EA022496B1 - Polymorphous form of dabigatran etexilate hydrochloride - Google Patents

Abstract

The present invention relates to a novel polymorphous salt of dabigatran etexilate hydrochloride of the formula 11 and process for the preparation thereof.

Description

3 - [(2 - {[4- (Hexyloxycarbonylaminoiminomethyl) phenylamino] methyl} -1-methyl-1Nbenzimidazole-5-carbonyl) pyridin-2-yl-amino] propionate ethyl ester (international nonproprietary name: dabigatran etexilate) of the formula:

is an oral anticoagulant that has the direct effect of a thrombin inhibitor.

The present invention is to obtain a new polymorphic form of the salt of dabigatran etexilate and a method for producing a new salt of dabigatran etexilate. The present invention also relates to pharmaceutical preparations containing a new salt of dabigatran etexilate, and their use for the prevention and treatment of postoperative deep vein thrombosis and stroke.

In more detail, the purpose of the present invention is to provide a new and morphologically uniform polymorph of the dabigatran etexilate salt formed with hydrochloric acid, a method for its preparation, its pharmaceutical composition and its use for the prevention and treatment of postoperative deep vein thrombosis and stroke.

The current level of technology

Dabigatran etexilate was first described in EP 966454 B1 by Howell (Naie1) et al. According to Example 113 of the above patent, dabigatran etexilate of formula 11 is prepared in a similar manner in the method described in Example 90 by reacting 1-methyl-2- [Y- (4amidinophenyl]) aminomethyl] -5-benzimidazole-carbonate Y- (2-pyridyl ) -H- [2- (ethoxycarbonyl) ethyl] amide hydrochloride and hexyl chloroformate.

The base thus prepared was characterized by thin layer chromatography and mass spectrometry. In the above description there is no data related to the crystallographic properties of the base of dabigatran etexilate.

The same method described in the above patent is disclosed in a publication by Howel et al (I. May. Sies. 2002, 45, 1757-1766), where the base of dabigatran etexilate is characterized by a melting point (128-129 ° C) and 'H-NMR (nuclear magnetic resonance).

Three polymorphic forms of dabigatran etexilate mesylate are described in ΛΘ 2005/028468. Polymorphic forms obtained from the base by crystallization (form I, II and hemihydrate) were characterized by a powder X-ray diffractogram and differential scanning calorimetry curves.

In ΛΘ 2006/114415, 6 salts of dabigatran etexilate are described, such as hydrochloride, citrate, tartrate, malonate, maleate and salicylate. These salts were not characterized by X-ray powder diffraction patterns, only differential scanning calorimetry curves. The melting points are arranged in order as follows: 135, 170, 160, 100, 120, 155 ° C.

In ΛΘ 2006/131491, 3 polymorphic forms of the dabigatran etexilate base are described. The polymorphic forms obtained by crystallization were characterized by a powder X-ray diffractogram, differential scanning calorimetry curves, and measurement of thermogravimetric data.

ΛΘ 2008/043759 describes other salts of dabigatran etexilate and their polymorphic forms, such as two polymorphs (I and II) of a salt formed with phosphoric acid, two polymorphs (III and IV) of a salt formed with fumaric acid, three polymorphs (I, II and V) salts formed with oxalic acid, three polymorphs (II, V, and VI) of a salt formed with hydrochloric acid, and four polymorphs (I, V, VI, and VII) of a salt formed with p-toluenesulfonic acid. Polymorphic forms were characterized by powder x-ray diffractogram. In addition, Form IV of the salt formed with fumaric acid and the four forms of salt (I, V, VI, and VII) formed with p-toluenesulfonic acid were also characterized by differential scanning calorimetry curves.

In ΛΘ 2008/059029 two more anhydrous forms and three solvates of the dabigatran etexilate base are described. Anhydrous forms II and IV, monohydrate forms I and II, and a nitrobenzene solvate of form I were characterized by a powder X-ray diffractogram and differential scanning calorimetry curves.

