SI22297A - Preparation of salt of telmisartan - Google Patents

Abstract

New salts of telmisartan in amorphous and crystalline forms together with new polymorphous forms of telmisartan potassium have been prepared by crystallization, solvent evaporation and spray drying or liophylization and included into a pharmaceutical formulation.

Description

Preparation of telmisartan salts

The present invention relates to novel telmisartan salts and / or new telmisartan salt polymorphs, to processes for their preparation and to pharmaceutical formulations containing them.

Telmisartan with its chemical name 4 '- [2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-ylmethyl] biphenyl-2-carboxylic acid is a non-peptide angiotensin II receptor antagonist, type AT _b used to treat hypertension. It can be used alone or in combination with another pharmaceutically effective compound, e.g. hydrochlorothiazide.

Displayed in EP 502314 and in J. Med. Chem., 36 (25), 40404051 (1993), and its polymorphs are known from EP 1144386 and J. Pharm. Sci., 89 (11), 1465-1479 (2000).

The object of the present invention is to provide salts of telmisartan and / or its polymorphs to be used for the preparation of solid pharmaceutical oral dosage forms on an industrial scale, thus solving the problem of poor solubility of telmisartan under physiological conditions.

WO 2004/028505 describes 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 having substantially amorphous telmisartan where the alkali to telmisartan ratio is greater than one.

WO 2003/037876 provides the sodium salt of telmisartan and describes its preparation from acid addition salts prepared with hydrochloric, hydrobromic, toluenesulfonic and methanesulfonic acid.

US 2003/0130331 and WO 2006/050509 describe polymorphic forms of telmisartan sodium. WO 2004/096215 also provides crystalline sodium telmisartan as well as telmisartan hydrochloride addition salt.

WO 2006/050921 describes the alkali and alkaline earth salts of telmisartan, together with their crystalline and amorphous forms.

WO 2006/044754 describes the preparation of the bisulfate and potassium salts of telmisartan.

CN 1548421 describes the preparation of alkali, earth alkaline, arginine and lysine salts, which involves the reaction of telmisartan with organic and inorganic alkali, arginine and lysine in an organic solvent or water at 20-150 ° C, although only the preparation of alkali salts is described in the Examples.

Short description of the pictures

Figure 1 shows the X-ray powder diffraction spectrum of the telmisartan amorphous ammonium salt.

Figure 2 shows the X-ray powder diffraction spectrum of the telmisartan amorphous choline salt.

Figure 3 shows the X-ray powder diffraction spectra of the amorphous choline salt of telmisartan with different hydration levels.

Figure 4 shows the X-ray powder diffraction spectrum of /ert.- butylamine salts of telmisartan, a form I polymorph.

Figure 5 shows the X-ray powder diffraction spectrum of telmisartan tert.-butylamine salt, polymorphic form II.

Figure 6 shows the X-ray powder diffraction spectrum of the meglumine salt of telmisartan.

Figure 7 shows the X-ray powder diffraction spectrum of the telmisartan diethylamine salt.

Figure 8 shows the X-ray powder diffraction spectrum of the telmisartan tris- (hydroxymethyl) amine salt.

Figure 9 shows the X-ray powder diffraction spectrum of the telmisartan sulfate salt.

Figure 10 shows the X-ray powder diffraction spectrum of the telmisartan L-arginine salt.

Figure 11 shows the X-ray powder diffraction spectrum of the potassium salt of telmisartan, polymorph A.

Figure 12 shows the X-ray powder diffraction spectrum of the potassium salt of telmisartan, polymorph B.

DETAILED DESCRIPTION OF THE INVENTION

Surprisingly and unexpectedly, new forms of telmisartan salts have now been prepared, including salts of ammonium, choline (trimethyl-ethanolamine), tert-butylamine (erbumin), arginine, meglumine (N-methylglucamine), ethanolamine, piperazine, and dimethylamine , sulfuric acid and tris (hydroxymethyl) amine, as well as novel polymorphic forms of potassium telmisartan, which have the desired properties. These salt forms as such are pharmaceutically acceptable and can be used to prepare pharmaceutical formulations. Thus, the present invention provides the base and acid addition salts of telmisartan which are pure, have good stability and have favorable formulation properties compared to the acidic form of telmisartan.

Melting points were measured on a Koffler melting point apparatus, and IR spectra were recorded on a Paragon 100 Perkin-Elmer FT-IR spectrometer.

X-ray powder diffraction patterns were obtained with a Phillips PW3040 / 60 X'Pert PRO diffractometer using a CuK _α- irradiation of 1.541874.

FT-IR analysis was performed on a FT-IR SPECTRUM GX system Perkin Elmer [4000400] cm ^_1 . 4 cm ^-1 resolution, KBr tablet.

Salts of telmisartan can be prepared by crystallization: a salt of telmisartan or a mixture of telmisartan, or a salt of telmisartan with an organic or inorganic base dissolved in a polar solvent such as: DMF, DMA, DMSO, alcohol (eg methanol, ethanol, isopropanol), acetone, acetonitrile or H ₂ O, or mixtures thereof, at a temperature in the range from room temperature to the reflux temperature of the solvent used. The solution can be filtered and then cooled to a temperature between -10 ° C and 30 ° C, preferably to room temperature. Optionally, activated carbon can be used to purify the active ingredient or a mixture of the active ingredient with an organic or inorganic base. The precipitate is filtered off and the product is dried at a temperature between 10 ° C and 60 ° C, preferably between 40 ° C and 50 ° C. The term drying as used herein generally refers to solvent removal until the telmisartan salt prepared contains less than about 5000 ppm of solvent residue. Drying can be achieved e.g. using heat and preferably carried out at atmospheric or reduced pressure, or by contacting telmisartan salts with moist air in a vortex dryer, the atmosphere in the vortex dryer having at least 15% humidity. Preferably, vacuum drying is used in a commercially available vacuum dryer. Organic amines, ammonium and alkali and alkaline earth hydroxides can be used as bases.

