WO2011110876A1 - Novel salts for the manufacture of pharmaceutical compositions - Google Patents
Novel salts for the manufacture of pharmaceutical compositions Download PDFInfo
- Publication number
- WO2011110876A1 WO2011110876A1 PCT/HU2011/000014 HU2011000014W WO2011110876A1 WO 2011110876 A1 WO2011110876 A1 WO 2011110876A1 HU 2011000014 W HU2011000014 W HU 2011000014W WO 2011110876 A1 WO2011110876 A1 WO 2011110876A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- dabigatran etexilate
- formula
- powder diffraction
- ray powder
- diffraction pattern
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 17
- 238000004519 manufacturing process Methods 0.000 title claims description 14
- 150000003839 salts Chemical class 0.000 title abstract description 33
- KSGXQBZTULBEEQ-UHFFFAOYSA-N dabigatran etexilate Chemical class C1=CC(C(N)=NC(=O)OCCCCCC)=CC=C1NCC1=NC2=CC(C(=O)N(CCC(=O)OCC)C=3N=CC=CC=3)=CC=C2N1C KSGXQBZTULBEEQ-UHFFFAOYSA-N 0.000 claims abstract description 242
- 229960000288 dabigatran etexilate Drugs 0.000 claims abstract description 234
- 238000000034 method Methods 0.000 claims abstract description 53
- 239000000203 mixture Substances 0.000 claims description 174
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 97
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 56
- 239000012453 solvate Substances 0.000 claims description 48
- 239000002798 polar solvent Substances 0.000 claims description 43
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 42
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 37
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical class OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 36
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 36
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 33
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- VCSZKSHWUBFOOE-UHFFFAOYSA-N dioxidanium;sulfate Chemical compound O.O.OS(O)(=O)=O VCSZKSHWUBFOOE-UHFFFAOYSA-N 0.000 claims description 13
- 239000004480 active ingredient Substances 0.000 claims description 12
- FWFGVMYFCODZRD-UHFFFAOYSA-N oxidanium;hydrogen sulfate Chemical compound O.OS(O)(=O)=O FWFGVMYFCODZRD-UHFFFAOYSA-N 0.000 claims description 12
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- 239000007858 starting material Substances 0.000 description 11
- -1 Form I Chemical class 0.000 description 10
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- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
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- QAGYKUNXZHXKMR-HKWSIXNMSA-N nelfinavir Chemical compound CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-HKWSIXNMSA-N 0.000 description 2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Definitions
- Novel salts lor the manufacture of pharmaceutical compositions
- the object of the present invention is to provide novel salts of dabigatran etexilate, polymorphic forms, aixhydrates, hydrates, solvates thereof and a process for the preparation of the novel dabigatran etexilate salts.
- the present invention further relates to pharmaceutical formulations containing the novel salts of dabigatran etexilate and the use thereof for the prevention and treatment of postoperative deep vein thrombosis and stroke.
- the object of the present invention is to provide novel and morphologically uniform polymorphs of salts of dabigatran etexilate formed with phosphoric acid, sulfuric acid, maleic acid, methansulfonic acid, oxalic acid, hydrochloric acid and p-toulenesulfonic acid, a process for preparing thereof, pharmaceutical compositions containing thereof and the use thereof for the prevention and treatment of postoperative deep vein thrombosis and stroke.
- Dabigatran etexilate was first described in EP 966 454 B l by Hauel et al. According to Example 1 13 of said patent specification dabigatran etexilate of the formula 1 1 is prepared in an analogous manner to the process described in Example 90 by reacting l -methyl-2-[N-(4- amidino-pheny])-aminomethyl]-5-benzirnidazol-carbonate-N-(2-pyridyl)-A )' -[2-(ethoxy- carbonyl)-ethyl]-amid hydrochloride and hexyl chloroformate. The thus-formed base is characterized by thin layer chomatography and mass spectrometry. No information is provided in the description relating to the crystallographic properties of the dabigatran etexilate base
- salts of dabigatran etexilate are described, such as the hydrochloride, citrate, tartarate, malonate, maleate and salicilate salts. These salts are not characterized by powder X-ray diffraction patterns, only by differential scanning calorimetry curves. The melting points ranked in order are as follows: 135 °C, 170 °C, 160 °C, 100 °C, 120 °C, 1 55
- WO 2006/131491 polymorphic forms of the dabigatran etexilate base are described.
- the polymorphic forms obtained by crystallization are characterized by X-ray powder diffraction patterns, differential scanning calorimetry curves and thermogravimetric measurements data.
- WO 2008/043759 further dabigatran etexilate salts and polymorphic forms thereof are described, such as two polymorfs (I and II) of the salt formed with phosphoric acid, two polymorfs (III and IV) of the salt formed with fumaric acid, three polymorfs (I, II and V) of the salt formed with oxalic acid, three polymorfs (II, V and VI) of the salt formed with hydrogen chloride and four polymorfs (I, V, VI and VII) of the salt formed with p- toluenesulfonic acid.
- the polymorphic forms are characterized by X-ray powder diffraction pattern.
- Form IV of the salt formed with fumaric acid and four Forms (I, V, VI and VII) of the salt formed with p-toluenesulfonic acid are characterized by differential scanning calorimetry curves, too.
- two further anhydrous forms and three solvates of the dabigatran etexilate base are described.
- the anhydrous forms II and IV, the monohydrate forms I and I I and the nitrobenzene solvate form I are characterized by X-ray powder diffraction pattern and differential scanning calorimetry curves
- the objects of the present invention are the novel salts of dabigatran etexilate and polymorphic forms thereof and the process for the preparation thereof.
- the present invention further relates to pharmaceutical formulations containing the novel salts of dabigatran etexilate and the use thereof for the prevention and treatment of postoperative deep vein thrombosis and stroke.
- the dabigatran-etexilate salts of the present invention are as follows: t phosphoric acid salt of dabigatran etexilate (1 : 1 ) (form III) of the formula 1
- the preparation of a morphologically uniform product is important also from technological point of view considering that the polymorphic forms possess different processing (filtering, drying, dissolving and tabletting) properties. Furthermore, it is very important from economical point of view that the process is suitable for an industrial scale application, can be reproduced easily and results in a morphologically uniform product.
- the aim of the present invention was to provide morphological uniform salts of dabigatran etexilate, which meet the pharmaceutical requirements regarding the physical-chemical properties and stability, and which can be produced in a reproducible manner even in industrial scale.
- An object of the present invention is the phosphoric acid salt of dabigatran etexilate (1 : 1 ) (form III) of the formula 1.
- Figure 1 shows the X-ray powder diffraction pattern of the phosphoric acid salt and Table 1 shows its characteristic powder diffraction peaks.
- Sample non-powder, measured and stored at room temperature.
- the phosphoric acid salt of dabigatran etexilate (1 : 1 ) (form III) of the fomiula 1 of the present invention has the following most characteristic powder diffraction peaks: 2 ⁇ 0,2° 2 ⁇ ): 3.620: 7,320; 10,620; 18,480; 22,620; 26, 180.
- Another object of the present invention is the fumaric acid salt of dabigatran etexilate ( 1 : 1 ) (form V) of the formula 2.
- Figure 2 shows the X-ray powder diffraction pattern of the fumaric acid salt and Table 2 shows its characteristic powder diffraction peaks.
- the fumaric acid salt of dabigatran etexilate (1 : 1 ) (form V) of the formula 2 of the present invention has the following most characteristic powder diffraction peaks:20 ( ⁇ 0,2° 2 ⁇ ):.4,280; 7,460; 15,700; 20.500; 21 ,540; 24,640.
- Yet another object of the present invention is the sulfuric acid salt of dabigatran etexilate ( 1 : 1 ) (form I) of the formula 3.
- Figure 3 shows the X-ray powder diffraction pattern of the sulfuric acid salt and Table 3 shows its characteristic pow r der diffraction peaks.
- the sulfuric acid salt of dabigatran etexilate (1 : 1 ) (form I) of the formula 3 of the present invention has the following most characteristic powder diffraction peaks: 2 ⁇ ( ⁇ 0,2° 2 ⁇ ): 3.560; 7, 120; 10,700; 17,960; 25,320.
- a further object of the present invention is the sulfuric acid dihydrate salt of dabigatran etexilate (1 : 1 :2) (form I) of the formula 4.
- Figure 4 shows the X-ray powder diffraction pattern of the sulfuric acid dihydrate salt and Table 4 show s its characteristic powder diffraction peaks.
- the sulfuric acid dihydrate salt of dabigatran etexilate (1 : 1 :2) (form I) of the formula 4 of the present invention has the following most characteristic pow ler diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 3 ,840; 7,740; 9,700; 12,540; 14,740; 15,440; 17,840; 20,660; 21 ,600.
- a still further object of the present invention is the sulfuric acid monohydrate salt of dabigatran etexilate ( 1 : 1 : 1 ) (form I) of the formula 5.
- Figure 5 shows the X-ray powder diffraction pattern of the sulfuric acid monohydrate salt and T able 5 shows its characteristic powder diffraction peaks.
- the sulfuric acid monohydrate salt of dabigatran etexilate ( 1 : 1 : 1) (form 1) of the formula 5 of the present invention has the following most characteristic powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 4,880; 6,980: 10,000; 14,620; 15,580; 19,400: 25, 1 00: 26,800.
- ⁇ still further object of the present invention is the maleic acid salt of dabigatran etexilate ( 1 : 1 ) (form II) of the formula 6.
- Figure 6 shows the X-ray powder diffraction pattern of the maleic acid salt and Table 6 shows its characteristic powder diffraction peaks.
- the measurement conditions were t e same as ment one a ove.
- the maieic acid salt of dabigatran etexilate (1 : 1 ) (form II) of the formula 6 of the present invention has the following most characteristic powder diffraction peaks:20 ( ⁇ 0,2° 2 ⁇ ): 4.240; 7,600; 10,700; 12,740; 17,540; 20,600; 21 ,960; 24,640.
- a still further object of the present invention is the oxalic acid salt of dabigatran etexilate (1 : 1 ) (form VI) of the formula 7.
- Figure 7 shows the X-ray powder diffraction pattern of the oxalic acid salt and Table 7 shows its characteristic powder diffraction peaks.
- the oxa!ic acid salt of dabigatran etexilate (1 : 1) (form VI) of the formula 7 of the present invention has the following most characteristic powder diffraction peaks:20 ( ⁇ 0,2° 2 ⁇ ): 3.700; 7,460; 9,840; 10,920; 17,960; 19,980; 20,760; 21 ,740: 24,140.
- a still further object of the present invention is the hydrochloride salt of dabigatran etexilate (1 : 1 ) (form VII) of the formula 8.
- Figure 8 shows the X-ray powder diffraction pattern of the hvdrochloric acid salt and Table 8 shows its characteristic powder diffraction peaks.
- the hydrochloride salt of dabigatran etexilate (1 : 1 ) (form VII) of the formula 8 of the present invention has the following most characteristic powder diffraction peaks: 2 ⁇ ( ⁇ 0,2° 2 ⁇ ): 4.740: 8.960: 1 1.680: 16.740; 21 .040; 23,620; 24.580.
- Yet still another object of the present invention is the hydrochloride salt of dabigatran etexilate ( 1 : 1 ) (form VIII) of the formula 8.
- Figure 9 show s the X-ray powder diffraction pattern of the hydrochloric acid salt and Table 9 shows its characteristic powder diffraction peaks.
- the hydrochloride salt of dabigatran etexilate ( 1 : 1 ) (form VIII) of the formula 8 of the present invention has the following most characteristic powder diffraction peaks: 2 ⁇ ( ⁇ 0,2° 2 ⁇ ): 3,860; 12,280; 19,480; 21 , 160; 21 ,400: 22,480; 22,840; 23 ;420.
- a still further object of the present invention is the hydrochloride salt of dabigatran etexilate ( 1 : 1 ) (form IX) of the formula 8.
- Figure 10 shows the X-ray powder diffraction pattern of the hydrochloric acid salt and Table 10 shows its characteristic powder diffraction peaks.
- the hydrochloride salt of dabigatran etexilate (1 : 1 ) (form IX) of the formula 8 of the present invention has the following most characteristic powder diffraction peaks: 2 ⁇ ( ⁇ 0,2° 2 ⁇ ): 4,720; 8,080; 15,340; 23,420.
- the hydrochloride salt of dabigatran etexilate (1 : 1 ) (form IX) of the formula 8 of the present invention has the following most characteristic powder diffraction peaks: 2 ⁇ ( ⁇ 0,2° 2 ⁇ ): 4,720; 8,080; 9,540; 10,480; 1 1 ,320; 15,340; 18,460; 19, 140; 23,420.
- a still further object of the present invention is the hydrochloride salt of dabigatran etexilate ( 1 : 1 ) (form X) of the formula 8.
- Figure 1 1 shows the X-ray powder diffraction pattern of the hydrochloric acid salt and Table 1 shows its characteristic powder diffraction peaks.
- Table 1 1 Position of the peaks and relative intensity (>9 %)
- the hydrochloride salt of dabigatran etexilate ( 1 : 1 ) (form X) of the formula 8 of the present invention has the following most characteristic powder diffraction peaks: 2 ⁇ ( ⁇ 0,2° 2 ⁇ ): 4.940; 7,400; 8.940; 16.680; 18,920; 20,640; 20,980; 23,440.
- a still further object of the present invention is the p-toluenesulfonic acid salt of dabigatran etexilate ( 1 : 1) (form VIII) of the formula 9.
- Figure 12 shows the X-ray powder diffraction pattern of the p-toluenesulfonic acid salt and Table 12 shows its characteristic powder diffraction peaks.
- the p-toluenesulfonic acid salt of dabigatran etexilate (1 : 1) (form VIIl) of the formula 9 of the present invention has the following most characteristic powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ) : 3,360; 10.240: 1 1 , 360; 20,860; 24,680; 27,060.
- a still further object of the present invention is the p-toluenesulfonic acid salt of dabigatran etexilate (1 : 1 ) (form IX) of the formula 9.
- Figure 33 show's the X-ray powder diffraction pattern of the p-toluenesulfonic acid salt and Table 13 shows its characteristic powder diffraction peaks.
- the p-toluenesulfonic acid salt of dabigatran etexilate ( 1 : 1 ) (form IX) of the formula 9of the present invention has the following most characteristic powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 4, 160; 8,400; 13.260; 17,560; 19,560; 21 ,060; 25,340.
- Yet another object of the present invention is the mesylate salt of dabigatran etexilate (1 : 1) (form IV) of the formula 10.
- Figure 14 shows the X-ray powder diffraction pattern of the mesylate salt and Table 10 shows its characteristic powder diffraction peaks.
- the mesylate salt of dabieatran etexilate ( 1 : 1 ) (form IV) of the formula 10 of the present invention has the following most characteristic powder diffraction peaks: 2 ⁇ ( ⁇ 0,2° 2 ⁇ ): 4,460; 9,320; 1 1 ,060; 13,560; 18,740; 20,440; 20,980; 22,360; 26,840.
- Still another object of the present invention is the phosphoric acid salt of dabigatran etexilate ( 1 : 1 ) (form III) of the formula 1 . It has been found that the X-ray powder diffraction partem of the Form III of the phosphoric acid salt is significantly different from that of the known phosphoric acid salt of dabigatran etexilate, such as Form I and II disclosed in WO2008/043759.
- the known forms are prepared by adding phosphoric acid into a solvent mixture of acetone and THF and by recrystallization of the crude product obtained by evaporation. Form I is recrystallized from isopropyl-acetate, Form II is recrystallized from 1 ,4-dioxane.
- the phosphoric acid salt of dabigatran etexilate ( 1 : 1 ) (form III) of the formula 1 is prepared by dissolving a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof in the mixture of phosphoric acid and a polar solvent or a mixture of polar solvents, preferably at 50- 120 °C.
- the solution is stirred at this temperature until complete dissolution, cooled gradually, preferably in 2- 1 0 hours and crystallized at 0-25 °C for 8-24 hours.
- a polymorphic or amorphous phosphoric acid salt of dabigatran etexilate, solvate, hydrate or mixtures thereof are suspended or dissolved in a polar solvent or a mixture of polar solvents, preferably at 50- 120 °C. Then the solution is cooled gradually, preferably in 2- 10 hours and crystallized at 0-25 °C for 8-24 hours. If necessary, seed crystals are added to the mixture..
- the known method wherein the crystalline product is dissolved and obtained again in crystalline form.
- the process wherein a known polymorphic or amorphous compound is dissolved and a different polymorphic form of the crystalline compound is obtained by recrystallization.
- the term "recrystallization” implies the process, wherein a known polymorphic or amorphous compound is suspended in an appropriate solvent (the solubility is 0, 1 - 100 mg/ ' ml at the recrystallization temperature) at a temperature required for the change of the polymorphic form.
- an appropriate solvent the solubility is 0, 1 - 100 mg/ ' ml at the recrystallization temperature
- a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof or a polymorphic or amorphous phosphoric acid salt of dabigatran etexilate or mixtures thereof are suspended in N,N-dimethyl-formamide while warming at a temperature of 50- 120 °C, and 50- 100 w/w%, preferably 85 w/w% phosphoric acid is added to the mixture. After complete dissolution the solution is cooled and crystall ized at 0-25 °C. If necessary, seed crystals are added to the mixture. The precipitated product is filtered, washed and dried. When applying the phosphoric acid salt of dabigatran etexilate as starting compound further addition of phosphoric acid is unnecessary.
- a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof are suspended in N .N-dimethyl- formamide. 1 .0 equivalent 85 w/w% phosphoric acid is added to the suspension and it is dissolved in 0,5-2 hours at 60-70 °C. The solution is cooled to 25 °C in two hours and crystallized for 10- 16 hours at 0-5 °C. The precipitated product is filtered, washed and dried.
- a further object of the present invention is the fumaric acid salt of dabigatran etexilate ( 1 : 1 ) (form V) of the formula 2. It has been found that the X-ray powder diffraction pattern of the Form III of the phosphoric acid salt is significantly different from that of the known fumaric acid salt of dabigatran etexilate, such as Form III and IV disclosed in WO2008/043759.