Summary of the invention

Despite the fact that many salts of dabigatran etexilate and their polymorphic forms are already known, it was unexpectedly discovered that some new chemically and morphologically stable salts of dabigatran etexilate and their polymorphic forms can be obtained. The object of the present invention is a new polymorphic salt form of dabigatran etexilate and a method for its preparation. The present invention also relates to pharmaceutical preparations containing a new salt of dabigatran etexilate, and their use for the prevention and treatment of postoperative deep vein thrombosis and strokes. The dabigatran etexilate salt of the present invention is a hydrochloride salt

- 1 022496 acid and dabigatran etexilate (1: 1) (form IX) of formula 8

DETAILED DESCRIPTION OF THE INVENTION

Recently, in the pharmaceutical industry there has been a serious demand for a method that provides a product in a reproducible manner, in a morphologically homogeneous and pure form, in order to meet the stringent requirements of pharmaceutical standards. Various polymorphic forms are known to exhibit differences in important characteristics, such as dissolution time, biological yield, and chemical stability.

Obtaining a morphologically homogeneous product is also important from a technological point of view, given that polymorphic forms have different technological properties (during filtration, drying, dissolution and tabletting). Moreover, from an economic point of view, it is very important that the method is suitable for industrial scaling, can be easily reproduced, and lead to a morphologically homogeneous product.

So far, no method for preparing morphologically homogeneous salts of dabigatran formed with sulfuric or maleic acid has been described in the literature, and no analytical data (IR spectrum, powder X-ray diffraction patterns or single-crystal X-ray diffraction patterns) used to characterize crystalline forms of was provided.

The aim of the present invention was to provide a morphologically homogeneous salt of dabigatran etexilate, which meets the pharmaceutical requirements for physico-chemical properties and stability and which can be obtained in a reproducible manner even on an industrial scale.

The aforementioned goal was achieved by obtaining a new crystalline form of the salt of dabigatran etexilate using hydrochloric acid, and a method for its preparation.

It was unexpectedly discovered that the aforementioned new salt of dabigatran etexilate can be obtained in a new form, which is morphologically homogeneous, and the characteristics of the powder x-ray diffractogram and DSC data (differential scanning calorimetry) differ from the characteristics of the known forms of salts of dabigatran etexilate.

An object of the present invention is dabigatran etexilate hydrochloride (1: 1) (Form IX) of Formula 8. FIG. 1 shows a powder x-ray diffraction pattern of hydrochloric acid salt, and in table. 1 shows the characteristics of the peaks of the powder x-ray diffractogram.

Table 1. Peak position and relative intensity (> 6%).

Peak 2 theta ά (Α) Intensity one 4,720 18.7061 one hundred 2 8,080 10.9333 41 3 9,540 9.2631 22 4 10,480 8.4342 thirty 5 11,320 7.8102 27 6 11,640 7.5962 nine

- 2 022496

7 15,040 5.8857 eighteen 8 15,340 5.7713 89 nine 17,060 5.1931 nine 10 18,160 4.8810 14 eleven 18,460 4.8023 28 12 18,800 4.7162 eighteen thirteen 19,140 4.6332 31 14 21,040 4,2189 17 fifteen 22,280 3.9868 10 sixteen 22,540 3.9414 14 17 22,920 3.8769 sixteen eighteen 23,420 3,7953 46 nineteen 23,820 3,7324 7 twenty 24,020 3,7018 eleven 21 24,800 3,5871 12 22 25,160 3,5366 eighteen 23 28,380 3.1422 thirteen 24 28,800 3.0974 6

The conditions for measuring the powder x-ray diffractogram were as follows:

Apparatus: MiiLsh II powder diffractometer (Rigaku Corporation, Ktdaki SotrotaNop);

Irradiation: TokYa A-20, CuKa, (λ = 1.54059 A), CuKa ₂ (λ = 1.54439 A);

Voltage: 30 kV;

Anode current: 15 mA;

Accessories: Soller slots, automatic sample change;

Standard sample: 8KKR-432759, silicon powder a = 5.430758 A;

The measurement was stable theta / theta scanning: 4 ° -50.00 ° 2-theta;

Step size: 0.02 °;

Sample: not powder; measured and stored at room temperature.

Dabigatran etexilate hydrochloride (1: 1) (Form IX) of Formula 8 of the present invention has the following most characteristic powder diffraction peaks: 2-theta (± 0.2 ° 2-theta): 4.720; 8,080; 15,340; 23,420.

In more detail, dabigatran etexilate hydrochloride (1: 1) (Form IX) of formula 8 of the present invention has the following most characteristic powder diffraction peaks: 2-theta (± 0.2 ° 2theta): 4.720; 8,080; 9,540; 10,480; 11,320; 15,340; 18,460; 19,140; 23,420.

