HK1157760B - Benzimidazol-carbonyl-pyridinyl-amino-propionic acid ethyl ester hemihydrate and use thereof - Google Patents

Description

Benzimidazole carbonyl pyridine amino ethyl propionate hemihydrate and use thereof

This application is a divisional application of the chinese invention application (application No. 200480024952.1, application date: 24/8/2004; title of the invention: 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionic acid ethyl ester-methanesulfonate and its use as a medicament).

Technical Field

The present invention relates to crystals which are 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionic acid ethyl ester-methanesulfonate hemihydrate and their use as pharmaceutical compositions.

Background

The subject of the present invention is the 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionic acid ethyl ester-methanesulfonate of the compound of formula A and its use as a pharmaceutical composition,

the formula A is:

the bases of the compounds of formula a are known from WO 98/37075, wherein compounds are disclosed which have thrombin inhibiting effect and prolong the thrombin action time, named 1-methyl-2- [ N- [4- (N-hexyloxycarbonyl-amidino) phenyl ] -amino-methyl ] -benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (2-ethoxycarbonylethyl) -amide. The compound of formula I is a composite Prodrug (Doppel-Prodrug) of the compound of formula (B),

that is, the compound of formula a (BIBR 1048 MS) is first converted in vivo to the actually effective compound (i.e., the compound of formula B). The main indications for the compounds of formula a range from postoperative prevention of deep vein thrombosis and prevention of stroke.

The above-mentioned pharmacologically advantageous properties of the disubstituted bicyclic heterocycles disclosed in the prior art are the main prerequisites for the effective use of these compounds as medicaments. However, the active substance must also meet other requirements in order to be able to be used as a medicament. These parameters are to a large extent related to the physicochemical properties of the active substance.

Without being limited by the examples set forth herein, these parameters are the stability of the activity of the starting material under different ambient conditions, the stability during the preparation of the pharmaceutical formulation and the stability of the final composition of the pharmaceutical formulation. Therefore, the pharmaceutically active substance used for the preparation of the pharmaceutical composition should have high stability, which should be ensured even under different environmental conditions. This situation is absolutely necessary to prevent the use of pharmaceutical compositions which contain, for example, decomposition products thereof in addition to the active substance itself. In such cases, the amount of active found in the pharmaceutical formulation may be less than the specified amount.

The absorption of water reduces the content of the pharmaceutically active substance due to the weight gain caused by the absorption of water. Pharmaceutical compositions having a tendency to absorb moisture must be protected from moisture upon storage, for example, by the addition of suitable desiccants or by storing the drug in a moisture-protected environment. Furthermore, if the drug substance is exposed to the environment without preventing moisture in any way, the uptake of moisture during manufacture may reduce the content of the pharmaceutically active substance. Therefore, the preferred pharmaceutically active substance should have only slight hygroscopicity.

Since the crystal modification of the active substance is important for the reproducible active substance content of the formulation, it is necessary to elucidate as far as possible the polymorphism of the active substance in the crystal form. If different polymorphic modifications of the active substance are present, it must be ensured that the crystalline modification of the substance does not change during subsequent pharmaceutical preparation. Otherwise, this has a detrimental effect on the reproducible efficacy of the drug. Due to this background, the active substance preferably has only a slight polymorphism.

Another criterion which is particularly important in the exceptional case in terms of the choice of formulation or the choice of manufacturing process is the solubility of the active substance. For example, if a pharmaceutical solution is prepared (e.g. for infusion), the active substance must be sufficiently soluble in a physiologically acceptable solvent. For orally administered drugs, sufficient solubility of the active substance is also very important.

The main task of the present invention is to provide a pharmaceutically active substance which not only features a high pharmacological efficiency but also meets the above-mentioned physicochemical requirements as far as possible.

Summary of The Invention

The present invention relates in a first aspect to a crystalline form of 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino group]-methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino]-ethyl propionate-mesylate, characterized by: melting Point T_m.p..180 ± 3 ℃ (form I),wherein the melting point is determined by DSC; evaluating with the maximum peak value; heating rate: 10 deg.C/min.

In a second aspect, the invention relates to a crystalline form of 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino]-methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino]-ethyl propionate mesylate, characterized by: melting Point T_m.p..190 ± 3 ℃ (form II), wherein the melting point is determined by DSC; evaluating with the maximum peak value; heating rate: 10 deg.C/min.

In a third aspect, the invention relates to a crystalline form of 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino]-methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino]-ethyl propionate mesylate, characterized by: melting Point T_m.p..120 ± 5 ℃ (hemihydrate), wherein the melting point is determined by DSC; evaluating with the maximum peak value; heating rate: 10 deg.C/min.

