WO2007147889A2 - Préparation de sels de telmisartan - Google Patents

Préparation de sels de telmisartan Download PDF

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Publication number
WO2007147889A2
WO2007147889A2 PCT/EP2007/056251 EP2007056251W WO2007147889A2 WO 2007147889 A2 WO2007147889 A2 WO 2007147889A2 EP 2007056251 W EP2007056251 W EP 2007056251W WO 2007147889 A2 WO2007147889 A2 WO 2007147889A2
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Prior art keywords
telmisartan
salt
hydrate
solvate
theta
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PCT/EP2007/056251
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English (en)
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WO2007147889A3 (fr
Inventor
Silvo Zupancic
Matej Smrkolj
Tadej Stropnik
Miha Vrbinc
Renata Osolnik
Gregor Sedmak
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Krka, Tovarna Zdravil, D.D., Novo Mesto
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Application filed by Krka, Tovarna Zdravil, D.D., Novo Mesto filed Critical Krka, Tovarna Zdravil, D.D., Novo Mesto
Priority to EP07765564A priority Critical patent/EP2046756A2/fr
Publication of WO2007147889A2 publication Critical patent/WO2007147889A2/fr
Publication of WO2007147889A3 publication Critical patent/WO2007147889A3/fr

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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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/12Antihypertensives

