ZA200104771B - Telmisartan polymorphs, methods for producing same and their use in the preparation of a medicament. - Google Patents
Telmisartan polymorphs, methods for producing same and their use in the preparation of a medicament. Download PDFInfo
- Publication number
- ZA200104771B ZA200104771B ZA200104771A ZA200104771A ZA200104771B ZA 200104771 B ZA200104771 B ZA 200104771B ZA 200104771 A ZA200104771 A ZA 200104771A ZA 200104771 A ZA200104771 A ZA 200104771A ZA 200104771 B ZA200104771 B ZA 200104771B
- Authority
- ZA
- South Africa
- Prior art keywords
- telmisartan
- organic solvent
- water
- process according
- mixture
- Prior art date
Links
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 title claims description 91
- 239000005537 C09CA07 - Telmisartan Substances 0.000 title claims description 46
- 229960005187 telmisartan Drugs 0.000 title claims description 46
- 238000000034 method Methods 0.000 title claims description 16
- 238000002360 preparation method Methods 0.000 title description 3
- 239000003814 drug Substances 0.000 title 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 24
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 21
- 235000019253 formic acid Nutrition 0.000 claims description 21
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 18
- 239000003960 organic solvent Substances 0.000 claims description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 6
- 239000013078 crystal Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 238000012986 modification Methods 0.000 claims description 5
- 230000004048 modification Effects 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 238000002076 thermal analysis method Methods 0.000 claims 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000007786 electrostatic charging Methods 0.000 description 3
- 238000011031 large-scale manufacturing process Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- WADSJYLPJPTMLN-UHFFFAOYSA-N 3-(cycloundecen-1-yl)-1,2-diazacycloundec-2-ene Chemical compound C1CCCCCCCCC=C1C1=NNCCCCCCCC1 WADSJYLPJPTMLN-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- -1 1-methylbenzimidazol-2-yl Chemical group 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 229940123413 Angiotensin II antagonist Drugs 0.000 description 1
- 229940123073 Angiotensin antagonist Drugs 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- ZZIZZTHXZRDOFM-XFULWGLBSA-N tamsulosin hydrochloride Chemical compound [H+].[Cl-].CCOC1=CC=CC=C1OCCN[C@H](C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 ZZIZZTHXZRDOFM-XFULWGLBSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 208000026533 urinary bladder disease Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/20—Two benzimidazolyl-2 radicals linked together directly or via a hydrocarbon or substituted hydrocarbon radical
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Description
S018-850.201
Case 1/1075-Dr. Wy/ks BOEHRINGER INGELHEIM PHARMA KG
Polymorphs of telmisartan, processes for preparing them and their use in the preparation of a pharmaceutical composition
The invention relates to polymorphs of 4'-[2-n-propyl-4- methyl-6- (1-methylbenzimidazol-2-yl)benzimidazol-1- ylmethyllbiphenyl-2-carboxylic acid (INN: telmisartan), particularly the polymorphic form B, mixtures of the polymorphs, processes for preparing telmisartan containing form B and the use thereof for preparing a pharmaceutical composition. 15 .
The compound telmisartan is known from European Patent
EP 505 314 Bl and has the following chemical structure:
Me 0
N N at oy
C (I)
Telmisartan and the design physiologically acceptable salts thereof have valuable pharmacological properties.
Telmisartan is an angiotensin antagonist, particularly an angiotensin-II-antagonist which by virtue of its pharmacological properties may be used for example to treat hypertension and cardiac insufficiency, to treat ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), to prevent the progression of cardiac insufficiency after myocardial infarct, to treat diabetic neuropathy, glaucoma, gastrointestinal diseases and bladder diseases. Other possible therapeutic applications can be found in EP 502314 Bl, the contents of which are hereby referred to.
In the course of the synthesis of telmisartan, the final step of the synthesis comprises saponifying the tert.butyl ester (II) according to Diagram 1.
