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Telmisartan amorphous crystal and preparation method thereof

A technology of telmisartan and crystal form, which is applied in the field of pharmaceutical engineering and cardiovascular disease treatment drugs, can solve the problems of difficulty in obtaining telmisartan amorphous crystal form, small amount of drying, long cycle, etc., and achieve easy industrialization The effect of production, good dissolution rate and safe preparation method

Active Publication Date: 2015-04-29
JIANGSU ZHONGBANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

What this method obtains is a kind of telmisartan composition of amorphous form, it is difficult to obtain pure telmisartan amorphous crystal form, and the cost of spraying is high, the amount of spray drying at one time is small, and the cycle is long

Method used

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  • Telmisartan amorphous crystal and preparation method thereof
  • Telmisartan amorphous crystal and preparation method thereof
  • Telmisartan amorphous crystal and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Add 38.9kg of crude telmisartan to a 1000L crystallization kettle, pump in 110kg of methanol, pump in 21.6kg of ammonia water at room temperature, heat to 75-85°C and reflux until the solid is completely dissolved, filter the insoluble matter while the system is hot, and evaporate the solvent , add 116.7kg of water to the system, add 11-12kg of acetic acid in batches at room temperature to adjust the pH to 5-6 (the amount of acetic acid is adjusted to the pH value of 5-6), after acidification is completed, centrifuge, and wash with purified water to pH 6-7, the material was taken out, and vacuum-dried at 80-125°C to obtain 37.12kg of telmisartan in amorphous crystal form, yield: 95.4%, XRD pattern of telmisartan in amorphous crystal form mp: 255.4°C.

[0043] 1HNMR(DMSO): δ=1.01(t,J=7.5Hz,3H,CH3); δ=1.82(m,2H,CH2); δ=2.63(s,3H,CH3); δ=2.93(t,J =7.5Hz, 2H, CH2); δ = 3.83 (s, 3H, CH3); δ = 5.63 (s, 2H, CH2); δ = 7.17-7.73 (m, 14H, CH). MS (EI): 514 (m+).

[0044] Its ...

Embodiment 2

[0054]Add 38.9kg of crude telmisartan to a 1000L crystallization kettle, pump in 116.7kg of ethanol, pour in a solution of 16kg of sodium carbonate and 20kg of drinking water prepared in advance at room temperature, heat to 75-85°C and reflux until the solid is completely dissolved , the system filtered the insoluble matter while it was hot, evaporated the solvent, added 116.7kg of water to the system, added 10% hydrochloric acid in batches at room temperature to adjust the pH to 5-6 (the consumption of hydrochloric acid is adjusted to 5-6 based on the pH value), After acidification, centrifuge, wash with purified water until the pH is 6-7, take out the material, and dry it in vacuum at 80-125° C. to obtain 30.9 kg of telmisartan in amorphous crystal form.

Embodiment 3

[0056] Add 38.9kg of crude telmisartan to a 500L crystallization kettle, pump in 77.8kg of ethanol, pour in a solution of 6.05kg of sodium hydroxide and 15kg of drinking water prepared in advance at room temperature, heat at 75-85°C and reflux until the solid is completely Dissolve, filter the insoluble matter while the system is hot, distill off the solvent, add 116.7kg of water to the system, cool the system to 0°C, and slowly add concentrated sulfuric acid to adjust the pH to 5-6 after the temperature stabilizes (the amount of concentrated sulfuric acid is determined by pH The value is adjusted to 5-6 as the criterion), acidification is completed, centrifuged, washed with purified water until the pH is 6-7, the material is taken out, and vacuum-dried at 80-125°C to obtain 32.8kg of telmisartan in amorphous crystal form.

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Abstract

The invention discloses a telmisartan amorphous crystal and a preparation method thereof. An X-ray powder diffraction spectrum of the telmisartan amorphous crystal is as shown in figure 1, and no peak exists on a specific 2 theta characteristic peak position. The preparation method of the telmisartan amorphous crystal comprises the following steps of: a, mixing a crude telmisartan product and an organic solvent, wherein the organic solvent is alcohol; b, adding an alkali, and salifying and dissolving telmisartan under heating; c evaporating out the solvent, selectively metering and adding water at the same time, and adding acid at a temperature below 40 DEG C till no precipitate is separated out; d carrying out centrifugal separation on the precipitate product, and drying a detergent. The telmisartan amorphous crystal is provided by adopting the organic solvent with very low toxicity. The preparation method disclosed by the invention is safe, simple and high in operability; in addition, the obtained product is single in crystal form and can be used for preparing a medicament which contains amorphous telmisartan due to good dissolvability.

Description

technical field [0001] The invention belongs to medical engineering and drugs for treating cardiovascular diseases, in particular to a crystal form of telmisartan and a preparation method thereof. technical background [0002] Telmisartan is a new type of AT antagonist with long-acting, high-efficiency and low-toxicity. It was developed by German Bellinger-Ingelheim Pharmaceutical Company and launched in 1997. It is also a non-peptide angiotensin II receptor antagonist that selectively and irreversibly blocks the AT1 receptor without affecting other receptor systems, especially those involved in the cardiovascular system. The structural formula is as follows: [0003] [0004] Those skilled in the art can prepare telmisartan through the methods disclosed in WO2004 / 87676, US2004 / 236113, WO2006 / 44648, WO2012 / 28925, WO2011 / 102645, EP2305650, US2006 / 211866, WO2006 / 136916, WO2010 / 4385. [0005] When a substance is crystallized, due to the influence of various factors, the bo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/18
CPCC07D235/18
Inventor 陈国萍黄双徐强李维思周颖赵光荣
Owner JIANGSU ZHONGBANG PHARMA
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