The term recrystallization used in this description means a known method in which a crystalline product is dissolved and obtained again in crystalline form. In addition, this implies a method in which a known polymorphic or amorphous compound is dissolved and, by recrystallization, various polymorphic forms of a crystalline compound are obtained.

Moreover, the term recrystallization refers to a method in which a known polymorphic or amorphous compound is suspended in a suitable solvent (solubility 0.1-100 mg / ml at a crystallization temperature) at a temperature necessary to change the polymorphic form, for a sufficient time and with the addition of seed crystals (if necessary) designed to induce and / or enhance precipitation. After filtering the suspension, this method leads to the formation of a crystalline compound with a polymorphic form other than the parent compound.

Another object of the present invention is dabigatran etexilate hydrochloride (1: 1) (Form IX) of Formula 8. It has been found that the X-ray powder diffraction pattern of Form IX of the hydrochloride salt is different from the known hydrochloride salts of Dabigatran Etexilate, such as Forms II, V and VI disclosed in \ UO 2008/043759. In addition, the melting point of the polymorphic forms of the present invention, which was determined by the maximum peak of the DSC curve, is as follows: Form IX: 181 ° C. This melting point differs from the melting point of Form I (135 ° C), disclosed in UO 2006/114415. The known form I is obtained by adding hydrochloric acid to ethanol, forms II, V and VI are obtained by adding hydrochloric acid to a mixture of solvents - acetone and THF, and recrystallization of the crude product obtained by evaporation. Form I is prepared by suspending the product in ethyl acetate and acetone. Form II is recrystallized from 1,2-dimethoxyethane, form V is recrystallized from isopropyl acetate, and form VI is recrystallized from THF.

Another object of the present invention is a method for producing dabigatran etexilate hydrochloride (1: 1) (Form IX) of formula 8.

In accordance with the present invention, the hydrochloride salt form IX is prepared by dissolving the polymorphic or amorphous base of dabigatran etexilate, its solvate, hydrate or mixture thereof in a polar solvent or a mixture of polar solvents at a temperature of 25-110 ° C, and after dissolution, hydrochloric acid is added to the mixture. After cooling, the solution crystallizes at a temperature of 0-25 ° C for 8-168 hours.

In accordance with another variant of the method, a polymorphic or amorphous salt of hydrochloric acid and dabigatran etexilate, its solvate, hydrate or a mixture thereof are suspended or dissolved in a polar solvent or mixture of polar solvents at a temperature of 25-110 ° C. The solution is crystallized at a temperature of 0-25 ° C for 8-168 hours. If necessary, seed crystals are added to the mixture.

According to a preferred embodiment of the method, the polymorphic or amorphous base of dabigatran etexilate, its solvate, hydrate or a mixture thereof, or the polymorphic or amorphous salt of hydrochloric acid and dabigatran etexilate, or a mixture thereof, are suspended or dissolved in an aliphatic alcohol or mixture of aliphatic alcohols, or in an aliphatic ketone at a temperature 25-110 ° C and further to the solution add a mixture of anhydrous or aqueous hydrochloric acid and aliphatic alcohol or gaseous hydrochloric acid. The solution is cooled and crystallized at a temperature of 0-25 ° C for 8-168 hours. If necessary, seed crystals are added to the mixture. The precipitated product is filtered off, washed and dried. When salts of hydrochloric acid and dabigatran etexilate are used as the starting compound, further addition of hydrochloric acid is not necessary.

According to the present invention, the aliphatic alcohol used in the preparation of Form IX of dabigatran etexilate hydrochloride may be selected from C1-4 alcohols, preferably methanol, ethanol, 1-propanol, 2-propanol, 1-butanol or tert-butanol, and most preferably ethanol. The aliphatic ketone may be selected from C1-3 ketones in the form of a chain or ring, preferably methyl ethyl ketone, acetone, cyclohexanone, methyl cyclohexanone, and most preferably acetone.

According to a most preferred embodiment of the method, the polymorphic or amorphous base of dabigatran etexilate, its solvate, hydrate or a mixture thereof is dissolved in ethanol at 40-45 ° C in the presence of isopropyl alcohol containing hydrochloric acid. The solution crystallizes at 0-5 ° C for 1-7 days. The precipitated product is filtered off, washed and dried.