In one aspect of the present invention, the acid addition salts of telmisartan are prepared by suspending a mixture of telmisartan salts or a mixture of telmisartan, or a telmisartan salt with an organic or inorganic acid in a polar solvent, such as: DMF, DMA, DMSO, alcohol (eg methanol, ethanol, isopropanol) , acetone, acetonitrile and H ₂ O, or mixtures thereof, at a temperature in the range from room temperature to the reflux temperature of the solvent. The suspension can be cooled to a temperature between -10 ° C and 30 ° C, preferably to room temperature. The suspension is filtered and the product is dried at a temperature between 10 ° C and 60 ° C, preferably between 40 ° C and 50 ° C, preferably in a vacuum oven, and other drying methods described above may be used.

Salts of telmisartan can also be prepared by lyophilization or spray drying of a solution of telmisartan or a telmisartan salt and an organic or inorganic base in a polar solvent such as: DMF, DMA, DMSO, alcohol (eg methanol, ethanol, isopropanol), acetone, acetonitrile and H ₂ O or mixtures thereof, at a temperature from room temperature to the reflux temperature of the solvent. Optionally, activated carbon may be used to purify the active ingredient or mixture thereof with the organic or inorganic base used. The solution is spray dried or freezed with liquid nitrogen and lyophilized. The resulting solid product is collected and, if necessary, further dried as described above. Isolated products are telmisartan salts. In the case of spray drying, the solution is spray dried at a temperature between 20 ° C and 100 ° C. Solution spray drying as described in the Examples is carried out using a Buchi Mini-Spray Drier 190 dryer. A similar device may also be used. Organic amines, ammonium and alkali and earth alkaline hydroxides may be used as the organic or inorganic base.

From a further aspect of the present invention, telmisartan salts can be prepared by evaporation of the solvent and trituration of the residue. A mixture of telmisartan, telmisartan or telmisartan salts with an organic or inorganic base is dissolved in a polar solvent such as: DMF, DMA, DMSO, alcohol (eg methanol, ethanol, isopropanol), acetone, acetonitrile and H ₂ O, or mixtures thereof, at temperature ranging from room temperature to solvent reflux temperature. Optionally, activated carbon may be used to purify the active ingredient or mixture thereof with the organic or inorganic base used. The solution is optionally filtered and the solvent is evaporated, preferably at a temperature between 20 ° C and 100 ° C under reduced pressure. The residue is suspended in an organic solvent such as: alcohols (e.g. methanol, ethanol, isopropanol), esters (e.g. methyl acetate, ethyl acetate, isopropyl acetate, propyl acetate, butyl acetate, isobutyl acetate, tert-butyl acetate), ethers (e.g. diethyl ether, diisopropyl ether, tert -butyl methyl ether), acetone or mixtures thereof. The product is filtered, dried at a temperature between 10 ° C and 60 ° C, preferably between 40 ° C and 50 ° C, preferably in a vacuum oven. Organic amines and hydroxides can be used as bases.

From the first aspect, the present invention relates to the telmisartan ammonium salt, characterized by the X-ray powder diffraction pattern shown in Figure 1 and a melting interval of 150-158 ° C.

In another aspect, the invention relates to the amorphous choline salt of telmisartan or its solvates or hydrates, characterized by a melting interval of 80-110 ° C and an x-ray powder diffraction pattern shown in Figure 2. We also prepared hydrated forms of the amorphous choline salt of telmisartan labeled with a melting point 65-80 ° C interval and X-ray powder diffraction patterns shown in the figure

3.

In a third aspect, the present invention relates to the telecisartan / tert-butylamine salt and its polymorphs I and II, characterized by a melting interval of 264-268 ° C, respectively. 168-175 ° C and with X-ray powder diffraction patterns shown in Fig. 4 oz. 5.

The characteristic X-ray diffraction pattern of the polymorphic form I /ert.-butylamine salt of telmisartan is listed in Table 1 below, where the degrees are 2-Θ (± 0.2 °), together with the corresponding intensities.

Table 1:

No. Position 2-0 / ° Distance c // nm Rel. int. % 1 5.7 1,559 th most common 4 2 6.6 1,344 th most common 100 3 9.0 0.981 5 4 10.7 0.826 7 5 13.2 0.671 93 6 13,8 0.640 16 7 14.1 0.630 27 8 14.7 0.602 8 9 15.2 0,584 th most common 9 10 16.1 0.550 7 11 16.5 0.537 8 12 17,0 0.522 21 13 17.5 0,508 th most common 19 14 17,8 0.498 14 15 18,1 0,490 th most common 12 16 19.5 0,455 th most common 34 17 19,9 0,446 th most common 10 18 20.3 0,438 th most common 8 19 20.9 0,425 th most common 16 20 21.5 0,413 th most common 17 21 22.1 0.402 17 22 22,8 0.390 6 23 23.5 0,378 17 24 23,8 0,374 10 25 24.6 0.361 7

26 25.6 0.348 6 27 26.1 0.341 7 28 26.6 0,336 th most common 12 29 27,4 0.326 9 30 28,4 0.314 5 31 30.0 0.298 7

The polymorphic Form I /ert.- butylamine salt of telmisartan is preferably characterized by an X-ray powder diffraction pattern with peaks at (6.6, 13.2, 14.1, 17.0, 19.5) ° ± 0.2 °.

The characteristic X-ray diffraction pattern of polymorphic form II / tert.-butylamine salt of telmisartan is listed in the following table 2, where degrees 2 {J (± 0.2 °) are given, together with the corresponding intensities.