Me Me
M M
CI "CO
N N N N as 0.0 I Os OH © OXY © TC (i) @® mn @®
Diagram 1:
The corresponding experimental procedure which may be carried out on a laboratory scale can be found in EP 502314 Bl. Surprisingly, however, it proved to be simple to transfer the method of synthesis already known to a large-scale industrial manufacturing process. The telmisartan synthesised on an industrial scale according to Diagram 1 is obtained after working up in the form of a product which has to be subjected to a further crystallisation step to complete the purification. In this obligatory crystallisation step the morphology of the end product which crystallises out leads to unforeseen problems.
The product which is precipitated as a solid in the form of long needles is difficult to filter, wash and isolate, is further characterised by a very long drying time on account of the presence of solvent and forms large, very hard fragments during the drying process. Grinding these fragments produces a dry powder which exhibits a strong tendency to electrostatic charging and is virtually impossible to pour.
The disadvantageous properties of a product as described above have always proved to be a serious obstacle to the large-scale manufacture of a compound, as reproducible manufacture of large amounts of the compound in highly pure form is only possible with considerable difficulty or with high additional technical costs.
The aim of the present invention is therefore to prepare telmisartan in a form which permits the large-scale synthesis, working up, purification and isolation of telmisartan in which the above disadvantages are overcome.
Surprisingly, it has been found that telmisartan may occur as a solid in different crystalline modifications.
Depending on the nature of the crystallisation process it may be converted into two different polymorphic forms A and B.
Polymorph A is a form of telmisartan which is obtainable according to the prior art, and which gives rise to the abovementioned problems in large-scale manufacture or purification, isolation and drying of the product.
The polymorphic form B of telmisartan which was surprisingly found, however, shows virtually no tendency to electrostatic charging, is easy to suction filter, centrifuge, wash and dry and is free-flowing even without being ground up.
The following procedure is used according to the invention to prepare the polymorphic form B of telmisartan.
Crude telmisartan product (crystallised for example from dimethylformamide, dimethylacetamide or the like) is taken up, in a suitably sized stirring apparatus, optionally with 1-5 wt.-%, preferably with 3 wt.-% of activated charcoal in a mixture of solvents consisting of water; formic acid and a suitable organic solvent and then dissolved at elevated temperature, preferably at a temperature of from 50-90°C, most preferably at 60-80°C.
According to the invention it is essential to use the solvent mixture of formic acid and water with an organic solvent which must satisfy the following criteria according to the invention. It must be capable of forming a solution with the mixture of formic acid and water. It must be largely chemically inert relative to the mixture of formic acid and water and it must be capable of being separated from the mixture of formic acid and water by .15 distillation. Organic carboxylic acid esters, ketone or ethers may be used. Acetone, methylethylketone, methyl acetate, ethyl acetate, ethyl formate, ethyleneglycol dimethylether or tetrahydrofuran may be mentioned by way of example. Acetone, methylethylketone, methyl acetate, ethyl acetate and THF are preferred according to the invention, while ethyl acetate is particularly preferred.
According to the invention, the mixture of solvents should be made up of 0.3-0.7 1 of water, 10-15 mol of formic acid and 0.3-0.9 1 of the organic solvent per mol of telmisartan. A ratio of 0.4-0.6 1 of water, 11-13 mol of formic acid and 0.4-0.7 1 of the organic solvent based on 1 mol of telmisartan is preferred. A ratio of about 0.5 1 of water, about 11.5-12 mol of formic acid and about 0.5 1 of the organic solvent based on 1 mol of telmisartan is particularly preferred. :
According to the invention, after the abovementioned heating, the solution obtained is filtered and washed with a mixture of the abovementioned organic solvent and formic acid. The washing solution may contain 0.3-1.0 mol, preferably 0.4-0.6 mol, most preferably about
0.5 mol of formic acid per mol of telmisartan. The quantity of washing solution will naturally depend on the quantity of dissolved telmisartan. According to the . invention, 0.1-0.4, preferably 0.15-0.3, most preferably 0.2 1 of the organic solvent are used to each mol of telmisartan.