- the known forms are prepared by adding fumaric acid into a solvent mixture of acetone and THF and by recrystallization of the crude product obtained by evaporation. Form III is recrystallized from teit. -butyl -methyl-ether, Form IV is recrystallized from water.
- the fumaric acid salt of dabigatran etexilate (1 : 1 ) (form V) of the formula 2 is prepared by dissolving a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof and fumaric acid in a polar solvent or a mixture of polar solvents, preferably at 50- 1 10 °C. The solution is stirred at this temperature until complete dissolution, cooled gradually, preferably in 2- 10 hours and crystallized at 0-25 °C for 8-24 hours.
- the polymorphic or amorphous fumaric acid salt of dabigatran etexilate ( 1 : 1 ), solvate, hydrate or mixtures thereof are suspended or dissolved in a polar solvent or a mixture of polar solvents, preferably at 50- 1 10 °C.
- the solution is cooled gradually, preferably in 2- 10 hours at room temperature and crystallized at 0-50 °C for 8-24 hours. If necessary, seed crystals are added to the mixture.
- a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof or a polymorphic fumaric acid salt of dabigatran etexilate or mixtures thereof are suspended in an aliphatic alcohol at 50- 1 10 °C, and then fumaric acid is added to the mixture. The solution or suspension is cooled and crystallized. If necessary seed crystals are added to the mixture.. The precipitated product is filtered off and dried. When applying the fumaric acid salt of dabigatran etexilate as starting compound further addition of phosphoric acid is unnecessary.
- a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof are suspended in ethanol and fumaric acid is added to the suspension. While warming at 60-65 °C the mixture is dissolved in 0,5-2 hours and the solution is cooled in 2 hours at 20-25 °C. It is crystallized for 10- 16 hours at 0-5 °C. The precipitated product is filtered off, washed and dried.
- Further objecst of the present invention are the sulfuric acid salt of dabigatran etexilate ( 1 : 1 ) (form 1) of the formula 3 , the sulfuric acid dihydrate salt of dabigatran etexilate ( 1 : 1 :2) (form I) of the formula 4 and the sulfuric acid monohydrate salt of dabigatran etexilate ( 1 : 1 : 1 ) (form I) of the formula 5.
- the above-mentioned salts have not been described yet.
- a further object of the present invention is a process for preparing the sulfuric acid salt of dabigatran etexilate (1 : 1 ) (form 1) of the formula 3, the sulfuric acid dihydrate salt of dabigatran etexilate (1 : 1 :2) (form I) of the formula 4 and the sulfuric acid monohydrate salt of dabigatran etexilate (1 : 1 : 1) (form I) of the formula 5
- the sulfuric acid salt, monohydrate and dihydrate forms of dabigatran etexilate are prepared by dissolving a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof in the mixture of sulfuric acid and a polar solvent or a mixture of polar solvents, preferably at 25-1 10 °C.
- the solution is stirred at this temperature until complete dissolution and - if necessray - it is evaporated to half volume.
- the solution is cooled and crystallized at 0-25 °C for
- a polymorphic or amorphous sulfuric acid salt of dabigatran etexilate solvate, hydrate or mixtures thereof are suspended or dissolved in a polar solvent or a mixture of polar solvents, preferably at 25- 1 10 °C. The solution is stirred at this temperature and crystallized at 0-50 °C for 8-24 hours. If necessray, seed crystals are added to the mixture .
- the anhydrous sulfuric acid salt of dabigatran etexilate is ecrystallized to a hydrous form by adding 1-5 w/w% water to the solvent mixture.
- a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof or a polymorphic sulfuric acid salt of dabigatran etexilate or mixtures thereof are suspended or dissolved in the solvent mixture of an aliphatic alcohol and an aliphatic esther in case of sulfuric acid salt of formula 3, in a solvent mixture of an aliphatic ether and a ketone in case of sulfuric acid dihydrate ( 1 : 1 :2) o the formula 4 and in a nitrile-type solvent or solvent mixture in case of the sulfuric acid monohydrate (1 : 1 : 1 ) of the formula 5 while warming at room temperature and then adding 10-50 w/w% sulfuric acid to the mixture.
- the solution is crystallized at 0-25 °C. If necessarry, seed crystals are added to the mixture. The precipitated product is filtered off, washed and dried. When the sulfuric acid salt of dabigatran etexilate is used as starting compound, further addition of sulfuric acid is unnecessary.
- a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof or a polymorphic sulfuric acid salt of dabigatran etexilate or mixtures thereof is dissolved at 40-45 °C in the mixture of ethanol and ethyl-acetate in case of sulfuric acid salt of formula 3, in a mixture of THF and acetone in case of sulfuric acid dihydrate ( 1 : 1 :2) of the formula 4 and in acetonitrile in case of the sulfuric acid monohydrate ( 1 : 1 : 1 ) of the formula 5, 1 ,0 equivalent 50 w w% sulfuric acid is added to the solution ( 1 0 w/w% sulfuric acid is used in case of the sulfuric acid dihydrate (1 : 1 :2) of the formula 4).
- the solution is crystallized at 0-5 °C in case of the compounds of the formulae 3 and IV, and at 20-25 °C in case of the compound of
- An object of the present invention is the maleic acid salt of dabigatran etexiiate ( 1 : 1 ) (form II) of the formula 6. It has been found that the maleic acid of the present invention has a melting point (according to the maximum value of DCS curve, 1 16 °C) different from that of the known maleic acid salt described in WO2006/1 14415 ( 120 °C).
- the known compound is prepared by dissolving the base in ethyl acetate and adding maleic acid to the solvent.. The solution is crystallized at room temperature for 3 hours. The precipitated product is filtered off .
- a further object of the present invention is a process for preparing the maleic acid salt of dabigatran etexiiate (1 : 1 ) (form II) of the formula 6.
- the maleic acid salt of dabigatran etexiiate (1 : 1 ) (form II) of the formula 6 is prepared by dissolving a polymorphic or amorphous dabigatran etexiiate base, solvate, hydrate or mixtures thereof in the mixture of maleic acid and a polar solvent or a mixture of polar solvents, preferably at 50-1 10 °C. The solution is stirred at this temperature until complete dissolution and the solution is cooled and crystallized at (-25)-25 °C for 8-96 hours.
- a polymorphic or amorphous maleic acid salt of dabigatran etexiiate, solvate, hydrate or mixtures thereof are suspended or dissolved in a polar solvent or a mixture of polar solvents, preferably at 50- 1 10 °C.
- the solution is cooled and crystallized at (-20)-0 °C for 8-96 hours. If necessary, seed crystals are added to the mixture.
- a polymorphic or amorphous dabigatran etexiiate base, soh ate, hydrate or mixtures thereof or a polymorphic or amorphous maleic acid salt of dabigatran etexiiate or mixtures thereof are suspended in ⁇ , ⁇ -dimethyl-formamide at 50- 1 20 °C and maleic acid is added to the mixture. The solution is cooled and crystallized at (-20)-0 °C. If necessary, seed crystals are added to the mixture. The precipitated product is filtered, washed and dried. When the maleic acid salt of dabigatran etexiiate is used as starting compound further addition of maleic acid is unnecessary.
- a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof are suspended in N,N-dimethyl- formamide. 1 ,0 equivalent of maleic acid is added to the suspension and it is dissolved at 50- 55 °C. The solution is cooled and crystallized for 10- 16 hours at 0-5 °C at (-20)-(- 15) °C. The precipitated product is filtered off, washed and dried.
- a further object of the present invention is the oxalic acid salt of dabigatran etexilate (1 : 1) (form VI) of the formula 7. It has been found that the X-ray powder diffraction pattern of the Form VI of the oxalic acid salt is significantly different from that of the known oxalic acid salts of dabigatran etexilate, such as Form I, II and V disclosed in WO2008/043759.
- the known forms are prepared by adding oxalic acid into a solvent mixture of acetone and THF and by recrystallization of the crude product obtained by evaporation. Form I is recrystallized from acetonitrile, Form II is recrystallized from isopropyl acetate and Form V is recrystallized from isopropyl alcohol.
- a still iiirther object of the present invention is a process for preparing the oxalic acid salt of dabigatran etexilate (1 : 1) (form VI) of the formula 7.
- the oxalic acid salt of dabigatran etexilate (1 : 1 ) (form VI) of the formula 7 is prepared by dissolving a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof in the mixture of oxalic acid and polar solvent or polar solvent mixture, preferably at 25- 1 10 °C.
- the solution is evaporated gradually in 1 -7 days at room temperature.
- the residue is dissolved in an aliphatic polyol at 25- 1 10 °C and the solution is cooled and crystallized at 0-25 °C for 8-24 hours.
- a polymorphic or amorphous oxalic acid salt of dabigatran etexilate, solvate, hydrate or mixtures thereof are suspended or dissolved in a polar solvent or polar solvent mixture, preferably at 25-1 10 °C.
- the solution is cooled to 0-25 oC and crystallized at this temperature for 8-24 hours. If necessary, seed crystals are added to the mixture.
- a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof or a polymorphic or amorphous oxalic acid salt of dabigatran etexilate or mixtures thereof are suspended in an aliphatic ether or keton or mixtures thereof at 25- 1 10 °C and oxalic acid is added to the mixture.
- the solution is evaporated gradually in 1 -7 days at room temperature.
- the residue is dissolved in an aliphatic glycol at 25- 1 10 °C and the solution is cooled and crystallized at 0-25 °C for 8-24 hours.
- the oxalic acid salt of dabigatran etexilate is used as starting compound further addition of oxal ic acid is unnecessary.
- a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof are dissolved in the mixture of THF and acetone at 20-25 °C. Then 1 ,0 equivalent of oxalic acid is added to the solution. It is evaporated gradually in 3 days at 20-25 °C. The residue is dissolved in diethylene glycol at 50-55 °C and the solution is cooled and crystallized at 0-5 °C for 1 5-20 hours. The precipitated product is filtered off, washed and dried.
- a further object of the present invention is the hydrochloride salt of dabigatran etexilate (3 : 1 ) (forms VII, VIII, IX and X) of the formula 8. . It has been found that (he X-ray powder diffraction patterns of the Forms VII, VIII, IX and X of the hydrochloride salt are different from that of the known hydrochloride salt of dabigatran etexilate, such as Forms II, V and VI disclosed in WO2008/043759.
- the melting point of the polymorphic forms of the present invention are as follows: Form VII: 152 °C, Form VIII: 160 °C, Form IX: 181 °C and Form X: 1 4 °C, which were determined by the peak maximum of the DCS curve. These melting points differ form the melting point of the Form I (1 35 °C), disclosed in WO2006/1 14415.
- the known Form I is prepared by adding hydrochloric acid into ethanol
- Forms II, V and VI are prepared by adding hydrochloric acid into a solvent mixture of acetone and THF and by recrystallization of the crude product obtained by evaporation.
- Form I is prepared by suspending it in ethyl-acetate and acetone.
- Form II is recrystallized from 1 ,2- dimethoxy-ethane
- Form V is recrystallized from isopropyl acetate
- Form VI is recrystallized from THF.
- a further object of the present invention is a process for preparing the hydrochloride salts of dabigatran etexilate ( 1 : 1 ) (forms VII, VIII, IX and X) of the formula 8.
- Form VII of the hydrochloride acid salt is prepared by dissolving a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof in a polar solvent or a mixture of polar solvents at 25- 1 10 °C and after dissolving hydrochloric acid is added to the solution. After cooling it is crystallized at 0-25 °C for 8-48 hours.
- a polymorphic or amorphous hydrochloric acid salt of dabigatran etexilate solvate, hydrate or mixtures thereof are suspended or dissolved in a polar solvent or a mixture of polar solvents at 25- 1 10 °C. It is crystallized at 0-25 °C for 8-48 hours. If necessary, seed crystals are added to the mixture.
- a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof or a polymorphic or amorphous hydrochloric acid salt of dabigatran etexilate or mixtures thereof are suspended or dissolved in an aliphatic alcohol or a mixture of aliphatic alcohol and aliphatic esther at 25- 1 10 °C and a mixture of anhydrous or hydrous hydrochloric acid and aliphatic alcohol or gaseous hydrochloric acid is added to the mixture.
- the solution is cooled and crystallized at 0-20 °C for 8-48 hours. If necessarry, seed crystals are added to the mixture.
- the precipitated product is filtered off, washed and dried.
- hydrochloric acid salt of dabigatran etexilate is used as starting compound further addition of hydrochloric acid is unnecessary.
- a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof is dissolved in the mixture of isopropyl alcohol and ethyl-acetate at 40-45 °C in the presence of hydrochloric acid.
- the solution is crystallized at 0-5 °C for 2 days.
- the precipitated product is filtered off, washed and dried.
- the Form VIII of hydrochloride acid salt is prepared by dissolving a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof in a polar solvent or a mixture of polar solvents at 25-1 10 °C and after dissolving hydrochloric acid is added to the solution. After cooling it is crystallized at 20-60 °C for 8-24 hours.
- a polymorphic or amorphous hydrochloric acid salt of dabigatran etexilate, solvate, hydrate or mixtures thereof are suspended or dissolved in a polar solvent or a mixture of polar solvents at 25- 1 10 °C. it is crystallized at 20-60 °C for 8-24 hours, if necessary, seed crystals are added to the mixture.
- a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof or a polymorphic or amorphous hydrochloric acid salt of dabigatran etexilate or mixtures thereof are suspended or dissolved in an aliphatic alcohol or a mixture of an aliphatic alcohol and an aliphatic esther at 25-1 10 °C and the mixture of anhydrous or hydrous hydrochloric acid and aliphatic alcohol or gaseous hydrochloric acid is added to the mixture.
- the solution is cooled and crystallized at 20-60 °C for 8-24 hours. If necessarry, seed crystals are added to the mixture.
- the precipitated product is filtered off, washed and dried.
- hydrochloric acid salt of dabigatran etexilate is used as starting compound further addition of hydrochloric acid is unnecessary.
- a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof is dissolved in the mixture of isopropyl alcohol and ethyl-acetate at 40-45 °C in the presence of hydrochloric acid containing isopropyl alcohol.
- the solution is crystallized at 20-25 °C for 15-20 hours.
- the precipitated product is filtered off, washed and dried.
- the Form IX of hydrochloride acid salt is prepared by dissolving a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof in a polar solvent or a mixture of polar solvents at 25-1 10 °C and after dissolving hydrochloric acid is added to the solution. After cooling it is crystallized at 0-25 °C for 8- 1 68 hours.
- a polymorphic or amorphous hydrochloric acid salt of dabigatran etexilate, solvate, hydrate or mixtures thereof are suspended or dissolved in a polar solvent or a mixture of polar solvents at 25- 1 10 °C. It is crystallized at 0-25 °C for 8-168 hours. If necessary, seed crystals are added to the mixture.
- a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof or a polymorphic or amorphous hydrochloric acid salt of dabigatran etexilate or a mixtures thereof are suspended or dissolved in an aliphatic alcohol or a mixture thereof or aliphatic keton at 25- 1 10 °C and mixture of anhydrous or hydrous hydrochloric acid and aliphatic alcohol or gaseous hydrochloric acid is added to the mixture.
- the solution is cooled and crystallized at 0-25 °C for 8- 168 hours. If necessarry, seed crystals are added to the mixture.
- the precipitated product is filtered off, washed and dried.
- hydrochloric acid salt of dabigatran etexilate is used as starting compound further addition of hydrochloric acid is unnecessary.
- the aliphatic alcohol used by the preparation of the Form IX of dabigatran etexilate hydrochloride salt could be selected from C l -4 alcohols, preferably methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol or t-butanol, most preferably ethanol.
- Aliphatic keton could be selected from C I -3 chain or ring ketons, preferably methyl-ethyl keton, acetone, cyclohexanon, methyl-cyclohexanon, most preferably acetone.
- a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof is dissolved in ethanol at 40-45 °C in the presence of isopropyl alcohol containing hydrochloric acid.
- the solution is crystallized at 0-5 °C for 1 -7 days.
- the precipitated product is filtered off, washed and dried.
- a polymorphic or amorphous hydrochloric acid salt of dabigatran etexilate, solvate, hydrate or mixtures thereof is dissolved in ethanol at 40-45 °C. It is crystallized at 0-5 °C for 1 -7 days. The precipitated product is filtered off, washed and dried.
- a polymorphic or amorphous hydrochloric acid salt of dabigatran etexilate, solvate, hydrate or mixtures thereof are suspended in acetone at 20-30 °C and Form IX hydrochloride salt is added to the mixture. It is crystallized at 20-30 °C for 8-48 hours.
- the Form X of hydrochloride acid salt is prepared by dissolving a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof is dissolved in a polar solvent or a mixture of polar solvents at 25-1 10 °C and after dissolving hydrochloric acid is added to the solution and if necessray the solution is concentrated. After addition of aliphatic keton and cooling it, the solution is crystallized at 0- 25 °C for 0.1 -24 hours.
- a polymorphic or amorphous hydrochloric acid salt of dabigatran etexilate, solvate, hydrate or mixtures thereof are suspended or dissolved in a polar solvent or a mixture of polar solvents at 25- 1 10 °C. It is crystallized at 20-60 °C for 8-24 hours. If necessary, seed crystals are added to the mixture.
- a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof or a polymorphic or amorphous hydrochloric acid salt of dabigatran etexilate or mixtures thereof are suspended or dissolved in an aliphatic alcohol or mixtures thereof at 25- 1 10 °C and mixture of anhydrous or hydrous hydrochloric acid and an aliphatic alcohol or gaseous hydrochloric acid is added to the mixture and the thus obtained mixture is partially evaporated and an aliphatic keton is added to the mixture.
- the solution is cooled and crystallized at 0-25 °C for 0, 1 -24 hours. If necessary, seed crystals are added to the mixture.
- the precipitated product is filtered off, washed and dried.
- a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof is dissolved in the ethanol at room temperature and hydrochloric acid containing isopropyl alcohol is dropwise added to the solution. After 1 hour long stirring the solution is evaporated to the half part and while stirring acetone is added to it. The obtained suspension is cooled to the temperature of 0-5 °C and after 10 minutes it is filtered off and dried.