Table 2:

No. Position 2-0 / ° Distance <7 / nm Rel. int. % 1 4.5 1,971 th most common 20 2 6,8 1,309 th most common 6 3 7.1 1,247 th most common 4 4 8.4 1,054 th most common 3 5 9.1 0.971 10 6 9,4 0.938 4 7 11,8 0.753 3 8 13.3 0.665 55 9 13.7 0.649 100

10 14.3 0.617 10 11 14.9 0.596 14 12 15.8 0.562 7 13 16.1 0,552 th most common 8 14 16.9 0,526 th most common 9 15 17.2 0,515 th most common 8 16 18.3 0,485 th most common 15 17 19,1 0,465 th most common 45 18 20,0 0,444 th most common 15 19 21.1 0,422 th most common 30 20 21.5 0,414 th most common 15 21 22.1 0.402 13 22 22,9 0.388 8 23 23.4 0,381 8 24 25,4 0.351 14 25 26,0 0.342 10 26 27.5 0,324 th most common 9 27 28,0 0.318 11 28 29.1 0.307 8 29 30.0 0.298 8

The polymorphic Form II tert.-butylamine salt of telmisartan is preferably characterized by an X-ray powder diffraction pattern with peaks at 2-0; (4.5, 13.3, 13.7, 19.1, 21.1) ° ± 0.2 °.

In a fourth aspect, the present invention relates to the meglumine salt of telmisartan (Nmethylglucamine salt of telmisartan), characterized by a melting point of 198-205 ° C and an X-ray powder diffraction pattern shown in Figure 6.

The typical X-ray diffraction pattern of the telmisartan meglumine salt is listed in Table 3 below, where the degrees are 2-0 (± 0.2 °), together with the corresponding intensities.

Table 3

No. Position 2-0 / ° Distance J / nm Rel. int. % 1 5,3 1,655 th most common 9 2 6,9 1,285 th most common 84 3 9.7 0.911 8 4 10.7 0.824 31 5 12.5 0.707 28 6 13.3 0.668 37 7 14.3 0.618 41 8 14.9 0.593 20 9 15.5 0,571 th most common 100 10 16.7 0.530 55 11 17.3 0,513 th most common 29 12 17,9 0,495 th most common 95 13 19,0 0.467 40 14 19,4 0.458 41 15 20,4 0,436 th most common 34 16 21.2 0,419 th most common 17 17 22.1 0,403 73 18 22.5 0.394 53 19 22,8 0.391 52 20 23.4 0.380 81 21 23,8 0,374 40

22 24.1 0.370 27 23 24,9 0.358 36 24 26,0 0,343 22 25 27,4 0.326 33 26 27.5 0,324 th most common 28 27 29.5 .303 14 28 30.0 0.297 17

The meglumine salt of telmisartan is preferably characterized by an X-ray powder diffraction pattern with peaks at 2-0; (6.9, 15.5, 17.9, 22.1, 23.4) ± 0.2 °.

Fifthly, the present invention relates to the ethanolamine salt of telmisartan, characterized by a melting interval of 265-268 ° C.

From the sixth aspect, the present invention relates to the piperazine salt of telmisartan, characterized by a melting interval of 155-160 ° C.

From the seventh point of view, the present invention relates to the diethylamine salt of telmisartan, characterized by a melting interval of 120-135 ° C and an X-ray powder diffraction pattern shown in Figure 7.

The typical X-ray diffraction pattern of the telmisartan diethylamine salt is listed in Table 4 below, where the degrees are 2-0 (± 0.2 °), together with the corresponding intensities.

Table 4

No. Position 2-0 / ° Distance (7 / nm Rel. int. % 1 6.0 1,464 th most common 100 2 7.0 1,271 th most common 23 3 8.3 1,070 th most common 7 4 9.8 0.903 9 5 10.6 0.834 8 6 11.5 0.768 28 7 12,1 0.734 19 8 12.3 0.717 16 9 13,0 0.682 15 10 13,9 0.636 27 11 14.5 0.609 16 12 15.1 0,587 th most common 16 13 15.6 0,569 th most common 18 14 15.9 0,556 th most common 14 15 17,0 0.520 11 16 18,1 0,490 th most common 16 17 18.6 0,478 th most common 13 18 19.7 0,451 th most common 8 19 20.9 0,425 th most common 13 20 21.6 0,412 th most common 17 21 22.5 0,395 16 22 22,9 0.389 18 23 23.5 0,378 17 24 24,8 0.359 14

25 25,4 0.351 11 26 25.9 0.344 11 27 26.7 0.334 10 28 27.1 0.329 8 29 28.7 0.311 9

The diethylamine salt of telmisartan is preferably characterized by an X-ray powder diffraction pattern with peaks at 2-0: (6.0, 7.0, 11.5, 12.1, 13.9) ° ± 0.2 °.

In the eighth aspect, the present invention relates to the tris- (hydroxymethyl) amine salt of telmisartan, characterized by a melting interval of 189-198 ° C and an X-ray powder diffraction pattern shown in Figure 8.

The typical X-ray diffraction pattern of the telmisartan tris- (hydroxymethyl) amine salt is listed in Table 5 below, where the degrees are 2-0 (± 0.2 °), together with the corresponding intensities.