Definitions

  • the present invention relates to novel telmisartan salts, and/or novel polymorphs of telmisartan salts, together with processes for their preparation and pharmaceutical formulations containing them.
  • Telmisartan with its chemical name 4 '- [2 -n-propyl-4-methyl-6- (l-methylbenzimid-azol-2-yl ) benzimidazol-1-ylmethyl] biphenyl- 2-carboxylic acid is a non-peptide angiotensin II receptor type ATi antagonist used for the treatment of hypertension. It might be used alone or in combination with another pharmaceutically active compound, e.g. hydrochlorothiazide.
  • the object of the present invention is to provide salts of telmisartan and/or its polymorphs, which are to be used for the preparation of solid pharmaceutical oral dosage forms on industrial scale thus overcoming the problem of the poor solubility of telmisartan under physiological conditions.
  • WO 2004/028505 discloses a solid oral dosage form consisting of telmisartan, a basic agent, a surfactant, and a water- soluble diluent and WO 03/059327 describes a tablet matrix with substantially amorphous telmisartan wherein the ratio of alkali versus telmisartan is above one.
  • WO 2003/037876 provides telmisartan sodium salt and describes its preparation from acid addition salts, prepared with hydrochloride, hydrobromide, toluene sulphonic and methane sulphonic acid.
  • telmisartan sodium US 2003/0130331 and WO 2006/050509 disclose polymorphic forms of telmisartan sodium.
  • WO 2004/096215 also provides telmisartan sodium in crystalline form, as well as the hydrochloride addition salt of telmisartan.
  • WO 2006/050921 describes alkali and earth alkali salts of telmisartan, together with their crystalline and amorphous forms .
  • CN 1548421 discloses the preparation of alkali, earth alkali, arginine and lysine salts of telmisartan including the reaction of telmisartan with organic and inorganic alkali, arginine and lysine in an organic solvent or water, at 20°c to 15O 0 C, although only the preparation of alkali salts is described in the examples .
  • Figure 1 is an X-ray powder diffraction spectrum of amorphous telmisartan ammonium salt.
  • Figure 2 is an X-ray powder diffraction spectrum of amorphous telmisartan choline salt.
  • Figure 3 are X-ray powder diffraction spectra of amorphous telmisartan choline salt with different levels of hydratation.
  • Figure 4 is an X-ray powder diffraction spectrum of telmisartan tert-butylamine salt, polymorphic form I.
  • Figure 5 is an X-ray powder diffraction spectrum of telmisartan tert-butylamine salt, polymorphic form II.
  • Figure 6 is an X-ray powder diffraction spectrum of telmisartan meglumine salt.
  • Figure 7 is telmisartan meglumine as seen through a microscope .
  • Figure 8 is an X-ray powder diffraction spectrum of amorphous telmisartan meglumine salt.
  • Figure 9 is an X-ray powder diffraction spectrum of amorphous telmisartan ethanolamine salt.
  • Figure 10 is an X-ray powder diffraction spectrum of amorphous telmisartan piperazine salt.
  • Figure 11 is an X-ray powder diffraction spectrum of telmisartan diethylamine salt.
  • Figure 12 is an X-ray powder diffraction spectrum of telmisartan tris- (hydroxymethyl) amine salt.
  • Figure 13 is an X-ray powder diffraction spectrum of telmisartan sulphate salt.
  • Figure 14 is an X-ray powder diffraction spectrum of amorphous telmisartan L-arginine salt.
  • Figure 15 is an X-ray powder diffraction spectrum of telmisartan potassium salt, polymorph A.
  • Figure 16 is an X-ray powder diffraction spectrum of telmisartan potassium salt, polymorph B.
  • Figure 17 is an X-ray powder diffraction spectrum of telmisartan maleate.
  • Figure 18 is an X-ray powder diffraction spectrum of telmisartan tartrate.
  • Figure 19 is an X-ray powder diffraction spectrum of telmisartan citrate
  • Figure 20 is an X-ray powder diffraction spectrum of telmisartan fumarate.
  • Figure 21 is an X-ray powder diffraction spectrum of telmisartan 2-naphthalenesulphonate .
  • Figure 22 is an X-ray powder diffraction spectrum of telmisartan oxalate.
  • Figure 23 is an X-ray powder diffraction spectrum of telmisartan benzenesulfonate .
  • the present invention provides novel telmisartan salts and polymorphs thereof suitable for pharmaceutical use. It is known from US 6,358,986 that crystals of telmisartan polymorph form A are in the shape of long needles with an electrostatic charge that could cause many problems in large scale production of the substance and in the production of pharmaceutical compositions containing such substance as for example difficulties during filtration, washing up, isolation, drying. The need to further re-crystallization leads to higher content of residual solvents and lower yield. Therefore there exists a constant need for a preparation method for telmisartan and/or salts thereof having such physical properties that enable easy handling during the preparation of pharmaceutical compositions as for example having particles without an electrostatic charge and being not in the shape of long needles in high yield. This goal is achieved by the preparation of novel telmisartan salts according to the present invention.
  • telmisartan including salts with ammonium, choline ( trimethyl-ethanolamine) , tert-butyl amine (erbumine) , arginine, meglumine (N-methylglucamine) , ethanolamine, piperazine, diethylamine, sulfuric acid, maleic acid, tartaric acid, citric acid, fumaric acid, oxalic acid, benzenesulfonic acid, naphthalene-2-sulphonic acid, tris- (hydroxymethyl ) amine, as well as new polymorphic forms of telmisartan potassium, which have desirable properties and can be prepared in high yield.
  • telmisartan salts according to the present invention are characterized by having a different crystal shape than needles.
  • these salt forms are pharmaceutically acceptable and can be readily used in the preparation of pharmaceutical formulations especially because the basic and acid salts of telmisartan have a much higher solubility than telmisartan itself.
  • the present invention provides basic and acid addition salts of telmisartan that are pure, have good stability, and have advantageous formulation properties compared to the free acid form of telmisartan.
  • X-ray powder diffraction patterns were obtained by a Phillips PW3040/60 X' Pert PRO diffractometer using CuK ⁇ radiation of 1,541874 A.
  • Telmisartan salts according to the present invention may be prepared by crystallization: a telmisartan salt, or a mixture of telmisartan or a telmisartan salt with an organic or inorganic base is dissolved in a polar solvent, such as: N, N, -dimethylformamide (DMF), N, N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO) , alcohols such as for example methanol, ethanol and isopropanol, acetone, acetonitrile or water, or any mixtures thereof, at a temperature ranging from room temperature to reflux temperature of the solvent applied.
