NO326465B1 - Crystalline sodium salt of Telmiseartan, process for the preparation of such, pharmaceutical formulations containing them and its use as a drug - Google Patents

Description

The invention relates to a crystalline sodium salt of 4'-[2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)benzimidazol-1-ylmethyl]biphenyl-2-carboxylic acid (INN: Telmisartan), method for its manufacture, as well as its use for the manufacture of a medicinal product.

Background for the invention

The compound Telmisarten is known from the European Patent

EP 502 314 B1 and has the following chemical structure:

Telmisartan, as well as the physiologically acceptable salts, have valuable pharmacological properties. Telmisartan is an angiotensin antagonist, in particular an angiotensin-ll antagonist, which, on the basis of its pharmacological properties, can for example be used for the treatment of hypertension and heart failure, for the treatment of ischemic peripheral blood flow disorders, myocardial ischemia (angina), for the prevention of progressive heart failure after myocardial infarction, for the treatment of diabetic neuropathy, of glaucoma, of gastrointestinal diseases and of bladder diseases. Further possible fields of therapy appear from EP 502314 B1, the content of which is referred to here.

Telmisartan is commercially available under the trade name Micardis<®>. Based on the free acid of Telmisartan, the administration form, with the help of which Telmisartan is marketed, is produced through a complicated spray drying method. On the basis of the weak solubility of the free acid, less complicated methods for the preparation of an alternative form of administration are difficult to realize.

It is the task of the present invention to provide Telmisartan in a form which enables the preparation of an administration form of this active substance in a less cumbersome form. Here it must be taken into account that, in general, the preparation of mixtures containing an active medicinal substance is based on different parameters, which are connected to the nature of the active medicinal substance itself. Without limitation, examples of these parameters are the stability of action of the starting substance under different environmental conditions, stability during the manufacture of the pharmaceutical formulation as well as stability in the final compositions of the drug. The medicinal active substance used for the production of the aforementioned medicinal compositions should be as pure as possible, and its stability during long-term storage must be present under different environmental conditions. This is absolutely necessary in order to prevent medicinal compositions from being used, in which next to the actual active substance, for example, breakdown products of this are present. In such a case, a subsequently found content of active substance in administration forms could be lower than specified.

A further significant aspect for the production of solid administration forms lies in the fact that for the pharmaceutical quality of a drug formulation, a possible stable, crystalline morphology of the active substance should be present. If this is not the case, a change in the morphology of the active substance can occur under certain circumstances under the manufacturing conditions for the administration form. Such a change can in turn have an influence on the reproducibility of the manufacturing method and thus lead to final formulations that do not satisfy the high quality requirements that must be set for the drug formulation. To that extent, it must generally be taken into account that every change in the state of the solid substance in a drug, which can improve its physical and chemical stability, provides a significant advantage compared to less stable forms of the same drug.

The task of the invention thus consists in the production of a new, stable form of Telmisartan, which satisfies the previously mentioned high requirements, which must be set for an active pharmaceutical ingredient.

Detailed description of the invention

It was surprisingly found that Telmisartan in the form of its sodium salt with the formula 1

can be obtained in crystalline form. By suitable selection of the manufacturing conditions, the polymorphic form of the crystalline sodium salt, which satisfies the initially mentioned requirements, can be obtained in a selective manner.

This crystalline form of the Telmisartan sodium salt is characterized by a melting point of T=245 ± 5°C (determined through DSC=differential Scanning Calorimetry; heating rate: 10 K/min).

The present invention therefore relates to crystalline Telmisartan sodium salt characterized by a melting point of T=245 ± 5°C (determined by DSC).

The above value was measured using a DSC821 from the company Mettler-Toledo.

The crystalline form of the Telmisartan sodium salt according to the invention was examined spectroscopically. The obtained X-ray powder diagram is shown in Figure 1. The subsequent Table 1 summarizes the data obtained by this spectroscopic analysis:

In the preceding table, the value "2 0 [°]" stands for the bending angle in degrees and the value "d [Å]" for the determined lattice plane distance in Å.