Table 5

No. Position 2-0 / ° Distance ri / nm Rel. int. % 1 5.1 1,737 th most common 15 2 7.2 1,219 th most common 32 3 10.3 0.858 21 4 12,0 0.738 32 5 12.5 0.710 26 6 13,1 0.677 55 7 13.5 0.657 43

8 14,0 0.631 78 9 14.3 0.619 89 10 15.6 0,569 th most common 94 11 16.5 0.537 33 12 16.9 0,524 th most common 60 13 17.5 0,507 th most common 40 14 19,4 0.458 40 15 20,2 0,441 th most common 76 16 20.5 0,433 th most common 77 17 22.3 0.399 41 18 23.4 0,381 44 19 24.1 0.370 100 20 24.6 0.362 78 21 25.7 0.347 42 22 26,2 0.340 49 23 27.1 0.329 37 24 29.0 0.308 48

The Tris- (hydroxymethyl) amine salt of telmisartan is preferably characterized by an X-ray powder diffraction pattern with peaks at 2-0: (14.0, 14.3, 15.6, 20.2, 20.5, 24.1) ° ± 0.2 °.

From the ninth point of view, the present invention relates to the sulfate salt of telmisartan, characterized by a melting interval of 218-227 ° C and an X-ray powder diffraction pattern shown in Figure 9.

The typical X-ray diffraction pattern of the telmisartan sulfate salt is listed in Table 6 below, where the degrees are 2-0 (± 0.2 °), together with the corresponding intensities.

Table 6

No. Position 2-Θ / ⁰ Distance and // nm Rel. int. % 1 5.9 1,491 th most common 19 2 7.2 1,234 th most common 31 3 7,6 1,159 th most common 26 4 8.2 1,074 th most common 10 5 9,4 0.937 13 6 11.7 0.755 45 7 12.3 0.719 41 8 12,8 0.690 76 9 13.6 0.652 72 10 14.3 0.618 21 11 14.9 0,595 39 12 15.1 0,588 th most common 43 13 15.8 0.562 49 14 15.9 0,556 th most common 57 15 16.5 0,536 th most common 93 16 16.9 0,526 th most common 53 17 17,1 0,517 th most common 38 18 17,8 0.497 76 19 18,4 0.483 36 20 18.7 0,474 th most common 44 21 19,1 0,465 th most common 24 22 19.7 0,451 th most common 34 23 20,4 0,436 th most common 27 24 20.9 0,425 th most common 52 25 21.4 0,415 th most common 100

26 21.8 0,407 th most common 66 27 22.5 0,395 71 28 23.4 0.380 69 29 23,8 0,374 44 30 24.6 0.362 81 31 25,4 0.350 44 32 26,8 0.333 49 33 28,0 0.319 32 34 29.1 0.306 40 35 30.0 0.298 21

The telmisartan sulfate salt is preferably characterized by an X-ray powder diffraction pattern with peaks at 2-0 / (12.8, 13.6, 16.5, 17.8, 21.4) ° ± 0.2 °.

In the tenth aspect, the present invention relates to the amorphous L-arginine salt of telmisartan, characterized by a melting interval of 165-173 ° C and an X-ray powder diffraction pattern shown in Figure 10.

In the eleventh aspect, the present invention relates to a new polymorphic form of the telmisartan potassium salt, characterized by a melting interval of 182-194 ° C or. 205-225 ° C and with X-ray powder diffraction patterns shown in Figures 11 and 12.

The typical X-ray diffraction pattern of polymorphic form A of the potassium salt of telmisartan is listed in Table 7 below, where the degrees are 2-Θ (± 0.2 °), together with the corresponding intensities.

Table 7

v St. Position 2-0 / ° Distance ri / nm Rel. int. % 1 3,40 2,600 5 2 5.76 1,533 th most common 100 3 10,34 0.856 7 4 11,57 0.765 28 5 12.51 0.708 12 6 13,55 0.653 35 7 13,73 0.645 28 8 15,77 0.562 14 9 17,41 0,509 th most common 9 10 17,97 0.494 16 11 21.05 0,422 th most common 8 12 22,67 0.392 11 13 23,26 0.382 11 14 24,29 0.366 31 15 25.11 0,355 th most common 14 16 25.49 0.350 13 17 26.03 0.342 13 18 26,79 0.333 11 19 27.63 0.323 17 20 28,21 .316 17 21 29.26 0.305 9

The polymorphic form A of the potassium salt of telmisartan is preferably characterized by an X-ray powder diffraction pattern with peaks at 2-Θ: (5.8, 11.6, 13.6, 13.7, 24.3) ° ± 0.2 °.

The characteristic X-ray diffraction pattern of the polymorphic form B of the potassium salt of telmisartan is listed in Table 8 below, where the degrees are 2-0 (± 0.2 °), together with the corresponding intensities.

Table 8

No. Position 2-0 / ° Distance c? / nm Rel. int. % 1 3.8 2,302 th most common 8 2 5.4 1,623 th most common 88 3 5.9 1,485 th most common 100 4 7.3 1,210 th most common 8 5 10.4 0.852 19 6 10.8 0.820 31 7 11.6 0.760 25 8 12,0 0.738 16 9 13.6 0.651 10 10 15.6 0,569 th most common 15 11 17.6 0,504 th most common 20 12 20,1 0,441 th most common 13 13 22,6 0.393 17 14 24.3 0.367 13 15 25.1 0,355 th most common 13 16 27.6 0,324 th most common 13

The polymorphic form B of the potassium salt of telmisartan is preferably characterized by an X-ray powder diffraction pattern with peaks at 2-0 / (5.4, 5.9, 10.4, 11.6, 17.6) ° ± 0.2 °.

A further embodiment of the present invention is a pharmaceutical composition for administering an effective amount of telmisartan salts in 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 , gliders, lubricants and other excipients, in the treatment procedures mentioned above. For the preparation of a solid oral dosage form, any preparatory process may be used, including a wet granulation process (with water or any other suitable and pharmaceutically acceptable organic solvent), a dry granulation process, and a direct compression process or any other known process.

Finally, the present invention relates to processes for the preparation of telmisartan salt forms.