- Another object of the present invention is the p-toluenesulfonic acid salt of dabigatran etexilate ( 1 : 1 ) (form VIII) of the formula 9. It has been found that the X-ray powder diffraction pattern of the Form VIII of the p-toluenesulfonic acid salt is significantly different from that of the known p-toluenesulfonic acid salts of dabigatran etexilate, such as Form 1, V, VI and VII disclosed in WO2008/043759.
- the known forms are prepared by adding p- toluenesulfonic acid into the mixture of acetone and THF and by recrvstallization of the crude product obtained by evaporation. Form I is recrystallized from ethyl-acetate, Form V is recrystallized from butane-2-one, Form VI is recrystallized from acetone, Form VII is recrystallized from propyl- acetate.
- a further object of the present invention is a process for preparation of p-toluenesulfonic acid salt of dabigatran etexilate (1 : 1) (form VIII) of the formula 9.
- the p-toluenesulfonic acid salt of dabigatran etexilate ( 1 : 1 ) (form VIII) of the formula 9 is prepared by dissolving a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof in the mixture of p- toluenesulfonic acid and aromatic solvent or a mixture of aromatic solvents, preferably at 25- 1 1 0 °C. The solution is cooled and crystallized at room temperature for 1 -24 hours
- a polymorphic or amorphous p-toluenesulfonic acid salt of dabigatran etexilate, solvate, hydrate or mixtures thereof are suspended in a polyol solvent at 25-1 10 °C.
- the solution is crystallized at 20-25 °C for 1 -24 hours. If necessary, seed crystals are added to the mixture.
- a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof or a polymorphic p-toluenesulfonic acid salt of dabigatran etexilate or mixtures thereof is dissolved or suspended in an aromatic solvent at 25-1 10 °C and p-toluenesulfonic acid is added to the mixture.
- the solution is crystallized at 20-25 °C for 1-24 hours. If necessary, seed crystals are added to the mixture.
- the precipitated product is filtered off, washed and dried.
- a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof is dissolved in toluene at the temperature of 60-70 °C and 1 ,0 equivalent p-toluenesulfonic acid is added to the solution.
- the solution is cooled and crystallized for 5 hours at room temperature.
- the precipitated product is filtered off, washed and dried.
- Yet another object of the present invention is the mesylate salt of dabigatran etexilate (1 : 1 ) (form IV) of the formula 10. It has been found that the X-ray powder diffraction pattern of the Form (IV) of the mesylate salt is significantly different from that of the known phosphoric acid salts of dabigatran etexilate, such as Form I, II and hemihydrate disclosed in US20050234104.
- the Form I and II are crystallized from the base dissolved in acetone by adding methansulfonic acid at 30-35 °C, and 40-45 °C.
- the hemihydrate compound is prepared form its base dissolved in the mixture of water, ethanol and ethyl-acetate by adding mesylate acid at 35-40 °C. 4
- a further object of the present invention is a process for preparing mesylate salt of dabigatran etexilate (1 : 1 ) (form IV) of the formula 10.
- the mesylate salt of dabigatran etexilate (1 : 1 ) (form IV) of the formula 10 is prepared by dissolving a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof in the mixture of methanesulfonic acid and a polar solvent or a mixture of polar solvents, preferably at 25-1 10 °C. The solution is cooled and crystallized at 0-25 °C for 0.5-24 hours.
- a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof is dissolved in aliphatic esther or the mixture of an aliphatic esther and a polar solvent at 25- 1 10 °C in the presence of methane sulfonic acid.
- the solution is cooled and crystallized at 0-25 °C for 0,5-24 hours
- a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof is dissolved in ethyl-acetate at 60-65 °C and 0,95 equivalent of methansulfonic acid dissolved in ethyl-acetate are added to the solution.
- the solution is cooled and crystallized for 0,5 hours at 0-5 °C.
- the precipitated product is filtered off, washed and dried.
- novel polymorphs of the present invention possess better stability properties compared to the stability of known polymorphs during different storage conditions.
- the Form II methanesulfonic acid salt ( 1 : 1 ) of the formula 10 is prepared according to US 20050234104. Comparative studies of the thermal stability of the Form II methanesulfonic acid salt (1 : 1 ) and Form IX hydrochloric acid salt (1 : 1 ) have been performed. The samples were stored at a temperature of 40 °C under relative humidity of 75 per cent in closed condition and at 70 °C in closed and opened conditions for 6 weeks.
- compositions of the samples were determined by HPLC at the starting time and after 6 weeks, the amounts of the impurities above 0,03 area% were added together and the resulted cumulated impurity values were compared to the cumulated impurity values measured at the starting time according to the following formula:
- a forced stability study (stress test) of the selected dabigatran etexilate salts has also been performed, wherein the samples were stored at 100 °C for 24 hours and the change in the amount of the cumulative impurity (AZimpurity) and the most characteristic degradation product, namely the compound of formula 12 ( ⁇ 12) were determined by LC/MS.
- a ⁇ impurity was calculated with the above formula, and the value of ⁇ 12 was calculated in a similar manner with the following formula:
- Harmful alkyl-mesylates can be formed in the presence of alcohols, especially ethyl alcohol in some procedural steps or technological operations thereof during the manufacturing process, e.g. in case of ethanol ethyl mesylate can be formed.
- Theirs mutagenic or carcinogenic effect is known form the literature: Thompson, L. H., Mutant Isolation. Meth. Enzymol. 1979, 58, 308-322; Alderson, T., Chemically Induced Delayed Germinal Mutation in Drosophila. Nature 1965, 207, 164-167; Jenkins, J.
- Viracept (nelfinavir) was withdrawn from the market in 2007 by Hoffmann-La Roche because it was contaminated by ethyl mesylate due to unsuitable technological process.
- European Medicine Agency published a notice, in which the EMA calls upon the pharmaceutical industry to perform tight control and further investigations in connection with compositions containing mesylate, tosylate and besylate salts (EMEA/44714/2008).
- Aurther object of the present invention is the use of the above-mentioned morphologically uniform polymorphs of dabigatran etexilate salts formed with phosphoric acid, sulfuric acid, maleic acid, methansulfonic acid, oxalic acid, hydrochloric acid and p-toulenesulfonic acid as pharmaceuticals.
- the present invention further relates to the pharmaceutical compositions, which contain as active ingredient a therapeutically effective amount of the above-mentioned dabigatran- etexilate together with one or more pharmaceutically acceptable excipients.
- the invention relates to the use thereof for the prevention and treatment of postoperative deep vein thrombosis and stroke.
- compositions of the present invention are administered preferably orally or parenterally.
- the orally administered compositions are e.g. tablets, capsules, dragees, solutions, elixirs, suspensions or emulsions.
- parenteral administration intravenous or intramuscular injections are used.
- compositions of the present invention may contain known pharmaceutical carriers and/or excipients generally applied in the pharmaceutical industry.
- Carriers may e.g. magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, targacant, methyl cellulose, sodium methyl cellulose, low melting point wax, cocoa butter etc.
- carrier is not necessary, if the capsule is composed of the carrier.
- Orally administered compositions further can be lozenges and bags. Solid formulations, such as tablets, powders, capsules, pills, bags and lozenges are preferably used for oral administration.
- the suppositories contain low melting point waxes (e.g. mixture of glycerides of fatty acid or cocoa butter).
- the wax is melted and the active ingredient is homogenized in it.
- the melted mixture is poured into a mould of an appropriate size and form and allowed to harden while cooling.
- the tablets are prepared by mixing the active ingredient with the appropriate excipients in the required ratio and tablets with appropriate size and form are pressed.
- Powders are prepared by mixing the fine pulverized active ingredient and carriers.
- Liquid solutions are suspensions and emulsions, which can provide, if necessary, a sustained release of the active ingredient.
- Solutions containing water or aqueous propylene glycols are preferably used.
- Liquid compositions for parenteral use can be prepared as solutions containing aqueous polyethylene glycols
- Aqueous solutions for oral administration are prepared by dissolving the active ingredient in water and by adding the required colorants, flavors, stabilizers and gelling agents to the solution.
- the active ingredient is suspended in water, in the presence of a thick liquid (e.g. natural or synthetic resins, rosins, methyl cellulose, sodium carboximethyl cellulose or any other suspending agent).
- a thick liquid e.g. natural or synthetic resins, rosins, methyl cellulose, sodium carboximethyl cellulose or any other suspending agent.
- Liquid compositions are solutions, suspensions or emulsions, which contains colorants, flavors, preservatives, buffers, artificial or natural sweeteners, dispersants, gelling agents etc. in addition to the active ingredient.
- the pharmaceutical compositions of the present invention are preferably prepared as unit doses.
- the unit doses contain the required amount of the active ingredient.
- the unit doses may be marketed in packagings containing separated amounts of the compositions (e.g. packed tablets, capsules, powders in ampoules or containers). Capsules, tablets, bags, lozenges and several single dose containing packages are unit doses as well.
- a further object of the present invention is a process for preparing the above-mentioned pharmaceutical compositions by mixing the phosphoric acid salt of dabigatran etexilate ( 1 : 1 ) (form III) of the formula 1 , or .the fumaric acid salt of dabigatran etexilate (1 : 1 ) (form V) of the formula 2, or the sulfuric acid salt of dabigatran etexilate (1 : 1 ) (form I) of the formula 3 , or the sulfuric acid dihydrate salt of dabigatran etexilate (1 : 1 :2) (form I) of the formula 4, or the sulfuric acid monohydrate salt of dabigatran etexilate (1 : 1 : 1 ) (form I) of the formula 5, or the maleic acid salt of dabigatran etexilate ( 1 : 1 ) (form II) of the formula 6, or the oxalic acid salt of dabigatran etexilate ( 1 : 1 ) (form VI) of
- compositions of the present invention are prepared by known methods of the pharmaceutical industry.
- compositions of the present invention may contain further pharmaceutically active ingredients compatible with the compounds of the formulae 1 to 10 or mixture thereof.
- a further object of the present invention is the use of the novel crystalline polymorphs of the compounds of the formulae 1 to 10 as a pharmaceutically active ingredients.
- Another object of the present invention is the use of the novel crystalline polymorphs of the compounds of the formulae 1 to 10 for the preparation of pharmaceutical compositions which prolong the thrombin time, inhibit thrombin and related serine proteases.
- a further object of the present invention is the use of the novel crystalline polymorphs of the compounds of the formulae 1 to 10 for prolongation of the thrombin time and/or the inhibition of thrombin and related serine proteases by administering a therapeutically acceptable dose of a compound of the formulae 1 to 10 to patients.
- the advantage of the present invention is that the novel crystalline compounds of the formulae 1 to 10 are morphologically uniform. Therefore the dissolution time, biological release, chemical stability and processing (filtering, drying, dissolving and tabletting) properties of the compounds are reproducible.
- the novel polymorphs of the present invention can he produced in a reproducible manner on industrial scale, too
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Abstract
The present invention relates to novel polymorphous salts of dabigatran etexilate of the formula 11 and process for the preparation thereof.
Description
Novel salts lor the manufacture of pharmaceutical compositions
Filed of the invention
Ethyl 3-[(2- { [4-(hexyloxycarbonylamino-imino-m
l H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate (INN: dabigatran etexilate) of the formula
is an oral anticoagulant which possesses direct thrombin inhibitor effect.
The object of the present invention is to provide novel salts of dabigatran etexilate, polymorphic forms, aixhydrates, hydrates, solvates thereof and a process for the preparation of the novel dabigatran etexilate salts. The present invention further relates to pharmaceutical formulations containing the novel salts of dabigatran etexilate and the use thereof for the prevention and treatment of postoperative deep vein thrombosis and stroke.
In more detail, the object of the present invention is to provide novel and morphologically uniform polymorphs of salts of dabigatran etexilate formed with phosphoric acid, sulfuric acid, maleic acid, methansulfonic acid, oxalic acid, hydrochloric acid and p-toulenesulfonic acid, a process for preparing thereof, pharmaceutical compositions containing thereof and the use thereof for the prevention and treatment of postoperative deep vein thrombosis and stroke.
The state of the art
Dabigatran etexilate was first described in EP 966 454 B l by Hauel et al. According to Example 1 13 of said patent specification dabigatran etexilate of the formula 1 1 is prepared in an analogous manner to the process described in Example 90 by reacting l -methyl-2-[N-(4- amidino-pheny])-aminomethyl]-5-benzirnidazol-carbonate-N-(2-pyridyl)-A)'-[2-(ethoxy- carbonyl)-ethyl]-amid hydrochloride and hexyl chloroformate. The thus-formed base is
characterized by thin layer chomatography and mass spectrometry. No information is provided in the description relating to the crystallographic properties of the dabigatran etexilate base
The same process described in the above patent is disclosed in a publication of Hauel et al. (J Med. Chem. 2002, 45, 1757-1766), wherein the dabigatran etexilate base is characterized by melting point ( 128- 129 °C) and Ή-NMR.
Three polymorphic forms of dabigatran etexilate mesylate are described in WO2005/028468. The polymorphic forms obtained from the base by crystallization (Form I, II and hemihydrate) are characterized by X-ray powder diffraction pattern and differential scanning calorimetry curves.
In WO2006/1 14415 6 salts of dabigatran etexilate are described, such as the hydrochloride, citrate, tartarate, malonate, maleate and salicilate salts. These salts are not characterized by powder X-ray diffraction patterns, only by differential scanning calorimetry curves. The melting points ranked in order are as follows: 135 °C, 170 °C, 160 °C, 100 °C, 120 °C, 1 55
°C
In WO 2006/131491 3 polymorphic forms of the dabigatran etexilate base are described. The polymorphic forms obtained by crystallization are characterized by X-ray powder diffraction patterns, differential scanning calorimetry curves and thermogravimetric measurements data.
In WO 2008/043759 further dabigatran etexilate salts and polymorphic forms thereof are described, such as two polymorfs (I and II) of the salt formed with phosphoric acid, two polymorfs (III and IV) of the salt formed with fumaric acid, three polymorfs (I, II and V) of the salt formed with oxalic acid, three polymorfs (II, V and VI) of the salt formed with hydrogen chloride and four polymorfs (I, V, VI and VII) of the salt formed with p- toluenesulfonic acid. The polymorphic forms are characterized by X-ray powder diffraction pattern. Furthermore, Form IV of the salt formed with fumaric acid and four Forms (I, V, VI and VII) of the salt formed with p-toluenesulfonic acid are characterized by differential scanning calorimetry curves, too.
In WO 2008/059029 two further anhydrous forms and three solvates of the dabigatran etexilate base are described. The anhydrous forms II and IV, the monohydrate forms I and I I and the nitrobenzene solvate form I are characterized by X-ray powder diffraction pattern and differential scanning calorimetry curves
Summary of the invention
It has been surprisingly found that several chemically and morphologically stable novel salts of dabigatran etexilate and polymorphic forms thereof could be prepared, in spite of the fact that a lot of salts of dabigatran etexilate and polymorphic forms thereof had already been known. The objects of the present invention are the novel salts of dabigatran etexilate and polymorphic forms thereof and the process for the preparation thereof. The present invention further relates to pharmaceutical formulations containing the novel salts of dabigatran etexilate and the use thereof for the prevention and treatment of postoperative deep vein thrombosis and stroke. The dabigatran-etexilate salts of the present invention are as follows: t phosphoric acid salt of dabigatran etexilate (1 : 1 ) (form III) of the formula 1
the sulfuric acid salt of dabi atran etexilate (1 : 1 ) (form I) of the formula 3
th sulfuric acid monohydrate salt of dabigatran etexilate (1:1:1) (form I) of the formula 5
. the maleic acid salt of dabigatran etexilate (1:1) (form II) of the formula 6
oxalic acid salt of dabigatran etexilate (1:1) (form VI) of the formula 7
t hydrochloride salt of dabigatran etexilate (1:1) (form VII) of the formula 8
the /7-toluenesulfonic acid salt of dabigatran etexilate (1:1) (form VIII) of the formula 9
the / toluenesulfonic acid salt of dabigatran etexilate (1 : 1 ) (form IX) of the formula 9, the mes late salt of dabigatran etexilate (1 : 1 ) (form IV) of the formula 1 0
Detailed description of the invention
Recently a serious demand has emerged in the pharmaceutical industry for a method providing the product in a reproducible manner in a morphologically uniform and pure form in order to meet the strict requirements of the pharmaceutical authorities. It is known that the different polymorphic forms show difference in important characteristics, such as the dissolution time, biological release and chemical stability.
The preparation of a morphologically uniform product is important also from technological point of view considering that the polymorphic forms possess different processing (filtering, drying, dissolving and tabletting) properties. Furthermore, it is very important from economical point of view that the process is suitable for an industrial scale application, can be reproduced easily and results in a morphologically uniform product.
So far no process for the preparation of morphologically uniform salts of dabigatran formed with sulfuric or maleic acid has been described in the literature, and no analytical data (IR spectra. X-ray powder diffraction patterns or single-crystal x-ray diffraction patterns) serving to characterize the crystalline forms have been provided.
The aim of the present invention was to provide morphological uniform salts of dabigatran etexilate, which meet the pharmaceutical requirements regarding the physical-chemical
properties and stability, and which can be produced in a reproducible manner even in industrial scale.
The above aim has been achieved by the novel crystalline forms of the salts of dabigatran etexilate formed with phosphoric, sulfuric, maleic. methansulfonic, oxalic, hydrochloric and p-toulenesulfonic acid and the process for the preparation thereof.
It has been surprisingly found that the above-mentioned novel salts of dabigatran etexilate can be prepared in a new form which is morphologically uniform, and the characteristic powder diffraction pattern and DCS data are different form the data of the known forms of the dabigatran etexilate salts.
An object of the present invention is the phosphoric acid salt of dabigatran etexilate (1 : 1 ) (form III) of the formula 1. Figure 1 shows the X-ray powder diffraction pattern of the phosphoric acid salt and Table 1 shows its characteristic powder diffraction peaks.
Table 1 : Position of the peaks and relative intensity (>3 %)
Apparatus: Rigaku Corporation, Miniflex II. Powder diffractometer
Radiation: Toshiba Λ-20, CuKa, (λ=1 .54059 A), CuKa2 (λ= 1.54439Α)
Voltage: 30 kV
Anode current: 1 5 niA
Accessories: Soller-slit, sample changer
Referent sample: SRRP -432759 silicon powder a=5,430758 A.
