HRP20010514A2 - Telmisartan polymorphs, methods for producing same and their use in the preparation of a medicament - Google Patents

Description

The invention relates to polymorphic 4'-[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazol-1-ylmethyl]biphenyl-2-carboxylic acids (INN: telmisartan), in particular, polymorphic form B, a mixture of polymorphic forms, a process for the production of telmisartan containing form B, as well as their use for the production of a drug.

Background of the invention

The compound telmisartan is known from the European patent EP 505 314 BI and has the following chemical structure:

[image]

Telmisartan, as well as its physiologically tolerable salts, have valuable pharmacological properties. Telmisartan represents angiotensin-antagonists, especially angiotensin-11-antagonists, which due to their pharmacological properties can be used, for example, for the treatment of hypertension and heart failure, for the treatment of ischemic peripheral blood supply disorders, myocardial ischemia (angina), for the prevention of the progression of heart failure after myocardial infarction, for the treatment of diabetic neuropathy, glaucoma, gastrointestinal diseases as well as bladder diseases. Further possible areas of therapy can be found in EP 502314 BI, which is hereby incorporated by reference.

During the synthesis of telmisartan, as the final step of the synthesis, the saponification of tert-butyl ester (II) is carried out according to scheme l.

[image]

A suitable experimental procedure which can be carried out on a laboratory scale can be found in EP 502314 BI. However, the transfer of the already known synthesis process to the production process on a technical scale could not be carried out without difficulties. Telmisartan, synthesized on a technical scale according to scheme 1, precipitates after processing in the form of a product that must be subjected to crystallization due to final purification. In the mentioned, forced crystallization, the morphology of the crystallizing final product leads to unpredictable difficulties.

The product that settles in the form of long needles can be very difficult to filter, rinse and isolate, and due to the influence of the solvent, a very long drying time is also required and very hard pieces are formed during drying. The crushing of these pieces leads to a dry powder that shows a great tendency to electrostatic charging and is practically not loose.

The above unfavorable properties prove to be an extraordinary hindrance in the production of the compound on a technical scale, because the preparation of reproducible production on a large scale and high purity is possible only with great difficulty or additional, high technical costs.

Therefore, the task of the proposed invention is to produce telmisartan in a form that enables the synthesis, processing, purification and isolation of telmisartan on a technical scale, whereby the previously mentioned disadvantages are overcome.

Description of the invention in detail

It has surprisingly been found that telmisartan can exist as a solid in different crystalline modifications. Depending on the method of crystallization, it can be translated into two different polymorphic forms A and B.

Polymorph A is a form of telmisartan that is available from the state of the art, which causes the aforementioned difficulties during large-scale production, i.e. during cleaning, isolation and drying of the product.

In contrast, the surprisingly found polymorphic form B of telmisartan shows almost no tendency to electrostatic charge, can be suctioned, centrifuged, rinsed and dried very well and is free from chipping.

According to the invention, the production of polymorphic form B of telmisartan takes place in the following way.

In a mixer of appropriate dimensions, telmisartan as a raw product (crystallized for example from dimethylformamide, dimethylacetamide or the like) as needed with 1 - 5 wt. %, favorable with 3 wt. % of activated carbon is placed in a solvent mixture consisting of water, formic acid and a suitable organic solvent and then dissolved at an elevated temperature, preferably at a temperature of 50-90°C, particularly preferably at 60-80°C.

According to the invention, it is important to use a solvent mixture of formic acid/water with an organic solvent, which according to the invention must meet the following criteria. It must be favorable for the formation of a solution with a mixture of formic acid and water. It must be chemically maximally inert towards the mixture of formic acid and water and it must be able to be separated by distillation from the mixture of formic acid and water. Organic esters of carboxylic acids, ketones or ethers can be used. Examples may include acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, ethyl formate, ethylene glycol dimethyl ether or tetrahydrofuran. According to the invention, acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, THF are preferred, and ethyl acetate is particularly preferred.

According to the invention, per mole of telmisartan, the solvent mixture must be composed of 0.3-0.7 l of water, 10-15 moles of formic acid and 0.3-0.9 l of organic solvent. A favorable ratio is 0.4-0.6 l of water, 11-13 mol of formic acid and 0.4-0.7 l of organic solvent in relation to 1 mol of telmisartan. A particularly favorable ratio of approx. 0.5 l of water, approx. 11.5-12 moles of formic acid and approx. 0.5 l of organic solvent in relation to 1 mol of telmisartan.

According to the invention, the solution obtained after the aforementioned heating is filtered and washed with a mixture of the aforementioned organic solvent and formic acid. The rinsing solution may contain 0.3-1.0 mol, preferably 0.4-0.6 mol per mole of telmisartan, particularly preferably approx. 0.5 moles of formic acid. The amount of rinsing solution is of course determined according to the amount of dissolved telmisartan. According to the invention, 0.1-0.4, preferably 0.15-0.3, especially advantageously 0.2 l of organic solvent is placed per mole of telmisartan.