The invention is further described by the following non-limiting Examples.

EXAMPLES:

I.) Crystallization

Tert-butylamine salt of telmisartan, polymorph I g (2 mmol) of temisartan was added to 13 mL of DMF and 0.21 mL (2 mmol) of tertbutylamine, and the mixture was heated until all telmisartan had dissolved. The solution was cooled to room temperature. The precipitate formed is filtered, washed with water and dried. 0.65 g of tert-butylamine salt of telmisartan is isolated.

M.p .: 264-268 ° C

IR: 2629, 1640, 1540, 1389, 1221, 1006, 851, 745, 658 XRD: crystalline

Tert-butylamine salt of telmisartan, polymorph II g (2 mmol) of telmisartan was added to 10 mL of isopropanol and 0.3 mL (2.9 mmol) of tert, butylamine and the mixture refluxed for 3 h. The solution was cooled to room temperature. The precipitate formed is filtered, washed with water and dried. Isolate 1 g of tert-butylamine salt of telmisartan.

M.p .: 168-175 ° C

IR: 2627, 1635, 1558, 1534, 1387, 1225, 1006, 843, 743

XRD: crystalline

The telmisartan sulfate salt g (2 mmol) of telmisartan was added to 10 mL of water and 0.2 mL (3.6 mmol) of concentrated sulfuric acid and the suspension was stirred at room temperature for 1 h. The suspension was filtered, washed with water and dried at 45 ° C in a vacuum oven. 1.16 g of the sesquihydrate sulfate salt of telmisartan is isolated.

M.p .: 218-227 ° C

IR: 1696, 1566, 1472, 864, 762, 577

XRD: crystalline

II.) Lyophilization and spray drying

The choline salt of telmisartan 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 the components have dissolved. The solution was lyophilized and isolated 1.20 g of the choline salt of telmisartan.

M.p .: 80-110 ° C

IR: 1583, 1450, 1380, 1280, 1088, 953, 848, 745

XRD: amorphous

The choline salt of telmisartan g (2 mmol) of telmisartan is added to 10 mL of water and 0.56 mL (2 mmol) of choline and the suspension is stirred until all the components have dissolved. The solution was lyophilized and isolated 0.84 g of the telmisartan choline salt in hemihydrate form.

M.p .: 65-80 ° C

IR: 1583, 1450, 1381, 1282, 1089, 953, 747

XRD: amorphous

L-arginine salt of telmisartan g (2 mmol) of telmisartan was added to 10 mL of methanol and 0.35 mL (2 mmol) of L-arginine and the suspension warmed until all components were dissolved. The solution was lyophilized and isolated 1.07 g of the telmisartan L-arginine salt in sesquihydrate form.

M.p .: 165-173 ° C

IR: 1635, 1546, 1383, 845, 744, 657 XRD: amorphous

The ammonium salt of telmisartan g (2 mmol) of telmisartan is added to 5 mL of methanol and 0.6 mL of 25% (w / w) NH ₃ and the suspension is stirred until telmisartan is dissolved. 10 mL of water was added and the solution was lyophilized. Isolate 1.0 g of the telmisartan ammonium salt.

M.p .: 150-158 ° C

IR: 1700, 1598, 1457, 1405, 1128, 1089, 1006, 744

XRD: amorphous

III.) Evaporation of solvent and trituration of residue

The meglumine salt of telmisartan g (2 mmol) of telmisartan is added to 10 mL of methanol and 0.39 g (2 mmol) of meglumine and the suspension is heated until all components are dissolved. The solution was cooled to room temperature and the volatiles were evaporated. 10 mL of isopropyl acetate was added and the mixture was stirred at room temperature. The precipitate was filtered and dried for 1 h in a vacuum oven at 40 ° C. 1.2 g of product are isolated.

M.p .: 198-205 ° C

IR: 1603, 1557, 1456, 1384, 1079, 1031, 751 XRD: crystalline

The choline salt of telmisartan g (2 mmol) 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 have dissolved. Evaporate the volatile components, add 10 mL / tert -butylmethyl ether and evaporate the volatile components until a solid product is obtained, which is further dried in a vacuum oven at about 45 ° C for 2 h. 1.26 g of product is isolated.

M.p .: 65-85 ° C

IR: 1583, 1454, 1382, 1281, 1085, 952, 754 XRD: amorphous

L-arginine salt of telmisartan 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. The volatile components were evaporated and 1 mL of isopropanol and 10 mL of isopropyl acetate were added. The precipitate was filtered and dried in a vacuum oven at about 45 ° C for 2 h. We isolate

1.3 g of product as methanol solvate.

M.p .: 162-172 ° C

IR: 1636, 1550, 1457, 1387, 846, 746

XRD: amorphous

The ethanolamine salt of telmisartan g (2 mmol) of telmisartan was added to 8 mL of DMF and 0.12 mL (2 mmol) of ethanolamine and the suspension warmed until all components were dissolved. Evaporate the volatile components and add 5 mL of diethyl ether. The precipitate was filtered and dried in a vacuum oven at about 45 ° C for 2 h. 0.72 g of product is isolated.

M.p .: 265-268 ° C

IR: 1669, 1599, 1382, 1267, 1129, 863, 740 XRD: amorphous

The piperazine salt of telmisartan g (2 mmol) of telmisartan was added to 8 mL of DMF and 0.168 g (2 mmol) of piperazine and the suspension warmed until all components were dissolved. Evaporate the volatile components until a solid product is obtained, which is further dried for 2 hours in a vacuum oven at about 45 ° C. Isolate 1.1 g of product in monohydrate form.