  • a polar solvent such as: N, N, -dimethylformamide (DMF), N, N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO)
  • alcohols such as for example methanol, ethanol and isopropanol, acetone, acetonitrile or water
  • the solution can be filtered and then cooled to a temperature between about -10 and about 30 0 C, preferably to room temperature.
  • active charcoal may be applied in order to purify the active ingredient or the mixture containing the active ingredient and an organic or inorganic base.
  • the precipitate is filtered and the product is dried at a temperature between about 10 0 C and about 60 0 C, preferably between about 40 0 C and about 50 0 C.
  • drying generally refers to a removal of solvent until the telmisartan salt prepared contains less than about 5000 ppm residual solvents. Drying may be achieved e.g.
  • telmisartan salt via application of heat, preferably carried out under ambient or reduced pressure or via contacting a telmisartan salt with humid air in a fluidized bed drier, wherein the atmosphere in the fluidized bed drier has at least 15% humidity.
  • vacuum drying in a commercially available vacuum dryer is applied.
  • bases organic amines, ammonium, and alkali and earth alkali hydroxides may be used.
  • acid addition salts of telmisartan according to the present invention are prepared by suspending a mixture of a telmisartan salt, or a mixture of telmisartan or a telmisartan salt with an organic or inorganic acid, in a polar solvent such as: N, N,- dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO) , alcohols such as for example methanol, ethanol, and isopropanol, acetone, acetonitrile and water, or any mixtures thereof, at a temperature ranging from room temperature to the reflux temperature of the solvent.
  • a polar solvent such as: N, N,- dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO)
  • alcohols such as for example methanol, ethanol, and isopropanol, acetone, acetonitrile and water
  • the suspension may be cooled to a temperature between about - 10 and about 3O 0 C, preferably to room temperature.
  • the suspension is filtered and the product is dried at a temperature between about 10 0 C and about 60 0 C, preferably between about 40 0 C and about 50 0 C, preferably in a vacuum drier, but also other means of drying as described above may be used.
  • Telmisartan salts according to the present invention may also be prepared by lyophilization or by spray-drying of a solution of telmisartan, or a telmisartan salt, and an organic or inorganic base, in a polar solvent such as: N, N,- dimethylformamide (DMF), N, N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO) , alcohols such as for example methanol, ethanol and isopropanol, acetone, acetonitrile and water, or any mixtures of them, at a temperature ranging from room temperature to reflux temperature of the solvent.
  • a polar solvent such as: N, N,- dimethylformamide (DMF), N, N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO) , alcohols such as for example methanol, ethanol and isopropanol, acetone, acetonitrile and water, or any mixtures of them,
  • active charcoal may be applied in order to purify the active ingredient or the mixture containing the active ingredient and an organic or inorganic base applied.
  • the solution is spray-dried or freezed with liquid nitrogen and then lyophilized.
  • the obtained solid product is collected and if necessary additionally dried as described above.
  • the isolated products are telmisartan salts.
  • spray- drying the solution is spray-dried at a temperature between about 20 0 C and about 100 0 C.
  • the spray-drying of the solution as described in the examples was performed with a B ⁇ chi Mini- Spray Drier 190.
  • similar equipment can be used.
  • organic or inorganic base organic amines, ammonium, and alkali and earth alkali hydroxides can be used.
  • telmisartan salts according to the present invention are prepared by evaporation of the solvent and the trituration of the residue.
  • a telmisartan salt, or a mixture of telmisartan or a telmisartan salt with an organic or inorganic base is dissolved in a polar solvent such as: N, N, -dimethylformamide (DMF), N, N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), alcohols such as for example methanol, ethanol and isopropanol, acetone, acetonitrile and water, or mixtures of them, at a temperature ranging from room temperature to the reflux temperature of the solvent.
  • a polar solvent such as: N, N, -dimethylformamide (DMF), N, N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), alcohols such as for example methanol, ethanol and isopropanol, acetone,
  • active charcoal may be applied in order to purify the active ingredient or the mixture containing the active ingredient and an organic or inorganic base applied.
  • the solution is optionally filtered and the solvent is evaporated, preferably at a temperature between about 20 and about 100 0 C, under reduced pressure.
  • the residue is suspended in an organic solvent such as alcohols such as for example methanol, ethanol and isopropanol, esters such as for example methyl acetate, ethyl acetate, isopropyl acetate, propyl acetate, butyl acetate, isobutyl acetate and tert-butyl acetate, ethers such as for example diethyl ether, diisopropyl ether and tert-butyl methyl ether, acetone or any mixtures thereof.
  • the product is filtered, dried at a temperature between about 10 0 C and about 60 0 C, preferably between about 40 0 C and about 50 0 C, preferably in a vacuum drier.
  • organic amines and hydroxides can be used.
  • telmisartan in the above mentioned preparations of telmisartan salts according to the present invention, it can be prepared by any method known from the prior art .
  • telmisartan is obtained from 4 ' - ( (1, 7 ' -dimethyl-2 ' -propyl-IH, 3 ⁇ -2 , 5 ' - dibenzo [d] imidazol-3 ' -yDmethyl) biphenyl-2-carbonitrile by hydrolysis of the cyano group in a solvent.
  • the hydrolysis could be carried out by the addition of strong bases such as for example NaOH, KOH, LiOH, Ca(OHh, and similar compounds.
  • the hydrolysis could be carried out by the addition of strong acids such as for example H2SO4, HCl, HBr, H3PO4, HNO 3 , HClO 4 , p-toluene sulphonic acid, methane sulphonic acid, benzene sulphonic acid, and similar.
  • strong acids such as for example H2SO4, HCl, HBr, H3PO4, HNO 3 , HClO 4 , p-toluene sulphonic acid, methane sulphonic acid, benzene sulphonic acid, and similar.
  • the isolation of telmisartan is performed by optional addition of water and adjustment of pH to about 5 to about 7.
  • the obtained telmisartan can be in any polymorph form.
  • a first aspect of the present invention is directed towards amorphous telmisartan ammonium salt characterized by the X-ray powder diffraction pattern as shown in Figure 1, and a melting interval of 150-158 0 C.
