SK10202001A3 - Telmisartan polymorphs, methods for producing same and their use in the preparation of a medicament - Google Patents

Telmisartan polymorphs, methods for producing same and their use in the preparation of a medicament Download PDF

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Publication number
SK10202001A3
SK10202001A3 SK1020-2001A SK10202001A SK10202001A3 SK 10202001 A3 SK10202001 A3 SK 10202001A3 SK 10202001 A SK10202001 A SK 10202001A SK 10202001 A3 SK10202001 A3 SK 10202001A3
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Slovakia
Prior art keywords
telmisartan
characterized
organic solvent
form
preparation
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SK1020-2001A
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Slovak (sk)
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SK285429B6 (en
Inventor
Heinrich Schneider
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Boehringer Ingelheim Pharma Kg
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Filing date
Publication date
Priority to DE1999101921 priority Critical patent/DE19901921C2/en
Application filed by Boehringer Ingelheim Pharma Kg filed Critical Boehringer Ingelheim Pharma Kg
Priority to PCT/EP2000/000065 priority patent/WO2000043370A1/en
Publication of SK10202001A3 publication Critical patent/SK10202001A3/en
Publication of SK285429B6 publication Critical patent/SK285429B6/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D235/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/20Two benzimidazolyl-2 radicals linked together directly or via a hydrocarbon or substituted hydrocarbon radical

Abstract

The invention relates to polymorphs of 4'-[2-n-propyl-4-methyl-6(1- methylbenzimidazol -2-yl) benzimidazol -1-ylmethyl] biphenyl-2-carboxylic acid (INN: telmisartan), and in particular the polymorphous form B of formula (I), characterized by an endothermic peak at 183 +/- 2 DEG C during thermal analysis by differential scanning calorimetry. The invention also relates to mixtures of said polymorphs, methods for producing telmisartan containing form B and to the use thereof in the preparation of a medicament.

Description

Technical field

The invention relates to a polymorph of 4 '- [2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-ylmethyl] biphenyl-2-carboxylic acid (INN: telmisartan), in particular a polymorphic form B of formula I, which is characterized by an endothermic maximum of 183 ± 2 ° C during differential analysis by thermal scanning calorimetry. The invention also relates to mixtures of said polymorphs, processes for the preparation of telmisartan containing Form B, as well as their use in the preparation of a medicament.

BACKGROUND OF THE INVENTION

The compound telmisartan is known from European patent EP 505 314 B1 and has the following chemical structure:

Telmisartan, as well as its physiologically acceptable salts, have valuable pharmacological properties. Telmisartan is an angiotensin antagonist, especially an angiotensin II antagonist, which may be useful in the treatment of hypertonia and cardiac insufficiency, in the treatment of ischemic peripheral blood supply disorders, myocardial ischemia (angina), in the prevention of heart failure progression after myocardial infarction, myocardial infarction, , gastrointestinal diseases, as well as bladder diseases. Other possible therapeutic areas are in EP 502314 B1, which is hereby incorporated by reference.

During the synthesis of telmisartan, the saponification of the tert-butyl ester of formula II according to Scheme 1 is carried out as the final synthesis step.

Scheme 1

The corresponding experimental operating instructions, which can be carried out on a laboratory scale, are found in EP 502314 B1. Surprisingly, however, the application of the already known method of preparation on an industrial scale could not be carried out without problems. Telmisartan synthesized on an industrial scale according to Scheme 1 is obtained after processing as a product in such a form that an additional crystallization step is required for its final purification. During this necessary crystallization, the morphology of the crystallized end product led to unforeseen difficulties.

The product obtained in the form of long needles can be difficult to filter, wash and isolate as a solid, furthermore has a very long drying time for the incorporation of the solvent and forms large, very hard lumps during drying. Crushing these lumps yields a dry powder that tends to charge by electrostatic charge and is virtually non-flowing.

The above-mentioned disadvantageous properties of the product prove to be extremely disturbing during the industrial preparation of the compound, since they allow its reproducible preparation in larger quantities and in high purity only under great difficulty or with the use of other technically demanding means.