Measurement was steady Θ/Θ scan: 4°-50.00° 2Θ.
Step size: 0.02°
Sample: non-powder, measured and stored at room temperature.
The phosphoric acid salt of dabigatran etexilate (1 : 1 ) (form III) of the fomiula 1 of the present invention has the following most characteristic powder diffraction peaks: 2Θ 0,2° 2Θ): 3.620: 7,320; 10,620; 18,480; 22,620; 26, 180.
Another object of the present invention is the fumaric acid salt of dabigatran etexilate ( 1 : 1 ) (form V) of the formula 2. Figure 2 shows the X-ray powder diffraction pattern of the fumaric acid salt and Table 2 shows its characteristic powder diffraction peaks.
Table 2: Position of the peaks and relative intensity (>4 %)
The measurement conditions were the same as mentioned above.
The fumaric acid salt of dabigatran etexilate (1 : 1 ) (form V) of the formula 2 of the present invention has the following most characteristic powder diffraction peaks:20 (±0,2° 2Θ):.4,280; 7,460; 15,700; 20.500; 21 ,540; 24,640.
Yet another object of the present invention is the sulfuric acid salt of dabigatran etexilate ( 1 : 1 ) (form I) of the formula 3. Figure 3 shows the X-ray powder diffraction pattern of the sulfuric acid salt and Table 3 shows its characteristic powrder diffraction peaks.
Table 3: Position of the peaks and relative intensity (>1 %)
The measurement conditions were the same as mentioned above.
The sulfuric acid salt of dabigatran etexilate (1 : 1 ) (form I) of the formula 3 of the present invention has the following most characteristic powder diffraction peaks: 2Θ (±0,2° 2Θ): 3.560; 7, 120; 10,700; 17,960; 25,320.
A further object of the present invention is the sulfuric acid dihydrate salt of dabigatran etexilate (1 : 1 :2) (form I) of the formula 4. Figure 4 shows the X-ray powder diffraction
pattern of the sulfuric acid dihydrate salt and Table 4 show s its characteristic powder diffraction peaks.
Table 4: Position of the peaks and relative intensity (> 1 %)
The measurement conditions were the same as mentioned above.
The sulfuric acid dihydrate salt of dabigatran etexilate (1 : 1 :2) (form I) of the formula 4 of the present invention has the following most characteristic pow ler diffraction peaks: 2Θ (±0.2° 2Θ): 3 ,840; 7,740; 9,700; 12,540; 14,740; 15,440; 17,840; 20,660; 21 ,600.
A still further object of the present invention is the sulfuric acid monohydrate salt of dabigatran etexilate ( 1 : 1 : 1 ) (form I) of the formula 5. Figure 5 shows the X-ray powder diffraction pattern of the sulfuric acid monohydrate salt and T able 5 shows its characteristic powder diffraction peaks.
Table 5 : Position of the peaks and relative intensity (> 1 %)
Peak 2 Θ d (A) Intensity
The measurement conditions were the same as mentioned above.
The sulfuric acid monohydrate salt of dabigatran etexilate ( 1 : 1 : 1) (form 1) of the formula 5 of the present invention has the following most characteristic powder diffraction peaks: 2Θ (±0.2° 2Θ): 4,880; 6,980: 10,000; 14,620; 15,580; 19,400: 25, 1 00: 26,800.
Λ still further object of the present invention is the maleic acid salt of dabigatran etexilate ( 1 : 1 ) (form II) of the formula 6. Figure 6 shows the X-ray powder diffraction pattern of the maleic acid salt and Table 6 shows its characteristic powder diffraction peaks.
Table 6: Position of the peaks and relative intensity (>3 %)
The measurement conditions were t e same as ment one a ove.
The maieic acid salt of dabigatran etexilate (1 : 1 ) (form II) of the formula 6 of the present invention has the following most characteristic powder diffraction peaks:20 (±0,2° 2Θ): 4.240; 7,600; 10,700; 12,740; 17,540; 20,600; 21 ,960; 24,640.
A still further object of the present invention is the oxalic acid salt of dabigatran etexilate (1 : 1 ) (form VI) of the formula 7. Figure 7 shows the X-ray powder diffraction pattern of the oxalic acid salt and Table 7 shows its characteristic powder diffraction peaks.
Table 7: Position of the peaks and relative intensity (>2 %)
The measurement conditions were the same as mentioned above.
The oxa!ic acid salt of dabigatran etexilate (1 : 1) (form VI) of the formula 7 of the present invention has the following most characteristic powder diffraction peaks:20 (±0,2° 2Θ): 3.700; 7,460; 9,840; 10,920; 17,960; 19,980; 20,760; 21 ,740: 24,140.
A still further object of the present invention is the hydrochloride salt of dabigatran etexilate (1 : 1 ) (form VII) of the formula 8. Figure 8 shows the X-ray powder diffraction pattern of the hvdrochloric acid salt and Table 8 shows its characteristic powder diffraction peaks.
Table 8: Position of the peaks and relative intensity (>8 %)
13
11 12. i
The measurement conditions were the same as mentioned above.
The hydrochloride salt of dabigatran etexilate (1 : 1 ) (form VII) of the formula 8 of the present invention has the following most characteristic powder diffraction peaks: 2Θ (±0,2° 2Θ): 4.740: 8.960: 1 1.680: 16.740; 21 .040; 23,620; 24.580.
Yet still another object of the present invention is the hydrochloride salt of dabigatran etexilate ( 1 : 1 ) (form VIII) of the formula 8. Figure 9 show s the X-ray powder diffraction pattern of the hydrochloric acid salt and Table 9 shows its characteristic powder diffraction peaks.
Table 9: Position of the peaks and relative intensity (>8 %)
The measurement conditions were the same as mentioned above.
The hydrochloride salt of dabigatran etexilate ( 1 : 1 ) (form VIII) of the formula 8 of the present invention has the following most characteristic powder diffraction peaks: 2Θ (±0,2° 2Θ): 3,860; 12,280; 19,480; 21 , 160; 21 ,400: 22,480; 22,840; 23 ;420.
A still further object of the present invention is the hydrochloride salt of dabigatran etexilate ( 1 : 1 ) (form IX) of the formula 8. Figure 10 shows the X-ray powder diffraction pattern of the hydrochloric acid salt and Table 10 shows its characteristic powder diffraction peaks.
Table 10: Position of the peaks and relative intensity (>6 %)
The measurement conditions were the same as mentioned above.
The hydrochloride salt of dabigatran etexilate (1 : 1 ) (form IX) of the formula 8 of the present invention has the following most characteristic powder diffraction peaks: 2Θ (±0,2° 2Θ): 4,720; 8,080; 15,340; 23,420.
In more details, the hydrochloride salt of dabigatran etexilate (1 : 1 ) (form IX) of the formula 8 of the present invention has the following most characteristic powder diffraction peaks: 2Θ (±0,2° 2Θ): 4,720; 8,080; 9,540; 10,480; 1 1 ,320; 15,340; 18,460; 19, 140; 23,420.
A still further object of the present invention is the hydrochloride salt of dabigatran etexilate ( 1 : 1 ) (form X) of the formula 8. Figure 1 1 shows the X-ray powder diffraction pattern of the hydrochloric acid salt and Table 1 shows its characteristic powder diffraction peaks.
Table 1 1 : Position of the peaks and relative intensity (>9 %)
The measurement conditions were the same as mentioned above.
The hydrochloride salt of dabigatran etexilate ( 1 : 1 ) (form X) of the formula 8 of the present invention has the following most characteristic powder diffraction peaks: 2Θ (±0,2° 2Θ): 4.940; 7,400; 8.940; 16.680; 18,920; 20,640; 20,980; 23,440.
A still further object of the present invention is the p-toluenesulfonic acid salt of dabigatran etexilate ( 1 : 1) (form VIII) of the formula 9. Figure 12 shows the X-ray powder diffraction pattern of the p-toluenesulfonic acid salt and Table 12 shows its characteristic powder diffraction peaks.
Table 12: Position of the peaks and relative intensity (>2 %)
The measurement conditions were the same as mentioned above.
The p-toluenesulfonic acid salt of dabigatran etexilate (1 : 1) (form VIIl) of the formula 9 of the present invention has the following most characteristic powder diffraction peaks: 2Θ (±0.2° 2Θ) : 3,360; 10.240: 1 1 , 360; 20,860; 24,680; 27,060.
A still further object of the present invention is the p-toluenesulfonic acid salt of dabigatran etexilate (1 : 1 ) (form IX) of the formula 9. Figure 33 show's the X-ray powder diffraction pattern of the p-toluenesulfonic acid salt and Table 13 shows its characteristic powder diffraction peaks.
Table 13 : Position of the peaks and relative intensity (>3 %)
The measurement conditions were the same as mentioned above.
The p-toluenesulfonic acid salt of dabigatran etexilate ( 1 : 1 ) (form IX) of the formula 9of the present invention has the following most characteristic powder diffraction peaks: 2Θ (±0.2° 2Θ): 4, 160; 8,400; 13.260; 17,560; 19,560; 21 ,060; 25,340.
Yet another object of the present invention is the mesylate salt of dabigatran etexilate (1 : 1) (form IV) of the formula 10. Figure 14 shows the X-ray powder diffraction pattern of the mesylate salt and Table 10 shows its characteristic powder diffraction peaks.
Table 14: Position of the peaks and relative intensity (
The measurement conditions were the same as mentioned above.
The mesylate salt of dabieatran etexilate ( 1 : 1 ) (form IV) of the formula 10 of the present invention has the following most characteristic powder diffraction peaks: 2Θ (±0,2° 2Θ): 4,460; 9,320; 1 1 ,060; 13,560; 18,740; 20,440; 20,980; 22,360; 26,840.
Still another object of the present invention is the phosphoric acid salt of dabigatran etexilate ( 1 : 1 ) (form III) of the formula 1 . It has been found that the X-ray powder diffraction partem of the Form III of the phosphoric acid salt is significantly different from that of the known phosphoric acid salt of dabigatran etexilate, such as Form I and II disclosed in WO2008/043759. The known forms are prepared by adding phosphoric acid into a solvent mixture of acetone and THF and by recrystallization of the crude product obtained by evaporation. Form I is recrystallized from isopropyl-acetate, Form II is recrystallized from 1 ,4-dioxane.
According to the present invention the phosphoric acid salt of dabigatran etexilate ( 1 : 1 ) (form III) of the formula 1 is prepared by dissolving a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof in the mixture of phosphoric acid and a polar solvent or a mixture of polar solvents, preferably at 50- 120 °C. The solution is stirred at this temperature until complete dissolution, cooled gradually, preferably in 2- 1 0 hours and crystallized at 0-25 °C for 8-24 hours.
According to another process variant a polymorphic or amorphous phosphoric acid salt of dabigatran etexilate, solvate, hydrate or mixtures thereof are suspended or dissolved in a polar solvent or a mixture of polar solvents, preferably at 50- 120 °C. Then the solution is cooled gradually, preferably in 2- 10 hours and crystallized at 0-25 °C for 8-24 hours. If necessary, seed crystals are added to the mixture..
The term "recristallization" used throughout the present specification implies
the known method, wherein the crystalline product is dissolved and obtained again in crystalline form. Moreover it implies the process, wherein a known polymorphic or amorphous compound is dissolved and a different polymorphic form of the crystalline compound is obtained by recrystallization.
Furthermore, the term "recrystallization" implies the process, wherein a known polymorphic or amorphous compound is suspended in an appropriate solvent (the solubility is 0, 1 - 100 mg/'ml at the recrystallization temperature) at a temperature required for the change of the polymorphic form. During the process sufficient time and the addition of seed crystals (if necessary) are provided in order to induce and/or enhance the precipitation. After filtering the suspension, the process results in a crystalline compound with polymorphic form different from the starting compound.
According to a preferable process variant, a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof or a polymorphic or amorphous phosphoric acid salt of dabigatran etexilate or mixtures thereof are suspended in N,N-dimethyl-formamide while warming at a temperature of 50- 120 °C, and 50- 100 w/w%, preferably 85 w/w% phosphoric acid is added to the mixture. After complete dissolution the solution is cooled and crystall ized at 0-25 °C. If necessary, seed crystals are added to the mixture. The precipitated product is filtered, washed and dried. When applying the phosphoric acid salt of dabigatran etexilate as starting compound further addition of phosphoric acid is unnecessary.
According to a more preferable process variant a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof are suspended in N .N-dimethyl- formamide. 1 .0 equivalent 85 w/w% phosphoric acid is added to the suspension and it is dissolved in 0,5-2 hours at 60-70 °C. The solution is cooled to 25 °C in two hours and crystallized for 10- 16 hours at 0-5 °C. The precipitated product is filtered, washed and dried.
A further object of the present invention is the fumaric acid salt of dabigatran etexilate ( 1 : 1 ) (form V) of the formula 2. It has been found that the X-ray powder diffraction pattern of the Form III of the phosphoric acid salt is significantly different from that of the known fumaric acid salt of dabigatran etexilate, such as Form III and IV disclosed in WO2008/043759. The known forms are prepared by adding fumaric acid into a solvent mixture of acetone and THF and by recrystallization of the crude product obtained by evaporation. Form III is recrystallized from teit. -butyl -methyl-ether, Form IV is recrystallized from water.
According to the present invention the fumaric acid salt of dabigatran etexilate (1 : 1 ) (form V) of the formula 2 is prepared by dissolving a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof and fumaric acid in a polar solvent or a mixture of
polar solvents, preferably at 50- 1 10 °C. The solution is stirred at this temperature until complete dissolution, cooled gradually, preferably in 2- 10 hours and crystallized at 0-25 °C for 8-24 hours.
According to another process variant the polymorphic or amorphous fumaric acid salt of dabigatran etexilate ( 1 : 1 ), solvate, hydrate or mixtures thereof are suspended or dissolved in a polar solvent or a mixture of polar solvents, preferably at 50- 1 10 °C. The solution is cooled gradually, preferably in 2- 10 hours at room temperature and crystallized at 0-50 °C for 8-24 hours. If necessary, seed crystals are added to the mixture.
According to a preferable process variant a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof or a polymorphic fumaric acid salt of dabigatran etexilate or mixtures thereof are suspended in an aliphatic alcohol at 50- 1 10 °C, and then fumaric acid is added to the mixture. The solution or suspension is cooled and crystallized. If necessary seed crystals are added to the mixture.. The precipitated product is filtered off and dried. When applying the fumaric acid salt of dabigatran etexilate as starting compound further addition of phosphoric acid is unnecessary.
According to a more preferable process variant, a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof are suspended in ethanol and fumaric acid is added to the suspension. While warming at 60-65 °C the mixture is dissolved in 0,5-2 hours and the solution is cooled in 2 hours at 20-25 °C. It is crystallized for 10- 16 hours at 0-5 °C. The precipitated product is filtered off, washed and dried.
Further objecst of the present invention are the sulfuric acid salt of dabigatran etexilate ( 1 : 1 ) (form 1) of the formula 3 , the sulfuric acid dihydrate salt of dabigatran etexilate ( 1 : 1 :2) (form I) of the formula 4 and the sulfuric acid monohydrate salt of dabigatran etexilate ( 1 : 1 : 1 ) (form I) of the formula 5. The above-mentioned salts have not been described yet.
A further object of the present invention is a process for preparing the sulfuric acid salt of dabigatran etexilate (1 : 1 ) (form 1) of the formula 3, the sulfuric acid dihydrate salt of dabigatran etexilate (1 : 1 :2) (form I) of the formula 4 and the sulfuric acid monohydrate salt of dabigatran etexilate (1 : 1 : 1) (form I) of the formula 5
According to the present invention the sulfuric acid salt, monohydrate and dihydrate forms of dabigatran etexilate are prepared by dissolving a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof in the mixture of sulfuric acid and a polar solvent or a mixture of polar solvents, preferably at 25-1 10 °C. The solution is stirred at this temperature until complete dissolution and - if necessray - it is evaporated to half volume. The solution is cooled and crystallized at 0-25 °C for 8-24 hours.
According to another process variant a polymorphic or amorphous sulfuric acid salt of dabigatran etexilate. solvate, hydrate or mixtures thereof are suspended or dissolved in a polar solvent or a mixture of polar solvents, preferably at 25- 1 10 °C. The solution is stirred at this temperature and crystallized at 0-50 °C for 8-24 hours. If necessray, seed crystals are added to the mixture . The anhydrous sulfuric acid salt of dabigatran etexilate is ecrystallized to a hydrous form by adding 1-5 w/w% water to the solvent mixture.
According to a preferable process variant, a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof or a polymorphic sulfuric acid salt of dabigatran etexilate or mixtures thereof are suspended or dissolved in the solvent mixture of an aliphatic alcohol and an aliphatic esther in case of sulfuric acid salt of formula 3, in a solvent mixture of an aliphatic ether and a ketone in case of sulfuric acid dihydrate ( 1 : 1 :2) o the formula 4 and in a nitrile-type solvent or solvent mixture in case of the sulfuric acid monohydrate (1 : 1 : 1 ) of the formula 5 while warming at room temperature and then adding 10-50 w/w% sulfuric acid to the mixture. The solution is crystallized at 0-25 °C. If necessarry, seed crystals are added to the mixture. The precipitated product is filtered off, washed and dried. When the sulfuric acid salt of dabigatran etexilate is used as starting compound, further addition of sulfuric acid is unnecessary.
According to a more preferable process variant, a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof or a polymorphic sulfuric acid salt of dabigatran etexilate or mixtures thereof is dissolved at 40-45 °C in the mixture of ethanol and ethyl-acetate in case of sulfuric acid salt of formula 3, in a mixture of THF and acetone in case of sulfuric acid dihydrate ( 1 : 1 :2) of the formula 4 and in acetonitrile in case of the sulfuric acid monohydrate ( 1 : 1 : 1 ) of the formula 5, 1 ,0 equivalent 50 w w% sulfuric acid is added to the solution ( 1 0 w/w% sulfuric acid is used in case of the sulfuric acid dihydrate (1 : 1 :2) of the formula 4). The solution is crystallized at 0-5 °C in case of the compounds of
the formulae 3 and IV, and at 20-25 °C in case of the compound of the formula 5. The precipitated product is filtered off, washed and dried.
