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Maleic acid levorotation amlodipine drug active pharmaceutical composition and preparation method thereof

A technology of levamlodipine and drug activity, applied in the direction of drug combination, pharmaceutical formula, organic active ingredients, etc., can solve the problems of not being able to know the product of levamlodipine maleate, not being able to fully reflect, not being able to know the stability, etc.

Inactive Publication Date: 2013-04-03
CSPC OUYI PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The disclosed impurity composition of the above-mentioned amlodipine maleate product cannot fully reflect the impurities of the levamlodipine maleate product, and its disadvantages are: (1) The above-mentioned product is amlodipine maleate, which is a racemate , did not study the impurities produced in the process of optical resolution to form the L-isomer, so it cannot fully reflect the impurity composition of the product of levamlodipine maleate; (2) only for amlodipine aspartate and amlodipine Impurity D has been studied, but other impurities have not been systematically studied, so the composition and content of other impurities cannot be determined, which will affect the safety of medication
[0019] The crystal form of the drug is an important factor that affects the stability and bioavailability of the drug. Through the search of the prior art, we cannot know what crystal form the levamlodipine maleate product exists in, nor can we know the crystal form of the product. The stability of the existing form of the crystal, and what impact it will have on the stability, quality uniformity, bioavailability, preparation, etc. of the drug

Method used

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  • Maleic acid levorotation amlodipine drug active pharmaceutical composition and preparation method thereof
  • Maleic acid levorotation amlodipine drug active pharmaceutical composition and preparation method thereof
  • Maleic acid levorotation amlodipine drug active pharmaceutical composition and preparation method thereof

Examples

Experimental program
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Effect test

preparation example 1

[0099] Preparation Example 1: Preparation of Racemic Amlodipine

[0100] (1) Preparation of phthaloyl amlodipine

[0101] Add 5Kg of ethyl 4-(2-phthalimidoethoxy)acetoacetate, 20L of anhydrous methanol, 2.3Kg of o-chlorobenzaldehyde, and 5.5Kg of methyl 3-aminobutenoate into the ring-closure kettle , heat preservation reaction for 22 hours, reclaim methanol under reduced pressure, after recovery, add 10kg of glacial acetic acid, stir at 15°C for about 12 hours, and filter in a centrifuge to obtain 5.1Kg of phthaloyl amlodipine crude wet product.

[0102] Add the crude amlodipine phthaloyl amlodipine into 7.0L of mixed solvent (toluene: glacial acetic acid = 1:1), heat to dissolve it completely, cool down to 10°C and keep it warm for 1 hour, shake off the filter, and dry under reduced pressure , to obtain 2.6Kg of phthaloyl amlodipine.

[0103] (2) Preparation of racemic amlodipine

[0104] Add 2.6Kg of phthaloyl amlodipine, 12.0Kg of toluene and 16.5Kg of 40wt% monomethyl...

preparation example 2

[0106] Preparation example 2: The preparation of levamlodipine, according to the preparation method disclosed in Chinese patent CN101528697

[0107] (1) Preparation of (S)-(-)-amlodipine solvate

[0108] 500 g of racemic amlodipine was dissolved in 2.5 L of N,N-methylacetamide (DMAC), then 190 g of L-tartaric acid was added thereto, the resulting mixture was cooled to 5° C. and stirred for 3 hours, and the precipitate was removed by filtration. Add 2.0L of dichloromethane and 14L of n-hexane to the filtrate, stir for 1.0 hour, filter, wash the filter cake with 800ml of n-hexane, and dry under reduced pressure at 50°C to obtain S-(-)-amlodipine-semi-L-tartaric acid Salt-DMAC solvate.

[0109] (2) Preparation of Levoamlodipine

[0110] The resulting S-(-)-amlodipine-hemi-L-tartrate-DMAC solvate was added to 5 L of methanol, heated for 7 hours, cooled to room temperature, filtered, and the obtained precipitate was dissolved in 2 L of dichloromethane, Add 1.5L of 2N NaOH solu...

preparation example 3

[0111] Preparation example 3: The preparation of levamlodipine, according to the preparation method disclosed in Chinese patent CN1927836

[0112] (1) Preparation of methyl ethyl sulfoxide:

[0113] Add 35L of acetone and 200mol of methyl ethyl sulfide to the reaction kettle, cool down to 0°C, add 200mol of hydrogen peroxide (concentration: 31%), control the temperature below 40°C during the addition, and keep warm at 25-35°C for 4 Hours, 65 ° C under reduced pressure to remove excess methyl ethyl sulfide, acetone and water, to obtain crude methyl ethyl sulfoxide 17.2Kg, water content of 4.8%, gas chromatography purity of 99.4%.

[0114] Take 17.2Kg of crude methyl ethyl sulfoxide (water content 4.8%), add 15.0Kg of calcium oxide, raise the temperature to 70°C, dry for 5 hours, filter after cooling down to room temperature, filter the filtrate, and distill under reduced pressure to obtain 14.8Kg of methyl ethyl sulfoxide, The water content is 0.35%, and the gas chromatograp...

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Abstract

The invention provides a maleic acid levorotation amlodipine drug active pharmaceutical composition which comprises the following components: component I: maleic acid levorotation amlodipine; component II: dextrorotation amlodipine; component III: aspartic acid amlodipine; component IV: impurity D; and the active pharmaceutical composition does not contain impurity A, impurity B, impurity C, impurity E, impurity F, impurity G and impurity H basically. The active pharmaceutical composition is stable in quality, and can completely meet the quality requirement of maleic acid levorotation amlodipine preparation on active pharmaceutical composition; and the prepared preparation is safe, effective and controllable in quality, and ensures the clinical effect and medication safety of the maleic acid levorotation amlodipine preparation.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a 4s-(-)-2-(-aminoethoxy)-4-(2-chlorophenyl)-6-methyl-1,4-dihydro - A pharmaceutically active composition of 3,5-pyridinedicarboxylic acid-3-ethyl-5-methyl ester maleate (levamlodipine maleate) and a process for its preparation. Background technique [0002] Amlodipine, the chemical name is 6-methyl-2-(2-aminoethoxy)methyl-4-(2-chlorophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate Ethyl ester, the chemical structural formula is as shown in formula 1. [0003] [0004] Amlodipine is a new generation of calcium antagonists, developed by Pfizer, first listed in the UK in 1990, it effectively overcomes the second-generation calcium antagonists diltiazem, nifedipine blood pressure instability, large adverse reactions Disadvantages, it is clinically used to treat hypertension and stable angina pectoris, which is characterized by remarkable curative effect, stable onset, long drug e...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4422A61P9/12A61P9/10
Inventor 郑雪清韩彩霞杨晓灿李瑞建孙成勇王建明
Owner CSPC OUYI PHARM CO LTD
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