Stable micronized candesartan cilexetil and methods for preparing thereof

A technology of candesartan cilexetil and candesartan, which is applied in the field of stable micronized candesartan cilexetil and its preparation, can solve the problems of candesartan cilexetil particle size reduction and unfavorable chemical stability, etc.

Inactive Publication Date: 2008-04-30
TEVA PHARMA IND LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, a decrease in the particle size of candesartan cilexetil was shown to have an adverse effect on its chemical stability

Method used

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  • Stable micronized candesartan cilexetil and methods for preparing thereof
  • Stable micronized candesartan cilexetil and methods for preparing thereof
  • Stable micronized candesartan cilexetil and methods for preparing thereof

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preparation example Construction

[0029] The present invention also includes a process for the preparation of fine particle size stable candesartan cilexetil. The method includes:

[0030] a) provide fine-grained candesartan cilexetil samples;

[0031] b) in at least one C 1 -C 4 Slurrying the sample in alcohol for about 16 to about 48 hours;

[0032] c) recovery of fine particle size stable candesartan cilexetil.

[0033] Preferably, the candesartan cilexetil obtained by the method is crystal form I.

[0034] preferred, C 1 -C 4 Alcohol is methanol or ethanol. The slurrying in step b) is preferably carried out at a temperature of at least about 15°C, more preferably between about 15°C and about 50°C, most preferably between about 25°C and about 35°C. Preferably, the samples are slurried for about 20 to about 30 hours.

[0035] The fine particles can be recovered by any method known in the art such as cooling the sample; filtering off the solvent; washing the particles, preferably with the solvent add...

Embodiment 1

[0065] Embodiment 1: the preparation of candesartan cilexetil

[0066] Trityl candesartan cilexetil (TCS, 1000g, 1172mmol), toluene (3000mL), methanol (6000mL) and water (50mL) solution was refluxed for about 3-4 hours (HPLC control), under reduced pressure in The solvent was evaporated at 50°C to give a thick oily residue. The residue was dissolved in a toluene / methanol mixture (2960 g, 95:5, w / w) at 50°C. The mixture was then cooled to (-5)°C to (5)°C and maintained at this temperature for about 12 hours. The solid precipitate was filtered off, washed on the filter with cold toluene (1000 mL), then dried under reduced pressure at 60 °C to afford crude candesartan cilexetil Form I (~600 g, L.O.D=17%).

Embodiment 2

[0067] Embodiment 2: the preparation of candesartan cilexetil I type

[0068] 601 g of crude CNS with LOD C for 20-30 hours. The precipitated solid was filtered off and washed with cold absolute ethanol (550 mL) to obtain 644 g of wet matter (LOD=30-40%-80%), then 429 g was dried at 60°C under reduced pressure to obtain candesartancil Ester Form I (-274.5 g, L.O.D. = 0.12%).

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Abstract

The invention encompasses sable candesartan cilexetil of fine particle size, wherein desethyl-candesartan (desethyl-CNS) within the stable candesartan cilexetil does not increase to more than about 0.1%w/w by HPLC relative to the initial amount of candesartan cilexetil, when the stable candesartan cilexetil is maintained at a temperature of about 550 DEG C for at least 2 weeks, methods of making the same and pharmaceutical compositions thereof.

Description

[0001] related application [0002] This application claims the benefit of the following applications: U.S. Provisional Application Nos. 60 / 679,952, filed May 10, 2005; 60 / 680,115, filed May 11, 2005; 684,455, 60 / 707,417 filed 10 August 2005, 60 / 709,954 filed 19 August 2005, 60 / 716,995 filed 13 September 2005, 29 September 2005 Serial No. 60 / 722,388 filed on the date of , which patent applications are incorporated herein by reference. field of invention [0003] The present invention includes stable candesartan cilexetil of fine particle size, its preparation method and its pharmaceutical composition. Background of the invention [0004] Candesartan (CNS) is an effective, long-acting, selective AT 1 Subtype angiotensin II receptor antagonist. Candesartan is an effective therapeutic drug for treating circulatory system diseases such as hypertension, heart disease (such as cardiac hypertrophy, heart failure, myocardial infarction, etc.), stroke, cerebral apoplexy and nephr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/10A61P9/10A61K31/4184
Inventor Z·库尔甘M·佩萨乔维奇
Owner TEVA PHARMA IND LTD
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