After the filter residue has been washed with the washing solution described above, the organic solvent is distilled off as much as possible whilst water is added simultaneously. The temperature is kept in the range from 60-100°C, preferably from 70-100°C. The total quantity of water added corresponds substantially to the total amount of solvent distilled off. Almost total distillation of the organic solvent is desirable according to the invention.
Accordingly, the distillation is continued until water is also distilled off, partly azeotropically. The organic solvent distilled off may be used again in subsequent reactions, if necessary after removal of the aqueous phase.
In order to precipitate the telmisartan-polymorphic B it is then cooled to a temperature in the range from 15-60°C, preferably to 20-30°C, and precipitated with a base. The quantity of base to be used depends on the amount of formic acid used. Preferably, 0-2 mol less base is added than there is formic acid present. Most preferably, 0.3- 1.5 mol less base is added than there is formic acid present. It is most particularly preferred to add 0.5-1 mol less base than there is formic acid present. Suitable bases might be either aqueous solutions of potassium hydroxide, sodium hydroxide, lithium hydroxide or ammonia.
It is also possible to use suitable organic bases such as triethylamine, diisopropylethylamine or DBU (diazabicycloundecene) . Particularly preferred bases are the abovementioned aqueous solutions of the potassium hydroxide, sodium hydroxide, lithium hydroxide or ammonia, the aqueous solutions of ammonia being particularly important.
The product precipitated is centrifuged, washed with water : and normally dried in vacuo at 120-125°C.
A sample taken directly after centrifuging and dried in a thin layer in a circulating air drier in the laboratory typically shows a content of 95-99% of crystalline form B.
After centrifugation, the product begins to change partially into form A, depending on the temperature, pH, retention time, and water content, towards the end of the drying. Therefore, in working mixtures, ratios of form A to form B of at best about 10:90 are obtained after drying, but ratios of 60:40 may also be obtained.
However, even a content of form B as low as this guarantees that the product will have the positive qualities required for large-scale production (e.g. a low tendency to electrostatic charging, a low tendency to clumping, free-flowing characteristics etc.). What is essential to the invention in the crystallisation process mentioned above is that initially only form B is produced, with its characteristic macroscopic crystalline form. This macroscopic crystalline form is largely retained under the drying conditions, in spite of partial microscopic rearrangement into form A.
Other highly advantageous aspects of the procedure according to the invention are the high space/time yield of the present process and the high yield of pure telmisartan product, which can be isolated in virtually quantitative amounts.
The telmisartan of form A which can be obtained by the manufacturing process known from the prior art differs from the telmisartan obtainable according to the invention, which is characterised in that it contains some polymorphic form B, in the advantageous qualities of the product already mentioned hereinbefore. Other distinguishing features will be described hereinafter:.
Telmisartan of form A crystallises as long, fine or thin needles which cling together in a felt-like manner. The crystal modification of telmisartan of form B produces very compact cubic to spherical crystals which trickle like sand or silica gel.
The two polymorph forms A and B of telmisartan differ considerably in their melting point. Form B melts at 183+/-2°C (determined by DSC), form A at 269+/-2°C (determined by DSC). After melting, the lower-melting form
B of telmisartan crystallises out again as form A. This results, for example, in the endothermic maximum at 183+/- 2°C determined by DSC being followed by a characteristic exothermic maximum which reflects the crystallisation of the melt of form B into the high-melting form A. The DSC diagrams (DSC=Differential Scanning Calorimetry) obtained with a Mettler DSC-20, TA8000 system are shown in Figure 1.
The polymorphs A and B also differ in their IR spectrum.
On the basis of this difference, the IR spectroscopy may optionally be used for quantitative determination of the ratio of the two crystal modifications in the end product after drying. Pure polymorph A has a characteristic band at 815cm ' in the IR spectrum. In polymorph B this oscillation is shifted to 830cm "'. Since these two characteristic bands of polymorphs A and B are sufficiently far apart, they are particularly suitable for the abovementioned quantitative determination of the ratio of the two crystal modifications.