After washing the residue after filtration with the previously described washing solution, the organic solvent is distilled off as much as possible with the simultaneous addition of water. In doing so, the temperature is maintained in the range of 60-100°C, preferably between 70-100°C. The total amount of water added corresponds mostly to the total amount of distilled solvent. According to the invention, it is desirable to practically completely distill off the organic solvent. Accordingly, the distillation is carried out until the water begins to azeotropically distill. The distilled organic solvent can, if necessary, be reused in the next conversion after separation of the aqueous phase.

Then, to precipitate polymorph B telmisartan, it is cooled to a temperature in the range of 15-60°C, preferably to 20-30°C, and precipitated with a base. The amount of base used depends on the amount of formic acid used. Preferably, 0-2 moles of base less than the formic acid content is added. It is particularly advantageous to add 0.3-1.5 moles of base less than the formic acid content. It is most advantageous to add 0.5-1 mol of base less than the content of formic acid. Also suitable as bases are aqueous solutions of potassium hydroxide, sodium hydroxide, lithium hydroxide or ammonia. Furthermore, suitable organic bases such as triethylamine, diisopropylethylamine or also DBU (diazabicycloundecene) can be used. As bases, the aforementioned aqueous solutions of potassium hydroxide, sodium hydroxide, lithium hydroxide or ammonia are particularly favorable, of which the aqueous ammonia solution is of particular importance.

The precipitated product is separated by centrifugation, washed with water and dried in the usual way in a vacuum at 120-125°C.

A sample taken immediately after centrifugation and dried in the laboratory in a thin layer in a circulating air drier typically shows a content of 95-99% crystalline modification B.

After centrifugation, until the end of drying, the product begins to change into modification A depending on temperature, pH factor, duration of standing and water content. For this reason, in power plants after drying, the ratio of form A to form B is obtained in the best case of approx. 10:90, but also a ratio of 60:40.

Admittedly, even such a lower content of form B during production on a technical scale guarantees positive properties of the product (eg lower tendency towards electrostatic charging, lower tendency to clumping, flowability, etc.). In the aforementioned crystallization process according to the invention, it is important that only form B with its characteristic macroscopic crystal form is formed first. This macroscopic crystal form is largely retained under drying conditions despite partial microscopic conversion to the A form.

A further, very favorable aspect of the process according to the invention is the high space-time utilization of the proposed process as well as the high utilization of the pure product telmisartan, which can be isolated almost quantitatively.

And the form of telmisartan obtained by the process known from the state of the art differs from the telmisartan obtained by the process according to the invention, which is characterized by the content of polymorphic form B, by the useful properties of the product already mentioned in the introduction. Further distinguishing features will be described below.

And the form of telmisartan crystallizes slowly in fine, that is, thin needles that are deposited on top of each other like a desert. The crystalline modification of form B of telmisartan forms very compact, cubic to spherical crystals that have a flowability similar to sand or silica gel.

The two polymorphic forms A and B of telmisartan mixers differ in their melting points. Form B melts at 183+/-2°C (determined by DSC), while Form A melts at 269+/-2°C (determined by DSC). After melting, the lower-melting form B of telmisartan crystallizes again as form A. The consequence of this is, for example, that the endothermic maximum at 183+/-2°C, determined by DSC, is followed by a characteristic exothermic maximum, which again causes the melting of form B into form A high melting point. DSC diagrams (DSC = Differential Scanning Calorimetry) obtained with the Mettler DSC-20, TA8000 system are shown in Figure 1.

Polymorphs A and B also differ in their IR spectrum. Based on this difference, IR spectroscopy can be used to quantitatively determine the ratio of two crystalline modifications after drying in the final product. Pure polymorph A has a characteristic band at 815 cm-1 in the IR spectrum. In polymorph B, this oscillation is shifted to 830 cm-1. Since these two characteristic bands of polymorphs A and B are far enough apart from each other, they are particularly suitable for the aforementioned quantitative determination of the ratio of the two crystal modifications.

IR spectroscopic characterization of the two polymorphic forms A and B was performed with a Nicolet FTIR spectrometer Magna - IR 550 in KBr (2.5 μmol per 300 mg KBr; Nicolet software package OMNIC, version 1.20).

The following examples serve to illustrate the purification and crystallization during the production of polymorphic form B of telmisartan. They are considered only as possible examples of the process shown and the invention is not limited to their content.