  • the invention is directed to amorphous telmisartan choline salt, or solvates or hydrates thereof, characterized by a melting interval of 65-110 0 C and by the X- ray powder diffraction pattern as shown in Figure 2. Also the hydrated forms of amorphous telmisartan choline salt, characterized by a melting interval of 65-80 0 C and by the X- ray powder diffraction patterns as shown in Figure 3, were prepared.
  • the present invention is directed to the telmisartan tert-butylamine salt, and the polymorphs I and II thereof characterized by a melting interval of 264-268 0 C and 168-175 0 C, respectively, and by the X-ray powder diffraction patterns as shown in Figures 4 and 5, respectively.
  • a typical X-ray diffraction pattern of polymorphic form I of telmisartan tert-butylamine salt is given in the following Table 1 by listing 2-theta degrees ( ⁇ 0.2 degrees 2-theta) together with the corresponding intensities.
  • Polymorphic form I of telmisartan tert-butylamine salt is preferably characterized by an X-ray powder diffraction pattern having peaks at: 6.6, 13.2, 14.1, 17.0and 19.5 ⁇ 0.2 degrees 2-theta.
  • a typical X-ray diffraction pattern of polymorphic form II of telmisartan tert-butylamine salt is given in the following Table 2 by listing 2-theta degrees ( ⁇ 0.2 degrees 2-theta) together with the corresponding intensities.
  • Polymorphic form II of telmisartan tert-butylamine salt is preferably characterized by an X-ray powder diffraction pattern having peaks at: 4.5, 13.3, 13.7, 19.1, 21.1 ⁇ 0.2 degrees 2-theta.
  • the present invention is directed to telmisartan meglumine salt (telmisartan N-methylglucamine salt) characterized by a melting interval of 198-205 0 C, and by the X-ray powder diffraction pattern as shown in Figure 6.
  • telmisartan meglumine salt A typical X-ray diffraction pattern of telmisartan meglumine salt is given in the following Table 3 by listing 2-theta degrees ( ⁇ 0.2 degrees 2-theta) together with the corresponding intensities.
  • Telmisartan meglumine salt is preferably characterized by an X-ray powder diffraction pattern having peaks at: 6.9, 15.5, 17.9, 22.1, 23.4 ⁇ 0.2 degrees 2-theta.
  • the present invention is directed to amorphous telmisartan meglumine salt (telmisartan N- methylglucamine salt) characterized by a melting interval of 86-91 0 C, and by the X-ray powder diffraction pattern as shown in Figure 8.
  • the present invention is directed to the amorphous ethanolamine salt of telmisartan characterized by a melting interval of 265-268 0 C and by the X-ray powder diffraction pattern as shown in Figure 9.
  • the present invention is directed to the amorphous piperazine salt of telmisartan characterized by a melting interval of 155-160 0 C and by the X-ray powder diffraction pattern as shown in Figure 10.
  • the present invention is directed to telmisartan diethylamine salt characterized by a melting interval of 120-135 0 C, and by the X-ray powder diffraction pattern as shown in Figure 11.
  • telmisartan diethylamine salt A typical X-ray diffraction pattern of telmisartan diethylamine salt is given in the following Table 4 by listing 2-theta degrees ( ⁇ 0.2 degrees 2-theta) together with the corresponding intensities.
  • Telmisartan diethylamine salt is preferably characterized by an X-ray powder diffraction pattern having peaks at: 6.0, 7.0, 11.5, 12.1, 13.9 ⁇ 0.2 degrees 2-theta.
  • the present invention is directed to telmisartan tris- (hydroxymethyl) amine salt characterized by a melting interval of 189-198 0 C, and by the X-ray powder diffraction pattern as shown in Figure 12.
  • a typical X-ray diffraction pattern of telmisartan tris- (hydroxymethy1) amine salt is given in the following Table 5 by listing 2-theta degrees ( ⁇ 0.2 degrees 2-theta) together with the corresponding intensities.
  • Telmisartan tris- (hydroxymethyl) amine salt is preferably characterized by an X-ray powder diffraction pattern having peaks at: 14.0, 14.3, 15.6, 20.2, 20.5, 24.1 ⁇ 0.2 degrees 2- theta.
  • the present invention is directed to telmisartan sulphate salt characterized by a melting interval of 218-227°C and by the X-ray powder diffraction pattern as shown in Figure 13.
  • telmisartan sulphate salt A typical X-ray diffraction pattern of telmisartan sulphate salt is given in the following Table 6 by listing 2 -theta degrees ( ⁇ 0.2 degrees 2-theta) together with the corresponding intensities.
  • Telmisartan sulphate salt is preferably characterized by an X-ray powder diffraction pattern having peaks at: 12.8, 13.6, 16.5, 17.8, 21.4 ⁇ 0.2 degrees 2-theta.
  • the present invention is directed to the amorphous telmisartan L- arginine salt characterized by a melting interval of about 160-175 0 C and by the X-ray powder diffraction pattern as shown in Figure 14.
  • the present invention is directed to the novel polymorphic forms of telmisartan potassium salt characterized by a melting interval of 182 - 194°C (form A), and 205-225 0 C (form B), respectively, and by the X-ray powder diffraction patterns as shown in Figures 15 (form A) and 16 ( form B) .
  • a typical X-ray diffraction pattern of polymorphic form A of telmisartan potassium salt is given in the following Table 7 by listing 2-theta degrees ( ⁇ 0.2 degrees 2-theta) together with the corresponding intensities.
  • Polymorphic form A of telmisartan potassium salt is preferably characterized by an X-ray powder diffraction pattern having peaks at: 5.8, 11.6, 13.6, 13.7, 24.3 ⁇ 0.2 degrees 2-theta.
  • a typical X-ray diffraction pattern of polymorphic form B of telmisartan potassium salt is given in the following Table 8 by listing 2-theta degrees ( ⁇ 0.2 degrees 2-theta) together with the corresponding intensities.
  • Polymorphic form B of telmisartan potassium salt is preferably characterized by an X-ray powder diffraction pattern having peaks at: 5.4, 5.9, 10.4, 11.6, 17.6 ⁇ 0.2 degrees 2-theta.
  • the present invention is directed to the telmisartan maleate salt characterized by a melting interval of about 265-270 0 C and by the X-ray powder diffraction pattern as shown in Figure 17 and in Table 9.
  • the present invention is directed to the telmisartan tartrate salt characterized by a melting interval of about 230-235 0 C and by the X-ray powder diffraction pattern as shown in Figure 18 and in Table 10.
  • the present invention is directed to the telmisartan citrate salt characterized by a melting interval of about 267-271°C and by the X-ray powder diffraction pattern as shown in Figure 19 and in Table 11.
  • the present invention is directed to the telmisartan fumarate salt characterized by a melting interval of about 121-130 0 C and by the X-ray powder diffraction pattern as shown in Figure 20 and in Table 12.
  • the present invention is directed to the telmisartan 2-naphthalenesulphonate salt characterized by a melting interval of about 258-264°C and by the X-ray powder diffraction pattern as shown in Figure 21 and in Table 13.