Corresponding to the results shown in Table 1, the present invention relates to crystalline Telmisartan sodium salt, characterized in that in the X-ray powder diagram it has, among others, the characteristic values d= 20.95 Å, 17.72 Å, 13.97 Å and 13.63 Å .

The X-ray powder diagram was recorded within the scope of the present invention with the help of a Bruker D8 Advanced with an OED (= location hostile detector) (CuKa - radiation, X = 1.5418 Å, 30 kV, 40 mA).

The present invention further relates to the crystalline Telimsartan sodium salt according to the invention in the form of its solvates and hydrates, preferably in the form of its hydrates, particularly preferably in the form of its hemihydrate.

A further aspect of the present invention relates to a method for producing the crystalline Telmisartan sodium salt according to the invention.

As starting material for the production of crystalline Telmisartan sodium salt according to the invention, the free acid Telmisartan can serve, which can be produced according to methods known in the state of the art (e.g. according to EP 502314 A1).

For the production of the crystalline sodium salt according to the invention, the free acid of Telmisartan is taken up in a suitable solvent, preferably in an organic aprotic solvent, particularly preferably in an organic, aprotic and non-polar solvent. As a solvent according to the invention, toluene, chloroform, dichloromethane, tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, acetone, methyl isobutyl ketone, benzene or acetonitrile are particularly preferred, among which toluene, benzene and methyl isobutyl ketone are particularly preferred. According to the invention, toluene is of greatest importance as a solvent.

Per gram of Telimsartan (free acid) preferably between 0.5 and 5 ml, preferably between 1 and 3 ml, particularly preferably between 1.5 and 2.5 ml of the aforementioned solvent are used.

A suitable sodium salt is then added to this solution or suspension as a base. Suitable sodium salts within the scope of the present invention include sodium hydroxide, sodium hydride, sodium carbonate, sodium bicarbonate or sodium alcoholates. By sodium alcoholates is meant the sodium salts formed with lower alcohols, preferably with alcohols selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, tert-butanol, sec.-butanol, iso-butanol, n-butanol and tert.-amyl alcohol. According to the invention, sodium salts selected from the group consisting of sodium hydroxide, sodium hydride, sodium ethanolate and sodium methanolate are of particular interest, among which the sodium hydroxide and sodium methanolate according to the invention are of particular importance. The aforementioned sodium salts can be added to the reaction mixture as solids. In the case of sodium hydroxide, however, the addition in the form of aqueous solutions is preferred. Here, concentrated aqueous solutions of sodium hydroxide are particularly preferred. For example, caustic soda in a concentration of approx. 45% by weight is used.

The quantity of the sodium salt to be used necessarily depends on the quantity of the free acid Temisartan used. According to the invention, per mol Telmisartan at least 1 mol sodium salt is added. An addition of excess sodium salt is also possible according to the invention. Preferably added per mol of acid used Telmisartan 1-2.5, preferably 1-2, particularly preferably 1-1.5 mol sodium salt.

If sodium hydroxide is used as the sodium salt, and this, according to a preferred embodiment of the method according to the invention, is added in the form of the aqueous solution, it may possibly be appropriate to add a water-miscible organic solvent. This is preferably selected from the group consisting of methanol, ethanol, isopropanol, acetone, tetrahydrofuran, tert.-butanol, 2-butanol, butanol, glycol, ethyl diglycol, 1,3-butanediol, 1,4-butanediol, tert.-amyl alcohol, acetonitrile, nitromethane, formamide, dimethylformamide, N-methylpyrrolidinone, dimethylsulfoxide, dimethylacetamide, nitroethane, methoxy-2-propanol, among which the aforementioned alcohols take on particular importance. Particularly preferably, methanol or ethanol is used within the scope of the method according to the invention, ethanol is particularly preferably used. According to the invention, per mole of Telmisartan used, 50 and 500 ml, particularly preferably between 100 and 400 ml, further preferably between 200 and 350 ml of this solvent are used.