The IR-sgpectroscopic characterisation of the two polymorphic forms A and B was carried out using the
Nicolet FTIR Spectrometer Magna - IR 550 in KBr (2.5umol per 300 mg KBr; Nicolet software package OMNIC, version 1.20). -
The Examples which follow serve to illustrate purification and crystallisation processes carried out by way of example in order to prepare the polymorphic form B of telmisartan. They should be regarded purely as possible procedures described by way of example, without restricting the invention to their contents.
Example 1 205.6 kg of recrystallised telmisartan (recrystallised from dimethylformamide or dimethylacetamide), 6.2 kg of activated charcoal, 205.6 1 of water, 211.6 kg of formic acid (99-100%) and 205.6 1 of ethyl acetate are placed in a 1200 1 stirring apparatus. The mixture is stirred for about 1 h at 70 - 80°C and then filtered into another 1200 1 stirring apparatus and washed with a mixture of 82.2 1 of ethyl acetate and 9.2 kg of formic acid (99- 100%). About 308 1 of solvent are distilled off at 80 - 100°C whilst simultaneously 308 1 of water are added. The mixture is then cooled to 20 - 30°C and precipitated by the metered addition of 313 kg of 25 % ammonia solution.
The product precipitated is centrifuged, washed with water and dried at 120-125°C.
Yield : 200 kg telmisartan (97.3 % of theory)
Example 2 185 kg of recrystallised telmisartan (recrystallised from dimethyl formamide or dimethylacetamide), 5.6 kg of activated charcoal, 185 1 of water, 190.4 kg of formic acid (99-100%) and 185 1 of tetrahydrofuran are placed in a 1200 1 stirring apparatus. The mixture is stirred for about 1 h at 60 - 70°C and then filtered into another 1200 1 stirring apparatus and washed with a mixture of 74 1 of tetrahydrofuran and 8.3 kg of formic acid (99-100%) .
About 278 1 of solvent are distilled off at 70 - 100°C whilst simultaneously 278 1 of water are added. The mixture is then cooled to 20 - 30°C and precipitated by the metered addition of 281.5 kg of 25 % ammonia solution.
The product precipitated is centrifuged, washed with water and dried at 120-125°C.
Yield : 180 kg telmisartan (97.3 % of theory)
Example 3 185 kg of recrystallised telmisartan (recrystallised from dimethylformamide or dimethylacetamide), 5.6 kg of activated charcoal, 185 1 of water, 190.4 kg of formic acid (99-100%) and 185 1 of methylethylketone are placed in a 1200 1 stirring apparatus. The mixture is stirred for about 1 h at 60 - 70°C and then filtered into another 1200 1 stirring apparatus and washed with a mixture of 74 1 of methylethylketone and 8.3 kg of formic acid (99- 100%). About 278 1 of solvent are distilled of f at 80 - 100°C whilst simultaneously 278 1 of water are added. The mixture is then cooled to 20 - 30°C and precipitated by the metered addition of 281.5 kg of 25 % ammonia solution.
The product precipitated is centrifuged, washed with water and dried at 120-125°C.
Yield : 178 kg of telmisartan (96.2 % of theory)
Comparison Example 150 kg of telmisartan (recrystallised from dimethylformamide or dimethylacetamide), 7.5 kg of activated charcoal, 750 1 of ethanol and 30 kg of 25% aqueous ammonia solution are placed in a 1200 1 stirring apparatus. The mixture is stirred for about 1 h and then filtered into another 1200 1 stirring apparatus and washed with 150 1 of ethanol. The mixture is heated to 70 -
80°C, 35 kg of glacial acetic acid are added and the mixture is stirred for a further 1.5 - 2 h at 75 - 80°C.
The mixture is then cooled to 0 - 10°C and stirred for a further 2 h. The product precipitated is centrifuged, washed with 300 1 of ethanol and with 300 1 of water and dried at 70 - 90°C.
