioavailability and operability. Crystalline drugs include polymorphic forms, hydrates, solvates, and salts of drug molecules. Different crystal forms of drugs have significant differences in their physical and chemical properties, which will directly affect their dissolution and absorption efficiency under physiological conditions, and further affect the bioavailability and clinical efficacy of drugs. [0003] As a fourth-generation dihydropyridine calcium ion antagonist antihypertensive drug for the treatment of hypertension, levamlodipine is deeply trusted by doctors and patients due to its high efficacy and small side effects, and is a com...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4422A61P9/12C07D211/90C07C57/15C07C51/41C07C51/43A61K9/20A61K47/36
CPCA61K31/4422A61P9/12C07D211/90C07C57/15C07C51/412C07C51/43A61K9/2059C07B2200/13
Inventor 凌云周亚明杨永泰刘小锋邓名莉陈珍霞贾瑜向睿卿
Owner FUDAN UNIV
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