The reaction mixture can then be heated and thus the course of the reaction is accelerated. Preferably, the reaction mixture is heated with good mixing to a temperature of >40°C, particularly preferably above 60°C. The maximum selectable temperature naturally depends on the boiling temperature of the solvent used. If, according to the invention, the previously described preferred solvent is used, it is preferably heated to above 70°C. This heating is usually carried out over a period of 15 minutes to 2 hours, preferably between 20 minutes and an hour. The resulting solution is then filtered and any solids left in the filter are washed with one or more of the previously mentioned solvents.

To an organic solvent heated to a temperature of >40°C, preferably to above 60°C, particularly preferably to the boiling temperature, the filtrate obtained according to the previously described method is added slowly, preferably dropwise. The solvent here is preferably an organic aprotic solvent, particularly preferably an organic, aprotic and non-polar solvent in consideration. As a solvent according to the invention, toluene, chloroform, dichloromethane, tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, acetone, methyl isobutyl ketone, benzene or acetonitrile are particularly preferred, among which toluene, benzene and methyl isobutyl ketone are particularly preferred, according to the invention of particular importance here the solvent toluene. At the same time, during the addition of the filtrate to the already heated solvent in a preferred embodiment of the method, parts of the solvent are distilled off (possibly azeotropically). After the addition is finished, any additional solvent (for example approx. 1-2 thirds of the total amount of solvent used up to this point) is removed by distillation.

The concentrated solution thus obtained is cooled, preferably to room temperature, during which Telmisartan sodium salt crystallizes out. After crystallization is completed, the crystals are separated, possibly washed with the initially mentioned organic solvent and dried.

In a further embodiment of the invention, according to the invention crystalline Telmisartan sodium salt becomes available from the acid addition salts with the formula 2

wherein H-X represents an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, toluenesulfonic acid or methanesulfonic acid. Among the previously mentioned acid addition salts with the formula 2, the salt in which H-X stands for hydrochloric acid is particularly important. In what follows, this acid addition salt is also referred to as Telmisartan hydrochloride.

The compounds with formula 2 are, for example, available from the prior art known 4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl] -biphenyl-2-carboxylic acid tert.-butyl ester (= Telmisartan tert.-butyl ester) by saponification in acetic acid in the presence of the acid H-X.

For the production of the crystalline Telmisartan sodium salt with the formula 1 according to the invention from the acid addition salts with the formula 2, according to the invention, the procedure can be proceeded as follows.

The compound with formula 2 is taken up in a suitable solvent and mixed with a suitable sodium salt.

The solvent is water and/or a suitable alcohol, such as methanol, ethanol or isopropanol mixed with an aprotic organic solvent selected from the group consisting of toluene, chloroform, dichloromethane, tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, acetone, methyl isobutyl ketone, benzene and acetonitrile into account. A particularly preferred solvent is water mixed with ethanol or isopropanol mixed with an aprotic organic solvent selected from the group consisting of toluene, benzene and methyl isobutyl ketone, particularly preferably toluene. A mixture of water, isopropanol and toluene has proven to be particularly suitable for this synthesis step.

The amount of solvent used or solvent mixture depends on the amount of acid addition salt used 2. Preferably, per moles of compound used 2 approx. 0.3 - 3.5 I, preferably approx. 1 - 2.5 I, particularly preferred approx. 1.5 - 2 I of the previously mentioned solvent or solvent mixture used. If one of the preferred solvent mixtures according to the invention is used as a solvent, which in addition to water and an aprotic organic solvent also contains an alcohol as a third solvent component, the volume ratio of water to the aprotic organic solvent according to the invention is preferably in a range from 1:5 to 1:50 and that of water to alcohol used in a ratio of 2:1 to 1:40. Preferably in such a solvent mixture the ratio of water to the aprotic organic solvent is in a range of 1:10 to 1:30, preferably in a range of 1:15 to 1:25 and that of water to the alcohol used in a ratio of 1 :1 to 1:20, preferably in a range of 1:5 to 1:15. Preferably, the aforementioned solvent contains resp. solvent mixture per mol 2 approx. 10 to 100 ml of water, preferably approx. 30 to 80 ml of water, particularly preferably approx. 40 to 70 ml of water. Preferably, the solvent used contains resp. solvent mixture per mol 2 further approx. 100 to 1000 ml of alcohol, preferably approx. 300 to 800 ml of alcohol, particularly preferably approx. 400 to 700 ml of alcohol. Finally, the solvent used contains resp. solvent mixture per mol 2 preferably as third solvent component approx. 200 to 2000 ml of the aforementioned aprotic organic solvent, preferably approx. 600 to 1600 ml, particularly preferred approx. 800 to 1400 ml of the aforementioned aprotic organic solvent.