M.p .: 155-160 ° C

IR: 1664, 1457, 1385, 1289, 762, 656

XRD: amorphous

The diethylamine salt of telmisartan 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. The volatile components were evaporated and 5 mL of isopropyl acetate was added. The precipitate was filtered off and dried for 3 h in a vacuum oven at about 45 ° C. 0.83 g of product is isolated.

Melting point: 120-135 ° C

IR: 1560, 1455, 1383, 1282, 1247, 842, 744, 660

XRD: amorphous

Tris- (hydroxymethyl) amine salt of telmisartan g (2 mmol) of telmisartan is added to 10 mL of methanol and 0.23 g (2 mmol) of tris (hydroxymethyl) amine and the suspension is heated until all components are dissolved. The volatile components were evaporated and 5 mL of tert-butyl methyl ether was added.

The precipitate was filtered and dried in a vacuum oven at about 45 ° C for 2 h. 1.19 g of product is isolated.

M.p .: 189-198 ° C

IR: 1550, 1453, 1395, 1056, 863, 747, 670

XRD: amorphous

The potassium salt of telmisartan, polymorph A g (2 mmol) of telmisartan was added to 10 mL of methanol and 1 mL of 2 M KOH and the suspension warmed until all components were dissolved. The solution was cooled, the volatiles were evaporated and 1 mL of isopropanol and 10 mL of isopropyl acetate were added. The precipitate was filtered off and dried for 1.5 h in a vacuum oven at about 45 ° C. 0.84 g of the product is isolated in sesquihydrate form.

M.p .: 182-194 ° C

IR: 1598, 1581, 1448, 1382, 1006, 741

XRD: crystalline

The potassium salt of telmisartan, polymorph B g (2 mmol) of telmisartan was added to 10 mL of methanol and 1 mL of 2 M KOH and the suspension warmed until all components were dissolved. Evaporate the volatile components and add 10 mL of acetone. The mixture was stirred for 1 h at room temperature and the precipitate was filtered and dried for 1 h in a vacuum oven at about 40 ° C. Isolate 1 g of product as monohydrate.

M.p .: 205-225 ° C

IR: 1558, 1458, 1385, 1220, 1006, 760, 741

XRD: crystalline

IV.) Pharmaceutical formulations comprising telmisartan salts

Table 9

Formulation Al WOULD Cl Dl El Fl Gl potassium salt 43 mg 43 mg 43 mg 43 mg 43 mg 43 mg 43 mg telmisartan meglumine (1) or / / / 10 mg 10 mg 10 mg 10 mg KOH (2) or (D d) d) (1) NaOH (3) 4 mg 4 mg 4 mg 4 mg (2) (2) (2) (2) 3 mg 3 mg 3 mg 3 mg (3) (3) (3) (3) poloxamer 188 3 mg / / 3 mg / / / tween 80 / 3 mg / / 3 mg / / sodium / / 3 mg / / 3 mg / laurilsulfate lactose 43 mg 43 mg 43 mg 43 mg 43 mg 43 mg 43 mg microcrystalline 139 mg 139 mg 139 mg 129 mg 129 mg 129 mg 132 mg cellulose (1) (1) d) (1) 135 mg 135 mg 135 mg 138 mg (2) (2) (2) (2) 136 mg 136 mg 136 mg 139 mg (3) (3) (3) (3) anhydrous 5 mg 5 mg 5 mg 5 mg 5 mg 5 mg 5 mg colloidal silicon dioxide

magnesium stearate 7 mg 7 mg 7 mg 7 mg 7 mg 7 mg 7 mg total 240 mg 240 mg 240 mg 240 mg 240 mg 240 mg 240 mg

In Dl-Gl formulations, the amount of microcrystalline cellulose varies depending on the base used in the formulation.

Table 10

Formulation A2 B2 C2 D2 E2 F2 G2 tributylamine 45 mg 45 mg 45 mg 45 mg 45 mg 45 mg 45 mg salt of telmisartan meglumine (1) or / / / 10 mg 10 mg 10 mg 10 mg KOH (2) or d) (1) (1) (1) NaOH (3) 4 mg 4 mg 4 mg 4 mg (2) (2) (2) (2) 3 mg 3 mg 3 mg 3 mg (3) (3) (3) (3) poloxamer 188 3 mg / / 3 mg / / / tween 80 / 3 mg / / 3 mg / / sodium / / 3 mg / / 3 mg / laurilsulfate lactose 43 mg 43 mg 43 mg 43 mg 43 mg 43 mg 43 mg microcrystalline 137 mg 137 mg 137 127 mg 127 mg 127 mg 130 mg cellulose mg (1) (D (1) (1) 133 mg 133 mg 133 mg 136 mg (2) (2) (2) (2) 134 mg 134 mg 134 mg 137 mg (3) (3) (3) (3)

anhydrous colloidal silicon dioxide 5 mg 5 mg 5 mg 5 mg 5 mg 5 mg 5 mg magnesium stearate 7 mg 7 mg 7 mg 7 mg 7 mg 7 mg 7 mg total 240 mg 240 mg 240 mg 240 mg 240 mg 240 mg 240 mg

In D2-G2 formulations, the amount of microcrystalline cellulose varies depending on the base used in the formulation.

