MXPA01006995A

MXPA01006995A - Telmisartan polymorphs, methods for producing same and their use in the preparation of a medicament

Info

Publication number: MXPA01006995A
Application number: MXPA/A/2001/006995A
Authority: MX
Inventors: Heinrich Schneider
Original assignee: Boehringer Ingelheim Pharma Gmbh&Ampco Kg
Priority date: 1999-01-19
Filing date: 2001-07-10
Publication date: 2002-05-09

Abstract

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

Description

Polymorphs of Telmisartan, procedure for its preparation and its use for the preparation of a medicine The invention relates to polymorphs of 4 '- [2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benziraidazol-1-ylmethyl] -biphenyl-2-carboxylic acid (INN: Telmisartan) , in particular the polymorphous form B, to mixtures of the polymorphs, to a process for the preparation of Telmisartan with content in the form B, as well as to its use for the preparation of a medicament.

BACKGROUND OF THE INVENTION The Telmisartan compound is known from the European patent EP 505 314 Bl and has the following chemical structure: Telmisartan, as well as its physiologically compatible salts, possess valuable pharmacological properties. Telmisartan represents an angiotensin antagonist, in particular an angiotensin II antagonist which, in Ref: 129901 due to its pharmacological properties, it can find application, for example, for the treatment of hypertonia and heart failure, for the treatment of peripheral ischemic disorders of the blood supply, of myocardial ischemia (angina), for the prevention of progression of heart failure after myocardial infarction, for the treatment of diabetic neuropathy, glaucoma, gastrointestinal diseases, as well as diseases of the bladder. Other possible therapeutic sectors can be deduced from EP 502 314 Bl, to which reference is made here to its content. In the course of the synthesis of Telraisartán, the saponification of the tert-butyl ester (II) according to the reaction scheme 1 is carried out as the final stage of the synthesis.

Reaction scheme 1: The corresponding prescription for experimental work, which can be performed on a laboratory scale, can be deduced from EP 502 314 Bl. Surprisingly, however, the transformation of the already known synthesis process into a large-scale preparation process could not be carried out without problems. The Temisartan synthesized on a large scale according to Reaction Scheme 1 precipitates, after processing, in the form of a product which, for the subsequent purification, has to be subjected to another crystallization step. In the aforementioned stage of crystallization, necessarily necessary, the morphology of the final product separated by crystallization leads to unforeseen difficulties. The product that precipitates as solid in the form of long needles can only be filtered, washed and isolated with difficulty and, furthermore, by virtue of the inclusion of solvent, it is distinguished by a very long drying time and in the drying process forms large lumps, very hard. A crumbling of these lumps leads to a dry powder which exhibits a high tendency to electrostatic charge and is practically unable to flow. The disadvantageous prior properties of a product are manifested in the large-scale preparation of a compound always as extremely embarrassing, since they make it possible to make it available in a large quantity and high purity in a reproducible manner only with great difficulties or with a high additional technical complexity. Therefore, it is an object of the present invention to provide Telmisartan in a form that allows the synthesis, which can be carried out on a large scale, for the preparation, purification and isolation of Telmisartan in which the aforementioned disadvantages are overcome.

DETAILED DESCRIPTION OF THE INVENTION Surprisingly, it was found that Telmisartan, as a solid, can occur in different crystalline modifications. Depending on the type of crystallization process. It can be transformed into two different polymorphic A and B forms. In the case of polymorph A, it is a form of Telmisartan accessible according to the state of the art, which causes the difficulties mentioned above in the large-scale preparation or in the purification, isolation and drying of the product. On the contrary, the polymorphic form B of Telmisartan, surprisingly found, shows almost no tendency to electrostatic charge, can be suctioned, centrifuged, washed and dried extraordinarily and is also able to flow without crushing.

