BG65027B1 - Telmisartan polymorphs, methods for producing same and their use in the preparation of a medicament - Google Patents

Abstract

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

Description

Technical field

The invention relates to polymorphic forms of 4 '- [2n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-ylmethyl] biphenyl-2-carboxylic acid (INN: telmisartan), in particular to polymorph B, mixtures of polymorphs, a method for preparing telmisartan containing form B, and to its use for the preparation of a medicament.

BACKGROUND OF THE INVENTION

The telmisartan compound is known from EP 505 314 B1 and has the following chemical structure:

- (I) Telmisartan, as well as its physiologically acceptable salts, have valuable pharmacological properties. Telmisartan is an angiotensin antagonist, in particular an angiotensin II antagonist, which, based on its pharmacological properties, can be used, for example, for the treatment of hypertension and heart failure, for the treatment of ischemic peripheral circulatory disorders, myocardial ischemia, prevention of progressive heart failure after myocardial infarction, treatment of diabetic neuropathy, glaucoma, gastrointestinal diseases, and bladder diseases. Other possible areas of therapy are described in EP 502314 B1, for which content reference is made at this point.

During telmisartan synthesis, tertiary butyl ester (II) saponification according to Scheme 1 is carried out as a final synthesis step.

Scheme 1:

The relevant laboratory-specified technological requirements must be taken from EP 502314 B1. Of course, reproduction of the already known method of synthesis in an industrial production process is seamless. According to Scheme 1, synthesized industrial telmisartan is precipitated after processing as a product to be subjected to a subsequent crystallisation step for final purification. At the required required crystallization step, the morphology of the crystallized final product leads to unforeseen difficulties.

The precipitated solid as a long needle product can only be filtered, washed and difficult to isolate, further due to incorporation, the solvent is characterized by too long drying and forms large and very solid pieces during the drying process. The crushing of these pieces results in a dry powder, which shows a tendency for electrostatic loading and is practically not loose.

In the industrial production of a single compound, the aforementioned disadvantages of the product are always extremely difficult, since they allow for its reproducibility in greater quantities and in greater purity only with great difficulty or additional higher technical cost.

Therefore, the problem that is solved with the present invention is to obtain telmeni zartan in a form that allows industrial synthesis, processing, purification and isolation, while overcoming the aforementioned disadvantages.

SUMMARY OF THE INVENTION

It has surprisingly been found that telmisartan as a solid may exist in various crystalline modifications. Depending on the method and process of crystallization, it is possible to undergo two polymorphic forms A and B.

Polymorph Form A is a form of telmisartan available from the prior art which causes the above mentioned difficulties in industrial production, respectively purification, isolation and drying of the product.

Surprisingly, the polymorphic form B found in telmisartan, on the contrary, does not show a tendency to electrostatic load, can be very well filtered with a water pump, centrifuged, washed and dried, and without fragmentation without any fluidity.

To obtain polymorphic form B of telmisartan, proceed as follows:

In a suitably sized industrial stirrer, the crude product telmisartan (crystallized from, for example, dimethylformamide, dimethylacetamide or the like) is taken up, if necessary, by 1 to 5 wt. %, preferably 3 wt. % of activated carbon in a solvent mixture consisting of water, formic acid and a suitable organic solvent and then dissolved at a higher temperature, preferably a temperature of 50-90 ° C, especially preferably 6080 ° C.

It is essential according to the invention to use a formic acid / water solvent mixture with an organic solvent, which according to the invention must satisfy the following criteria. It must be suitable for the formation of a solution with formic acid / water mixture. It must be substantially inert to the formic acid / water mixture and must be capable of being separated by distillation from the formic acid / water mixture. Organic carboxylic acid ester, ketone or ether may be used. For example, acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, ethyl formate, ethylene glycol dimethyl ether or tetrahydrofuran could be mentioned. Acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, tetrahydrofuran are particularly preferred according to the invention, in particular ethyl acetate.

The solvent mixture according to the invention for mol telmisartan should consist of 0.3-0.7 l water, 10-15 mol formic acid and 0.3-0.91 organic solvent. A ratio of 0.4-0.6 1 water, 11-13 molar formic acid and 0.4-0.71 organic solvent relative to 1 mol telmisartan is preferred. Particularly preferred is a ratio of 0.5 l of water, about 11.5-12 mol of formic acid and about 0.5 1 of an organic solvent per 1 mol of thermisartan.

According to the invention, after the heating mentioned above, the solution is filtered and washed with a mixture of the aforementioned formic acid organic solvent. For mol telmisartan, the washing solution may contain 0.3-1.0 mol, preferably 0.4-0.6 mol, especially preferably about 0.5 mol of formic acid. The amount of wash solution is determined according to the amount of telmisartan dissolved. For mol telmisartan according to the invention 0.1-0.4, preferably 0.15-0.3, particularly preferably 0.21 of the organic solvent is used.