It is therefore an object of the present invention to provide telmisartan in a form that allows the synthesis, processing, purification and isolation of telmisartan, while avoiding the above-mentioned disadvantages.

-3 · ··· ···············

It has surprisingly been found that telmisartan as a solid may be present in various crystalline modifications. Depending on the crystallization method, it can be converted into various polymorphic forms A and B.

Polymorph A is the available form of telmisartan which, according to the state of the art, causes the abovementioned difficulties in the industrial preparation or purification, isolation and drying of the product.

SUMMARY OF THE INVENTION

The present invention is therefore based on polymorphic form B of telmisartan, which shows almost no tendency to charge by electrostatic charge, can be excellently sucked off, centrifuged, washed and dried and is free-flowing even without crushing.

The preparation of telmisartan polymorph form B according to the invention is carried out as follows.

In an apparatus with a stirrer of appropriate dimensions, the crude product of telmisartan (crystallized, for example, from dimethylformamide, dimethylacetamide and the like) is optionally mixed with 1-5% by weight, preferably 3% by weight of activated carbon in a solvent mixture consisting of water, formic acid and a suitable organic the solvent and subsequently dissolve at an elevated temperature, preferably at a temperature of 50 to 90 ° C, preferably at a temperature of 60 to 80 ° C.

Important according to the invention is the use of a solvent mixture consisting of formic acid and water with an organic solvent, which according to the invention must meet the following criteria. It must be able to form a solution with a mixture of water and formic acid. It must be chemically substantially inert with respect to the formic acid / water mixture and be separable from the formic acid / water mixture by distillation. Organic carbonic acid esters, ketones or ethers can be used. Examples are acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, ethyl formate, ethylene glycol dimethyl ether or tetrahydrofuran. According to the invention, acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, THF are preferred, and ethyl acetate is particularly preferred.

According to the invention, the solvent mixture should consist of 0.3 to 0.7 l of water, 10 to 15 mol of formic acid and 0.3 to 0.9 l of organic solvent per mole of telmisartan. A ratio of 0.4 to 0.6 L of water, 11 to 13 mol of formic acid and

0.4 to 0.7 of organic solvent per mole of telmisartan. Particularly preferred is a ratio of about 0.5 L of water, about 11.5-12 moles of formic acid and about 0.5 L of organic solvent per mole of telmisartan.

According to the invention, the solution obtained after heating as mentioned above is filtered and washed with a mixture of the above organic solvent and formic acid. The washing solution may contain 0.3 to 1.0 mol, preferably 0.4 to 0.6 mol, particularly preferably 0.5 mol of formic acid per 1 mol of telmisartan. The amount of wash solution is determined naturally from the amount of dissolved telmisartan. According to the invention, 0.1 to 0.4, preferably 0.15 to 0.3, particularly preferably 0.2 l of organic solvent is used per mole of telmisartan.

After additional washing of the filter residue with the above-described wash solution, the organic solvent is distilled off, preferably with the addition of water. The temperature is maintained between 60 and 100 ° C, preferably between 70 and 100 ° C. The total amount of water added corresponds essentially to the total amount of distilled solvent. According to the invention, practically complete distillation of the organic solvent is desirable. Accordingly, the distillation is effected to such an extent that the water, partly azeotropic, is also distilled off. The distilled organic solvent can, optionally after separation of the aqueous phase, be used again in subsequent reactions.

To precipitate telmisartan polymorph B, it is subsequently cooled to a temperature in the range of 15 to 60 ° C, preferably to 20 to 30 ° C, and precipitated by means of a base. The amount of base used depends on the amount of formic acid used. Preferably, 0 to 2 moles less base than the formic acid content is used. It is particularly preferred to use 0.3 to 1.5 moles less base than the formic acid content. Most preferably, 0.5 to 1 mol less base is added than the formic acid content. Suitable bases are aqueous solutions of potassium hydroxide, sodium hydroxide, lithium hydroxide or ammonia. Furthermore, suitable organic bases such as triethylamine, diisopropylethylamine or even DBU (diazabicycloundecene) can be used. As bases, the above-mentioned aqueous solutions of potassium hydroxide, sodium hydroxide, lithium hydroxide or ammonia are particularly preferred, of which aqueous ammonia solutions are of particular importance.