  • the present invention is directed to the telmisartan oxalate salt characterized by a melting interval of about 223-225 0 C and by the X-ray powder diffraction pattern as shown in Figure 22 and in Table 14.
  • the present invention is directed to the telmisartan benzenesulfonate salt characterized by a melting interval of about 220-225 0 C and by the X-ray powder diffraction pattern as shown in Figure 23 and in Table 15.
  • telmisartan salts according to the present invention prepared in high purity in a stoichiometric ratio of 1:1 which means the molar ratio of telmisartan in salt is from about 0.35 to about 0.65, preferably from about 0.40 to about 0.50 and more preferably from about 0.45 to about 0.55
  • telmisartan salts according to the present invention characterized by having water content less than 2%, preferably less than 1%, more preferably less than 0.5%.
  • telmisartan salts according to the present invention characterized by having a different shape than needles as for example telmisartan meglumine salt according to the present invention has a crystal shape in the form of a round shape.
  • a still further embodiment of the present invention is a pharmaceutical composition for administering an effective amount of a telmisartan salt according to the present invention in a unit dosage form, alone or in combination with another active ingredient such as hydrochlorothiazide and pharmaceutically acceptable carriers comprising inactive ingredients such as fillers (diluents), binders, disintegrants , glidants, lubricants, and other excipients.
  • active ingredient such as hydrochlorothiazide
  • pharmaceutically acceptable carriers comprising inactive ingredients such as fillers (diluents), binders, disintegrants , glidants, lubricants, and other excipients.
  • Any manufacturing process for the solid oral dosage form preparation may be applied, including the wet granulation process (with water or any other suitable and pharmaceutically acceptable organic solvent) , the dry granulation process, and the direct compression method, or any other method known in the art.
  • compositions may be administered to a patient in any dosage form, such as for example tablet, pill, troche, lozenge, capsule, powder, liquid, suppository, sachet, elixir, solution, syrup, suspension etc.
  • dosage forms may be adapted for administration to the patient by for example oral, buccal, parenteral, ophthalmic, rectal and transdermal route.
  • a telmisartan salt according to the present invention can be included in the pharmaceutical composition or it can be formed in- situ during the preparation of the pharmaceutical composition. In the latter case telmisartan is placed in a solvent together with a corresponding basic agent and mixed together. A dissolved salt form of telmisartan is obtained.
  • the telmisartan salt can be used directly either in a spray- drying or in a fluid-bed process.
  • telmisartan salt according to the present invention when used in a pharmaceutical composition according to the present invention, no surfactant is needed for the preparation of the final composition of telmisartan.
  • telmisartan is prepared by a spray-drying method
  • either the salt form of telmisartan or telmisartan together with a basic agent and optionally a crystallization retarder is dissolved in an appropriate solvent (water or organic solvent) and spray-dried.
  • the spray-dried granulate is mixed further with other excipients to form the final composition ready for tabletting.
  • excipients are placed in the fluid- bed granulating machine and sprayed together with the granulation liquid.
  • the granulate is dried and optionally mixed with additional excipients like flow control agent and/or lubricant to form the final composition ready for tabletting.
  • the lubricant and flow control agent may be selected from, but not restricted to hydrophobic lubricants like magnesium stearate, calcium stearate, stearic acid and hydrogenated vegetable oil or hydrophilic lubricants like sodium stearyl fumarate and glyceryl .
  • binders and fillers can be used.
  • the binder may be selected from, but not restricted to starch paste, pregelatinized starch, gum acacia, gelatin, alginates, cellulose derivatives like methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone and copovidone etc.; and any mixtures thereof.
  • the filler may be selected from water-soluble or water-insoluble fillers.
  • fillers are, but are not restricted to sucrose, dextrose, dextrates, fructose, sorbitol, xylitol, maltodextrin, lactose, mannitol, copovidone, calcium phosphates, calcium sulphates, starch, cellulose and its derivatives like microcrystalline cellulose etc. and mixtures of these. Surprisingly, it was found that similar dissolution profiles can be obtained with both, water-soluble and water-insoluble fillers.
  • the amount of water soluble or water insoluble fillers can be between about 20 to about 95 wt%, preferably between about 50 to 95 wt%, more preferably between about 70 to about 95wt% and most preferably between about 70 to 80 wt %.
  • a disintegrant is needed.
  • the disintegrant may be selected from, but not restricted to traditional products like starch and pregelatinized starch, alginic acid and amberlite resins as well as super disintegrants like sodium starch glycolate, croscarmellose sodium, crospovidone and soy polysaccharide etc.; and mixtures of these.
  • the present invention provides a method of treating a disease state prevented, ameliorated or eliminated by the administration of an angiotensin II receptor antagonist to a patient in need of such treatment.
  • telmisartan 1 g (2 mmol) of telmisartan is added to 13 mL of DMF and 0.21 mL (2 mmol) tert-butylamine, and the mixture is heated until all telmisartan is dissolved. The solution is cooled to room temperature. The precipitate formed is filtered, washed with water and dried. 0.65 g of telmisartan tert-butylamine salt is isolated.
  • Example 6 Telmisartan tert-butylamine salt, polymorph II I g (2 mmol) of telmisartan is added to 10 mL of isopropanol and 0.3 mL (2.9 mmol) tert-butylamine, and the mixture is heated under reflux for 3 h. The solution is cooled to room temperature. The precipitate formed is filtered, washed with water and dried. 1 g of telmisartan tert-butylamine salt is isolated.
  • telmisartan 1 g (2 mmol) of telmisartan is added to 10 mL of water and 0.2 mL (3.6 mmol) concentrated sulfuric acid, and the suspension is mixed at room temperature for 1 h. The suspension is filtered, washed with water and dried at 45°C in a vacuum drier. 1.16 g of sesquihydrate telmisartan sulphate salt is isolated.
  • telmisartan maleate is isolated.
  • telmisartan tartrate is isolated.
  • telmisartan citrate is isolated.