Yield : 135 kg of telmisartan (90 % of theory) pure form A
In the preparation process according to the invention, as a result of the partial conversion of the polymorphic form
B into the polymorphic form A during the drying process, telmisartan occurs as a pure substance in a mixture of two polymorphic forms. However, this does not affect the properties of the pharmaceutical composition, as in the course of the manufacture of telmisartan tablets, for example, the mixture of the polymorphic forms A and B is dissolved in 0.1 N NaOH solution and converted by spray drying into a homogeneous and totally amorphous granulate which is then subjected to the other tablet making steps.
For more detailed information on the use of the products according to the invention for preparing a pharmaceutical composition, cf. EP 502314 Bl, the contents of which are hereby referred to.
Claims (9)
- Patent Claims 1) Polymorphic crystal modification B (form B) of - telmisartan (formula I),Me N N SS eh 4 Sh characterised by an endothermic maximum at 183%2°C which occurs during thermal analysis using DSC.
- 2) Telmisartan, characterised in that it contains form B according to claim 1.
- 3) Process for preparing telmisartan according to one of claims 1 and 2, characterised in that a) telmisartan is taken up in a mixture of solvents: consisting of water, formic acid and an organic solvent miscible therewith, heated, and the resulting solution is then filtered, b) the organic solvent is distilled off, optionally while water is simultaneously added in metered amounts, c) the telmisartan form B is precipitated out of the remaining solution by the addition of a base and d) the product precipitated is centrifuged, washed and dried.
- 4) Process according to claim 3, characterised in that organic carboxylic acid esters, ketones or ethers are used as the organic solvent.
- 5) Process according to claim 3 or 4, characterised in that acetone, methylethylketone, methyl acetate, ethyl acetate, ethyl formate, ethyleneglycol dimethylether or tetrahydrofuran is used as the organic solvent.
- 6) Process according to claim 3, 4 or 5, characterised in that acetone, methylethylketone, methyl acetate, ethyl acetate or tetrahydrofuran is used as the organic solvent.
- 7) Process according to claim 3, 4, 5 or 6,characterised in that ethyl acetate is used as the organic solvent.
- 8) Process according to claim 3, 4, 5, 6 or 7, characterised in that ammonia is used as the base.
- 9) Use of telmisartan according to claim 1 or 2 for preparing a pharmaceutical composition.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19901921A DE19901921C2 (en) | 1999-01-19 | 1999-01-19 | Polymorphs of telmisartan, process for their preparation and their use in the manufacture of a medicament |
Publications (1)
Publication Number | Publication Date |
---|---|
ZA200104771B true ZA200104771B (en) | 2002-12-02 |
Family
ID=7894715
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ZA200104771A ZA200104771B (en) | 1999-01-19 | 2001-06-12 | Telmisartan polymorphs, methods for producing same and their use in the preparation of a medicament. |
Country Status (36)
Country | Link |
---|---|
EP (1) | EP1144386B1 (en) |
JP (1) | JP4700813B2 (en) |
KR (1) | KR100658959B1 (en) |
CN (1) | CN1144790C (en) |
AR (1) | AR035475A1 (en) |
AT (1) | ATE252564T1 (en) |
AU (1) | AU765081B2 (en) |