According to another variant of the method, the polymorphic or amorphous salt of hydrochloric acid and dabigatran etexilate, its solvate, hydrate or a mixture thereof are dissolved in ethanol at 4CM5 ° C. The solution crystallizes at 0-5 ° C for 1-7 days. The precipitated product is filtered off, washed and dried.

According to another variant of the method, a polymorphic or amorphous salt of hydrochloric acid and dabigatran etexilate, its solvate, hydrate or a mixture thereof are suspended in acetone at 20-30 ° C, and the hydrochloride salt of Form IX is added to the mixture. The solution crystallizes at 20-30 ° C for 8-48 hours.

It was unexpectedly discovered that the new polymorph of the present invention has better stability properties compared with the stability of known polymorphs in various storage conditions.

During a detailed study, it was found that the new form IX of the hydrochloric acid salt and dabigatran etexilate (1: 1) of formula 8 is more stable than the form II of methanesulfonic acid (1: 1) described in I8 20050234104 and which is part of Pradax ( Rgabaha).

Form II methanesulfonic acid (1: 1) of formula 10 is prepared in accordance with I820050234104. Comparative studies of the thermal stability of form II methanesulfonic acid (1: 1) and form IX of hydrochloric acid (1: 1) were carried out. Samples were stored at a temperature of 40 ° C and at a relative humidity of 75% in the closed state, and at 70 ° C in closed and open conditions for 6 weeks.

The composition of the samples was determined using high performance liquid chromatography (HPLC) at the beginning of the experiment and after 6 weeks; amounts of impurities in excess of 0.03% by area are pooled, and the resulting values of the content of impurities are compared with the resulting values of the content of impurities, measured at the initial moment, in accordance with the following formula:

(Σ ™ impurities) - (£ _k impurities) (£ b impurities) * 100%

The symbols in the above formula have the following meanings: (ΔΣ impurities) [%] - increase in the amount of total impurity in percent; impurities) - the sum of the total impurities at the initial moment; (Σ _ο impurities) - the sum of the total impurities after 6 weeks.

Changes in the amount of total impurity calculated by the above formula,

- 4 022496 are given in table. fifteen.

Table 15. The change in the amount of total impurities during storage

Conditions Salt form II methanesulfonic acid Salt form IX acid 40’s relative humidity 75% 70’s 4O’s relative humidity 75% 70 ° C 6 weeks Open space 67% 48% No change 37% 6 weeks Closed space There is no data 55% There is no data 21%

According to the table. 15, in the case of form II of methanesulfonic acid salt and dabigatran etexilate, a significant increase (67%) in the amount of total impurity can be observed, especially at moderate temperature (40 ° C), in contrast to form IX of hydrochloric acid salt with improved temperature stability; moreover, the increase in impurities is not significant at this temperature. A similar trend can be observed during storage at a temperature of 70 ° C.

A forced stability study (stress test) of the selected salt of dabigatran etexilate was also carried out, in which the samples were stored at 100 ° C for 24 hours, and the change in the amount of total impurity (ΔΣ impurities) and the most characteristic degradation product, namely, the compound of formula 12 (Δ12) were determined by LC / MS (liquid chromatography with mass spectrometry). ΔΣ of impurities was calculated according to the above formula, and Δ12 was calculated in a similar way by the following formula:

(Δ12) [%) = (C _m -C0 * yo%

Ck

The symbols in the above formula have the following meanings:

(Δ12) [%] - increase in the amount of degradation product, the compounds of formula 12 in percent; C _t is the amount of the compound of formula 12 after 6 weeks;

With _to - the amount of the compounds of formula 12 at the initial moment.

The results are presented in table. sixteen.

Table 16. Change in the amount of total impurities during a stress test

Conditions Salt form II methanesulfonic acid Salt form IX acid D £ impurities 39% eleven% Δ12 109% 71%

According to the table. 16 and an increase in the amount of total impurity, and the most characteristic degradation product (compound of formula 12), are significantly higher for form II of methanesulfonic acid salt than for form IX of hydrochloric acid salt.

A comparative study of thermal stability and a forced stability study (stress test) simulate the degradation processes in a pharmaceutical composition in an accelerated manner. The results show that Form IX of the hydrochloric acid salt is more stable in the composition than Form II of the methanesulfonic acid salt. This beneficial property of Form IX of the hydrochloric acid salt is of great importance with respect to the preparation and storage of the pharmaceutical composition and minimization of harmful side effects on the human body.