Table 11

Formulation A3 B3 C3 D3 E3 F3 G3 meglumine salt 54 mg 54 mg 54 mg 54 mg 54 mg 54 mg 54 mg telmisartan meglumine (1) or / / / 10 mg 10 mg 10 mg 10 mg KOH (2) or (1) (1) (1) (1) NaOH (3) 4 mg 4 mg 4 mg 4 mg (2) (2) (2) (2) 3 mg 3 mg 3 mg 3 mg (3) (3) (3) (3) poloxamer 188 3 mg / / 3 mg / / / tween 80 / 3 mg / / 3 mg / / sodium / / 3 mg / / 3 mg / laurilsulfate lactose 43 mg 43 mg 43 mg 43 mg 43 mg 43 mg 43 mg

microcrystalline cellulose 128 mg 128 mg 128 mg 118 mg (1) 124 mg (2) 125 mg (3) 118 mg (1) 124 mg (2) 125 mg (3) 118 mg (1) 124 mg (2) 125 mg (3) 121 mg (1) 127 mg (2) 128 mg (3) anhydrous colloidal silicon dioxide 5 mg 5 mg 5 mg 5 mg 5 mg 5 mg 5 mg magnesium stearate 7 mg 7 mg 7 mg 7 mg 7 mg 7 mg 7 mg total 240 mg 240 mg 240 mg 240 mg 240 mg 240 mg 240 mg

In D3-G3 formulations, the amount of microcrystalline cellulose varies depending on the base used in the formulation.

Claims (34)