An object of the present invention is the maleic acid salt of dabigatran etexiiate ( 1 : 1 ) (form II) of the formula 6. It has been found that the maleic acid of the present invention has a melting point (according to the maximum value of DCS curve, 1 16 °C) different from that of the known maleic acid salt described in WO2006/1 14415 ( 120 °C). The known compound is prepared by dissolving the base in ethyl acetate and adding maleic acid to the solvent.. The solution is crystallized at room temperature for 3 hours. The precipitated product is filtered off .
A further object of the present invention is a process for preparing the maleic acid salt of dabigatran etexiiate (1 : 1 ) (form II) of the formula 6.
According to the present invention the maleic acid salt of dabigatran etexiiate (1 : 1 ) (form II) of the formula 6 is prepared by dissolving a polymorphic or amorphous dabigatran etexiiate base, solvate, hydrate or mixtures thereof in the mixture of maleic acid and a polar solvent or a mixture of polar solvents, preferably at 50-1 10 °C. The solution is stirred at this temperature until complete dissolution and the solution is cooled and crystallized at (-25)-25 °C for 8-96 hours.
According to another process variant a polymorphic or amorphous maleic acid salt of dabigatran etexiiate, solvate, hydrate or mixtures thereof are suspended or dissolved in a polar solvent or a mixture of polar solvents, preferably at 50- 1 10 °C. The solution is cooled and crystallized at (-20)-0 °C for 8-96 hours. If necessary, seed crystals are added to the mixture.
According to a preferable process variant, a polymorphic or amorphous dabigatran etexiiate base, soh ate, hydrate or mixtures thereof or a polymorphic or amorphous maleic acid salt of dabigatran etexiiate or mixtures thereof are suspended in Ν,Ν-dimethyl-formamide at 50- 1 20 °C and maleic acid is added to the mixture. The solution is cooled and crystallized at (-20)-0 °C. If necessary, seed crystals are added to the mixture. The precipitated product is filtered, washed and dried. When the maleic acid salt of dabigatran etexiiate is used as starting compound further addition of maleic acid is unnecessary.
According to a more preferable process variant a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof are suspended in N,N-dimethyl- formamide. 1 ,0 equivalent of maleic acid is added to the suspension and it is dissolved at 50- 55 °C. The solution is cooled and crystallized for 10- 16 hours at 0-5 °C at (-20)-(- 15) °C. The precipitated product is filtered off, washed and dried.
A further object of the present invention is the oxalic acid salt of dabigatran etexilate (1 : 1) (form VI) of the formula 7. It has been found that the X-ray powder diffraction pattern of the Form VI of the oxalic acid salt is significantly different from that of the known oxalic acid salts of dabigatran etexilate, such as Form I, II and V disclosed in WO2008/043759. The known forms are prepared by adding oxalic acid into a solvent mixture of acetone and THF and by recrystallization of the crude product obtained by evaporation. Form I is recrystallized from acetonitrile, Form II is recrystallized from isopropyl acetate and Form V is recrystallized from isopropyl alcohol.
A still iiirther object of the present invention is a process for preparing the oxalic acid salt of dabigatran etexilate (1 : 1) (form VI) of the formula 7.
According to the present invention the oxalic acid salt of dabigatran etexilate (1 : 1 ) (form VI) of the formula 7 is prepared by dissolving a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof in the mixture of oxalic acid and polar solvent or polar solvent mixture, preferably at 25- 1 10 °C. The solution is evaporated gradually in 1 -7 days at room temperature. The residue is dissolved in an aliphatic polyol at 25- 1 10 °C and the solution is cooled and crystallized at 0-25 °C for 8-24 hours.
According to another process variant a polymorphic or amorphous oxalic acid salt of dabigatran etexilate, solvate, hydrate or mixtures thereof are suspended or dissolved in a polar solvent or polar solvent mixture, preferably at 25-1 10 °C. The solution is cooled to 0-25 oC and crystallized at this temperature for 8-24 hours. If necessary, seed crystals are added to the mixture.
According to a preferable process variant, a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof or a polymorphic or amorphous oxalic acid salt of dabigatran etexilate or mixtures thereof are suspended in an aliphatic ether or keton or
mixtures thereof at 25- 1 10 °C and oxalic acid is added to the mixture. The solution is evaporated gradually in 1 -7 days at room temperature. The residue is dissolved in an aliphatic glycol at 25- 1 10 °C and the solution is cooled and crystallized at 0-25 °C for 8-24 hours. When the oxalic acid salt of dabigatran etexilate is used as starting compound further addition of oxal ic acid is unnecessary.
According to a more preferable process variant a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof are dissolved in the mixture of THF and acetone at 20-25 °C. Then 1 ,0 equivalent of oxalic acid is added to the solution. It is evaporated gradually in 3 days at 20-25 °C. The residue is dissolved in diethylene glycol at 50-55 °C and the solution is cooled and crystallized at 0-5 °C for 1 5-20 hours. The precipitated product is filtered off, washed and dried.
A further object of the present invention is the hydrochloride salt of dabigatran etexilate (3 : 1 ) (forms VII, VIII, IX and X) of the formula 8. . It has been found that (he X-ray powder diffraction patterns of the Forms VII, VIII, IX and X of the hydrochloride salt are different from that of the known hydrochloride salt of dabigatran etexilate, such as Forms II, V and VI disclosed in WO2008/043759. Furthermore, the melting point of the polymorphic forms of the present invention are as follows: Form VII: 152 °C, Form VIII: 160 °C, Form IX: 181 °C and Form X: 1 4 °C, which were determined by the peak maximum of the DCS curve. These melting points differ form the melting point of the Form I (1 35 °C), disclosed in WO2006/1 14415. The known Form I is prepared by adding hydrochloric acid into ethanol, Forms II, V and VI are prepared by adding hydrochloric acid into a solvent mixture of acetone and THF and by recrystallization of the crude product obtained by evaporation. Form I is prepared by suspending it in ethyl-acetate and acetone. Form II is recrystallized from 1 ,2- dimethoxy-ethane, Form V is recrystallized from isopropyl acetate and Form VI is recrystallized from THF.
A further object of the present invention is a process for preparing the hydrochloride salts of dabigatran etexilate ( 1 : 1 ) (forms VII, VIII, IX and X) of the formula 8.
According to the present invention Form VII of the hydrochloride acid salt is prepared by dissolving a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof in a polar solvent or a mixture of polar solvents at 25- 1 10 °C and after dissolving
hydrochloric acid is added to the solution. After cooling it is crystallized at 0-25 °C for 8-48 hours.
According to another process variant a polymorphic or amorphous hydrochloric acid salt of dabigatran etexilate. solvate, hydrate or mixtures thereof are suspended or dissolved in a polar solvent or a mixture of polar solvents at 25- 1 10 °C. It is crystallized at 0-25 °C for 8-48 hours. If necessary, seed crystals are added to the mixture.
According to a preferable process variant, a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof or a polymorphic or amorphous hydrochloric acid salt of dabigatran etexilate or mixtures thereof are suspended or dissolved in an aliphatic alcohol or a mixture of aliphatic alcohol and aliphatic esther at 25- 1 10 °C and a mixture of anhydrous or hydrous hydrochloric acid and aliphatic alcohol or gaseous hydrochloric acid is added to the mixture. The solution is cooled and crystallized at 0-20 °C for 8-48 hours. If necessarry, seed crystals are added to the mixture. The precipitated product is filtered off, washed and dried. When hydrochloric acid salt of dabigatran etexilate is used as starting compound further addition of hydrochloric acid is unnecessary.
According to a more preferable process variant, a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof is dissolved in the mixture of isopropyl alcohol and ethyl-acetate at 40-45 °C in the presence of hydrochloric acid. The solution is crystallized at 0-5 °C for 2 days. The precipitated product is filtered off, washed and dried.
According to the present invention the Form VIII of hydrochloride acid salt is prepared by dissolving a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof in a polar solvent or a mixture of polar solvents at 25-1 10 °C and after dissolving hydrochloric acid is added to the solution. After cooling it is crystallized at 20-60 °C for 8-24 hours.
According to another process variant a polymorphic or amorphous hydrochloric acid salt of dabigatran etexilate, solvate, hydrate or mixtures thereof are suspended or dissolved in a polar solvent or a mixture of polar solvents at 25- 1 10 °C. it is crystallized at 20-60 °C for 8-24 hours, if necessary, seed crystals are added to the mixture.
According to a preferable process variant, a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof or a polymorphic or amorphous hydrochloric acid salt of dabigatran etexilate or mixtures thereof are suspended or dissolved in an aliphatic alcohol or a mixture of an aliphatic alcohol and an aliphatic esther at 25-1 10 °C and the mixture of anhydrous or hydrous hydrochloric acid and aliphatic alcohol or gaseous hydrochloric acid is added to the mixture. The solution is cooled and crystallized at 20-60 °C for 8-24 hours. If necessarry, seed crystals are added to the mixture. The precipitated product is filtered off, washed and dried. When hydrochloric acid salt of dabigatran etexilate is used as starting compound further addition of hydrochloric acid is unnecessary.
According to a more preferable process variant, a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof is dissolved in the mixture of isopropyl alcohol and ethyl-acetate at 40-45 °C in the presence of hydrochloric acid containing isopropyl alcohol. The solution is crystallized at 20-25 °C for 15-20 hours. The precipitated product is filtered off, washed and dried.
According to the present invention the Form IX of hydrochloride acid salt is prepared by dissolving a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof in a polar solvent or a mixture of polar solvents at 25-1 10 °C and after dissolving hydrochloric acid is added to the solution. After cooling it is crystallized at 0-25 °C for 8- 1 68 hours.
According to another process variant a polymorphic or amorphous hydrochloric acid salt of dabigatran etexilate, solvate, hydrate or mixtures thereof are suspended or dissolved in a polar solvent or a mixture of polar solvents at 25- 1 10 °C. It is crystallized at 0-25 °C for 8-168 hours. If necessary, seed crystals are added to the mixture.
According to a preferable process variant, a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof or a polymorphic or amorphous hydrochloric acid salt of dabigatran etexilate or a mixtures thereof are suspended or dissolved in an aliphatic alcohol or a mixture thereof or aliphatic keton at 25- 1 10 °C and mixture of anhydrous or hydrous hydrochloric acid and aliphatic alcohol or gaseous hydrochloric acid is added to the mixture. The solution is cooled and crystallized at 0-25 °C for 8- 168 hours. If necessarry, seed crystals are added to the mixture. The precipitated product is filtered off, washed and dried.
When hydrochloric acid salt of dabigatran etexilate is used as starting compound further addition of hydrochloric acid is unnecessary.
According to the present invention the aliphatic alcohol used by the preparation of the Form IX of dabigatran etexilate hydrochloride salt could be selected from C l -4 alcohols, preferably methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol or t-butanol, most preferably ethanol. Aliphatic keton could be selected from C I -3 chain or ring ketons, preferably methyl-ethyl keton, acetone, cyclohexanon, methyl-cyclohexanon, most preferably acetone.
According to the most preferable process variant, a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof is dissolved in ethanol at 40-45 °C in the presence of isopropyl alcohol containing hydrochloric acid. The solution is crystallized at 0-5 °C for 1 -7 days. The precipitated product is filtered off, washed and dried.
According to another process variant a polymorphic or amorphous hydrochloric acid salt of dabigatran etexilate, solvate, hydrate or mixtures thereof is dissolved in ethanol at 40-45 °C. It is crystallized at 0-5 °C for 1 -7 days. The precipitated product is filtered off, washed and dried.
According to another process variant a polymorphic or amorphous hydrochloric acid salt of dabigatran etexilate, solvate, hydrate or mixtures thereof are suspended in acetone at 20-30 °C and Form IX hydrochloride salt is added to the mixture. It is crystallized at 20-30 °C for 8-48 hours.
According to the present invention the Form X of hydrochloride acid salt is prepared by dissolving a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof is dissolved in a polar solvent or a mixture of polar solvents at 25-1 10 °C and after dissolving hydrochloric acid is added to the solution and if necessray the solution is concentrated. After addition of aliphatic keton and cooling it, the solution is crystallized at 0- 25 °C for 0.1 -24 hours.
According to another process variant a polymorphic or amorphous hydrochloric acid salt of dabigatran etexilate, solvate, hydrate or mixtures thereof are suspended or dissolved in a polar
solvent or a mixture of polar solvents at 25- 1 10 °C. It is crystallized at 20-60 °C for 8-24 hours. If necessary, seed crystals are added to the mixture.
According to a preferable process variant, a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof or a polymorphic or amorphous hydrochloric acid salt of dabigatran etexilate or mixtures thereof are suspended or dissolved in an aliphatic alcohol or mixtures thereof at 25- 1 10 °C and mixture of anhydrous or hydrous hydrochloric acid and an aliphatic alcohol or gaseous hydrochloric acid is added to the mixture and the thus obtained mixture is partially evaporated and an aliphatic keton is added to the mixture. The solution is cooled and crystallized at 0-25 °C for 0, 1 -24 hours. If necessary, seed crystals are added to the mixture. The precipitated product is filtered off, washed and dried. When hydrochloric acid salt of dabigatran etexilate is used as starting compound further addition of hydrochloric acid and evaporation is unnecessary.
According to the most preferable process variant, a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof is dissolved in the ethanol at room temperature and hydrochloric acid containing isopropyl alcohol is dropwise added to the solution. After 1 hour long stirring the solution is evaporated to the half part and while stirring acetone is added to it. The obtained suspension is cooled to the temperature of 0-5 °C and after 10 minutes it is filtered off and dried.
Another object of the present invention is the p-toluenesulfonic acid salt of dabigatran etexilate ( 1 : 1 ) (form VIII) of the formula 9. It has been found that the X-ray powder diffraction pattern of the Form VIII of the p-toluenesulfonic acid salt is significantly different from that of the known p-toluenesulfonic acid salts of dabigatran etexilate, such as Form 1, V, VI and VII disclosed in WO2008/043759. The known forms are prepared by adding p- toluenesulfonic acid into the mixture of acetone and THF and by recrvstallization of the crude product obtained by evaporation. Form I is recrystallized from ethyl-acetate, Form V is recrystallized from butane-2-one, Form VI is recrystallized from acetone, Form VII is recrystallized from propyl- acetate.
A further object of the present invention is a process for preparation of p-toluenesulfonic acid salt of dabigatran etexilate (1 : 1) (form VIII) of the formula 9.
According to the present invention the p-toluenesulfonic acid salt of dabigatran etexilate ( 1 : 1 ) (form VIII) of the formula 9 is prepared by dissolving a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof in the mixture of p- toluenesulfonic acid and aromatic solvent or a mixture of aromatic solvents, preferably at 25- 1 1 0 °C. The solution is cooled and crystallized at room temperature for 1 -24 hours
According to another process variant a polymorphic or amorphous p-toluenesulfonic acid salt of dabigatran etexilate, solvate, hydrate or mixtures thereof are suspended in a polyol solvent at 25-1 10 °C. The solution is crystallized at 20-25 °C for 1 -24 hours. If necessary, seed crystals are added to the mixture.
According to a preferable process variant, a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof or a polymorphic p-toluenesulfonic acid salt of dabigatran etexilate or mixtures thereof is dissolved or suspended in an aromatic solvent at 25-1 10 °C and p-toluenesulfonic acid is added to the mixture. The solution is crystallized at 20-25 °C for 1-24 hours. If necessary, seed crystals are added to the mixture. The precipitated product is filtered off, washed and dried. When p-toluenesulfonic acid salt of dabigatran etexilate is used as starting compound further addition of p-toluenesulfonic acid is unnecessary.
According to a more preferable process variant, a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof is dissolved in toluene at the temperature of 60-70 °C and 1 ,0 equivalent p-toluenesulfonic acid is added to the solution. The solution is cooled and crystallized for 5 hours at room temperature. The precipitated product is filtered off, washed and dried.
Yet another object of the present invention is the mesylate salt of dabigatran etexilate (1 : 1 ) (form IV) of the formula 10. It has been found that the X-ray powder diffraction pattern of the Form (IV) of the mesylate salt is significantly different from that of the known phosphoric acid salts of dabigatran etexilate, such as Form I, II and hemihydrate disclosed in US20050234104. The Form I and II are crystallized from the base dissolved in acetone by adding methansulfonic acid at 30-35 °C, and 40-45 °C. The hemihydrate compound is prepared form its base dissolved in the mixture of water, ethanol and ethyl-acetate by adding mesylate acid at 35-40 °C.
4
30
A further object of the present invention is a process for preparing mesylate salt of dabigatran etexilate (1 : 1 ) (form IV) of the formula 10.
According to the present invention the mesylate salt of dabigatran etexilate (1 : 1 ) (form IV) of the formula 10 is prepared by dissolving a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof in the mixture of methanesulfonic acid and a polar solvent or a mixture of polar solvents, preferably at 25-1 10 °C. The solution is cooled and crystallized at 0-25 °C for 0.5-24 hours.
According to a preferable process variant a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof is dissolved in aliphatic esther or the mixture of an aliphatic esther and a polar solvent at 25- 1 10 °C in the presence of methane sulfonic acid. The solution is cooled and crystallized at 0-25 °C for 0,5-24 hours
According to a more preferable process variant, a polymorphic or amorphous dabigatran etexilate base, solvate, hydrate or mixtures thereof is dissolved in ethyl-acetate at 60-65 °C and 0,95 equivalent of methansulfonic acid dissolved in ethyl-acetate are added to the solution. The solution is cooled and crystallized for 0,5 hours at 0-5 °C. The precipitated product is filtered off, washed and dried.
It has been surprisingly found that the novel polymorphs of the present invention possess better stability properties compared to the stability of known polymorphs during different storage conditions.
During detailed investigation it has been surprisingly found that the novel Form IX hydrochloric acid salt of dabigatran etexilate (1 : 1 ) of the formula 8 is more stable than the Form II methanesulfonic acid salt (1 : 1 ) described in US20050234104, which can be found in the composition of Pradaxa8.