  • Example 11 Telmisartan fumarate I g (2 iranol) of telmisartan is suspended in 10 mL of methanol and then 0.232 g (2 mmol) of fumaric acid is added. The suspension is heated under reflux temperature for 0.5 h and then cooled to room temperature, filtered, washed with water and dried at 35°C in a vacuum drier. 1.08 g telmisartan fumarate is isolated.
  • telmisartan 1 g (2 mmol) of telmisartan is suspended in 10 mL of methanol and then 0.46 g (2 mmol) of naphthalene-2-sulphonic acid is added. The suspension is heated under reflux temperature for 0.5 h and then cooled to room temperature, filtered, washed with water and dried at 35°C in a vacuum drier. 1.39 g telmisartan 2-naphthalenesulphonate is isolated.
  • telmisartan I g (2 mmol) of telmisartan is suspended in 10 mL of methanol and then 0.18 g (2 mmol) of oxalic acid is added. The suspension is heated under reflux temperature for 0.5 h and then cooled to room temperature, filtered, washed with water and dried at 35 0 C in a vacuum drier. 1.14 g telmisartan oxalate is isolated. T : 223 -229 °C
  • IR 1700, 1472, 1263, 1235, 1130, 830, 763
  • telmisartan 1 g (2 inmol) of telmisartan is suspended in 10 mL of methanol and then 0.32 g (2 mmol) of benzenesulfonic acid is added. The suspension is heated under reflux temperature for 0.5 h and then cooled to room temperature, filtered, washed with water and dried at 35 0 C in a vacuum drier. 0.96 g telmisartan benzenesulfonate is isolated.
  • telmisartan 1 g (2 mmol) of telmisartan is added to 10 mL of methanol and 0.56 mL (2 mmol) of choline, and the suspension is stirred until all components are dissolved. The solution is lyophilized and 1.20 g of telmisartan choline salt is isolated.
  • IR 1583, 1450, 1380, 1280, 1088, 953, 848, 745
  • XRD amorphous, figure 2
  • Example 16 Telmisartan choline salt
  • telmisartan is added to 10 mL of water and 0.56 mL (2 mmol) of choline, and the suspension is stirred until all components are dissolved. The solution is lyophilized and 0.84 g of telmisartan choline salt in the hemihydrate form is isolated.
  • telmisartan 1 g (2 mmol) of telmisartan is added to 10 mL of methanol and 0.35 mL (2 mmol) of L-arginine, and the suspension is heated until all components are dissolved. The solution is lyophilized and 1.07 g of telmisartan L-arginine salt in the sesquihydrate form is isolated.
  • telmisartan ammonium salt is isolated.
  • telmisartan 1 g (2mmol ) of telmisartan is added to 10 mL of methanol and
  • IR 1560, 1557, 1457, 1388, 1283, 1079, 1033, 745
  • XRD amorphous, figure 8
  • telmisartan I g (2 iranol) of telmisartan is added to 10 mL of methanol and 0.56 g (2 mmol) of choline, and the suspension is stirred until all components are dissolved. Volatile components are evaporated, and 10 mL of tert-butyl methyl ether are added, and the volatile components are evaporated again untill a solid product is obtained, which is further dried for 2 h in a vacuum drier, at a temperature of about 45°C. 1.26 g of the product is isolated.
  • telmisartan 1 g ( 2 mmol) of telmisartan is added to 10 mL of methanol and 0.35 g (2 mmol) of L-arginine, and the suspension is heated until all components are dissolved. Volatile components are evaporated, and 1 mL of isopropanol and 10 mL of isopropyl acetate are added. The precipitate is filtered and dried for 2 h in a vacuum drier at a temperature of about 45 0 C. 1.3 g of the product in form of a methanol solvate is isolated.
  • telmisartan is added to 8 mL of DMF and 0.12 mL (2 mmol) of ethanolamine, and the suspension is heated until all components are dissolved. Volatile components are evaporated and 5 mL of diethyl ether are added. The precipitate is filtered and dried for 2 h in a vacuum drier at a temperature of about 45 0 C. 0.72 g of the product is isolated.
  • telmisartan 1 g (2 mmol) of telmisartan is added to 8 mL of DMF and 0.168 g (2 mmol) of piperazine, and the suspension is heated until all components are dissolved. Volatile components are evaporated untill a solid product is obtained which is further dried for 2 h in a vacuum drier at a temperature of about 45°C. 1.1 g of the product in the monohydrate form is isolated.
  • telmisartan 1 g (2 mmol) of telmisartan is added to 10 mL of methanol and 0.21 g (2 mmol) of diethylamine, and the suspension is stirred at room temperature until all components are dissolved. Volatile components are evaporated and 5 mL of isopropyl acetate is added. The precipitate is filtered and dried for 3 h in a vacuum drier at a temperature of about 45°C. 0.83 g of the product is isolated.
  • telmisartan 1 g (2 mmol) of telmisartan is added to 10 mL of methanol and 0.23 g (2 mmol) of tris- (hydroxymethy1 ) amine, and the suspension is heated until all components are dissolved. Volatile components are evaporated and 5 mL of teirt-butyl methyl ether is added. The precipitate is filtered and dried for 2 h in a vacuum drier at a temperature of about 45 0 C. 1.19 g of the product is isolated.
  • telmisartan is added to 10 mL of methanol and ImI of 2M KOH, and the suspension is heated until all components are dissolved. The solution is cooled, volatile components are evaporated, and 1 mL of isopropanol and 10 ml of isopropyl acetate are added. The precipitate is filtered and dried for 1.5 h in a vacuum drier, at a temperature of about 45 0 C. 0.84 g of the product in the sesquihydrate form is isolated. T : 182 -194 0 C
  • telmisartan 1 g (2mmol) of telmisartan is added to 10 mL of methanol and ImI of 2M KOH, and the suspension is heated until all components are dissolved. Volatile components are evaporated, and 10 mL of acetone is added. The mixture is stirred for Ih at room temperature and the precipitate is filtered and dried for 1 h in a vacuum drier, at a temperature of about 40 0 C. 1 g of the product as monohydrate is isolated.
  • the amount of microcrystalline cellulose varies, depending on the base used in the formulation .
  • compositions containing telmisartan can be prepared by various methods. Three of the appropriate methods are lyophilization, spray-drying and fluid-bed granulation. If telmisartan is prepared by the spray-drying method, telmisartan together with a basic agent and optionally a crystallization retarder is dissolved in an appropriate solvent (water or organic solvent) and spray- dried. The spray-dried granulate is mixed further with other excipients to form the final composition ready for tabletting. In case of fluid-bed granulation, telmisartan together with a basic agent and optionally a crystallization retarder is dissolved in an appropriate solvent (water or organic solvent) to form a granulation liquid.
  • an appropriate solvent water or organic solvent
  • excipients are placed in the fluid-bed granulating machine and sprayed together with the granulation liquid.
  • the granulate is dried and optionally mixed with additional excipients like a flow control agent and/or a lubricant to form the final composition ready for tabletting.