BG (1) | BG65027B1 (en) |
BR (1) | BR0007584A (en) |
CA (1) | CA2352436C (en) |
CO (1) | CO5150238A1 (en) |
CZ (1) | CZ297412B6 (en) |
DE (2) | DE19901921C2 (en) |
DK (1) | DK1144386T3 (en) |
EA (1) | EA003065B1 (en) |
EE (1) | EE04344B1 (en) |
ES (1) | ES2208265T3 (en) |
HK (1) | HK1041485B (en) |
HR (1) | HRP20010514B1 (en) |
HU (1) | HU227401B1 (en) |
IL (2) | IL143634A0 (en) |
MY (1) | MY122755A (en) |
NO (1) | NO319823B1 (en) |
NZ (1) | NZ513528A (en) |
PE (1) | PE20001362A1 (en) |
PL (1) | PL211829B1 (en) |
PT (1) | PT1144386E (en) |
RS (1) | RS50044B (en) |
SA (1) | SA99200838B1 (en) |
SK (1) | SK285429B6 (en) |
TR (1) | TR200102074T2 (en) |
TW (1) | TWI280241B (en) |
UA (1) | UA56358C2 (en) |
UY (1) | UY25980A1 (en) |
WO (1) | WO2000043370A1 (en) |
ZA (1) | ZA200104771B (en) |
Families Citing this family (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6737432B2 (en) | 2001-10-31 | 2004-05-18 | Boehringer Ingelheim Pharma Kg | Crystalline form of telmisartan sodium |
DE10153737A1 (en) * | 2001-10-31 | 2003-05-28 | Boehringer Ingelheim Pharma | Crystalline sodium salt of telmisartan, process for its preparation and its use for the manufacture of a medicament |
DK1854454T3 (en) † | 2002-01-16 | 2014-01-13 | Boehringer Ingelheim Pharma | Process for the preparation of amorphous telmisartan |
DE10314702A1 (en) | 2003-03-31 | 2004-10-21 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Process for the preparation of telmisartan |
GB2414019A (en) * | 2004-05-11 | 2005-11-16 | Cipla Ltd | One-step preparation of telmisartan by condensation and hydrolysis |
KR20080112424A (en) | 2004-10-15 | 2008-12-24 | 테바 파마슈티컬 인더스트리즈 리미티드 | Process for preparing telmisartan |
US7943781B2 (en) | 2004-10-18 | 2011-05-17 | Dr. Reddy's Laboratories Limited | Process for preparing telmisartan |
US8637078B2 (en) | 2005-11-24 | 2014-01-28 | Boehringer Ingelheim International Gmbh | Bilayer tablet comprising telmisartan and diuretic |
EP1908469A1 (en) | 2006-10-06 | 2008-04-09 | Boehringer Ingelheim Vetmedica Gmbh | Angiotensin II receptor antagonist for the treatment of systemic diseases in cats |
DE102008059206A1 (en) | 2008-11-27 | 2010-06-10 | Bayer Schering Pharma Aktiengesellschaft | Pharmaceutical dosage form containing nifedipine or nisoldipine and an angiotensin II antagonist and / or a diuretic |
EP2432452B1 (en) | 2009-05-20 | 2016-07-27 | Boehringer Ingelheim Vetmedica GmbH | Pharmaceutical telmisartan drink solution |
WO2010146187A2 (en) | 2009-06-19 | 2010-12-23 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Process for the preparation of telmisartan |
EP2277866A1 (en) | 2009-06-22 | 2011-01-26 | Inke, S.A. | Process for preparing telmisartan |
WO2011002425A2 (en) | 2009-07-02 | 2011-01-06 | Bilgig Mahmut | Pharmaceutical composition increasing solubility and stability |
WO2011002423A2 (en) | 2009-07-02 | 2011-01-06 | Mahmut Bilgic | Solubility enhancing pharmaceutical composition |
EA025946B1 (en) | 2010-10-27 | 2017-02-28 | Крка, Товарна Здравил, Д. Д., Ново Место | Multilayer pharmaceutical composition comprising telmisartan and amlodipine |
ITMI20102416A1 (en) * | 2010-12-27 | 2012-06-28 | Chemelectiva S R L | INTERMEDIATE FOR THE PREPARATION OF AN ACTIVE PRINCIPLE AND PROCESS FOR ITS PREPARATION |
