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Crystallization method for erythromycin ethylsuccinate with controllable crystal habit and particle size

A technology of erythromycin ethylsuccinate and crystallization is applied in the field of preparation of pharmaceutical compounds, and can solve the problems of uneven distribution, small product particle size, and difficulty in meeting European Pharmacopoeia standards and the like.

Active Publication Date: 2014-10-29
XIAN LIJUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] CN102659880A discloses erythromycin ethylsuccinate crystalline hydrate and its preparation and application. The hydrate has less hygroscopicity and better storage stability. The preparation method mainly adopts erythromycin ethylsuccinate separated after reaction The crude element is obtained by recrystallization from ethanol and water, recrystallization from isopropanol and water, recrystallization from acetone and water, recrystallization from isopropanol, acetone and water, recrystallization from ethanol, acetone and water, but the patent does not mention crystallization Effect of process and crystallization process on crystal habit and particle size distribution
At present, the raw materials of erythromycin ethylsuccinate that have been industrialized generally have problems such as small particle size and uneven distribution, and flaky crystals are easy to coalesce. Although the quality can meet the requirements of the Chinese Pharmacopoeia, it is difficult to meet the European Pharmacopoeia standard and cannot meet the requirements of the pharmaceutical industry. The need to further improve the quality of raw materials and preparations

Method used

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  • Crystallization method for erythromycin ethylsuccinate with controllable crystal habit and particle size
  • Crystallization method for erythromycin ethylsuccinate with controllable crystal habit and particle size
  • Crystallization method for erythromycin ethylsuccinate with controllable crystal habit and particle size

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089] Add 100L of erythromycin ethylsuccinate tetrahydrofuran reaction solution to the 500L crystallization kettle, control the stirring rate at 250rpm, control the temperature of the reaction solution at 40°C, add the initial amount of 100L of dissolving agent water through multiple feeding ports of the crystallizer coil, and A two-step program cooling method is adopted to precipitate crystals, that is, in the first step, the temperature of the reaction solution is lowered from 40°C to 35°C while continuing to add water to dissolve, and the amount of water added to the dissolution process is 100L, and the dissolution is completed; the second step is to react The liquid temperature was lowered from 35°C to 20°C. The time of the whole crystallization process of erythromycin ethylsuccinate was controlled at 1.0 hour. Filter and dry under reduced pressure to obtain 20.0 kg of erythromycin ethylsuccinate crystals. The obtained crystals are long rod-shaped crystals with a main par...

Embodiment 2

[0091] Add 100L erythromycin ethylsuccinate tetrahydrofuran reaction liquid in the 500L crystallization kettle, control the stirring rate at 300rpm, control the temperature of the reaction liquid at 40°C, add the initial amount of 110L of dissolving agent water through multiple feeding ports of the crystallizer coil, and A two-step step-by-step program cooling method is used to precipitate crystals, that is, the first step continues to add water to dissolve the temperature of the reaction solution from 40 ° C to 35 ° C, the amount of water added during the dissolution process is 200 L, and the dissolution is completed; the second step will be The temperature of the reaction solution was lowered from 35°C to 20°C. The time of the whole crystallization process of erythromycin ethylsuccinate was controlled within 2 hours. Filtration and drying under reduced pressure gave 21 kg of erythromycin ethylsuccinate crystals. The obtained crystals were long rod-shaped crystals with a main...

Embodiment 3

[0093] Add 100L erythromycin ethylsuccinate tetrahydrofuran reaction liquid in the 500L crystallization kettle, control the stirring rate at 400rpm, control the temperature of the reaction liquid at 40°C, add the initial amount of 100L of dissolving agent water through multiple feeding ports of the crystallizer coil, and A two-step step-by-step program cooling method is used to precipitate crystals, that is, in the first step, the temperature of the reaction solution is lowered from 40°C to 35°C while continuing to add water for dissolution, and the amount of water added during the dissolution process is 300L, and the dissolution is completed; The temperature of the reaction solution was lowered from 35°C to 20°C. The time of the whole crystallization process of erythromycin ethylsuccinate was controlled within 1 hour. Filter and dry under normal pressure to obtain 22.93 kg of erythromycin ethylsuccinate crystals. The obtained crystals are long rod-shaped crystals with a main ...

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Abstract

The invention relates to a crystallization method for erythromycin ethylsuccinate with controllable crystal habit and particle size. The method comprises the following steps: 1) reacting erythromycin or salts thereof with ethyl succinoyl halide in a tetrahydrofuran solution, to obtain a reaction mixture containing erythromycin ethylsuccinate and tetrahydrofuran after the reaction is over; 2) under the stirring condition, adding water into the reaction mixture, and cooling until separation by crystallization; 3) filtering and drying to obtain erythromycin ethylsuccinate crystals. The key step is to control the stirring speed to be 250-400rpm and separation by crystallization is realized by adopting two-step program cooling mode, the obtained crystals are long rod-like crystal habits, with main particle size of 100-180mu m, and the particle size distribution shows unimodal distribution. The technology avoids the problems that the existing method causes the coalescence and uneven particle size distribution of erythromycin ethylsuccinate industrial crystallization products, and the quality is obviously improved.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical compound, in particular to a crystallization method of erythromycin ethylsuccinate. Background technique [0002] Ethyromycin ethylsuccinate is a macrolide antibiotic. English name ErythromycinEthylsuccinate, Chinese aliases: erythromycin ethyl succinate, erythromycin succinate, ethyl succinate erythromycin, ethyl succinate erythromycin, the structural formula is as follows: [0003] [0004] Erythromycin ethylsuccinate is the ethyl succinate of erythromycin, which is more stable in gastric acid than erythromycin. It has antibacterial activity against Staphylococcus genus (except methicillin-resistant strains), various groups of Streptococcus and Gram-positive bacilli. Neisseria, Haemophilus influenzae, Bordetella pertussis, etc. are also sensitive to this product. This product also has antibacterial effect on various anaerobic bacteria except Bacteroides fragilis and Fusobacterium...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H17/08C07H1/00C07H1/06
Inventor 熊晓云程晓莉齐雁
Owner XIAN LIJUN PHARMA CO LTD
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