The precipitated product is centrifuged, washed with water and dried in the usual manner under vacuum at 120 to 125 ° C.

The sample taken directly after centrifugation and dried in the laboratory as a thin film in the desiccator typically has a content of 95 to 99% of crystalline modification B.

After centrifugation, the product, depending on temperature, pH, standing time and water content, will start to partially change to modification A until drying is complete. On industrial scale, therefore, after drying, the ratio of form A to form B is best obtained at approximately 10:90, even 60:40 ratio.

However, such a low content of Form B also guarantees the desired positive properties of the product in industrial preparation (for example, a slight tendency to electrostatic charge, a slight tendency to build up lumps, flowability, etc.). An important aspect of the invention in the above crystallization process is that only Form B with a characteristic macroscopic crystal shape is initially formed. This macroscopic shape of the crystals remains largely retained in the drying conditions despite a partial microscopic shape change to shape A.

Another very advantageous aspect of the process according to the invention is the high yield in time and space, as well as the high yield of pure telmisartan product, which can be isolated almost quantitatively.

Telmisartan form A obtained by the preparation method known in the prior art differs from telmisartan available according to the invention, which is characterized by the content of polymorph form B advantageous properties of the product mentioned above. Other differences will be described below.

Telmisartan Form A crystallizes in the form of long or thin needles which are held together as a felt. The crystalline modification of telmisartan Form B produces very compact, cubic to spherical crystals which are characterized by flowability as sand or silica gel.

The two polymorphic forms A and B of telmisartan differ significantly in melting point. Form B melts at 183 ± 2 ° C (determined by DSC), Form A melts at 269 ± 2 ° C (determined by DSC). Upon thawing, lower melting Form B of telmisartan crystallizes again as Form A. This is reflected, for example, in the fact that the endothermic maximum at 183 ± 2 ° C determined by DSC is followed by a characteristic exothermic. ·

-6maximum, which reflects the crystallization of Form B to form A with a high melting point. DSC (Differential Scanning Calorimetry) diagrams obtained by the Mettler DSC-20, TA8000 system are shown in the figure.

Polymorphs A and B also differ in their IR spectra. Due to this difference, IR spectroscopy can optionally be used after drying to quantitatively determine the ratios of both crystalline modifications in the end product. Pure polymorph A has a characteristic band at 815 cm -1 in the IR spectrum. For polymorph B, this variation is shifted to 830 cm -1 . Since both of these characteristic bands of polymorph A and B are sufficiently separated from each other, they are particularly suitable for the quantitative determination of the ratio of the two crystalline modifications mentioned above.

IR spectroscopic characterization of both polymorphic forms A and B was performed with a Nicolet FTIR Spectrometer Magna - IR 550 at KBr (2.5 pmol per 300 mg KBr; Nicolet OMNIC software package, version 1.20).

The following examples serve to illustrate purification and crystallization processes carried out exemplary for the preparation of telmisartan polymorph Form B. They are to be understood as possible, exemplary instructions, without limiting the scope of the invention.

Overview of the figures in the drawing

The figure shows DSC-Differential Scanning Calorimetry diagrams obtained by Mettler DSC-20, TA8000 for polymorph A, polymorph B, and a mixture containing 30% Form A and 70% Form B.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

To a 1200 liter mixer is added 205.6 kg of telmisartan crystallizate (crystallized from dimethylformamide or dimethylacetamide), 6.2 kg of activated carbon, 205.6 L of water, 211.6 kg of formic acid (99-100%). and

-7205.6 L of ethyl acetate. Stir for about 1 hour at 70-80 ° C, filter in an additional 1200 liter mixer and wash with a mixture consisting of 82.2 L of ethyl acetate and 9.2 kg of formic acid (99-100%). With the addition of 308 L of water, about 308 L of solvent is distilled off at 80 to 100 ° C. The mixture was then cooled to 20-30 ° C and the product precipitated by adding 313 kg of a 25% ammonia solution. The precipitated product is centrifuged, washed with water and dried at 120 to 125 ° C.