As suitable sodium salts for the conversion of 2 to 1 sodium hydroxide, sodium hydride, sodium carbonate, sodium hydrogen carbonate or sodium alcoholate come into consideration. By sodium alcoholates is meant the sodium salts formed with lower alcohols, preferably with the alcohols selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, tert-butanol, sec.-butanol, iso-butanol, n-butanol and tert.-amyl alcohol. According to the invention, of particular interest are sodium salts selected from the group consisting of sodium hydroxide, sodium hydride, sodium ethanolate and sodium methanolate, among which the sodium alcoholates sodium ethanolate and sodium methanolate, especially sodium methanolate are of particular importance for this reaction step according to the invention. The aforementioned sodium salts can be added to the reaction mixture as solids. In the case of sodium methanolate, however, the addition in the form of methanolic solutions is preferred. Methanolic solutions of sodium methanolate, which contain this in a concentration of at least 10%, particularly preferably of approx. 20-40% by weight. For example, the methanolic sodium methanolate solution can be used in a concentration of approx.

30% by weight.

The amount of sodium salt to be used necessarily depends on the amount of free acid Temisartan used. According to the invention, it must per moles used

Telmisartan acid addition salt with the formula 2 is added at least 2 mol sodium salt. An addition of excess sodium salt is also possible according to the invention.

If necessary, it may be appropriate to add activated carbon to the aforementioned reaction mixture. For example, this can be done in a quantity of approx. 5 - 50 g per mol used 2, preferably in an amount of approx. 10 - 40 g per moles used 2.

After completion of the addition of the sodium salt and any addition of activated carbon, the resulting reaction mixture is heated for a period of approx. 10

minutes to 2 hours, preferably for approx. 20-45 minutes to a temperature of approx. 50-100°C, preferably to approx. 60-90°C, particularly preferred to approx. 70-80°C. In connection with this heating, part of the solvent, preferably approx. 10-50%, particularly preferred approx. 20-40% of the total amount of solvent is distilled off.

The remaining suspension is then filtered, the filter residue optionally washed with one of the aforementioned aprotic organic solvents, preferably with the aprotic organic solvent, which is also used for carrying out the reaction. The resulting filtrate is then diluted with a solvent or solvent mixture. Here, a mixture of water and the aforementioned aprotic organic solvent is preferably used. Preferably, it will be here per mol originally used compound 2 used approx. 10 to 100 ml of water, preferably approx. 30 to 80 ml of water, particularly preferably approx. 40 to 70 ml of water. As an aprotic organic solvent used here preferably per mol originally used compound 2,250 to 3,000 ml, preferably approx. 800 to 2000 ml, particularly preferred approx. 1200 to 1800 ml.

After dilution, the resulting mixture is heated to reflux. Below that, per mol originally used compound 2 approx. 1-2 I, preferably approx. 1200 to 1800 ml of solvent distilled off. After distilling off the solvent, Telmisartan sodium salt 1 according to the invention crystallizes out. The crystals obtained are isolated, optionally washed with one of the previously mentioned aprotic organic solvents and finally dried.