The Form II methanesulfonic acid salt ( 1 : 1 ) of the formula 10 is prepared according to US 20050234104. Comparative studies of the thermal stability of the Form II methanesulfonic acid salt (1 : 1 ) and Form IX hydrochloric acid salt (1 : 1 ) have been performed. The samples
were stored at a temperature of 40 °C under relative humidity of 75 per cent in closed condition and at 70 °C in closed and opened conditions for 6 weeks.
The compositions of the samples were determined by HPLC at the starting time and after 6 weeks, the amounts of the impurities above 0,03 area% were added together and the resulted cumulated impurity values were compared to the cumulated impurity values measured at the starting time according to the following formula:
The symbols of the above formula have the following meaning: ~ Increase in the amount of the cumulative impurity in percentage he amount of the cumulative impurity at the starting time
^ impurit - The amount of the cumulative impurity after 6 weeks
The change in the amount of the cumulative impurity calculated with the above formula can be seen in Table 15.
Table 15
Change in the amount of the cumulative impurity during storage
A forced stability study (stress test) of the selected dabigatran etexilate salts has also been performed, wherein the samples were stored at 100 °C for 24 hours and the change in the amount of the cumulative impurity (AZimpurity) and the most characteristic degradation product, namely the compound of formula 12 (Δ12) were determined by LC/MS. A∑impurity was calculated with the above formula, and the value of Δ12 was calculated in a similar manner with the following formula:
The symbols in the formula have the following meaning:
(Δ\2)[%] - Increase in the amount of the degradtion product, compound of formula 12 in percentage
Cm - The amount of the compound of the formula 12 after 6 weeks
Ck - The amount of the compound of the formula 12 at the starting time
The results are summarized in table 16.
Table 16.
The change in the amount of the impurities during stress test
According to table 16 both the increase in the amount of the cumulative impurit}' and the most characteristic degradation product (compound of formula 12) are significantly higher in Form II methanesulfonic acid salt than in Form IX hydrochloric acid salt.
Comparative study of the thermal stability and forced stability study (stress test) imitate the degradation process in the pharmaceutical composition in an accelerated manner. The results indicate that the Form IX hydrochloric acid salt is more stable in compositions than the Form II methanesulfonic acid salt. This advantageous property of the Form IX hydrochloric acid salt is of high importance regarding the formulation and storage of the pharmaceutical composition and minimization of the harmful side effects on the human body.
A further general disadvantage of all methanesulfonic acid salts is that more attention should be paid to different processes during the manufacture of the active pharmaceutical ingredient. Harmful alkyl-mesylates can be formed in the presence of alcohols, especially ethyl alcohol in some procedural steps or technological operations thereof during the manufacturing process, e.g. in case of ethanol ethyl mesylate can be formed. Theirs mutagenic or carcinogenic effect is known form the literature: Thompson, L. H., Mutant Isolation. Meth. Enzymol. 1979, 58, 308-322; Alderson, T., Chemically Induced Delayed Germinal Mutation in Drosophila. Nature 1965, 207, 164-167; Jenkins, J. B., The Induction of Mosaic and Complete Dumpy Mutants in Drosophila Melanogaster with Ethyl Methanesulfonate. Mutat. Res. 1967, 4, 90- 92; Schalet, A. P., Interspecific Comparison of Ethyl Methanesulfonate-induced Mutation Rates in Relation to Genome Size. Mutat. Res. 1978, 49, 313-340.
Viracept (nelfinavir) was withdrawn from the market in 2007 by Hoffmann-La Roche because it was contaminated by ethyl mesylate due to unsuitable technological process. In connection with the withdrawal the European Medicine Agency published a notice, in which the EMA calls upon the pharmaceutical industry to perform tight control and further investigations in connection with compositions containing mesylate, tosylate and besylate salts (EMEA/44714/2008).
The majority of the active pharmaceutical ingredients in salt form - which are used for human therapy - turn into hydrochloride due to the strong acidic character of gastric acid (hydrochloric acid). Thus the acid, which is bounded by the active pharmaceutical ingredient, is liberated. The effect of the free acids, which arc present in the gastric fluid and which are weaker than the hydrochloric acid, such as methanesulfonic acid, p-touluenesulfonic acid and benzenesulfonic acid has not been investigated yet, still less its reaction with alcohols, such az
ethylalcohol, which results mesylate. Therefore, further investigations would be required before use them.
Aurther object of the present invention is the use of the above-mentioned morphologically uniform polymorphs of dabigatran etexilate salts formed with phosphoric acid, sulfuric acid, maleic acid, methansulfonic acid, oxalic acid, hydrochloric acid and p-toulenesulfonic acid as pharmaceuticals.
The present invention further relates to the pharmaceutical compositions, which contain as active ingredient a therapeutically effective amount of the above-mentioned dabigatran- etexilate together with one or more pharmaceutically acceptable excipients. The invention relates to the use thereof for the prevention and treatment of postoperative deep vein thrombosis and stroke.
The pharmaceutical compositions of the present invention are administered preferably orally or parenterally. The orally administered compositions are e.g. tablets, capsules, dragees, solutions, elixirs, suspensions or emulsions. For parenteral administration intravenous or intramuscular injections are used.
The pharmaceutical compositions of the present invention may contain known pharmaceutical carriers and/or excipients generally applied in the pharmaceutical industry. Carriers may e.g. magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, targacant, methyl cellulose, sodium methyl cellulose, low melting point wax, cocoa butter etc. The use of carrier is not necessary, if the capsule is composed of the carrier. Orally administered compositions further can be lozenges and bags. Solid formulations, such as tablets, powders, capsules, pills, bags and lozenges are preferably used for oral administration.
The suppositories contain low melting point waxes (e.g. mixture of glycerides of fatty acid or cocoa butter). The wax is melted and the active ingredient is homogenized in it. The melted mixture is poured into a mould of an appropriate size and form and allowed to harden while cooling.
The tablets are prepared by mixing the active ingredient with the appropriate excipients in the required ratio and tablets with appropriate size and form are pressed.
Powders are prepared by mixing the fine pulverized active ingredient and carriers. Liquid solutions are suspensions and emulsions, which can provide, if necessary, a sustained release of the active ingredient. Solutions containing water or aqueous propylene glycols are preferably used. Liquid compositions for parenteral use can be prepared as solutions containing aqueous polyethylene glycols
Aqueous solutions for oral administration are prepared by dissolving the active ingredient in water and by adding the required colorants, flavors, stabilizers and gelling agents to the solution. The active ingredient is suspended in water, in the presence of a thick liquid (e.g. natural or synthetic resins, rosins, methyl cellulose, sodium carboximethyl cellulose or any other suspending agent).
Another part of the solid pharmaceutical compositions according to the invention is converted into liquid compositions before use and administered orally. Liquid compositions are solutions, suspensions or emulsions, which contains colorants, flavors, preservatives, buffers, artificial or natural sweeteners, dispersants, gelling agents etc. in addition to the active ingredient.
The pharmaceutical compositions of the present invention are preferably prepared as unit doses. The unit doses contain the required amount of the active ingredient. The unit doses may be marketed in packagings containing separated amounts of the compositions (e.g. packed tablets, capsules, powders in ampoules or containers). Capsules, tablets, bags, lozenges and several single dose containing packages are unit doses as well.
A further object of the present invention is a process for preparing the above-mentioned pharmaceutical compositions by mixing the phosphoric acid salt of dabigatran etexilate ( 1 : 1 ) (form III) of the formula 1 , or .the fumaric acid salt of dabigatran etexilate (1 : 1 ) (form V) of the formula 2, or the sulfuric acid salt of dabigatran etexilate (1 : 1 ) (form I) of the formula 3 , or the sulfuric acid dihydrate salt of dabigatran etexilate (1 : 1 :2) (form I) of the formula 4, or the sulfuric acid monohydrate salt of dabigatran etexilate (1 : 1 : 1 ) (form I) of the formula 5, or the maleic acid salt of dabigatran etexilate ( 1 : 1 ) (form II) of the formula 6, or the oxalic acid
salt of dabigatran etexilate ( 1 : 1 ) (form VI) of the formula 7, or the hydrochloride salt of dabigatran etexilate ( 1 : 1 ) (form VII) of the formula 8, or the hydrochloride salt of dabigatran etexilate (1 : 1 ) (form VIII) of the formula 8, or the hydrochloride salt of dabigatran etexilate ( 1 : 1 ) (form IX) of the formula 8, or the hydrochloride salt of dabigatran etexilate ( 1 : 1 ) (form X) of the formula 8, or the /?-toluenesulfonic acid salt of dabigatran etexilate ( 1 : 1) (form VIII) of the formula 9, or the / toluenesulfonic acid salt of dabigatran etexilate ( 1 : 1) (form IX) of the formula 9, or the mesylate salt of dabigatran etexilate ( 1 : 1 ) (form IV) of the formula 1 0 or a mixture thereof with pharmaceutically acceptable solid or liquid diluents and/or excipients, and by bringing the mixture to galenic form.
The pharmaceutical compositions of the present invention are prepared by known methods of the pharmaceutical industry.
The pharmaceutical compositions of the present invention may contain further pharmaceutically active ingredients compatible with the compounds of the formulae 1 to 10 or mixture thereof.
A further object of the present invention is the use of the novel crystalline polymorphs of the compounds of the formulae 1 to 10 as a pharmaceutically active ingredients.
Another object of the present invention is the use of the novel crystalline polymorphs of the compounds of the formulae 1 to 10 for the preparation of pharmaceutical compositions which prolong the thrombin time, inhibit thrombin and related serine proteases.
A further object of the present invention is the use of the novel crystalline polymorphs of the compounds of the formulae 1 to 10 for prolongation of the thrombin time and/or the inhibition of thrombin and related serine proteases by administering a therapeutically acceptable dose of a compound of the formulae 1 to 10 to patients.
The advantage of the present invention is that the novel crystalline compounds of the formulae 1 to 10 are morphologically uniform. Therefore the dissolution time, biological release, chemical stability and processing (filtering, drying, dissolving and tabletting) properties of the compounds are reproducible.
The novel polymorphs of the present invention can he produced in a reproducible manner on industrial scale, too
The present invention is elucidated by the following examples without limiting the scope of the invention to the examples.
Examples
Example 1
Preparation of the phosphoric acid salt of dabigatran etexilate (1 : 1) (form III) of the formula 1.
486 mg (0,77 mmole) of dabigatran etexilate, 1 ,0 ml of N,N-dimethyl-formamide and 89 mg 85 w/w% of phosphoric acid (0,77 mmole) are measured into a 10 cm3roimd-bottom flask. While stirring the suspension is warmed to 65 °C. The mixture is completely dissolved at this temperature. Then it is cooled to room temperature in 2 hours and is kept at 5 °C for 1 night. The crystalline suspension is filtered, washed with a little amount of N.N-dimethyl-fonnamide and acetonitrile and dried at room temperature under vacuo to constant weight.
Yield: 590 mg (81 ,3 %).
p.: 154-156 °C.
HNMR (DMSO, 500 MHz): 8-10 (b, 5H), 8.38 (m, 1H), 7.92 (m, 2H), 7.54 (m, 1 H), 7.48 (d, J=l . l Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.16 (dd, Jl = 1 .5 Hz, J2=8.4 Hz, 1 H), 7.12 (m, 1 H), 7.0 (b, l H), 6.89 (m, 1 H), 6.78 (m, 2H), 4.60 (bs, 2H). 4.23 (t, J=7.0 Hz, 2H), 4.00 (m, 2H), 3.98 (q, J=7.1 Hz, 2H), 2.68 (t, J=7.2 Hz, 2H), 1.59 (m, 2H), 1 .30 (m, 6H), 1 .1 3 (t, J=7.2 Hz, 3H), 0.87 (m, 3H).
1R (KBr, cm" 1): 3323, 1736, 1682, 1648, 1586, 1530, 1231. Example 2
Preparation of the fumaric acid salt of dabigatran etexilate (1: 1) (form V) of the formula 2.
636 mg (1 ,0 mmole) of dabigatran etexilate, 2,5 ml of ethanol and 1 16 mg ( 1 ,0 mmole) of fumaric acid are added into a 10 cm3 round-bottom flask. While stirring the suspension is warmed up to 60 °C. The mixture is completely dissolved at this temperature. The mixture is cooled to room temperature in 2 hours and kept at 5 °C for 1 night. The crystalline suspension is filtered, washed with a little amount of ethanol and dried at room temperature under vacuo to constant weight.
Yield: 673 mg (90,5 %)
Mp..T 13-1 1 5 °C.
HNMR (DMSO, 500 MHz): 9 (b), 8.39 (m, 1 H), 7.80 (~d, J=8.8 Hz, 2H), 7.54 (m, 1 H), 7.48 (d, J=l . l Hz, 1 H), 7.40 (d, J=8.4 Hz, 1 H), 7. 16 (dd, J l =1 .5 Hz, J2=8.6 Hz, 111), 7. 12 (m, H J),
6.94 (bt, 1H), 6.89 (m, 1H), 6.77 (~d, J=8.8 Hz, 2H), 6.62 (s, 2H), 4.60 (d, J=5.1 Hz, 2H), 4.23 (t, J=7.2 Hz, 2H), 3.98 (m, 2H), 3.98 (q, J=7.0 Hz, 2H), 3.77 (s, 3H), 2.68 (t, .1=7.1 Hz, 2H), 1.58 (m, 2H), 1.39 (m, 6H), 1.13 (t, J=7.2 Hz, 3H), 0.87 (m, 1H).
IR (KBr, cm"1): 3298, 1715, 16100, 1322, 1242.
Example 3
Preparation of the sulfuric acid salt of dabigatran etexilate (1:1) (form I) of the formula 3.
630 mg (1,0 mmole) of dabigatran etexilate, 1,1 ml of ethanol and 8,0 ml of ethyl-acetate are added into a 25 cm3 round-bottom flask.0,2 g 50 w/w% of sulphuric acid (1,0 mmole) are added to the suspension. The mixture is kept at 5 °C for 1 night. The crystalline suspension is filtered, washed with a little amount of the mixture of ethyl-acetate and ethanol (10:1) and dried at room temperature under vacuo to constant weight.
Yield: 543 mg (74,6 %)
Mp.: 171-173 °C.
HNMR (DMSO, 500 MHz): 11.84 (b, 1H), 10.59 (b, 1H), 9.99 (b, 1H), 8.39 (m, 1H), 7.65 (~d, J=9.0 Hz, 1H), 7.59 (b, 1H), 7.55 (m, 1H), 7.47 (m, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.17 (dd, Jl=1.5 Hz, J2=8.4 Hz, 1H), 7.12 (m, 1H), 6.91 (m, 1H), 6.87 (~d, J=9.2 Hz, 2H), 4.69 (d, J=3.3 Hz, 2H), 4.25 (m, 2H), 4.22 (t, 3=7.1 Hz, 2H), 3.98 (q, J=7.1 Hz, 2H), 3.78 (s, 3H), 2.68 (t, J=7.1 Hz, 2H), 1.68 (m, 2H), 1.38 (m, 2H), 1.30 (m, 4H), 1.12 (t, J=7.1 Hz, 3H), 0.88 (m, 3H).
IR (KBr, cm"1): 3302, 1739, 1614, 1537, 1331, 1208. Example 4
Preparation of the sulfuric acid dihydrate salt of dabigatran etexilate (1:1:2) (form I) of the formula 4.
630 mg (1,0 mmole) of dabigatran etexilate, 4,0 ml 2:8 mixture of tetrahydrofurane-aceton and 1,0 ml 10 w/w% of sulphuric acid (1,0 mmole) are added into a 10 cm3 round-bottom flask. After dissolution the mixture is evaporated to the half part at room temperature under vacuo. The mixture is kept at 5 °C for 1 night. The crystalline suspension is filtered, washed with a little amount of the mixture of tetrahydrofurane and acetone (2:8) and dried at room temperature under vacuo to constant weight.
Yield: 97 mg(13 %)
Mp.: 106-108 °C.
HNMR (DMSO, 500 MHz): 11.84 (b, 1H), 10.59 (b, 1H), 9.99 (b, 1H), 8.39 (m, 1H), 7.65 (~d, J=9.0 Hz, 1H), 7.59 (b, 1H), 7.55 (m, 1H), 7.47 (m, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.17 (dd, Jl = 1.5 Hz, J2=8.4 Hz, 1H), 7.12 (m, 1H), 6.91 (m, 1H), 6.87 (~d, J=9.2 Hz, 2H), 4.69 (d, J=3.3 Hz, 2H), 4.25 (m, 2H), 4.22 (t, J=7.1 Hz, 2H), 3.98 (q, J=7.1 Hz, 2H), 3.78 (s, 3H), 2.68 (t, J=7.1 Hz, 2H), 1.68 (m, 2H), 1.38 (m, 2H), 1.30 (m, 4H), 1.12 (t, J=7.1 Hz, 3H), 0.88 (m, 3H).
IR (KBr, cm"1): 3308, 1736, 1608, 1470, 1326, 1239. Example 5
Preparation of the sulfuric acid monohydrate salt of dabigatran etexilate (1:1:1) (form I) of the formula 5.
630 mg (1,0 mmole) of dabigatran etexilate, 1,7 ml of acetonitrile and 0,2 g 50 w/w% of sulphuric acid (1,0 mmole) are added into a 10 cm' round-bottom flask. The suspension is warmed up to 40 °C. The mixture is completely dissolved at this temperature. After dissolution the solvent is crystallized at room temperature. The suspension is filtered and washed with a little amount of acetonitrile and dried at room temperature under vacuo to constant weight.
Yield: 599 mg (82,2 %)
Mp.: 131-133 °C.
HNMR (DMSO, 500 MHz): 11.84 (b, 1H), 10.59 (b, 1H), 9.99 (b, 1H), 8.39 (m, III), 7.65 (~d, J=9.0 Hz, 1H), 7.59 (b, 1H), 7.55 (m, 1H), 7.47 (m, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.17 (dd, Jl-1.5 Hz, J2-8.4 Hz, 1H), 7.12 (m, 1H), 6.91 (m, 1H), 6.87 (~d, J=9.2 Hz, 2H), 4.69 (d, J=3.3 Hz, 2H), 4.25 (m, 2H), 4.22 (t, J=7.1 Hz, 2H), 3.98 (q, J=7.1 Hz, 2H), 3.78 (s, 3H), 2.68 (t, J=7.1 Hz, 2H), 1.68 (m, 2H), 1.38 (m, 2H), 1.30 (m, 411), 1.12 (t, J=7.1 Hz, 3H), 0.88 (m, 3H).