Another common drawback of all salts of methanesulfonic acid is that in the production of active pharmaceutical ingredients more attention should be paid to various methods. Harmful alkyl mesylates can form in the presence of alcohols, especially ethyl alcohol in some procedural steps or in their technological operations during their production, for example, in the case of ethanol, ethyl mesylate can form. The mutagenic or carcinogenic effect of alkyl mesylates is known from the literature: Thotropop. N., Mi1ai1 [δοϊαΐίοη. Me1y. En / ut1. 1979, 58, 308-322; A1begkop T., Sötüa11u Shbiseb Eeaueb Segta1 Mi1a1yui ίη EgokorPa. Iaige 1965, 207, 164-167; Theorem 1. V., Thieu Schbisiop o Mokay apb Sotr1e1e Epuremus Mi1ap1k ίη EgokorIa Me1apodak1eg χνίΐΐτ E! Bу1 Ме1пеки11'ope1e. Mi1a1. Kek. 1967, 4, 90-92; 8cLa1e1, A.R., ShegkresShs Sotrapkop OG E! LU1 Me1epecki1 £ opae-tbiseb Mi1a1yup Ka1ek ίη Ke1a1yup1o Sepot δί / е. Mi1a1. Kek. 1978, 49, 313-340.

Virasept (Nelfinavir) was withdrawn from sale in 2007 by Neutapp-ba Cosier because it was contaminated with ethyl mesylate due to an inappropriate process. In connection with

- 5 022496 by this review, the European Medical Agency (EMA) issued a notice in which the EMA encourages the pharmaceutical industry to maintain strict control and to conduct further research on compositions containing mesylates, tosylates and besylates (EMEA / 44714/2008).

Most active pharmaceutical ingredients in the form of salt, which are used for human therapy, are converted to hydrochlorides due to the strongly acidic nature of stomach acid (hydrochloric acid). Thus, the acid that is bound by the active pharmaceutical ingredient is released. The effect of free acids, which are present in the gastric juice and which are weaker than hydrochloric acid, such as methanesulfonic acid, p-toluenesulfonic acid and benzenesulfonic acid, has not yet been studied, and even less data on their reaction with alcohols, such as ethyl alcohol, leading to the formation of mesylate. Thus, before using them, further research is needed.

Another object of the present invention is the use of the aforementioned morphologically homogeneous polymorphs of dabigatran etexilate salts formed with hydrochloric acid as medicaments.

The present invention also relates to a pharmaceutical composition having a thrombin inhibitor effect, which contains a therapeutically effective amount of the aforementioned dabigatran etexilate as an active ingredient together with one or more pharmaceutically acceptable excipients. The invention relates to its use for the prevention and treatment of postoperative deep vein thrombosis and stroke.

The pharmaceutical composition of the present invention is preferably administered orally or parenterally. Oral compositions are, for example, tablets, capsules, dragees, solutions, elixirs, suspensions or emulsions. For parenteral administration, intravenous or intramuscular injections are used.

The pharmaceutical composition of the present invention may contain known pharmaceutical carriers and / or excipients commonly used in the pharmaceutical industry. Pharmaceutical carriers can be, for example, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium methyl cellulose, low melting wax, cocoa butter, etc. The use of a carrier is not necessary if the capsule consists of a carrier. Compositions that are administered orally, among other things, can be lozenges and bags. Solid preparations such as tablets, powders, capsules, pills, packets and lozenges are preferably used for oral administration.

Suppositories contain low melting waxes (for example, a mixture of fatty acid glycerides or cocoa butter). Wax is melted and the active ingredient is homogenized in it. The molten mixture is poured into a mold of an appropriate size and shape and allowed to solidify upon cooling.

Tablets are prepared by mixing the active ingredient with appropriate excipients in the required proportions and compressing the tablets with suitable sizes and shapes.

Powders are prepared by mixing finely divided active ingredient and carriers. Liquid solutions are suspensions and emulsions, which can provide, if necessary, a slow release of the active ingredient. It is advisable to use solutions containing water or aqueous propylene glycols. Parenteral liquid compositions may be prepared in the form of solutions containing aqueous polyethylene glycols.

Aqueous solutions for oral administration are prepared by dissolving the active ingredient in water with the addition of the necessary colorants, flavors, stabilizers and gelling agents to the solution. The active ingredient is suspended in water in the presence of a viscous liquid (e.g., natural or synthetic resins, rosins, methyl cellulose, sodium carboxymethyl cellulose, or any other suspending agent).