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Abstract

De nouveaux sels de telmisartan, sous forme amorphe et cristalline, ainsi que deux nouvelles formes polymorphiques de telmisartan potassium, ont été préparés par cristallisation, évaporation du solvant, séchage par atomisation ou lyophilisation, et ont été inclus dans une formule pharmaceutique.
PCT/EP2007/056251 2006-06-23 2007-06-22 Préparation de sels de telmisartan WO2007147889A2 (fr)

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EP07765564A EP2046756A2 (fr) 2006-06-23 2007-06-22 Préparation de sels de telmisartan

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SI200600154A SI22297A (sl) 2006-06-23 2006-06-23 Priprava soli telmisartana
SIP-200600154 2006-06-23

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010146187A2 (fr) 2009-06-19 2010-12-23 Krka, Tovarna Zdravil, D.D., Novo Mesto Procédé pour la préparation de telmisartan
WO2011002423A2 (fr) 2009-07-02 2011-01-06 Mahmut Bilgic Composition pharmaceutique augmentant la solubilité
WO2011002425A2 (fr) 2009-07-02 2011-01-06 Bilgig Mahmut Composition pharmaceutique présentant une solubilité et une stabilité accrues
WO2011025467A1 (fr) * 2009-08-24 2011-03-03 Bilgic Mahmut Formes posologiques solides comprenant du telmisartan
WO2012055941A1 (fr) 2010-10-27 2012-05-03 Krka,Tovarna Zdravil, D. D., Novo Mesto Composition pharmaceutique multicouche comprenant du telmisartan et de l'amlodipine
JP2013227273A (ja) * 2012-03-29 2013-11-07 Tokuyama Corp 4′−[[2−n−プロピル−4−メチル−6−(1−メチルベンズイミダゾール−2−イル)−ベンズイミダゾール−1−イル]−メチル]−ビフェニル−2−カルボン酸の精製方法
JP2014502978A (ja) * 2011-01-20 2014-02-06 ジエンス ハンセン ファーマセウティカル カンパニー リミテッド アジルサルタン有機アミン塩、その製造方法及び使用
WO2014068507A1 (fr) * 2012-11-02 2014-05-08 Abbott Healthcare Pvt. Ltd. Compositions pharmaceutiques orales solides de telmisartan essentiellement exemptes de tensioactifs
JP2014210772A (ja) * 2013-04-04 2014-11-13 沢井製薬株式会社 テルミサルタン含有錠剤
WO2015099111A1 (fr) * 2013-12-27 2015-07-02 トーアエイヨー株式会社 Sel d'antagoniste des récepteurs de l'angiotensine ii
JP2016053006A (ja) * 2014-09-03 2016-04-14 株式会社トクヤマ テルミサルタンの製造方法
JP2016053009A (ja) * 2014-09-03 2016-04-14 株式会社トクヤマ テルミサルタンのアンモニウム塩の製造方法
CN105732509A (zh) * 2016-04-06 2016-07-06 浙江华海药业股份有限公司 一种替米沙坦铵盐晶型及其制备方法
WO2016153222A3 (fr) * 2015-03-20 2016-11-17 크리스탈지노믹스(주) Composition pharmaceutique comprenant un sel de potassium de telmisartan et procédé de préparation associé