EP2612658A1 (en) | 2012-01-05 | 2013-07-10 | Laboratorios Lesvi, S.L. | Pharmaceutical compositions of 4'-[(1,4'dimethyl-2'-propyl[2,6'-bi-1h-benzimidazol]-1'-yl)methyl]-[1,1'-biphenyl]-2-carboxylic acid and is 6-chloro-3,4-dihydro-2h-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide |
JP6147546B2 (en) * | 2013-04-10 | 2017-06-14 | 株式会社トクヤマ | Method for producing telmisartan A-type crystals with reduced acetic acid |
EP2979691A1 (en) | 2014-07-30 | 2016-02-03 | Boehringer Ingelheim International GmbH | Oral disintegrating tablet |
JP6275596B2 (en) * | 2014-09-03 | 2018-02-07 | 株式会社トクヤマ | Method for producing ammonium salt of telmisartan |
JP5871294B1 (en) | 2015-02-27 | 2016-03-01 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Immediate release oral tablets |
KR20170001921A (en) | 2015-06-26 | 2017-01-05 | 대원제약주식회사 | A pharmaceutical composition comprising telmisartan with increased stability and a preparation method thereof |
KR20170012703A (en) | 2015-07-22 | 2017-02-03 | 대원제약주식회사 | A pharmaceutical composition comprising telmisartan and a preparation method thereof |
WO2017207375A1 (en) | 2016-05-30 | 2017-12-07 | Boehringer Ingelheim International Gmbh | Fixed dose combination of telmisartan, hydrochlorothiazide and amlodipine |
KR102044223B1 (en) * | 2016-09-12 | 2019-11-13 | 성균관대학교산학협력단 | Solid dispersions comprising Telmisartan and the preparation method thereof |
CN106749037B (en) * | 2016-12-21 | 2019-06-21 | 山东大学 | A kind of unformed Telmisartan-glutaric acid eutectic and its preparation method and application |
CN106749036B (en) * | 2016-12-21 | 2019-06-21 | 山东大学 | A kind of unformed Telmisartan-pimelic acid eutectic and its preparation method and application |
CA3067918A1 (en) | 2017-07-07 | 2019-01-10 | Boehringer Ingelheim Vetmedica Gmbh | Angiotensin ii receptor antagonish for the prevention or treatment of hypertension in cats |
CN109851562A (en) * | 2019-01-30 | 2019-06-07 | 浙江省食品药品检验研究院 | A kind of Telmisartan crystal and preparation method thereof |
WO2023001880A1 (en) | 2021-07-22 | 2023-01-26 | Krka, D. D., Novo Mesto | Bilayer tablet comprising telmisartan and indapamide |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SI9210098B (en) * | 1991-02-06 | 2000-06-30 | Dr. Karl Thomae | Benzimidazoles, drugs with this compounds, and process for their preparation |
US5139114A (en) * | 1991-03-18 | 1992-08-18 | Abex Corporation | Visible brake block wear indicator |
-
1999
- 1999-01-19 DE DE19901921A patent/DE19901921C2/en not_active Expired - Fee Related
- 1999-12-17 PE PE1999001284A patent/PE20001362A1/en not_active Application Discontinuation
- 1999-12-26 SA SA99200838A patent/SA99200838B1/en unknown
-
2000
- 2000-01-07 AU AU22881/00A patent/AU765081B2/en not_active Ceased
- 2000-01-07 ES ES00901510T patent/ES2208265T3/en not_active Expired - Lifetime
- 2000-01-07 KR KR1020017008958A patent/KR100658959B1/en not_active IP Right Cessation
- 2000-01-07 JP JP2000594786A patent/JP4700813B2/en not_active Expired - Lifetime
- 2000-01-07 BR BR0007584-1A patent/BR0007584A/en active Pending
- 2000-01-07 NZ NZ513528A patent/NZ513528A/en not_active IP Right Cessation
- 2000-01-07 PT PT00901510T patent/PT1144386E/en unknown
- 2000-01-07 EE EEP200100375A patent/EE04344B1/en not_active IP Right Cessation
- 2000-01-07 HU HU0105148A patent/HU227401B1/en not_active IP Right Cessation
- 2000-01-07 TR TR2001/02074T patent/TR200102074T2/en unknown