Another part of the solid pharmaceutical composition in accordance with the invention is converted into liquid compositions before use and administered orally. Liquid compositions are solutions, suspensions or emulsions which, in addition to the active ingredient, contain colorants, flavors, preservatives, buffers, artificial or natural sweeteners, dispersants, gelling agents, etc.

The pharmaceutical composition of the present invention is preferably obtained in single doses. A single dose contains the required amount of active ingredient. Single doses may be sold in packages containing individual amounts of compositions (eg, packaged tablets, capsules, powders in ampoules or in containers). Capsules, tablets, sachets, lozenges and packages containing multiple single doses are also single doses.

Another object of the present invention is a method for producing the aforementioned pharmaceutical composition by mixing dabigatran etexilate hydrochloride (1: 1) (Form IX) of formula 8, with pharmaceutically acceptable solid or liquid solvents and / or excipients, and by bringing the mixture into a galenic form.

- 6 022496

The pharmaceutical composition of the present invention is obtained by methods known in the pharmaceutical industry.

The pharmaceutical composition of the present invention may contain additional pharmaceutically active ingredients compatible with the compounds of formula 8 or mixtures thereof.

Another object of the present invention is the use of new crystalline polymorphic compounds of formula 8 as pharmaceutically active ingredients.

Another object of the present invention is the use of new crystalline polymorphic compounds of formula 8 to obtain a pharmaceutical composition that prolongs thrombin time, inhibits thrombin and its associated serine proteases.

Another object of the present invention is the use of new crystalline polymorphic compounds of formula 8 for prolonging thrombin time and / or inhibition of thrombin and related serine proteases by administering a therapeutically acceptable dose of compounds of formula 8 to patients.

An advantage of the present invention is that the new crystalline compounds of formula 8 are morphologically homogeneous. Thus, properties of a compound such as dissolution time, bio-release, chemical stability, and processability (filtration, drying, dissolution, and tableting) are reproducible.

The new polymorphs of the present invention can also be obtained reproducibly on an industrial scale.

The present invention is illustrated by the following non-limiting examples.

Examples

Example 1. Obtaining dabigatran etexilate hydrochloride (1: 1) (Form IX) of formula 8.

630 mg (1.0 mmol) of dabigatran etexilate, 1.5 ml of ethanol and 130 mg of hydrochloric acid containing isopropyl alcohol (28 wt.%, 1.0 mmol) were added to a 10 cm ³ round bottom flask, the reaction mixture was heated to 45 ° C. The solution thus obtained was kept at 5 ° C for 1 week. The crystalline suspension was filtered, washed with a small amount of ethanol and dried at room temperature in vacuo to constant weight.

Yield: 335 mg (50.4%)

Mp (Melting point): 178-180 ° C.

NMR (DMSO, 500 MHz): 11.87 (b, 1H), 10.80 (b, 1H), 10.02 (b, 1H), 8.38 (t, 1H), 7.78 (b, 1H), 7.68 (~ ά, 1 = 9.0 Hz, 2H), 7.55 (t, 1H), 7.50 (ά, 1 = 0.9 Hz, 1H), 7.46 (ά , 1 = 8.4 Hz, 1H), 7.19 (άά, 11 = 1.5 Hz, 12 = 8.6 Hz, 1H), 7.12 (t, 1H), 6.93 (t, 1H) ), 6.89 (~ ά, 1 = 9.2 Hz, 2H), 4.73 (b, 2H), 4.26 (t, 2H), 4.22 (1, 1 = 7.1 Hz, 2H), 3.98 (q, 1 = 7.1 Hz, 2H), 3.81 (5, 3H), 2.68 (1, 1 = 7.1 Hz, 2H), 1.68 (t, 2H), 1.38 (t, 2H), 1.29 (t, 4H), 1.12 (1, 1 = 7.1 Hz, 3H), 0.88 (t, 3H).

IR (KBr, cm ¹ ): 3296, 1734, 1648, 1578, 1468, 1207.

