Dihydropyridine calcium antagonist co-crystal and preparation method and application thereof

Abstract

The invention relates to a dihydropyridine calcium antagonist co-crystal and a preparation method and application thereof. The molecular formula of the co-crystal is (C20H25ClN2O5).(C6H5COOH).(Y)n, wherein Y is any one of water molecule, ethanol molecule or isopropanol molecule, n is greater than or equal to 0 and less than or equal to 3, the co-crystal is crystallized in a triclinic crystal system and a P1 chiral space group, the unit cell dimensions are that alpha=97.1-97.5 degrees, beta=92.2-92.6 degrees, and gamma=111.5-112.1 degrees. According to the dihydropyridine calcium antagonist co-crystal and the preparation method and application thereof, the solubility and stability of an existing levamlodipine co-crystal crystal form are improved, and potentially, improvement of tablet stability of antihypertensive drugs and improvement of bioavailability in large-scale tablet production are facilitated.

Description

technical field

[0001] The invention relates to the technical field of crystalline drugs, in particular to a dihydropyridine calcium antagonist co-crystal and a preparation method and application thereof. Background technique

[0002] Due to the advantages of stability, reproducibility, bioavailability and operability, crystalline drugs are preferred in pharmaceutical preparations. 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 effect...

Examples

Embodiment 1

[0046] Preparation of Levoamlodipine Benzoate Crystals

[0047] 1) Weigh 2.04 grams of levoamlodipine free base, add it to 4.5 mL of aqueous solution, and stir at room temperature until completely dissolved;

[0048] 2) Prepare an aqueous solution of benzoic acid with a concentration of 1M at room temperature, and add 5 mL of the aqueous solution of benzoic acid to the solution of 1) dropwise within 30 seconds under stirring at room temperature;

[0049] 3) Transfer the above-mentioned salt-forming reaction solution to a reaction kettle, increase the temperature of the reaction solution to 50°C, keep it warm for 5 hours, and then let it stand and cool to 5°C to obtain a large number of needle-shaped or rod-shaped colorless, transparent, and uniform crystal product;

[0050] 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, figure 1 is a schematic diagram of the crystal st...

Embodiment 2-8

[0052] The preparation method is the same as in Example 1, and its specific process parameters are shown in Table 1.

[0053] Table 1 embodiment 2-8 process parameter

[0054]

Embodiment 9

[0056] X-ray single crystal diffraction test

[0057] Taking the levamlodipine benzoate eutectic crystal prepared in Example 1 as an example, the crystal quality and size of the selected crystal meet the requirements of the test instrument, and the X-ray single crystal diffractometer of the Apex Duo model of Bruker, Germany is used to test, and the test parameters Follow the strategy established by the instrument. The test temperature is 296K, with Mo-Kα radiation 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.

[0058] In the above measurement, the crysta...

technical field

[0001] The invention relates to the technical field of crystalline drugs, in particular to a dihydropyridine calcium antagonist co-crystal and a preparation method and application thereof. Background technique

[0002] Due to the advantages of stability, reproducibility, bioavailability and operability, crystalline drugs are preferred in pharmaceutical preparations. 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 effect...

Examples

Embodiment 1

[0046] Preparation of Levoamlodipine Benzoate Crystals

[0047] 1) Weigh 2.04 grams of levoamlodipine free base, add it to 4.5 mL of aqueous solution, and stir at room temperature until completely dissolved;

[0048] 2) Prepare an aqueous solution of benzoic acid with a concentration of 1M at room temperature, and add 5 mL of the aqueous solution of benzoic acid to the solution of 1) dropwise within 30 seconds under stirring at room temperature;

[0049] 3) Transfer the above-mentioned salt-forming reaction solution to a reaction kettle, increase the temperature of the reaction solution to 50°C, keep it warm for 5 hours, and then let it stand and cool to 5°C to obtain a large number of needle-shaped or rod-shaped colorless, transparent, and uniform crystal product;

[0050] 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, figure 1 is a schematic diagram of the crystal st...

Embodiment 2-8

[0052] The preparation method is the same as in Example 1, and its specific process parameters are shown in Table 1.

[0053] Table 1 embodiment 2-8 process parameter

[0054]

Embodiment 9

[0056] X-ray single crystal diffraction test

[0057] Taking the levamlodipine benzoate eutectic crystal prepared in Example 1 as an example, the crystal quality and size of the selected crystal meet the requirements of the test instrument, and the X-ray single crystal diffractometer of the Apex Duo model of Bruker, Germany is used to test, and the test parameters Follow the strategy established by the instrument. The test temperature is 296K, with Mo-Kα radiation 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.

[0058] In the above measurement, the crysta...

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