Patent claims An ammonium salt of telmisartan or a hydrate or solvate thereof. 2. The choline salt of telmisartan or its hydrate or solvate. 3. The tert.-butylamine salt of telmisartan or its hydrate or solvate. 4. The polymorph Form I of the tert.-butylamine salt of telmisartan or its hydrate or solvate according to claim 3 with an X-ray diffraction pattern containing the following peaks 2-0, measured using CuKa radiation: (6,6, 13,2, 14, 1, 17.0, 19.5) ° ± 0.2 °. The polymorphic Form I tert.-butylamine salt of telmisartan or its hydrate or solvate according to claims 3 and 4 with an X-ray diffraction pattern containing the following 2-Θ peaks measured using CuKa radiation: (5,7, 6,6, 9.0, 10.7, 13.2, 13.8, 14.1, 14.7, 15.2, 16.1, 16.5, 17.0, 17.5, 17.8, 18, 1, 19.5, 19.9, 20.3, 20.9, 21.5, 22.1, 22.8, 23.5, 23.8, 24.6, 25.6, 26.1, 26.6, 27.4, 28.4, 30.0) ± 0.2 °. 6. Polymorphic form II of the tert-butylamine salt of telmisartan or its hydrate or solvate according to claim 3, with an X-ray diffraction pattern containing the following peaks 2-0, measured using CuKa radiation: (4,5, 13,3, 13, 7, 19.1, 21.1) ° ± 0.2 °. 7. The polymorphic form II of the tert-butylamine salt of telmisartan or its hydrate or solvate according to claims 3 and 4 with an X-ray diffraction pattern containing the following peaks 2-0, measured using CuKa radiation: (4,5, 6,8, 7.1, 8.4, 9.1, 9.4, 11.8, 13.3, 13.7, 14.3, 14.9, 15.8, 16.1, 16.9, 17.2, 18.3, 19.1, 20.0, 21.1, 21.5, 22.1, 22.9, 23.4, 25.4, 26.0, 27.5, 28.0, 29.1, 30.0) ± 0.2 °. 8. Meglumine salt of telmisartan or its hydrate or solvate. The crystalline form of the meglumine salt of telmisartan or its hydrate or solvate according to claim 8, with an X-ray diffraction pattern containing the following peaks 2-0, measured using CuKa radiation: (6,9, 15,5, 17,9, 22, 1, 23.4) ° ± 0.2 °. The crystalline form of the meglumine salt of telmisartan or its hydrate or solvate according to claim 8 or 9, by X-ray diffraction pattern containing the following peaks 2-0, measured using CuKa radiation: (5,3, 6,9, 9,7, 10.7, 12.5, 13.3, 14.3, 14.9, 15.5, 16.7, 17.3, 17.9, 19.0, 19.4, 20.4, 21.2, 22.1, 22.5, 22.8, 23.4, 23, 8, 24.1, 24.9, 26.0, 27.4, 27.5, 29.5, 30.0) ± 0.2 °. 11. Telmisartan ethanolamine salt or hydrate or solvate thereof. 12. The piperazine salt of telmisartan or its hydrate or solvate. 13. The diethylamine salt of telmisartan or its hydrate or solvate. The crystalline form of the telmisartan diethylamine salt or hydrate or solvate thereof according to claim 13, with an x-ray diffraction pattern containing the following peaks 2θ, measured using CuKa radiation: (6.0, 7.0, 11.5, 12.1, 13.9) ± 0.2 °. The crystalline form of the telmisartan diethylamine salt or hydrate or solvate thereof according to claim 13 or 14 with an X-ray diffraction pattern containing the following peaks 2-0, measured using CuKa radiation: (6.0, 7.0, 8.3, 9.8, 10.6, 11.5, 12.1, 12.3, 13.0, 13.9, 14.5, 15.1, 15.6, 15.9, 17.0, 18, 1, 18.6, 19.7, 20.9, 21.6, 22.5, 22.9, 23.5, 24.8, 25.4, 25.9, 26.7, 27.1, 28.7) ± 0.2 °. 16. Tris- (hydroxymethyl) amine salt of telmisartan or a hydrate or solvate thereof. 17. The crystalline form of the tris- (hydroxymethyl) amine salt of telmisartan or its hydrate or solvate according to claim 16, with an X-ray diffraction pattern containing the following peaks 2-0, measured using CuKa radiation: (14,0, 14,3, 15 , 6, 20.2, 20.5, 24.1) ° ± 0.2 °. 18. The crystalline form of the tris- (hydroxymethyl) amine salt of telmisartan or its hydrate or solvate according to claim 16 or 17 with an X-ray diffraction pattern containing the following peaks 2-0, measured using CuKa radiation: (5,1, 7,2 , 10.3, 12.0, 12.5, 13.1, 13.5, 14.0, 14.3, 15.6, 16.5, 16.9, 17.5, 19.4, 20 , 2, 20.5, 22.3, 23.4, 24.1, 24.6, 25.7, 26.2, 27.1, 29.0) ° ± 0.2 °. 19. The telmisartan sulfate salt or hydrate or solvate thereof. 20. The crystalline form of the telmisartan sulfate salt or hydrate or solvate thereof according to claim 19, with an X-ray diffraction pattern containing the following peaks 2-0, measured using CuKa radiation: (12,8, 13,6, 16,5, 17, 8, 21.4) ° ± 0.2 °. 21. The crystalline form of the telmisartan sulfate salt or hydrate or solvate thereof according to claim 19 or 20 with an X-ray diffraction pattern containing the following peaks 2-0, measured using CuKa radiation: (5.9, 7.2, 7.6, 8.2, 9.4, 11.7, 12.3, 12.8, 13.6, 14.3, 14.9, 15.1, 15.8, 15.9, 16.5, 16.9, 17.1, 17.8, 18.4, 18.7, 19.1, 19.7, 20.4, 20.9, 21.4, 21.8, 22.5, 23.4, 23.8, 24.6, 25.4, 26.8, 28.0, 29.1, 30.0) ° ± 0.2 °. 22. Telmisartan L-arginine salt or hydrate or solvate thereof. 23. A process for the preparation of telmisartan salts according to claims 1-18 and claim 22, comprising the steps of: i) dissolving a mixture of telmisartan or a salt of telmisartan with an organic or inorganic base in a polar solvent at a temperature ranging from room temperature to the reflux temperature of the solvent used; ii) optionally, the use of activated carbon to purify the active ingredient or mixture of the active ingredient with an organic or inorganic base, and filter it in hot water; iii) cooling the solution to a temperature between -10 ° C and 30 ° C, preferably to room temperature; iv) filtering the precipitate and drying the product at a temperature between 10 ° C and 60 ° C, preferably between 40 ° C and 50 ° C. Process for the preparation of the telmisartan sulfate salt according to claim 23, characterized in that the polar solvent in which the telmisartan or telmisartan salt with an organic or inorganic base is dissolved, DMF, DMA, DMSO, alcohol (eg methanol, ethanol, isopropanol) , acetone, acetonitrile or H ₂ O, or mixtures thereof. 25. A process for the preparation of the acid addition salts of telmisartan, comprising the steps of: i) suspending a mixture of telmisartan salts or a mixture of telmisartan or telmisartan salts with organic or inorganic acid in a polar solvent at a temperature ranging from room temperature to the reflux temperature of the solvent; ii) cooling the suspension to a temperature between -10 ° C and 30 ° C, preferably to room temperature; iii) filtering the suspension and drying the product at a temperature between 10 ° C and 60 ° C, preferably between 40 ° C and 50 ° C. 26. A process for the preparation of telmisartan salt according to claim 25, characterized in that the polar solvent in which the telmisartan or telmisartan salt with organic or inorganic acid, DMF, DMA, DMSO, is an alcohol (eg methanol, ethanol, isopropanol), acetone, acetonitrile or H ₂ O, or mixtures thereof. 27. A process for the preparation of telmisartan salts according to claims 1-18 and 22, comprising the steps of: i) dissolving telmisartan salts or mixtures of telmisartan or telmisartan salts with an organic or inorganic base in a polar solvent at a temperature from room temperature to the reflux temperature of the solvent; ii) optionally, the use of activated carbon to purify the active ingredient or mixture of the active ingredient with an organic or inorganic base, and filter it in hot water; iii) freeze-drying or spray-drying the solution. 28. A process for the preparation of telmisartan salt according to claim 27, characterized in that the polar solvent in which the telmisartan or telmisartan salt with an organic or inorganic base is dissolved is DMF, DMA, DMSO, alcohol (eg methanol, ethanol, isopropanol), acetone, acetonitrile or H ₂ O, or mixtures thereof. A process for the preparation of telmisartan salts according to claim 27, characterized in that the solution is spray dried at a temperature between 20 ° C and 100 ° C. 30. A process for the preparation of telmisartan salts according to claims 1-18 and 22, comprising the steps of: i) dissolving a mixture of telmisartan or a salt of telmisartan with an organic or inorganic base in a polar solvent at a temperature ranging from room temperature to the reflux temperature of the solvent used; ii) optionally, the use of activated carbon to purify the active ingredient or mixture of the active ingredient with an organic or inorganic base, and filter it in hot water; iii) cooling the solution to a temperature between -10 ° C and 30 ° C, preferably to room temperature; iv) evaporation of the solvent, preferably at a temperature between 20 ° C and 100 ° C under reduced pressure; v) suspending the residue in an organic solvent and filtering and drying the product at a temperature between 10 ° C and 60 ° C, preferably between 40 ° C and 50 ° C. 31. A process for the preparation of telmisartan salt according to claim 30, characterized in that the polar solvent in which the telmisartan or telmisartan salt with an organic or inorganic base is dissolved, DMF, DMA, DMSO, alcohol (eg methanol, ethanol, isopropanol), acetone, acetonitrile or H ₂ O, or mixtures thereof. A process for the preparation of telmisartan salts according to claim 30, characterized in that the organic solvent in step c) is an alcohol (e.g. methanol, ethanol, isopropanol), an ester (e.g. methyl acetate, ethyl acetate, isopropyl acetate, propyl acetate, butyl acetate, isobutyl acetate, (tert -butyl acetate), ether (e.g. diethyl ether, diisopropyl ether, tert -butyl methyl ether), acetone or a mixture thereof. Use of the telmisartan salt of claims 1-22 as a medicament. A pharmaceutical composition comprising the salts of telmisartan according to claims 1-22.