- 2000-01-07 AT AT00901510T patent/ATE252564T1/en active
- 2000-01-07 EA EA200100730A patent/EA003065B1/en not_active IP Right Cessation
- 2000-01-07 CZ CZ20012634A patent/CZ297412B6/en not_active IP Right Cessation
- 2000-01-07 EP EP00901510A patent/EP1144386B1/en not_active Expired - Lifetime
- 2000-01-07 CA CA2352436A patent/CA2352436C/en not_active Expired - Fee Related
- 2000-01-07 WO PCT/EP2000/000065 patent/WO2000043370A1/en active IP Right Grant
- 2000-01-07 RS YUP-511/01A patent/RS50044B/en unknown
- 2000-01-07 DK DK00901510T patent/DK1144386T3/en active
- 2000-01-07 SK SK1020-2001A patent/SK285429B6/en not_active IP Right Cessation
- 2000-01-07 DE DE50004150T patent/DE50004150D1/en not_active Expired - Lifetime
- 2000-01-07 CN CNB00802880XA patent/CN1144790C/en not_active Expired - Fee Related
- 2000-01-07 IL IL14363400A patent/IL143634A0/en active IP Right Grant
- 2000-01-07 PL PL349425A patent/PL211829B1/en unknown
- 2000-01-17 TW TW089100637A patent/TWI280241B/en not_active IP Right Cessation
- 2000-01-17 MY MYPI20000130A patent/MY122755A/en unknown
- 2000-01-18 UY UY25980A patent/UY25980A1/en not_active Application Discontinuation
- 2000-01-18 CO CO00002435A patent/CO5150238A1/en unknown
- 2000-01-19 AR ARP000100241A patent/AR035475A1/en active Pending
- 2000-07-01 UA UA2001085811A patent/UA56358C2/en unknown
-
2001
- 2001-06-07 IL IL143634A patent/IL143634A/en not_active IP Right Cessation
- 2001-06-12 ZA ZA200104771A patent/ZA200104771B/en unknown
- 2001-06-27 BG BG105654A patent/BG65027B1/en active Active
- 2001-07-10 HR HR20010514A patent/HRP20010514B1/en not_active IP Right Cessation
- 2001-07-18 NO NO20013560A patent/NO319823B1/en not_active IP Right Cessation
-
2002
- 2002-04-24 HK HK02103090.1A patent/HK1041485B/en not_active IP Right Cessation
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2352436C (en) | Polymorphs of telmisartan, processes for preparing them and their use in the preparation of a pharmaceutical composition | |
US6358986B1 (en) | Polymorphs of telmisartan | |
JP5247728B2 (en) | Method for producing benzimidazole derivative | |
CN110615788A (en) | Preparation process of high-purity apixaban | |
WO2015124764A1 (en) | Synthesis process of dabigatran etexilate mesylate, intermediates of the process and novel polymorph of dabigatran etexilate | |
WO2014096214A1 (en) | A process for preparation of rivaroxaban | |
CN107531744A (en) | A kind of new crystalline form of shellfish cholic acid difficult to understand and preparation method thereof | |
CN114478837A (en) | Preparation method of sugammadex sodium derivative | |
MXPA01006995A (en) | Telmisartan polymorphs, methods for producing same and their use in the preparation of a medicament | |
CN106279108B (en) | A kind of method of industrialized production Rabeprazole and dextral-rabeprazole intermediate | |
CN111574463A (en) | Riagliptin intermediate compound IV | |
CN102382041A (en) | Preparation method of amlodipine maleate | |
CN114149360B (en) | Preparation method of high-purity nitrendipine bulk drug | |
CN108822097A (en) | A kind of preparation method of Azilsartan process impurity | |
US11932614B2 (en) | Method for preparing diazoxide | |
CN114560853A (en) | Preparation method of 5-chloro-N- [ (2S) -epoxy-2-yl-methyl ] thiophene-2-formamide | |
JP2003503306A (en) | Chemical acetylation of desacetyl-cephalosporin |