Yield: 200 kg of telmisartan (97.3% of theory).

Example 2

185 kg of telmisartan crystalline (crystallized from dimethylformamide or dimethylacetamide), 5.6 kg of activated carbon, 185 l of water, 190.4 kg of formic acid (99-100%) and 185 l of tetrahydrofuran are added to a 1200 liter mixer. . Stir for about 1 hour at 60-70 ° C, filter in another 1200 L mixer and wash with a mixture of 74 L tetrahydrofuran and 8.3 kg formic acid (99-100%). With the addition of 278 L of water, approximately 278 L of solvent is distilled off at 70 to 100 ° C. The mixture was then cooled to 20-30 ° C and the product precipitated by adding 281.5 kg of 25% ammonia solution. The precipitated product is centrifuged, washed with water and dried at 120 to 125 ° C.

Yield: 180 kg of telmisartan (97.3% of theory).

Example 3

185 kg of telmisartan crystallizate (crystallized from dimethylformamide or dimethylacetamide), 5.6 kg of activated carbon, 185 l of water, 190.4 kg of formic acid (99-100%) and 185 l of methyl ethyl ketone are added to a 1200 liter mixer. . Stir for about 1 hour at 60-70 ° C, filter in an additional 1200 L mixer and wash with a mixture of 74 L of methyl ethyl ketone and 8.3 kg of formic acid (99-100%). While adding 278 L of water, approximately 278 L of solvent is distilled off at 80 to 100 ° C.

············· · · ···

The mixture is then cooled to 20-30 ° C and the product precipitates by adding 281.5 kg of a 25% ammonia solution. The precipitated product is centrifuged, washed with water and dried at 120 to 125 ° C.

Yield: 178 kg of telmisartan (96.2% of theory).

Comparative example

150 kg of telmisartan crystallizate (crystallized from dimethylformamide or dimethylacetamide), 7.5 kg of activated carbon, 750 L of ethanol and 30 kg of a 25% aqueous ammonia solution are added to a 1200 liter mixer. Stir for about 1 hour, filter in an additional 1200 liter mixer and wash with 150 L of ethanol. The mixture is heated to 70-80 ° C, 35 kg of glacial acetic acid is added and stirred at 75-80 ° C for a further 1.5 to 2 hours. The mixture was then cooled to 0-10 ° C and stirred again for 2 hours. The precipitated product is centrifuged, washed with 300 L of ethanol and 300 L of water and dried at 70-90 ° C. Yield: 135 kg of telmisartan (90% of theory) in pure form A.

Telmisartan is produced during the process of the invention by partially converting polymorph form B to polymorph form A during drying as a pure substance in a mixture of two polymorph forms. However, this has no effect on the properties of the drug because, for example, in the preparation of telmisartan tablets, the mixture of polymorphic forms A and B is dissolved in a solution of 0.1 N NaOH and converted by drying to a homogeneous and completely amorphous granulate which is subsequently processed into tablets. Further details on the use of the products of the invention for the preparation of a medicament are given in EP 502314 B1, which is hereby incorporated by reference.

• ·· · ·· ·

Claims (9)