Example 2. Obtaining hydrochloride of dabigatran etexilate (1: 1) (form IX) of formula 8

500 mg (0.79 mmol) of dabigatran etexilate was added to a 10 cm ³ round bottom flask, suspended in 3 ml of acetone and a mixture of 75 μl of 32 wt.% Aqueous hydrochloric acid (0.79 mmol) was added dropwise at room temperature and 2 ml of acetone. The reaction mixture was stirred at room temperature for 1 h, and the corresponding seed crystals (for example, the compound obtained in accordance with Example 10) were added to the suspension. The suspension was stirred at room temperature for 16-24 hours. The crystalline suspension was filtered, washed with a small amount of acetone and dried at room temperature under vacuum to constant weight.

Yield: 470 mg (88%)

Mp: 178-180 ° C

H-NMR (DMSO, 500 MHz): 11.87 (b, 1H), 10.80 (b, 1H), 10.02 (b, 1H), 8.38 (t, 1H), 7.78 ( B, 1H), 7.68 (~ ά, 1 = 9.0 Hz, 2H), 7.55 (t, 1H), 7.50 (ά, 1 = 0.9 Hz, 1H), 7.46 (ά, 11 = 8.4 Hz, 1Н), 7.19 (άά, 11 = 1.5 Hz, 12 = 8.6 Hz, 1Н), 7.12 (t, 1Н), 6.93 (t, 1Н) ), 6.89 (~ ά, 1 = 9.2 Hz, 2H), 4.73 (b, 2H), 4.26 (t, 2H), 4.22 (1, 1 = 7.1 Hz, 2H), 3.98 (q, 1 = 7.1 Hz, 2H), 3.81 (5, 3H), 2.68 (1, 1 = 7.1 Hz, 2H), 1.68 (t, 2H), 1.38 (t, 2H), 1.29 (t, 4H), 1.12 (1, 1 = 7.1 Hz, 3H), 0.88 (t, 3H).

IR (KBr, cm ^-1 ): 3296, 1734, 1648, 1578, 1468, 1207.

Claims (10)

CLAIM 1. Dabigatran etexilate hydrochloride (1: 1) (Form IX) of Formula 8 showing an X-ray powder diffraction pattern with characteristic peaks - 7 022496 with a reflection angle of 2-theta (± 0.2 ° 2-theta) of approximately 4.720; 8,080; 15,340; 23,420. 2. Dabigatran etexilate hydrochloride (1: 1) (Form IX) of formula 8 according to claim 1, showing an X-ray powder diffraction pattern with characteristic peaks at a reflection angle of 2-theta (± 0.2 ° 2-theta) of about 4.720; 8,080; 9,540; 10,480; 11,320; 15,340; 18,460; 19,140; 23,420. 3. Dabigatran etexilate hydrochloride (1: 1) (Form IX) of formula 8 according to claim 1 or 2, showing an X-ray powder diffraction pattern in accordance with FIG. 10 and the following table: Peak position and relative intensity (> 6%) 4. The method of producing dabigatran etexilate hydrochloride (1: 1) (Form IX) of formula 8 according to any one of claims 1 to 3, which comprises crystallizing any polymorphic or amorphous dabigatran etexilate base or a mixture thereof from a polar solvent or a mixture of polar solvents in the presence of hydrochloric acids. 5. The method of producing dabigatran etexilate hydrochloride (1: 1) (Form IX) of formula 8 according to any one of claims 1 to 3, which includes crystallization of any polymorphic or amorphous salt of hydrochloric acid and dabigatran etexilate, its solvate, hydrate or mixtures thereof from polar solvent or mixture of polar solvents. 6. The use of dabigatran etexilate hydrochloride (1: 1) (Form IX) of formula 8 according to any one of claims 1 to 3 as a medicine having a thrombin inhibitor effect. 7. A pharmaceutical composition having the effect of a thrombin inhibitor, containing as the active ingredient a therapeutically effective amount of dabigatran etexilate hydrochloride (1: 1) (Form IX) of formula 8 according to any one of claims 1 to 3 together with one or more pharmaceutically acceptable excipients (excipients) ) 8. The use of the composition according to claim 7 for the prevention or treatment of postoperative deep vein thrombosis and stroke. 9. The use of dabigatran etexilate hydrochloride (1: 1) (Form IX) of formula 8 according to any one of claims 1 to 3 for the manufacture of a medicament for the prevention or treatment of postoperative deep vein thrombosis and stroke. 10. A method for the prevention and / or treatment of postoperative deep vein thrombosis and stroke, which comprises administering to a patient in need of such treatment a therapeutically effective amount of dabigatran etexilate hydrochloride (1: 1) (Form IX) of formula 8 according to any one of claims 1 to 3 .