IR (KBr, cm"1): 3297, 1736, 1588, 1536, 1299. Example 6
Preparation of the maleic acid salt of dabigatran etexilate (1:1) (form II) of the formula 6.
630 mg (1,0 mmole) of dabigatran etexilate, 1,0 ml of dimethyl -formamide and 118 mg maleic acid (1,0 mmole) are added into a 10 cmJ round-bottom flask. The suspension is warmed up to 50 °C. The mixture is completely dissolved at this temperature. The solution is
kept at -15 °C for 2 nights. The crystalline suspension is filtered and washed with a little amount of dimethyl-formamide and acetonitrile and dried at room temperature under vacuo to constant weight.
Yield: 229 mg (30,7 %)
Mp.: 116-118 °C.
HNMR (DMSO, 500 MHz): 11.87 (b), 9.38 (b, 1H), 8.38 (m, 1H), 7.69 (~d, J=9.0 Hz, 2H), 7.54 (m, 1H), 7.47 (m, 1H), 7.40 (d, J=8.7 Hz, 1H), 7.38 (b, 1H), 7.16 (dd, Jl = 1.5 Hz, J2=8.4 Hz, 1H), 7.12 (m, 1H), 6.90 (m, 1H), 6.84 (~d, J=9.0 Hz, 2H), 6.07 (s, 2H), 4.66 (d, J=5.3 Hz, 2H), 4.22 (t, J=7.1 Hz, 2H), 4.17 (m, 2H), 3.98 (q, J=7.1 Hz, 2H), 3.77 (s, 3H), 2.68 (t, J=7.1 Hz, 1H), 1.54 (m, 2H), 1.37 (m, 2H), 1.30 (m, 4H), 1.13 (t, J=7.1 Hz, 3H), 0.87 (m, 3H). IR ( Br, cm"1): 3307, 1717, 1536, 1324, 1159.
Example 7
Preparation of the oxalic acid salt of dabigatran etexilate (1:1) (form VI) of the formula 7.
126 mg (0,2 mmole) of dabigatran etexilate, 0,7 ml of a 2:8 mixture of tetrahydroiurane and aceton and 133 mg of oxalic dihydrate (0,106 mmole) dissolved in 10 w/w% acetone are added into a 10 cm3 round-bottom flask. The solution is evaporated in 3 days under vacuo at room temperature The remaining product is dissolved in 0,3 ml of ethylene-glycol at 50 °C. The solution is kept at 5 °C for 1 night. The crystalline suspension is filtered and washed with a little amount of ethanol and dried at room temperature under vacuo to constant weight.
Yield: 135 mg (53,6%)
Mp.: 73-75 °C.
HNMR (DMSO, 500 MHz): 8.39 (m, 1H), 7.76 (~d, J=9.0 Hz, 2H), 7.54 (m, 1H), 7.47 (m, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.16 (dd, Jl = 1.6 Hz, .12=8.4 Hz, 1H), 7.12 (m, 1H), 7.05 (b, 1H), 6.89 (m, 1H), 6.78 (~d, J=9.0 Hz, 2H), 4.61 (d, J=5.5 Hz, 2H), 4.22 (t, J=7.1 Hz, 2H), 4.03 (m, 2H), 3.98 (q, J=7.1 Hz, 2H), 3.76 (s, 3H), 2.5-5 (b), 1.60 (m, 2H), 1.33 (m, 2H), 1.29 (m, 4H), 1.12 (t, J=7.1 Hz, 3H), 0.87 (m, 2H).
IR (KBr, cm"1): 3284, 1731, 1609, 1321, 1230.
Example 8
Preparation of the hydrochloride salt of dabigatran etexilate (1:1) (form VII) of the formula 8.
630 nig (1,0 mmole) of dabigatran etexilate, 9,0 ml of ethyl acetate, 16,0 ml of isopropyl alcohol and 130 mg of hydrochloric acid containing isopropyl alcohol (28 w/w%; 1,0 mmole) are added into a 50 cm" round-bottom flask, and the reaction mixture is warmed up to 40 °C. The thus-obtained solution is kept at 5 °C for 2 days. The crystalline suspension is filtered and washed with a little amount of isopropyl alcohol and dried at room temperature under vacuo to constant weight.
Yield: 233 mg (35,0%)
Mp.: 155-157 °C.
HNMR (DMSO, 500 MHz): 11.87 (b, IH), 10.80 (b, IH), 10.02 (b, IH), 8.38 (m, IH), 7.78 (b, IH), 7.68 (~d, J=9.0 Hz, 2H), 7.55 (m, IH), 7.50 (d, J=0.9 Hz, IH), 7.46 (d, J=8.4 Hz, IH), 7.19 (dd, j 1 = 1.5 Hz, J2=8.6 Hz, IH), 7.12 (m, IH), 6.93 (m, IH), 6.89 (~d, J=9.2 Hz, 2H), 4.73 (b, 2H), 4.26 (m, 2H), 4.22 (t, J=7.1 Hz, 2H), 3.98 (q, J=7.1 Hz, 2H), 3.81 (s, 3H), 2.68 (t, J=7.1 Hz, 2H), 1.68 (m, 2H), 1.38 (m, 2H), 1.29 (m, 4H), 1.12 (t, J=7.1 Hz, 3H), 0.88 (m, 3H).
IR (KBr, cm"1): 3301, 1734, 1606, 1537, 1243. Example 9
Preparation of the hydrochloride salt of dabigatran etexilate (1:1) (form VIII) of the formula 8.
630 mg (1,0 mmole) of dabigatran etexilate, 9,0 g of a 30:1 mixture of ethyl-acetate and isopropyl alcohol and 130 mg of hydrochloric acid containing isopropyl alcohol (28 w/w%; 1,0 mmole) are added into a 10 cm3 round-bottom flask, and the reaction mixture is warmed up to 45 °C. The obtained solution is kept at room temperature for 1 night for crystallization. The crystalline suspension is filtered and washed with a little amount of ethanol and dried at room temperature under vacuo to constant weight.
Yield: 330 mg (49,7 %)
Mp.: 148-150 °C.
HNMR (DMSO, 500 MHz): 11.87 (b, IH), 10.80 (b, IH), 10.02 (b, IH), 8.38 (m, IH), 7.78 (b, IH), 7.68 (~d, J-9.0 Hz, 2H), 7.55 (m, IH).7.50 (d. J=0.9 Hz, IH), 7.46 (d, J-8.4 Hz, IH), 7.19 (dd, j 1=1.5 Hz, J2=8.6 Hz, IH), 7.12 (m, IH), 6.93 (m, IH), 6.89 (~d, J=9.2 Hz, 2H), 4.73 (b, 2H), 4.26 (m, 2H), 4.22 (t, J=7.1 Hz, 2H), 3.98 (q, J=7.1 Hz, 2H), 3.81 (s, 3H), 2.68 (t, J=7.1 Hz, 2H).1.68 (m, 2H), 1.38 (m, 2H), 1.29 (m, 4H).1.12 (t, J=7.l Hz, 3H), 0.88 (m, 3H).
IR (KBr, cm"1): 3222, 1742, 1654, 1603, 1234.
Example 10
Preparation of the hydrochloride salt of dabigatran etexilate (1 : 1) (form IX) of the formula 8.
630 mg (1 ,0 mmole) of dabigatran etexilate, 1 ,5 ml ethanol and 130 mg of hydrochloric acid containing isopropyl alcohol (28 w/w%; 1 ,0 mmole) are added into a 10 cm round-bottomed flask, and the reaction mixture is warmed up to 45 °C. The thus-obtained solution is kept at 5 °C for 1 week. The crystalline suspension is filtered and washed with a little amount of ethanol and dried at room temperature under vacuo to constant weight.
Yield: 335 mg (50,4 %)
Mp.: 178-180 °C.
HNMR (DMSO, 500 MHz): 1 1.87 (b, 1 H), 10.80 (b, 1 H), 10.02 (b, 1 H), 8.38 (m, 1 H), 7.78 (b, 1 H), 7.68 (~d, J=9.0 Hz, 2H), 7.55 (m, 1 H), 7.50 (d. J=0.9 Hz, 1 H), 7.46 (d, J=8.4 Hz, 1 H), 7.19 (dd, J l = 1 .5 Hz, J2=8.6 Hz, 1 H), 7.12 (m, 1 H), 6.93 (m, 1H), 6.89 (~d, J=9.2 Hz, 2H), 4.73 (b, 2H), 4.26 (m, 2H), 4.22 (t, J=7.1 Hz, 2H), 3.98 (q, J=7.1 Hz, 2H), 3.81 (s, 3IT), 2.68 (t, J=7.1 Hz, 2H), 1 .68 (m, 2H). 1 .38 (m, 2H), 1 .29 (m, 4H), 1 .12 (t, J=7.1 Hz, 3H), 0.88 (m, 3H).
IR (KBr, cm" 1): 3296, 1 734, 1648, 1578, 1468, 1207. Example 11
Preparation of the the hydrochloride salt of dabigatran etexilate (1 : 1 ) (form IX) of the formula 8.
500 mg (0,79 mmole) of dabigatran etexilate are added into a 10 cm round-bottomed flask, it is suspended in 3 ml of acetone and the mixture of 75 μ[ 32 w/w% aqueous hydrochloric acid (0,79 mmole) and 2 ml of acetone are added dropwise at room temperature. The reaction mixture is stirred at room temperature for 1 hour and the appropriate seed crystal (e.g. the compound prepared according to the example 1 0) is added to the suspension. The suspension is stirred at room temperature for 16-24 hours. The crystalline suspension is filtered and washed with a little amount of acetone and dried at room temperature under vacuo to constant weight.
Yield: 470 mg (88 %)
Mp. : 178-180 °C
HNMR (DMSO, 500 MHz): 1 1.87 (b, 1H), 10.80 (b, 1 H), 1 0.02 (b, 1 H), 8.38 (m, 1 H), 7.78 (b, HI), 7.68 (~d, J=9.0 Hz, 2H), 7.55 (m, 1 H), 7.50 (d, J=0.9 Hz, 1 H), 7.46 (d, .1=8.4 Hz,
1 H), 7.19 (dd, Jl = l .5 Hz, J2=8.6 Hz, 1 H), 7.12 (m, 1 H), 6.93 (m, 1 H), 6.89 (~d, J=9.2 Hz, 2H), 4.73 (b, 2H), 4.26 (m, 2H), 4.22 (t, J=7.1 Hz, 2H), 3.98 (q, J=7. 1 Hz, 2H), 3.81 (s, 3H), 2.68 (t, J=7.1 Hz, 2H), 1 .68 (m, 2H), 1 .38 (m, 2H), 1 .29 (m, 4H), 1.12 (t, J=7.1 Hz, 3H), 0.88 (m, 3H).
IR (KBr, cm" 1): 3296, 1 734, 1648, 1578, 2468, 1207. Example 12
Preparation of the hydrochloride salt of dabigatran etexilate (1 : 1) (form X) of the formula 8.
1000 mg (1 ,6 mmole) of dabigatran etexilate and 5 ml of ethanol are added into a 10 cm3 round-bottomed flask and after dissolution 210 mg of hydrochloric acid containing isopropyl alcohol (28 w/w%; 1 ,6 mmole) are added dropwise to the solution and the solution is stirred at room temperature for 1 hour. The mixture is evaporated to the half part at room temperature under reduced pressure and 10 ml of acetone are added while stirring. The suspension is stirred at room temperature form 10 minutes. The suspension is filtered and washed with a little amount of acetone and dried at 45 °C under vacuo to constant weight.
Yield: 654 mg (62 %)
Mp.: 152- 154 °C.
HNMR (DMSO, 500 MHz): 1 1 .84 (b, 1H), 10.56 (b, 1 H), 9.98 (b, 1 H), 8.38 (m, 1 H), 7.68 (~d, J=9.0 Hz, 1 H), 7.58 (b, 1 H), 7.55 (m, 1 H), 7.48 (~d, J=8.3 Hz, 2H), 7.48 (m, 1 H), 7.41 (d, J=8.6 Hz, Hi), 7.16 (m, 1 H), 7. 12 (m, 1 H), 7. 10 (m, 2H), 6.90 (m, 1 H), 6.87 (~d, J=9.0 Hz, 2H), 4.69 (d, J=4.2 Hz, 2H), 4.22 (m, 4H), 3.98 (q, J=7.3 Hz, 2H), 3.77 (s, 3H), 1 .67 (m, 2H), 1 .38 (m, 2H), 1 .30 (m, 4H), 1 .12 (t, J=7.1 Hz, 3H), 0.88 (m, 3H).
IR (KBr, cm"'): 3299, 1 734, 1652, 1607, 1534, 1242.
Example 13
Preparation of the /7-toluenesulfonic acid salt of dabigatran etexilate (1 : 1) (form VIII) of the formula 9.
630 mg (1 ,0 mmole) of dabigatran etexilate, 2.5 ml of toluene and 196 mg ( 1 ,0 mmole) of p- toluenesulfonic acid are added into a 10 cm3 round-bottomed flask, and the suspension is dissolved at 60 °C while stirring. The mixture is crystallized for 5 hours at room temperature. The suspension is filtered and washed with a little amount of a 1 : 10 mixture of ethanol and toluene and dried at room temperature under vacuo to constant weight.
Yield: 666 mg (80.9 %)
Μρ,: 102-104 °C.
HNMR (DMSO, 500 MHz): 11.84 (b, 1H) 10.56 (b, 1H), 9.98 (b, 1H), 8.38 (m, 1H), 7.68 (~d, J=9.0 Hz, 1H), 7.58 (b, 1H), 7.55 (m, 1H), 7.48 (~d, J=8.3 Hz, 2H), 7.48 (m, 1H), 7.41 (d, J=8.6 Hz, lH), 7.16 (m, 1H), 7.12 (m, 1H), 7.10 (m, 2H), 6.90 (m, 1H), 6.87 (~d, J=9.0 Hz, 2H), 4.69 (d, J=4.2 Hz, 2H), 4.22 (m, 4H), 3.98 (q, J=7.3 Hz, 2H), 3.77 (s, 3H), 1.67 (m, 2H), 1.38 (m, 2H), 1.30 (m, 4H), 1.12 (t, J=7.1 Hz, 3H), 0.88 (m, 3H).
IR (KBr, cm"1): 3350, 1736, 1613, 1327, 1211.
Example 14
Preparation of the p-toluenesulfonic acid salt of dabigatran etexilate (1:1) (form IX) of the formula 9.
630 mg (1,0 mmole) of dabigatran etexilate, 2,5 ml of acetonitrile and 190 mg (1,0 mmole) of jC-toluenesuIfonic acid are added into a 10 cm round-bottomed flask, and the suspension is dissolved at 60 °C. The mixture is crystallized for 1 day at room temperature. The crystalline suspension is filtered, washed with a little amount of acetonitrile and dried at room temperature under vacuo to constant weight.
Yield: 690 mg (83,8%)
Mp.: 150-152 °C.
HNMR (DMSO, 500 MHz): 11.84 (b, 1H), 10.56 (b, 1H), 9.98 (b, 1H), 8.38 (m, 1H), 7.68 (~d, J=9.0 Hz, 1H), 7.58 (b, 1H), 7.55 (m, 1H), 7.48 (~d, J=8.3 Hz, 2H), 7.48 (m, 1H), 7.41 (d, J=8.6 Hz, 1H), 7.16 (m, 1H), 7.12 (m, 1H), 7.10 (m, 2H), 6.90 (m, 1H), 6.87 (~d, J=9.0 Hz, 2H), 4.69 (d, J=4.2 Hz, 2H), 4.22 (m, 4H), 3.98 (q, J=7.3 Hz, 2H), 3.77 (s, 3H), 1.67 (m, 2H), 1.38 (m, 2H), 1.30 (m, 4H), 1.12 (t, J=7.1 Hz, 3H), 0.88 (m, 311).
IR (KBr, cm"1): 3245, 1734, 1606, 1536, 1326, 1231, 1174.
Example 15
Preparation of the mesylate salt of dabigatran etexilate (1:1) (form IV) of the formula 10.
630 mg (1,0 mmole) of dabigatran etexilate dissolved in 10 ml of ethyl-acetate at 60 °C while stirring are added into a 10 cm round-bottomed flask. 93 mg (0,97 mmole) of methanesulfonic acid dissolved in 5 ml of ethyl-acetate are added to the solution, and the mixture is stirred for 5 minutes at 60 °C. The thus-obtained suspension is cooled to room temperature in 30 minutes and the mixture is stirred for 30 minutes at 0-5 °C under cooling.
The crystalline suspension is filtered, washed with a little amount of ethyl-acetateand dried at room temperature under vacuo to constant weight.
Yield: 492 mg (68 %)
Mp.: 167-169 °C.
HNMR (DMSO, 500 MHz): 11.85 (b, IH), 10.61 (b, IH), 10.00 (b, IH), 8.39 (m, IH), 7.65 (~d, J=9.0 Hz, 2H), 7.59 (b, IH), 7.55 (m, IH), 7.47 (d, J=1.0 Hz, IH), 7.42 (d, J=8.6 Hz, IH), 7.17 (dd, Jl = 1.3 Hz, J2=8.2 Hz, IH), 7.12 (m, IH), 6.90 (m, IH), 6.87 (~d, J=9.0 Hz, 2H), 4.69 (d, J=2.7 Hz, 2H), 4.25 (m, 2H), 4.22 (t, J=7.1 Hz, 2H), 3.98 (q, J=7.1 Hz, 2H), 2.68 (t, J=7.1 Hz, 2H), 2.30 (s, 3H), 1.68 (m, 2H), 1.38 (m, 2H), 1.30 (m, 4H), 1.12 (t, J=7.1 Hz, 3H), 0.88 (m, 3H)
IR (KBr, cm"1): 3266, 1734, 1647, 1610, 1587, 1534, 1206.
Claims
Claims
1. The hydrochloride salt of dabigatran etexilate (1:1) (form IX) of the formula 8, which shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2Θ (±0,2° 2Θ) of about: 4,720; 8,080; 15,340; 23,420.