A further aspect of the present invention relates to crystalline Telmisartan sodium salt, optionally in the form of its solvates or hydrates, preferably in the form of its hydrates, particularly preferably in the form of its hemihydrate, which is available according to previously described methods.

Due to the central importance of the compounds of formula 2 as valuable starting materials for the direct synthesis of the Telmisartan sodium salt 1 according to the invention, a further aspect of the present invention relates to compounds of formula 2 as such

wherein H-X represents an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, toluenesulfonic acid or methanesulfonic acid. Among them, particularly preferred is the compound with the formula 2 in which H-X stands for hydrochloric acid, Telmisartan hydrochloride.

Particularly preferably, the present invention further relates to the previously mentioned compounds with the formula 2 in crystalline form.

Furthermore, due to the pharmaceutical effect of the crystalline Telmisartan sodium salt according to the invention, the present invention relates to its use as a medicine.

A further aspect of the present invention concerns, due to the pharmaceutical effect of the crystalline Telmisartan sodium salt according to the invention, its use for the manufacture of a medicine, in particular for the manufacture of a medicine for the prophylaxis or treatment of diseases, in which the application of therapeutically effective doses of one or more angiotensin-II antagonists may be of therapeutic benefit. Preferably, the present invention aims at the use of crystalline Telmisartan sodium salt for the manufacture of a medicament for the prophylaxis or treatment of diseases selected from the group consisting of hypertension, heart failure, ischemic peripheral blood circulation disorders, myocardial ischemia (angina), heart failure course after myocardial infarction, diabetic neuropathy, glaucoma, gastrointestinal diseases and bladder diseases, among which prophylaxis or treatment of hypertension is particularly preferred.

Accordingly, a further aspect of the present invention relates to pharmaceutical formulations characterized by a content of crystalline Telmisartan sodium salt.

The following synthesis example serves as an illustration of an example of a method of preparation for crystalline Telmisartan sodium salt. It should only be understood as a possible example of a shown method without limiting the invention to its content.

Synthesis example 1: Production of crystalline Telmisartan sodium salt from Telmisartan: As starting material for the production of crystalline Telmisartan sodium salt according to the invention, the free acid Telmisartan can serve, which can be produced according to known methods from the state of the art (e.g. according to EP 502314 A1) .

Place 154.4 g of Telmisartan in 308.8 ml of toluene in a suitable reaction vessel. The suspension is mixed with 27.8 g of 44.68% caustic soda and 84.9 ml of ethanol and heated to 78°C approx. 30 min. and the rate then filtered. Optionally, if larger amounts of solids remain in the filter, it can be washed with a mixture of 61.8 ml of toluene and 15.3 ml of ethanol.

In a further reaction vessel, 463.2 ml of toluene are placed and heated to reflux. While boiling, the filtrate obtained according to the previously described method is slowly added to it and distilled off azeotropically at the same time. After the addition is complete, the solution possibly obtained from the post-washing of the filter can also be dosed, and here too it is azeotropically distilled off. Distill to 103°C and allow the suspension to cool to room temperature. The crystals are filtered off, washed with 154.4 ml of toluene and dried in an air circulation drying cabinet at 60°C.

Yield: 154.6 g (96%), colorless crystals;

Synthetic example 2: Preparation of crystalline Telmisartan sodium salt from Telmisartan hydrochloride:

A) Preparation of Telmisartan hydrochloride:

411 g 4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid tert-butyl ester is suspended in 822 ml of glacial acetic acid and mixed with 213 g of concentrated aqueous hydrochloric acid (37%). The mixture is heated to reflux and distilled off approx. 640 ml solvent. The remaining residue is mixed at 50-60°C slowly with approx. 620 ml of water. 20 g of activated carbon (e.g. Norit SX 2 Ultra) is added to this mixture and the resulting mixture is stirred for approx. 10 min at constant temperature. After filtration, the residue is washed three times with 25 ml of glacial acetic acid each time and with approx. 620 ml of water. The resulting filtrate is reheated to approx. 50-60°C and mixed with approx. 2 In water. After stirring for approx. 12 hours at approx. 23°C, the formed crystals are filtered off and washed twice with approx. 500 ml of water, once with approx. 900 ml of acetone and then dried at approx. 60°C.