For the preparation of the polymorphic form B of Telmisartan, according to the invention, as follows. In an apparatus with agitator mechanism, correspondingly dimensioned, crude product of Telmisartan (crystallized, for example, in dimethylformamide, dimethylacetamide or the like) is collected, optionally with 1.5% by weight, preferably with 3% by weight of activated carbon, 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 50-90 ° C, particularly preferably at 60-80 ° C. For the invention, the use of the formic acid / water solvent mixture with an organic solvent is essential, which according to the invention must meet the following criteria. It must be capable of forming a solution with the formic acid / water mixture. Chemically, it must be largely inert to the formic acid / water mixture and must be able to be separated by distillation of the formic acid / water mixture. You can find esters of organic carboxylic acids, ketones or ethers. By way of example, acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, ethyl formate, ethylene glycol dimethyl ether or tetrahydrofuran can be mentioned. Acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, THF are preferred according to the invention, and ethyl acetate is particularly preferred. The solvent mixture should be composed, according to the invention, per mole of Telmisartan, of 0.3-0.7 1 of water, 10-15 moles of formic acid and 0.3-0.9 1 of the organic solvent. A ratio of 0.4-0.6 1 of water, 11-13 moles of formic acid and 0.4-0.7 1 of the organic solvent referred to 1 mole of Telmisartan is preferred. Particularly preferred is a ratio of about 0.5 1 of water, about 11.5-12 moles of formic acid and about 0.5 1 of the organic solvent based on 1 mole of Telmisartan. According to the invention, after the aforementioned heating, the obtained solution is filtered and further washed with a mixture of the aforementioned organic solvent with formic acid. For each mole of Telmisartan, the wash solution may contain 0.3-1.0 moles, preferably 0.4-0.6 moles, particularly preferably, about 0.5 moles of formic acid. The amount of wash solution is determined, by nature, by the amount of dissolved Telmisartan. According to the invention, for each mole of Telmisartan, 0.1-0.4, preferably 0.15-0.3, particularly preferably 0.2-1, of the organic solvent are incorporated. After the subsequent washing of the filtration residue with the above-described washing solution, the organic solvent is distilled off as completely as possible under simultaneous addition of water. In this case, the temperature is maintained in a range of 60-100 ° C, preferably between 70-100 ° C. The amount of water contributed together by dosage corresponds, in essence, to the total amount of solvent separated by distillation. According to the invention, a practically complete distillation of the organic solvent is desired. Correspondingly, the distillation is carried out in such a way that water, partly azeotropic, is also separated by distillation. The organic solvent separated by distillation can be used, optionally after the separation of the aqueous phase, again in the consecutive reactions. For the precipitation of polymorph B of Telmisartan, it is then cooled to a temperature range of 15-60 ° C, preferably up to 20-30 ° C, and precipitated with a base. The amount of base to be used depends on the amount of formic acid used.