2. The hydrochloride salt of dabigatran etexilate (1:1) (form IX) of the fomiula 8 according to claim 1 , which shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2Θ (±0,2° 2Θ) of about: 4,720; 8,080; 9,540; 10,480; 11,320; 15,340; 18,460; 19,140; 23,420.
3. The hydrochloride salt of dabigatran etexilate (1:1) (form IX) of the fomiula 8 according to claim 1 or 2, which shows an X-ray powder diffraction pattern according to the Figure 10 and the following table:
Position of the peaks and relative intensity (>6 %)
Peak 2Θ (A) Intensity
1 4,720 18,7061 100
2 8,080 10,9333 41
3 9,540 9,2631 22
4 10,480 8,4342 30
5 11,320 7,8102 27
6 11,640 7,5962 9
7 15,040 5,8857 18
8 15,340 5,7713 89
9 17,060 5,1931 9
10 18,160 4,8810 14
11 18,460 4,8023 28
12 18,800 4,7162 18
13 19,140 4,6332 31
14 21,040 4,2189 17
15 22,280 3,9868 10
16 22,540 3,9414 14
17 22,920 3,8769 16
18 23,420 3,7953 46
19 23,820 3,7324 7
20 24,020 3,7018 11
21 24,800 3,5871 1 2
22 25, 160 3,5366 1 8
23 28,380 3 , 1422 13
24 28,800 3,0974 6
4. Process for preparing the hydrochloride salt of dabigatran etexilate (1 : 1 ) (form IX) of the formula 8 according any of claims 1 to 3, which comprises crystallizing any polymorphic or amorphous dabigatran etexilate base or mixtures thereof from a polar solvent or a mixture of polar solvents in the presence of hydrochloric acid.
5. Process for preparing the hydrochloride salt of dabigatran etexilate (1 : 1 ) (form IX) of the formula 8 according to any of claims 1 to 3, which comprises crystallizing any polymorphic or amorphous hydrochloric acid salt of dabigatran etexilate, solvate, hydrate or mixtures thereof form a polar solvent or a mixture of polar solvents.
6. Use of the hydrochloride salt of dabigatran etexilate (1 : 1 ) (form IX) of the formula 8 according to any of claims 1 to 3 as a medicament.
7. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of the hydrochloride salt of dabigatran etexilate ( 1 : 1) (form IX) of the formula 8 as claimed in any of claims 1 to 3, together with one or more pharmaceutically acceptable excipient(s).
8. Use of the composition according to claim 7 for the prevention or treatment of postoperative deep vein thrombosis and stroke.
9. Use of the hydrochloride salt of dabigatran etexilate (1 : 1 ) (form IX) of the formula 8 according to any of claims 1 to 3 for the manufacture of a medicament for the prevention or treatment of postoperative deep vein thrombosis and stroke.
10. Process for the prevention and/or treatment of postoperative deep vein thrombosis and stroke, which comprises administering to a patient in need of such treatment a
therapeutically effective amount of the hydrochloride salt of dabigatran etexilate (1 : 1 ) (form IX) of the formula 8 according to any of claims 1 to 3.
1 1 . The phosphoric acid salt of dabigatran etexilate (1 : 1 ) (form III) of the formula 1 , which shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2Θ (±0,2° 2Θ) of about: 3,620; 7,320; 10,620; 18,480; 22,620; 26, 180.
12. The phosphoric acid salt of dabigatran etexilate (1 : 1 ) (form III) of the formula 1 according to claim 1 1 , which shows an X-ray powder diffraction pattern according to the Figure 1 and the following table:
Position of the peaks and relative intensity (>3 %)
13. The fumaric acid salt of dabigatran etexilate (1 : 1 ) (form V) of the formula 2, which shows X-ray powder diffraction pattern having characteristic peaks at reflection angle 2Θ (±0.2° 2Θ) of about: 4,280; 7,460; 1 5,700; 20,500; 21 ,540; 24,640.
14. The fumaric acid salt of dabigatran etexilate (1:1) (form V) of the formula 2 according to claim 13, which shows an X-ray powder diffraction pattern according to the Figure 2 and the following table:
Position of the peaks and relative intensity (>4 %)
15. The sulfuric acid salt of dabigatran etexilate (1:1) (fonn I) of the formula 3, which shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2Θ (±0,2° 2Θ) of about: 3,560; 7,120; 10,700; 17,960; 25,320.
16. The sulfuric acid salt of dabigatran etexilate (1:1) (fonn I) of the fomiula 3 according to claim 15, which shows an X-ray powder diffraction pattern according to the Figure 3 and the following table:
Position of the peaks and relative intensity (>1 %)
Peak 2Θ d(A) Intensity
1 3,560 24,7983 100
2 7,120 12,4051 4
3 10,160 8,6992 1
4 10,700 8,2613
5 11,440 7,7285 1
6 13,520 6,5438 1
7 14,380 6,1544 2
8 14,740 6,0049 2
9 17.960 4,9349 10
10 19,100 4,6428 2
11 20,560 4,3163 1
12 21,640 4,1033 2
13 22,820 3,8937 1
14 23,320 3,8113 1
15 23,920 3,7171 2
16 25,320 3,5146 7
17 26, 1 60 3,4036 1
18 27,320 3,2617 1
19 40,340 2,2339 1
17. The sulfuric acid dihydrate salt of dabigatran etexilate (1 : 1 :2) (form I) of the formula 4, which shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2Θ (±0,2° 2Θ) of about: 3,840; 7,740; 9,700; 12,540; 14,740; 15,440; 17,840; 20,660; 21 ,600.
18. The sulfuric acid dihydrate salt of dabigatran etexilate (1 : 1 :2) (form I) of the formula 4 according to claim 17, which shows an X-ray powder diffraction pattern according to the Figure 4 and the following table:
Position of the peaks and relative intensity (>1 %)
19. The sulfuric acid monohydrate salt of dabigatran etexilate (1 : 1 : 1) (form I) of the formula 5, which shows an X-ray powder diffraction pattern having characteristic peaks at
reflection angle 2Θ (±0,2° 2Θ) of about: 4,880; 6,980; 10,000; 14,620; 1 5,580; 19,400; 25,100; 26,800.
20. The sulfuric acid monohydrate salt of dabigatran etexilate (1 : 1 : 1 ) (form I) of the formula 5 according to claim 19, which shows an X-ray powder diffraction pattern according to the Figure 5 and the following table:
Position of the peaks and relative intensity (>1 %)
21. The maleic acid salt of dabigatran etexilate (1 : 1) (form II) of the formula 6, which shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2Θ (±0,2° 2Θ) of about: 4,240; 7,600; 10,700; 12,740; 1 7.540; 20,600: 21 ,960; 24.640.
22. The maleic acid salt of dabigatran etexilate ( 1 : 1 ) (form II) of the formula 6 according to claim 21 , which shows an X-ray powder diffraction pattern according to the Figure 6 and the following table:
Position of the peaks and relative intensity (>3 %)
The oxalic acid salt of dabigatran etexilate ( 1 : 1 ) (form VI) of the fonnula 7, which shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2Θ (±0,2° 2Θ) of about: 3,700; 7,460; 9,840; 10,920; 17,960; 19,980; 20,760; 21 ,740; 24, 140.
24. The oxalic acid salt of dabigatran etexilate (1 : 1 ) (form VI) of the formula 7 according to claim 23, which shows an X-ray powder diffraction pattern according to the Figure 7 and the following table:
Position of the peaks and relative intensity (>2 %)
25. The hydrochloride salt of dabigatran etexilate (1 : 1) (form VII) of the formula 8, which shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2Θ (±0,2° 2Θ) of about: 4,740; 8,960; 1 1 ,680; 16,740; 21 ,040; 23,620; 24,580.
26. The hydrochloride salt of dabigatran etexilate (1 : 1) (form VII) of the formula 8 according to claim 25, which shows an X-ray powder diffraction pattern according to the Figure 8 and the following table:
Position of the peaks and relative intensity (>8 %)
16 22, 160 4,0081 9
17 22,400 3,9657 9
18 23,360 3,8049 1 1
19 23,620 3,7636 12
20 23,800 3,7355 10
21 24,200 3,6747 9
22 24,580 3,6187 12
27. The hydrochloride salt of dabigatran etexilate (1 : 1 ) (form VIII) of the formula 8, which shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2Θ (±0,2° 2Θ) of about: 3,860; 12,280; 19,480; 21 ,160; 21 ,400; 22,480; 22,840; 23;420.
28. The hydrochloride salt of dabigatran etexilate (1 : 1) (form VIII) of the formula 8 according to claim 27, which shows an X-ray powder diffraction pattern according to the Figure 9 and the following table:
Position of the peaks and relative intensity (>8 %)
29. The hydrochloride salt of dabigatran etexilate (1 : 1) (form X) of the formula 8, which shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2Θ (±0,2° 2Θ) of about: 4,940; 7,400; 8,940; 16,680; 18,920; 20,640; 20,980; 23,440.
30. The hydrochloride salt of dabigairan etexilate (1:1) (form X) of the formula 8 according to claim 29, which shows an X-ray powder diffraction pattern according to the Figure 11 and the following table:
Position of the peaks and relative intensity (>9 %)
31. The p-toluenesulfonic acid salt of dabigatran etexilate (1:1) (form VIII) of the formula 9, which shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2Θ (±0,2° 2Θ) of about: 3,360; 10,240; 11,160; 20,860; 24,680; 27,060.
The p-toluenesulfonic acid salt of dabigatran etexilate (1:1) (form VIII) of the formula 9 according to claim 31 , which shows an X-ray powder diffraction pattern according to the Figure 12 and the following table:
Position of the peaks and relative intensity (>2 %)
Peak 2Θ d(A) Intensity
1 3,360 26,2739 100
2 10,240 8,6314 8
j 11,160 7,9218 ?
4 17,380 5,0982 2
5 18.700 4,7412 2
6 18,960 4,6768 Ί
7 19,140 4,6332 2
8 20.860 4,2549
9 24.140 3,6837 2
10 24,680 3,6043 3
1 1 26,940 3,3068 2
12 27,060 3,2924 2
13 28,040 3, 1 796 2
33. The p-toluenesulfonic acid salt of dabigatran etexilate (1 : 1) (form IX) of the fonnula 9, which shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2Θ (±0,2° 2Θ) of about: 4,160; 8,400; 33,260; 17,560; 19,560; 21 ,060; 25,340.
The p-toluenesulfonic acid salt of dabigatran etexilate (1 : 1 ) (form IX) of the formula 9 according to claim 33, which shows an X-ray powder diffraction pattern according to the Figure 13 and the following table:
Position of the peaks and relative intensity (>3 %)
35. The mesylate salt of dabigatran etexilate ( 1 : 1 ) (form IV) of the formula 10, which shows an X-ray powder diffraction pattern having characteristic peaks at reflection angle 2Θ
(±0,2° 2Θ) of about: 4,460; 9,320; 1 1 ,060; 13,560; 18,740; 20,440; 20,980: 22,360; 26,840.
36. The mesylate salt of dabigatran etexilate (1 : 1) (form IV) of the formula 10 according to claim 35, which shows an X-ray powder diffraction pattern according to the Figure 14 and the following table:
Position of the peaks and relative intensity (>3 %)
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| CN105348260A (en) * | 2014-08-19 | 2016-02-24 | 天津药物研究院 | Dabigatran etexilate hydrobromide, preparation method and applications thereof |
| CN106554370A (en) * | 2015-09-25 | 2017-04-05 | 陕西合成药业股份有限公司 | Dabigatran derivant containing phosphate ester and its production and use |
| CN116621815A (en) * | 2023-07-21 | 2023-08-22 | 成都苑东生物制药股份有限公司 | Industrial preparation method of dabigatran etexilate mesylate |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0966454B1 (en) | 1997-02-18 | 2003-05-07 | Boehringer Ingelheim Pharma GmbH & Co.KG | Disubstituted bicyclic heterocycles, their production and use as medicaments |
| WO2005018615A1 (en) * | 2003-08-16 | 2005-03-03 | Boehringer Ingelheim International Gmbh | Tablet containing 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]- methyl}-1-methyl-1h-benzimidazolo-5-carbonyl)-pyridino-2-yl- amino]-ethyl propionate or the salts thereof |
| WO2005028468A1 (en) | 2003-08-29 | 2005-03-31 | Boehringer Ingelheim International Gmbh | 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridine-2-yl-amino]-propionic acid ethyl ester methane sulphonate and use thereof as a medicament |
| WO2006114415A2 (en) | 2005-04-27 | 2006-11-02 | Boehringer Ingelheim International Gmbh | Physiologically acceptable salts of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazole-5-carbonyl)-pyridin-2-yl-amino] propionic acid ethyl ester |
| WO2006131491A1 (en) | 2005-06-04 | 2006-12-14 | Boehringer Ingelheim International Gmbh | Polymorphs of ethyl 3-[(2-{[4-(hexyloxycarbonylamino-iminomethyl)phenylamino]methyl}-1-methyl-1h-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate |
| WO2007071742A1 (en) * | 2005-12-21 | 2007-06-28 | Boehringer Ingelheim International Gmbh | Improved process for the preparation of 4-(benzimidazolylmethylamino)-benzamides and the salts thereof |
| WO2008009638A2 (en) * | 2006-07-17 | 2008-01-24 | Boehringer Ingelheim International Gmbh | New indications for direct thrombin inhibitors in the cardiovascular field |
| WO2008043759A1 (en) | 2006-10-10 | 2008-04-17 | Boehringer Ingelheim International Gmbh | Physiologically acceptable salts of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester |
| WO2008059029A2 (en) | 2006-11-16 | 2008-05-22 | Boehringer Ingelheim International Gmbh | New polymorphs of ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100556642C (en) * | 2007-06-06 | 2009-11-04 | 中国科学院化学研究所 | The regulate and control method of aliphatic poly adipic acid fourth diester material degradation performance |
-
2010
- 2010-02-02 HU HU1000069A patent/HUP1000069A2/en not_active IP Right Cessation
-
2011
- 2011-02-02 EA EA201290726A patent/EA022496B1/en not_active IP Right Cessation
- 2011-02-02 WO PCT/HU2011/000014 patent/WO2011110876A1/en active Application Filing
- 2011-02-02 CN CN2011800153251A patent/CN102858762A/en active Pending
-
2012
- 2012-08-20 ZA ZA2012/06254A patent/ZA201206254B/en unknown
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0966454B1 (en) | 1997-02-18 | 2003-05-07 | Boehringer Ingelheim Pharma GmbH & Co.KG | Disubstituted bicyclic heterocycles, their production and use as medicaments |
| WO2005018615A1 (en) * | 2003-08-16 | 2005-03-03 | Boehringer Ingelheim International Gmbh | Tablet containing 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]- methyl}-1-methyl-1h-benzimidazolo-5-carbonyl)-pyridino-2-yl- amino]-ethyl propionate or the salts thereof |
| WO2005028468A1 (en) | 2003-08-29 | 2005-03-31 | Boehringer Ingelheim International Gmbh | 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridine-2-yl-amino]-propionic acid ethyl ester methane sulphonate and use thereof as a medicament |
| US20050234104A1 (en) | 2003-08-29 | 2005-10-20 | Boehringer Ingelheim International Gmbh | 3-[(2-{[4-(hexyloxycarbonylaminoiminomethyl)phenylamino]methyl}-1-methyl-1H-benzimidazol-5-carbonyl)pyridin-2-ylamino]propionic acid ethylester methansulfonate and its use as medicament |
| WO2006114415A2 (en) | 2005-04-27 | 2006-11-02 | Boehringer Ingelheim International Gmbh | Physiologically acceptable salts of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazole-5-carbonyl)-pyridin-2-yl-amino] propionic acid ethyl ester |
| WO2006131491A1 (en) | 2005-06-04 | 2006-12-14 | Boehringer Ingelheim International Gmbh | Polymorphs of ethyl 3-[(2-{[4-(hexyloxycarbonylamino-iminomethyl)phenylamino]methyl}-1-methyl-1h-benzimidazole-5-carbonyl)pyridin-2-ylamino]propionate |
| WO2007071742A1 (en) * | 2005-12-21 | 2007-06-28 | Boehringer Ingelheim International Gmbh | Improved process for the preparation of 4-(benzimidazolylmethylamino)-benzamides and the salts thereof |
| WO2008009638A2 (en) * | 2006-07-17 | 2008-01-24 | Boehringer Ingelheim International Gmbh | New indications for direct thrombin inhibitors in the cardiovascular field |
| WO2008043759A1 (en) | 2006-10-10 | 2008-04-17 | Boehringer Ingelheim International Gmbh | Physiologically acceptable salts of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester |
| WO2008059029A2 (en) | 2006-11-16 | 2008-05-22 | Boehringer Ingelheim International Gmbh | New polymorphs of ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate |
Non-Patent Citations (5)
| Title |
|---|
| ALDERSON, T.: "Chemically Induced Delayed Germinal Mutation in Drosophila", NATURE, vol. 207, 1965, pages 164 - 167 |
| HAUEL ET AL., J MED CHEM., vol. 45, 2002, pages 1757 - 1766 |
| JENKINS, J. B.: "The Induction of Mosaic and Complete Dumpy Mutants in Drosophila Melanogaster with Ethyl Methanesulfonate", MUTAT. RES., vol. 4, 1967, pages 90 - 92 |
| SCHALET, A. P.: "Interspecific Comparison of Ethyl Methanesulfonate-induced Mutation Rates in Relation to Genome Size", MUTAT. RES., vol. 49, 1978, pages 313 - 340 |
| THOMPSON, L. H.: "Mutant Isolation", METH. ENZYMOL., vol. 58, 1979, pages 308 - 322 |
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Also Published As
| Publication number | Publication date |
|---|---|
| HUP1000069A2 (en) | 2012-05-02 |
| EA201290726A1 (en) | 2013-07-30 |
| ZA201206254B (en) | 2013-10-30 |
| EA022496B1 (en) | 2016-01-29 |
| WO2011110876A8 (en) | 2012-07-05 |
| CN102858762A (en) | 2013-01-02 |
| HU1000069D0 (en) | 2010-04-28 |
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