Example 1

205.6 kg of recrystallized telmisartan (recrystallized from dimethylformamide or dimethylacetamide), 6.2 kg of activated carbon, 205.6 l of water, 211.6 kg of formic acid (99-100%-tna) and 205 .6 l of ethyl acetate. Mix approx. 1 hour at 70-80°C and then it is filtered into another 1200 l mixer and washed with a mixture of 82.2 l of ethyl acetate and 9.2 kg of formic acid (99-100%-tna). With the simultaneous dosing of 308 l of water, at 80 - 100°C approx. 308 l of solvent. After that, it is cooled to 20 - 30°C and precipitated by adding 313 kg of 25% ammonia solution. The precipitated product is separated by centrifugation, washed with water and dried at 120-125°C. Utilization: 200 kg of telmisartan (97.3% of the theoretical).

Example 2

185 kg of recrystallized telmisartan (recrystallized from dimethylformamide or dimethylacetamide), 5.6 kg of activated carbon, 185 l of water, 190.4 kg of formic acid (99-100%-tna) and 185 l of tetrahydrofuran are placed in a 1200 l mixer. Mix approx. 1 hour at 70-80°C and then filtered into another 1200 l mixer and washed with a mixture of 74 l of tetrahydrofuran and 8.3 kg of formic acid (99-100%-tna). With the simultaneous dosing of 278 l of water, at 70 - 100°C, approx. 278 l of solvent. After that, it is cooled to 20 - 30°C and precipitated by adding 281.5 kg of 25% ammonia solution. The precipitated product is separated by centrifugation, washed with water and dried at 120-125°C. Utilization: 180 kg of telmisartan (97.3% of the theoretical).

Example 3

185 kg of recrystallized telmisartan (recrystallized from dimethylformamide or dimethylacetamide), 5.6 kg of activated carbon, 185 l of water, 190.4 kg of formic acid (99-100%-tna) and 185 l of methyl ethyl ketone are placed in a 1200 l mixer. Mix approx. 1 hour at 60 - 70°C and then filtered into another 1200 l mixer and washed with a mixture of 74 l of methyl ethyl ketone and 8.3 kg of formic acid (99-100%-tna). With the simultaneous dosing of 278 l of water, at 80 - 100°C approx. 278 l of solvent. After that, it is cooled to 20 - 30°C and precipitated by adding 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 theoretical).

Comparative example

150 kg of recrystallized telmisartan (recrystallized from dimethylformamide or dimethylacetamide), 7.5 kg of activated carbon, 750 l of ethanol and 30 kg of 25% aqueous ammonia solution are placed in a 1200 l mixer. Mix approx. 1 hour and then it is filtered into another mixer of 1200 l and washed with a mixture of 150 l of ethanol. It is heated to 70 - 80°C, 35 kg of glacial acetic acid is added and stirred for another 1.5-2 hours at 75 - 80°C. After that, it is cooled to 0 - 10°C and stirred for another 2 hours. The precipitated product is separated by centrifugation, washed with 300 l of ethanol and 300 l of water and dried at 70-90°C. Yield: 135 kg of telmisartan (90% of the theoretical) pure form A.

In the process according to the invention, telmisartan is precipitated on the basis of partial conversion of polymorphic form B into polymorphic form A during drying as a pure substance in a mixture of two polymorphic forms. However, this has no effect on the properties of the drug, because, for example, in the production of telmisartan tablets, the mixture of polymorphic forms A and B is dissolved in a 0.1 N NaOH solution and by spray drying it is transformed into a homogeneous and completely amorphous granulate, which is then in a further step, it is processed into tablets. For further, detailed information regarding the use of the product according to the invention for the production of medicine, reference is made to EP 502314 BI, which is hereby taken into account in its content.

Claims (9)

1. Polymorphic crystal modification B (form B) of telmisartan (formula I), [image] characterized by the fact that in the thermal analysis using DSC, the endothermic maximum appears at 183±2°C. 2. Telmisartan, characterized in that it contains form B according to claim 1. 3. The process for the production of telmisartan according to claim 1 or 2, characterized in that a) telmisartan is placed in a solvent consisting of water, formic acid and an organic solvent that is mixed with water and formic acid, heated and the resulting solution is filtered, b) the organic solvent is - if necessary with the simultaneous addition of water - distilled, c) form B of telmisartan is precipitated from the remaining solution by the addition of a base, i d) the precipitated product is centrifuged, washed and dried. 4. The method according to claim 3, characterized in that an organic carboxylic acid ester, ketone or ether is used as an organic solvent. 5. The method 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 is used as an organic solvent. 6. The method according to claim 3, 4 or 5, characterized in that acetone, methyl ethyl ketone, methyl acetate, ethyl acetate or tetrahydrofuran is used as an organic solvent. 7. The method according to claim 3, 4, 5 or 6, characterized in that ethyl acetate is used as an organic solvent. 8. Process according to claim 3, 4, 5, 6 or 7, characterized in that ammonia is used as a base. 9. The use of telmisartan according to claim 1 or 2, characterized in that it is used for the production of a medicine.