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1548421A (zh) * 2003-05-22 2004-11-24 上海医药工业研究院 替米沙坦盐及其制备方法
WO2006044754A2 (fr) * 2004-10-18 2006-04-27 Dr. Reddy's Laboratories Ltd. Procede pour preparer du telmisartan
WO2006050509A2 (fr) * 2004-11-03 2006-05-11 Teva Pharmaceutical Industries Ltd. Formes amorphes et polymorphes de sodium telmisartan

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Publication number Priority date Publication date Assignee Title
CN1548421A (zh) * 2003-05-22 2004-11-24 上海医药工业研究院 替米沙坦盐及其制备方法
WO2006044754A2 (fr) * 2004-10-18 2006-04-27 Dr. Reddy's Laboratories Ltd. Procede pour preparer du telmisartan
WO2006050509A2 (fr) * 2004-11-03 2006-05-11 Teva Pharmaceutical Industries Ltd. Formes amorphes et polymorphes de sodium telmisartan

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* Cited by examiner, † Cited by third party
Title
See also references of EP2046756A2 *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010146187A3 (fr) * 2009-06-19 2011-02-24 Krka, Tovarna Zdravil, D.D., Novo Mesto Procédé pour la préparation de telmisartan
WO2010146187A2 (fr) 2009-06-19 2010-12-23 Krka, Tovarna Zdravil, D.D., Novo Mesto Procédé pour la préparation de telmisartan
WO2011002423A2 (fr) 2009-07-02 2011-01-06 Mahmut Bilgic Composition pharmaceutique augmentant la solubilité
WO2011002425A2 (fr) 2009-07-02 2011-01-06 Bilgig Mahmut Composition pharmaceutique présentant une solubilité et une stabilité accrues
WO2011002425A3 (fr) * 2009-07-02 2011-03-03 Bilgig Mahmut Composition pharmaceutique présentant une solubilité et une stabilité accrues
WO2011002423A3 (fr) * 2009-07-02 2011-03-03 Mahmut Bilgic Composition pharmaceutique augmentant la solubilité
WO2011025467A1 (fr) * 2009-08-24 2011-03-03 Bilgic Mahmut Formes posologiques solides comprenant du telmisartan
WO2012055941A1 (fr) 2010-10-27 2012-05-03 Krka,Tovarna Zdravil, D. D., Novo Mesto Composition pharmaceutique multicouche comprenant du telmisartan et de l'amlodipine
JP2014502978A (ja) * 2011-01-20 2014-02-06 ジエンス ハンセン ファーマセウティカル カンパニー リミテッド アジルサルタン有機アミン塩、その製造方法及び使用
JP2013227273A (ja) * 2012-03-29 2013-11-07 Tokuyama Corp 4′−[[2−n−プロピル−4−メチル−6−(1−メチルベンズイミダゾール−2−イル)−ベンズイミダゾール−1−イル]−メチル]−ビフェニル−2−カルボン酸の精製方法
WO2014068507A1 (fr) * 2012-11-02 2014-05-08 Abbott Healthcare Pvt. Ltd. Compositions pharmaceutiques orales solides de telmisartan essentiellement exemptes de tensioactifs
JP2014210772A (ja) * 2013-04-04 2014-11-13 沢井製薬株式会社 テルミサルタン含有錠剤
WO2015099111A1 (fr) * 2013-12-27 2015-07-02 トーアエイヨー株式会社 Sel d'antagoniste des récepteurs de l'angiotensine ii
JP2016053006A (ja) * 2014-09-03 2016-04-14 株式会社トクヤマ テルミサルタンの製造方法
JP2016053009A (ja) * 2014-09-03 2016-04-14 株式会社トクヤマ テルミサルタンのアンモニウム塩の製造方法
WO2016153222A3 (fr) * 2015-03-20 2016-11-17 크리스탈지노믹스(주) Composition pharmaceutique comprenant un sel de potassium de telmisartan et procédé de préparation associé
CN105732509A (zh) * 2016-04-06 2016-07-06 浙江华海药业股份有限公司 一种替米沙坦铵盐晶型及其制备方法

Also Published As

Publication number Publication date
EP2046756A2 (fr) 2009-04-15
WO2007147889A3 (fr) 2008-05-08
SI22297A (sl) 2007-12-31

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