After further washing of the filtration residue with the washing solution described above, it is possible to completely separate the organic solvent by distillation with simultaneous dosing of water. In this case, a temperature of 60-100 ° C is maintained, preferably 70-100 ° C. The total amount of dispensed water essentially corresponds to the total amount of solvent separated by distillation. According to the invention, it is desirable that complete separation by distillation of the organic solvent is practically complete. Accordingly, distillation is carried out as long as the water is separated by distillation partially azeotropically with the solvent. The organic solvent separated by distillation, optionally after separation of the aqueous phase, can be reused in the process.

For precipitation, telmisartan polymorph B is cooled to a temperature of 15-60 ° C, preferably 20-30 ° C and precipitated with a base.

The amount of base used depends on the amount of formic acid used. It is preferable to add 0-2 mol less base than formic acid. In particular, it is preferable to add 0.3-1.5 mol less base than formic acid. It is generally preferred to add 0.5-1 mol less base than formic acid. Basics include aqueous solutions of potassium hydroxide, sodium hydroxide, lithium hydroxide and ammonia. Suitable organic bases such as triethylamine, diisopropylethylamine or DBU (diazabicycloundecene) may be useful. Particularly preferred as bases are the aforementioned aqueous solutions of potassium, sodium, lithium hydroxide or ammonia, of which aqueous ammonia solutions are of particular importance. The precipitated product was centrifuged, washed with water, and dried in vacuo at 120-125 ° C in the usual manner.

Directly taken after centrifugation and dried in the laboratory in a thin layer in a hot air circulation oven, the sample typically shows a 95-99% crystalline modification B content.

After centrifugation, depending on temperature, pH, treatment time and water content, the product begins, almost by the end of drying, to partially turn into modification A. For these reasons, form A ratios are obtained in production conditions after drying. to Form B from 10:90 to 60:40.

Undoubtedly, such a lower B content guarantees the necessary positive qualities of the product in industrial production (eg reduced tendency for electrostatic loading, reduced tendency for fragmentation, ability to flow, etc.). Crucially, according to the invention, in the above-mentioned crystallization process, it is firstly obtained exclusively Form B with its characteristic macroscopic crystalline form. This macroscopic crystalline form is retained under drying conditions, despite partial conversion further into Form A.

Other advantageous aspects of the process according to the invention are the large time volume yield of the present process as well as the high yield of pure telmisartan, which can be isolated almost quantitatively.

The method of manufacturing telmisartan produced by the prior art is different from the telmisartan produced according to the invention, which is characterized by polymorphic B content, in terms of the product advantages already mentioned in the beginning. Other distinguishing features will be described below.

Form A form telmisartan crystallizes as long, fine or resp. thin needles that are glued felt-like. The crystalline modification of Form B telmisartan forms too compact cubic-shaped to spherical crystals that exhibit flowability similar to sand or silica gel.

The two polymorphic forms A and B of telmisartanase differ too much in melting point. Form B melts at 183 +/- 2 ° C (determined by DSC), Form A melts at 269 +/- 2 ° C (determined by DSC). After melting, the low-melting form B of telmisartan crystallizes again as Form A. This has, for example, explained that a characteristic exothermic maximum at 183 +/- 2 ° C corresponds to the endothermic maximum at 183 +/- 2 ° C, which reflects the crystallization of the melt. Form B in high melting form A. Meter's DSC20, TA8000 system, DSC diagrams (DSC = Differential scanning Calorimetry) are shown in Figure 1.

The polymorphic forms A and B also differ in their IR spectrum. Based on this difference, IR spectroscopy can optionally be used to quantify the ratio of the two crystalline modifications in the final product after drying.

Pure polymorph A has a characteristic bandwidth at 815 cm @ ^-1 . In polymorphic form, this oscillation is offset by 830 cm ^-1 . Since these two characteristic frequency bands of polymorphic forms A and B are sufficiently separated from each other, they are particularly suitable for quantifying the ratio of the two crystal modifications mentioned above.

IR spectroscopic characterization of the two polymorphic forms A and B was performed with a Nicolet ETIR Spetrometer Magna-IR 550 in KBr (2.5 mol for 300 mg KBr; Nicolet software pacage OMNIC, version 1.20).

The following examples serve to illustrate the purification and crystallization method for the preparation of polymorph Form B of telmisartan. They should be understood only as possible exemplary methods of procedure, without limiting the invention to them.

Examples of carrying out the invention

Example 1.