Preferably, 0-2 moles less of base is used than formic acid is contained. In a particularly preferred way, 0.3-1.5 moles less of base than formic acid is used. In a more particularly preferred manner, 0.5-1 mole less base than formic acid is used. Suitable bases are aqueous solutions of potassium hydroxide, sodium hydroxide, lithium hydroxide or ammonia. In addition, suitable organic bases such as triethylamine, diisopropylethylamine or also DBU (diazabicycloundecene) can be used. Particularly preferred are the aqueous solutions of the aforementioned potassium hydroxide, sodium hydroxide, lithium hydroxide or ammonia, of which aqueous solutions of ammonia are particularly important. The precipitated product is separated by centrifugation, washed with water and usually dried in vacuum at 120-125 ° C. A sample taken directly after centrifugation and dried in the laboratory in a thin layer in a circulating air drying oven typically shows a 95-99% content of crystal modification B. After centrifugation, the product, depending on the The temperature, the pH, the residence time and the water content start, towards the end of the drying, to become partly part of the modification A. In the case of runs of operation, therefore, after drying, relations of form A to form B, in the best of cases, of approximately 10:90, but also relations of 60:40. However, such a low content of this type of form B also guarantees the positive properties of the product (for example low tendency to electrostatic charge, low tendency to caking, creep capacity, etc.), necessary for large-scale preparation . It is essential according to the invention in the aforementioned crystallization process that firstly only form B with its characteristic macroscopic crystalline form results. This macroscopic crystalline form is widely conserved in form A under the drying conditions, despite a partial microscopic conformation. Other very advantageous aspects of the procedure according to the invention are the high space-time yield in the present process, as well as the high yield in pure product of Telmisartan, which can be isolated almost quantitatively. The Telmisartan of form A obtainable according to the preparation process known from the state of the art differs from the accessible Telmisartan according to the invention, which is characterized by a content in polymorphous form B, in the advantageous product properties, already mentioned Start. Other differential characteristics are described in what follows. Telmisartan of form A crystallizes into long, thin or thin needles that adhere to one another like felt. The crystalline modification of Telmisartan of form B forms very compact crystals, in the form of cubes to spherical ones, which exhibit a flow behavior in the form of sand or silica gel. The two polymorphic A and B forms of Telmisartan differ strongly in their melting point. Form B melts at 183 ± 2 ° C (determined by CBD), form A at 269 ± 2 ° C (determined by CBD). After the fusion, it is again separated by crystallization as form A to form B of Telmisartan with a lower melting point. This form A finds its precipitate, for example, because the endothermic maximum at 183 ± 2 ° C, determined by CBD, is followed by a characteristic exothermic maximum that reflects the crystallization of the molten mass of form B in form A of high melting point. The CBD diagrams (CBD = differential scanning calorimetry) obtained with a Mettler DSC-20 system, TA8000 are represented in figure 1. Polymorphs A and B also differ in their IR spectrum. By virtue of this differentiation, IR spectroscopy can be used, if necessary, for the quantitative determination of the ratio of the two crystalline modifications after drying in the final product. Polymorph A pure presents in the IR spectrum a characteristic band at 815 cm-1. In the case of polymorph B, this oscillation shifts to 830 cm "1. Since these two characteristic bands of polymorphs A and B are sufficiently separated from each other, they are particularly suitable for the quantitative determination, mentioned above, of the ratio of the two crystalline modifications The IR spectroscopic characterization of the two polymorphic forms A and B was carried out with the spectrometer Magna-IR 550 from Nicolet FTIR in KBr (2.5 μmol per 300 mg KBr, OMNIC software package from 'Nicolet, version 1.20). The following Examples serve for the illustration of purification and crystallization processes carried out by way of example for the preparation of the polymorphic form B of Telmisartan. They must be understood only as possible ways of proceeding, represented by way of example, without limiting the invention to its content.

Example 1 205.6 kg of recrystallized product of Telmisartan (recrystallized from dimethylformamide or dimethylacetamide), 6.2 kg of active carbon, 205.6 1 of water, 211.6 kg of formic acid (99-100%) are incorporated in an apparatus with stirring mechanism of 1200 1. ) and 205.6 1 ethyl acetate. It is stirred for about 1 h at 70-80 ° C and then it is filtered on another apparatus with stirring mechanism of 1200 1 and it is further washed with a mixture of 82.2 1 of ethyl acetate and 9.2 kg of formic acid (99-100%) ). A total of 308 1 of solvent are distilled off at 80 - 100 ° C by the simultaneous addition of 308 1 of water. It is then cooled to 20-30 ° C and precipitated by the addition by metering of 313 kg of 25% ammonia solution. The precipitated product is separated by centrifugation, washed with water and dried at 120-125 ° C. Yield: 200 kg of Telmisartan (97.3% of theory).

Example 2 In an apparatus with stirring mechanism of 1200 1, 185 kg of recrystallized product of Telmisartan (recrystallized in dimethylformamide or dimethylacetamide), 5.6 kg of active carbon, 185 1 of water, 190.4 kg of formic acid (99-100%) are incorporated. ) and 185 1 tetrahydrofuran. It is stirred for about 1 h at 60-70 ° C and then it is filtered in another apparatus with stirring mechanism of 1200 1 and it is further washed with a mixture of 74 1 of tetrahydrofuran and 8.3 kg of formic acid (99-100%). A total of 278 1 of solvent are distilled off at 70 - 100 ° C by the simultaneous addition of 278 1 of water. It is then cooled to 20-30 ° C and precipitated by the introduction by metering of 281.5 kg of 25% ammonia solution. The precipitated product is separated by centrifugation, washed with water and dried at 120-125 ° C. Yield: 180 kg of Telmisartan (97.3% of theory).

