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Refining method for L-malic acid

A refining method, malic acid technology, applied in the field of medicine and chemical industry, to achieve the effect of mild conditions, good reproducibility and high yield

Active Publication Date: 2016-12-14
NANJING CHIA TAI TIANQING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are few literature studies on the impurity control methods of succinic acid

Method used

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  • Refining method for L-malic acid
  • Refining method for L-malic acid
  • Refining method for L-malic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Add 2.5kg L-malic acid (pharmaceutical excipient grade) and 12.5kg purified water into a clean and dry 50L glass reactor, stir at 28°C and 125r / min to dissolve. Add 20.1kg of isopropyl ether, stir and extract at 165r / min for 0.5h, then let stand for 0.5h to separate the liquid, and collect the lower aqueous phase. Add the water phase to a 50L glass reactor, add 20.1kg of isopropyl ether, stir and extract at 165r / min for 0.5h, then let it stand for 0.5h to separate the liquid, collect the lower layer of water phase, take about 5ml of the sample and concentrate it to dryness under reduced pressure before sending it to HPLC for inspection , Maleic acid, 0.035% succinic acid, and 0.0018% fumaric acid were not detected in the monitoring water phase. Suction filtration with a 0.45 μm filter membrane, and the filtrate was rotary evaporated at 60°C to 65°C until no liquid dripped out of the condenser, and continued rotary evaporation for 0.5h. Add 10.05 kg of isopropyl ether i...

Embodiment 2

[0061] Add 5kg of L-malic acid (pharmaceutical excipient grade) and 25kg of purified water into a clean and dry 100L glass reactor, stir at 20°C to 40°C and 130r / min to dissolve. Add 50kg of ethyl acetate, stir and extract at 130r / min for 0.5h, then let stand for 0.5h to separate the liquid, and collect the lower aqueous phase. Add the water phase to a 100L glass reactor, add 50kg of ethyl acetate, stir and extract at 130r / min for 0.5h, then let stand for 0.5h to separate the liquid, collect the lower layer of water phase, take about 5ml of the sample and concentrate it to dryness under reduced pressure, then send it to HPLC for inspection. No maleic acid, 0.051% succinic acid, and 0.0009% fumaric acid were detected in the monitoring water phase. Suction filtration with a 0.45 μm filter membrane, and the filtrate was rotary evaporated at 70°C to 75°C until no liquid dripped out of the condenser, and continued rotary evaporation for 0.5h. Add 25 kg of ethyl acetate into the ro...

Embodiment 3

[0063] Add 2kg of L-malic acid (pharmaceutical excipient grade) and 10kg of purified water into a clean and dry 50L glass reactor, stir at 26°C and 142r / min to dissolve. Add 17.96kg of n-butanol, stir and extract at 142r / min for 0.5h, then let stand for 0.5h to separate the liquid, and collect the lower aqueous phase. Then add the water phase into a 50L glass reactor, add 17.96kg of n-butanol, stir and extract at 142r / min for 0.5h, then let it stand for 0.5h to separate the liquid, collect the lower water phase, take about 5ml of the sample and concentrate it to dryness under reduced pressure, then send it to HPLC for inspection , Maleic acid, 0.064% succinic acid, and 0.0005% fumaric acid were not detected in the monitoring water phase. Suction filtration with a 0.45 μm filter membrane, and the filtrate was rotary evaporated at 70°C to 75°C until no liquid dripped out of the condenser, and continued rotary evaporation for 0.5h. Add 8.98 kg of n-butanol into the rotary evapor...

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Abstract

The invention relates to a refining method for L-malic acid. According to the refining method, the processes of extraction with a specific solvent, water removal through step-by-step distillation and beating are used in a combined mode, so that the content of succinic acid is reduced to 0.10% or lower, and auxiliary material level L-malic acid is refined into injection-level L-malic acid raw material medicine capable of being used for injections. Besides, according to the preparing method, a solvent is cheap, easy to obtain and capable of being recycled and reused, operation is simple and safe, the conditions are mild, repeatability is good, and monitoring is easy and convenient.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a method for refining L-malic acid. Background technique [0002] Compound Electrolytes Injection (Ⅱ) is a product launched by Braun Medical Co., Ltd. of Germany. The English name is Multiple Electrolytes Injection (Ⅱ). It is clinically used for isotonic dehydration accompanied or expected to occur with acidosis, and to supplement the loss of extracellular fluid. . Its main components are: every 1000ml contains 6.80g of sodium chloride, 0.30g of potassium chloride, 0.37g of calcium chloride, 0.20g of magnesium chloride, 3.27g of sodium acetate and 0.67g of L-malic acid. [0003] The main ingredient is L-malic acid, the English name is L-Malic acid, the structure is as follows: [0004] [0005] The industrial production of L-malic acid is mainly by enzyme engineering method or fermentation method. Due to the limitation of process control, the raw mat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C51/48C07C51/44C07C51/43C07C59/245
CPCC07C51/43C07C51/44C07C51/48C07C59/245
Inventor 李勤吴舰吴晶柴雨柱徐丹朱春霞田舟山
Owner NANJING CHIA TAI TIANQING PHARMA
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