Put in 1200 liter stirrer

205.6 kg telmisartan recrystallized (recrystallized from dimethylformamide or dimethylacetamide), 6.2 kg activated carbon, 205.6 1 water,

211.6 kg formic acid (99-100%) and

205.6 1 ethyl acetate. It was stirred for about 1 hour at 7030 ° C and then in another 1200 liter stirrer was filtered and further washed with a mixture of 82.2 l ethyl acetate and 9.2 kg formic acid (99-100%). At simultaneous dosing with 3,081 water, about 308 l of solvent is distilled off at 80-100 ° C. It was then cooled to 20-30 ° C and precipitated by dosing 313 kg of a 25% ammonia solution. The precipitated product was centrifuged, washed with water and dried at 120-125 ° C.

Yield: 200 kg telmisartan (97.3% theoretical).

Example 2.

185 kg of telmisartan recrystallizate (recrystallized from dimethylformamide or dimethylacetamide) were placed in a 1200 liter stirrer, 5.6 kg of activated carbon, 185 l of water, 190.4 kg of formic acid (99-100%) and 1851 of tetrahydrofuran. It was stirred for 1 h at 60-70 ° C and then filtered and washed in another 1200 liter stirrer and washed with a mixture of 74 l of tetrahydrofuran and 8.3 kg of formic acid (99-100%). With the simultaneous dosing of 278 l of water, about 278 l of solvent was distilled off at 70-100 ° C. It was then cooled to 20-30 ° C and precipitated by dosing 281.5 kg of a 25% ammonia solution. The precipitated product was centrifuged, washed with water and dried at 120-125 ° C.

Yield: 180 kg telmisartan (97.3% theoretical).

Example 3.

185 kg of telmisartan recrystallize (recrystallized from dimethylformamide or dimethylacetamide) are placed in a 1200 liter stirrer, 5.6 kg of activated carbon, 185 l of water, 190.4 kg of formic acid (99-100%) and 185 l of methylethyl ketone. The mixture was stirred for 1 hour at 60-70 ° C and then filtered and washed with another mixture of 741 methyl ethyl ketone and 8.3 kg formic acid (99-100%) in another 1200 liter stirrer. With simultaneous dosing with 278 l of water, about 278 l of solvent is distilled off at 80-100 ° C. It was then cooled to 20-30 ° C and precipitated by dosing with 281.5 kg of a 25% ammonia solution. The precipitated product was centrifuged, washed with water and dried at 120-125 ° C.

Yield: 178 kg telmisartan (96.2% theoretical).

Comparison example

In a 1200 liter stirrer, 150 kg telmisartan recrystallize (recrystallized from dimethylformamide or dimethylacetamide) 7.5 kg activated carbon, 750 1 ethanol, 30 kg 25% aqueous ammonia. The mixture was stirred for about 1 hour and then filtered and washed with another 150 liters of ethanol in another 1200 liter stirrer. It is heated to 70-30 ° C, glacial acetic acid is added and stirred for 1.5-2 hours at 75-80 ° C. It was then cooled to 0-10 ° C and stirred for another 2 h. The precipitated product was centrifuged, washed with 300 l ethanol and 300 l water and dried at 70-90 ° C.

Yield: 135 kg telmisartan (90% theoretical) pure form A.

In the manufacturing process of the invention, due to the partial conversion of polymorph Form B to polymorph Form A during the drying process, telmisartan is precipitated as a pure substance in a mixture of the two polymorph forms. This undoubtedly does not affect the properties of the drug, since during the production of telmisartan tablets, the mixture of polymorphs A and B is dissolved in 0.1 N sodium hydroxide solution and, when spray dried, becomes homogeneous and fully amorphous granulate, which is then introduced into the subsequent tablet manufacturing steps. For further, detailed information on the use of the product for the manufacture of the medicinal product, reference may be made to EP 502314 B1, the contents of which have been taken into account at this point.

Claims (9)

Claims 1. Polymorphic crystalline modification B (Form B) of telmisartan (Formula I) Me is characterized by an endothermic maximum at 183 ± 2 ° C, obtained by thermal analysis by DSC. 2. Telmisartan comprising Form B according to claim 1. Method for the preparation of telmisartan according to one of Claims 1 or 2, characterized in that: a) telmisartan in a solvent mixture consisting of water, formic acid and one miscible organic solvent is absorbed, heated and the resulting solution is then filtered; B) the organic solvent is optionally separated by distillation with 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 centrifuged, washed and dried. A process according to claim 3, characterized in that organic carboxylic acid esters, ketones or ethers are used as the organic solvent. A process according to claim 3 or 4, characterized in that acetone, methyl ethyl ketone, methyl acetate, ethyl acetate are used as the organic solvent; ethyl formate, ethylene glycol dimethyl ether or tetrahydrofuran. A 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. A method according to claim 3, 4, 5 or 5 6, characterized in that ethyl acetate is used as the organic solvent. The method of claim 3,4,5,6 or 7, characterized in that ammonia is used as the base. Use of telmisartan according to claim 1 or 2 for the preparation of a medicament.