EXAMPLE 3 185 kg of recrystallized Telmisartan product (recrystallized from dimethylformamide or dimethylacetamide), 5.6 kg of active carbon, 185 1 of water, 190.4 kg of formic acid (99-100%) are incorporated in an apparatus with stirring mechanism of 1200 1. ) and 185 1 of methyl ethyl ketone. Stir for about 1 h at 60 -70 ° C and then stir. it is filtered in another apparatus with an agitator mechanism of 1200 1 and it is continued to be washed with a mixture of 74 1 of methyl ethyl ketone and 8.3 kg of formic acid (99-100%). Under the incorporation by simultaneous dosing of 278 1 of water, they are separated by distillation, at 80-100 ° C, approximately 278 1 of solvent. It is then cooled to 20-30 ° C and precipitated by the introduction by dosing of 281.5 kg of 25% ammonia solution. The precipitated product is separated by centrifugation, washed with water and dried at 120-125 ° C. Yield: 178 kg of Telmisartan (96.2% of theory).Comparative Example In an apparatus with stirring mechanism of 1200 1 150 kg of Telmisartan (recrystallized in dimethylformamide or dimethylacetamide), 7.5 kg of active carbon, 750 1 of ethanol and 30 kg of 25% ammoniacal solution are incorporated. It is stirred for about 1 h and then it is filtered in another apparatus with stirring mechanism of 1200 1 and it is continued washing with 150 1 of ethanol. Heat to 70-80 ° C, add 35 kg of glacial acetic acid and stir for 1.5-2 h at 75-80 ° C. It is then cooled to 0-10 ° C and stirred again for 2 h. The precipitated product is separated by centrifugation, washed with 300 1 of ethanol and 300 1 of water and dried at 70-90 ° C. Yield: 135 kg of Telmisartan (90% theoretical) of pure A form.

Telmisartan precipitates in the preparation process according to the invention, by virtue of the partial transformation of the polymorphous form B into the polymorph form A during the drying process, as a pure substance in a mixture of two polymorphic forms. However, this has no influence on the properties of the medicament since, for example in the framework of the preparation of tablets of Telmisartan, the mixture of polymorphic forms A and B is dissolved in 0.1 N NaOH solution and, by drying by spraying, it is transformed into a homogeneous and completely amorphous granule which, then, is added to the other steps for the production of tablets. For more detailed and detailed information regarding the use of the products according to the invention for the preparation of a medicine, reference is made to EP 502 314 Bl, to which reference is made here to its content. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present invention.

Claims

CLAIMS Having described the invention as above, the content of the following claims is claimed as property. 1.- Crystal modification B (form B) polymorph of Telmisartan (formula I), characterized in that an endothermic maximum at 183 ± 2 ° C is manifested in the thermal analysis by CBD.
2. The Telmisartan, characterized by a content in form B in accordance with claim 1.
3.- The procedure for the preparation of Telmisartan according to one of claims 1 or 2, characterized in that a) Telmisartan is collected in a solvent mixture composed of water, formic acid and an organic solvent miscible therewith, heated and then the solution obtained is filtered b) the organic solvent is distilled off -eventually under incorporation by simultaneous dosing of water-, c) form B of Telmisartan is precipitated from the remaining solution by the addition of a base, and d) the precipitated product is separated by centrifugation , wash and dry.
4. The process according to claim 3, characterized in that esters of organic carboxylic acids, ketones or ethers are used as the organic solvent.
5. The process according to claim 3 or 4, characterized in that acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, ethyl formate, ethylene glycol dimethyl ether or tetrahydrofuran are used as the organic solvent.
6. The process according to claim 3, 4 or 5, characterized in that acetone, methyl ethyl ketone, methyl acetate, ethyl acetate or tetrahydrofuran are used as the organic solvent. 1 .
The process according to claim 3, 4, 5 or 6, characterized in that ethyl acetate is used as the organic solvent.
8. The process according to claim 3, 4, 5, 6 6 1, characterized in that ammonia is used as the base.
9. The use of Telmisartan in accordance with claim 1 6 2 for the preparation of a medicament. SUMMARY OF THE INVENTION The invention relates to polymorphs of 4 '- [2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-ylmethyl] -biphenyl-2-carboxylic acid polymorph ( INN: Telmisartan), in particular the polymorphic form B, to mixtures of the polymorphs, to a process for the preparation of Telmisartan with content in the form B, as well as its use for the preparation of a medicament.