Yield: 367 g (92.5%), colorless crystals, m.p.: = 278°C

B) Preparation of crystalline Telmisartan sodium salt from Telmisartan hydrochloride

55.1 g of Telmisartan hydrochloride are taken up in 110.2 ml of toluene, 5.5 ml of water, 55.1 ml of iso-propanol and this mixture mixed with 36.9 g of sodium methylate (30% in methanol) and 2 .75 g of active carbon (e.g. Sorit SX 2 Ultra). It is then heated to approx. 75°C and distilled at a constant temperature over approx. 30 minutes approx. 50 ml solvent mixture. The obtained suspension is filtered and the residue washed with approx. 20 ml of toluene. The filtrate is mixed with approx. 5 ml of water and approx. 150 ml of toluene. The resulting mixture is heated to reflux. There will be approx. 150 ml solvent mixture azeotropically distilled (at up to 102°C). It is allowed to crystallize completely for one hour at 100°C. The crystals are filtered off, washed with approx. 50 ml toluene and dried at approx. 60°C.

Yield: 53.6 g (99%), colorless crystals;

For the production of a medicinal product containing the active ingredient, particularly of an orally applicable medicinal product, particularly preferably a tablet, work can be carried out according to methods known in the state of the art.

Similarly, tablets can for example be prepared by mixing the active substance or active substances with known excipients, for example inert diluents, such as calcium carbonate, calcium phosphate or milk sugar, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and/or agents for obtaining of depot effect such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets can also consist of several layers.

In the following, some examples of pharmaceutical preparations which can be used according to the invention are given. These serve only to illustrate without limiting the subject matter of the invention to this.

Claims (11)

1. Crystalline Telmisartan sodium salt of formula 1 characterized by a melting point of T=245 ± 5°C. 2. Crystalline Telmisartan sodium salt according to claim 1, characterized in that in the X-ray powder diagram, among others, it has the characteristic values d= 20.95 Å, 17.72 Å, 13.97 Å and 13.63 Å. 3. Crystalline Telimsartan sodium salt according to one of claims 1 or 2, characterized in that it exists in the form of its solvates or hydrates, preferably in the form of its hydrates. 4. Process for the production of crystalline Telmisartan sodium salt 1, characterized in that the free acid of Telmisartan is taken up in a suitable solvent, this solution is then mixed with a suitable sodium salt, during which the pr. mol Telmisartan is added at least 1 mol sodium salt, then the reaction mixture is heated over a period of 15 minutes to 2 hours, then the solution obtained is filtered, and the filtrate thus obtained is slowly added to an organic solvent heated to a temperature of >40°C, parts of the solvent are possibly already distilled off during the addition of the aforementioned filtrate, the thereby obtained concentrated solution is then cooled, and the telmisartan sodium salt crystallising underneath is isolated, and is possibly dried after washing with the initially mentioned organic solvent. 5. Process for the production of crystalline Telmisartan sodium salt 1, characterized in that an acid addition salt with the formula 2 wherein H-X represents an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, toluenesulfonic acid or methanesulfonic acid, taken up in a suitable solvent and reacted with a suitable sodium salt, during which per mol of compound 2 used, at least 2 mol of sodium salt are used. 6. Crystalline Telmisartan sodium salt, available according to claim 4 or 5. 7. crystalline Telmisartan sodium salt according to one of claims 1-3 or 6 as a medicinal product. 8. Pharmaceutical formulations characterized by a content of crystalline Telmisartan sodium salt according to one of claims 1-3 or 6. 9. Compounds with formula 2 wherein H-X represents an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, toluenesulfonic acid or methanesulfonic acid. 10. Compound with formula 2 according to claim 9, wherein H-X stands for hydrochloric acid. 11. Compound according to claim 9 or 10, characterized in that they are in crystalline form.