  1. PATENT CLAIMS
    Polymorphic crystalline modification B - form B of telmisartan of the formula I, characterized by an endothermic maximum at 183 ± 2 ° C, which occurs in thermal analysis by DSC.
  2. Telmisartan comprising Form B according to claim 1.
  3. A process for the preparation of telmisartan according to claim 1 or 2, characterized in that it comprises the following steps:
    (a) the telmisartan is mixed, heated in a solvent mixture consisting of water, formic acid and an organic solvent miscible therewith, and the solution obtained is then filtered,
    (b) the organic solvent, optionally with the addition of water, being distilled off;
    (c) precipitation of telmisartan Form B from the remaining solution by addition of a base; and
    d) the precipitated product is centrifuged, washed and dried.
  4. Process according to claim 3, characterized in that organic carboxylic acid esters, ketones or ethers are used as the organic solvent.
  5. Process according to claim 3 or 4, characterized in that acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, ethyl formate, ethylene glycol dimethyl ether or tetrahydrofuran is used as the organic solvent.
    • ················
    - 10 e
  6. Process according to claim 3, 4 or 5, characterized in that acetone, methyl ethyl ketone, methyl acetate, ethyl acetate or tetrahydrofuran is used as the organic solvent.
  7. Process according to claim 3, 4, 5 or 6, characterized in that ethyl acetate is used as the organic solvent.
  8. Process according to claim 3, 4, 5, 6 or 7, characterized in that ammonia is used as the base.
  9. Use of telmisartan according to claim 1 or 2 for the preparation of a medicament.
    ·· ····
    1/1 τΡ 1060 - Z · o ········ · · · · · · · · · ·
    Temperature [° C]
SK1020-2001A 1999-01-19 2000-01-07 Polymorphic crystal modification B of telmisartan, process for its preparing and its use SK285429B6 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
DE1999101921 DE19901921C2 (en) 1999-01-19 1999-01-19 Polymorphs of telmisartan, to processes for their preparation and their use for the preparation of a medicament
PCT/EP2000/000065 WO2000043370A1 (en) 1999-01-19 2000-01-07 Telmisartan polymorphs, methods for producing same and their use in the preparation of a medicament

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Families Citing this family (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6737432B2 (en) 2001-10-31 2004-05-18 Boehringer Ingelheim Pharma Kg Crystalline form of telmisartan sodium
DE10153737A1 (en) * 2001-10-31 2003-05-28 Boehringer Ingelheim Pharma Crystalline sodium salt of telmisartan, a process for its preparation and its use for the manufacture of a medicament
PT1854454E (en) 2002-01-16 2014-01-09 Boehringer Ingelheim Pharma Method for the preparation of amorphous telmisartan
DE10314702A1 (en) 2003-03-31 2004-10-21 Boehringer Ingelheim Pharma Gmbh & Co. Kg A process for preparing telmisartan
GB2414019A (en) * 2004-05-11 2005-11-16 Cipla Ltd One-step preparation of telmisartan by condensation and hydrolysis
CN101039917A (en) 2004-10-15 2007-09-19 特瓦制药工业有限公司 Process for preparing telmisartan
EP1805146A4 (en) 2004-10-18 2009-01-14 Reddys Lab Ltd Dr Process for preparing telmisartan
US8637078B2 (en) 2005-11-24 2014-01-28 Boehringer Ingelheim International Gmbh Bilayer tablet comprising telmisartan and diuretic
EP1908469A1 (en) 2006-10-06 2008-04-09 Boehringer Ingelheim Vetmedica Gmbh Angiotensin II receptor antagonist for the treatment of systemic diseases in cats
DE102008059206A1 (en) 2008-11-27 2010-06-10 Bayer Schering Pharma Aktiengesellschaft Pharmaceutical dosage form containing nifedipine or nisoldipine and an angiotensin II antagonist and / or a diuretic
WO2010133638A1 (en) 2009-05-20 2010-11-25 Boehringer Ingelheim Vetmedica Gmbh Pharmaceutical oral telmisartan solution
EP2443094B1 (en) 2009-06-19 2013-03-20 Krka Tovarna Zdravil, D.D., Novo Mesto Process for the preparation of telmisartan
EP2277866A1 (en) 2009-06-22 2011-01-26 Inke, S.A. Process for preparing telmisartan
WO2011002423A2 (en) 2009-07-02 2011-01-06 Mahmut Bilgic Solubility enhancing pharmaceutical composition
WO2011002425A2 (en) 2009-07-02 2011-01-06 Bilgig Mahmut Pharmaceutical composition increasing solubility and stability
EA025946B1 (en) 2010-10-27 2017-02-28 Крка, Товарна Здравил, Д. Д., Ново Место Multilayer pharmaceutical composition comprising telmisartan and amlodipine
ITMI20102416A1 (en) * 2010-12-27 2012-06-28 Chemelectiva S R L Intermediate for the preparation of an active ingredient and the process for its preparation
EP2612658A1 (en) 2012-01-05 2013-07-10 Laboratorios Lesvi, S.L. Pharmaceutical compositions of 4'-[(1,4'dimethyl-2'-propyl[2,6'-bi-1h-benzimidazol]-1'-yl)methyl]-[1,1'-biphenyl]-2-carboxylic acid and is 6-chloro-3,4-dihydro-2h-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide
JP6147546B2 (en) * 2013-04-10 2017-06-14 株式会社トクヤマ Method for producing telmisartan A-type crystals with reduced acetic acid
EP2979691A1 (en) 2014-07-30 2016-02-03 Boehringer Ingelheim International GmbH Oral disintegrating tablet
JP6275596B2 (en) * 2014-09-03 2018-02-07 株式会社トクヤマ Method for producing ammonium salt of telmisartan
JP5871294B1 (en) 2015-02-27 2016-03-01 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Immediate release oral tablets
KR20170001921A (en) 2015-06-26 2017-01-05 대원제약주식회사 A pharmaceutical composition comprising telmisartan with increased stability and a preparation method thereof
KR20170012703A (en) 2015-07-22 2017-02-03 대원제약주식회사 A pharmaceutical composition comprising telmisartan and a preparation method thereof
WO2017207375A1 (en) 2016-05-30 2017-12-07 Boehringer Ingelheim International Gmbh Fixed dose combination of telmisartan, hydrochlorothiazide and amlodipine
CN106749036B (en) * 2016-12-21 2019-06-21 山东大学 A kind of unformed Telmisartan-pimelic acid eutectic and its preparation method and application
CN106749037B (en) * 2016-12-21 2019-06-21 山东大学 A kind of unformed Telmisartan-glutaric acid eutectic and its preparation method and application
AR112265A1 (en) 2017-07-07 2019-10-09 Boehringer Ingelheim Vetmedica Gmbh Receptor antagonist angiotensin II for the prevention or treatment of systemic diseases in cats

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SI9210098B (en) * 1991-02-06 2000-06-30 Dr. Karl Thomae Benzimidazoles, drugs with this compounds, and process for their preparation
US5139114A (en) * 1991-03-18 1992-08-18 Abex Corporation Visible brake block wear indicator

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CA2352436C (en) 2010-03-23
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CO5150238A1 (en) 2002-04-29
BR0007584A (en) 2001-11-06
PT1144386E (en) 2004-03-31
CN1144790C (en) 2004-04-07
AU765081B2 (en) 2003-09-11
HU227401B1 (en) 2011-05-30
ES2208265T3 (en) 2004-06-16
CZ20012634A3 (en) 2001-10-17
PL211829B1 (en) 2012-06-29
UY25980A1 (en) 2001-08-27
SK285429B6 (en) 2007-01-04
JP4700813B2 (en) 2011-06-15
EA003065B1 (en) 2002-12-26
NO20013560L (en) 2001-09-18
EP1144386A1 (en) 2001-10-17
DE19901921C2 (en) 2001-01-04
DK1144386T3 (en) 2004-01-12
AU2288100A (en) 2000-08-07
NO20013560D0 (en) 2001-07-18
PL349425A1 (en) 2002-07-29
HU0105148A3 (en) 2003-01-28
BG105654A (en) 2002-01-31
TWI280241B (en) 2007-05-01
IL143634A (en) 2006-10-05
HRP20010514A2 (en) 2002-08-31
EP1144386B1 (en) 2003-10-22
EE200100375A (en) 2002-10-15
IL143634D0 (en) 2002-04-21
AR035475A1 (en) 2004-06-02
JP2002535315A (en) 2002-10-22
RS50044B (en) 2008-11-28
NZ513528A (en) 2003-08-29
CN1336920A (en) 2002-02-20
ZA200104771B (en) 2002-12-02
WO2000043370A1 (en) 2000-07-27
HU0105148A2 (en) 2002-07-29
CZ297412B6 (en) 2006-12-13
DE50004150D1 (en) 2003-11-27
SA584B1 (en) 2006-03-06
EA200100730A1 (en) 2002-02-28
AT252564T (en) 2003-11-15
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PE20001362A1 (en) 2000-12-15
YU51101A (en) 2004-05-12
EE04344B1 (en) 2004-08-16
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