In a fourth aspect, the present invention relates to a pharmaceutical composition comprising the ethyl 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionate-methanesulfonate salt of any one of the above-described first to third aspects, optionally together with one or more inert carriers and/or diluents.

A fifth aspect of the present invention relates to the use of 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionic acid ethyl ester-methanesulfonate according to any one of the first to third aspects described above, for the preparation of a pharmaceutical composition suitable for the postoperative prevention of deep vein thrombosis and the prevention of stroke.

A sixth aspect of the present invention relates to a process for preparing the pharmaceutical composition of the fourth aspect, characterized by: the ethyl 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionate-methanesulfonate salt of any one of the first to third aspects is added non-chemically to one or more inert carriers and/or diluents.

The seventh aspect of the present invention relates to a process for the preparation of form I of BIBR1048 MS, characterized by:

a) slowly adding a slightly insufficient amount of methanesulfonic acid solution in acetone to a solution of BIBR1048 base in acetone at a temperature of about 30 ℃ to 36 ℃,

b) stirring the mixture at a temperature of about 26 ℃ to 33 ℃ for about 1 hour,

c) cooling the mixture to between about 17 ℃ and 23 ℃ and stirring at that temperature for an additional 40 to 80 minutes,

d) suction filtering the precipitated crystals of form I of BIBR1048 MS, and

e) the product thus obtained is dried under vacuum at a temperature of at most 50 ℃ for at least 4 hours.

An eighth aspect of the present invention relates to a process for the preparation of BIBR1048 MS polymorph II, characterized by:

a) slowly adding a slightly insufficient amount of methanesulfonic acid solution in acetone to a solution of BIBR1048 base in acetone at a temperature of about 40 ℃ to 46 ℃,

b) the mixture is optionally seeded with BIBR1048 polymorph form II crystals,

c) followed by stirring the mixture at a temperature of about 40 ℃ to 46 ℃ for about 1 hour,

d) cooling to about 17 ℃ to 23 ℃ and stirring at that temperature for a further 40 to 80 minutes,

e) air-suction filtering the precipitated crystals of form II of BIBR1048 MS, and

f) the product thus obtained is dried under vacuum at a temperature of at most 50 ℃ for at least 4 hours.

The ninth aspect of the present invention relates to a process for the preparation of BIBR1048 MS polymorph II, characterized by:

a) heating a suspension of BIBR1048 MS polymorph I in acetone with stirring at a temperature between 45 ℃ and 50 ℃ for about 4 hours,

b) optionally i) seeding with crystals of BIBR1048 polymorph II, or

II) seeding of BIBR1048 polymorphic form II crystals and additionally adding a small amount of BIBR1048 base,

c) followed by cooling to about 15 c,

d) air-suction filtering the precipitated crystals of form II of BIBR1048 MS, and

e) the product thus obtained is dried under vacuum at a temperature of at most 50 ℃ for at least 4 hours.

The tenth aspect of the present invention relates to a process for the preparation of BIBR1048 MS polymorph II, characterized by:

a) dissolving BIBR1048 MS polymorph I in acetone, and

b) optionally i) inoculating a small amount of BIBR1048 MS polymorph II, or

II) seeding of BIBR1048 polymorphic form II crystals and additionally adding a small amount of BIBR1048 base,

c) heating the mixture thus obtained at a temperature of between 40 ℃ and 46 ℃ for at least 1 hour with stirring,

d) followed by cooling to between about 17 ℃ and 23 ℃ and stirring at this temperature for a further 40 to 80 minutes,

e) separating the precipitated crystals of form II of BIBR1048 MS, and

f) the product thus obtained is dried under vacuum at a temperature of at most 50 ℃ for at least 4 hours.

An eleventh aspect of the present invention relates to a process for the preparation of BIBR1048 MS hemihydrate characterized by:

a) slowly adding one equivalent of methanesulfonic acid solution dissolved in ethyl acetate to BIBR1048 base solution dissolved in a mixture of 90% ethanol aqueous solution and ethyl acetate (about 2:5 by volume) at a temperature of about 35 ℃ to 40 ℃,

b) when the product begins to crystallize, ethyl acetate is optionally added for dilution,

c) stirring the mixture at a temperature of about 35 ℃ to 40 ℃ for about 30 minutes,

d) followed by stirring at ambient temperature for a further 30 minutes,

e) suction filtering the precipitate of BIBR1048 MS hemihydrate, and

f) dried in a circulating air drying cabinet at about 40 ℃.

A twelfth aspect of the present invention relates to a BIBR1048 MS polymorph I obtained according to the process of the seventh aspect.

A thirteenth aspect of the invention relates to a BIBR1048 MS polymorph il obtained by a process according to any one of the eighth, ninth or tenth aspects.

A fourteenth aspect of the invention relates to a BIBR1048 MS hemihydrate obtained by the process of the eleventh aspect.

Detailed Description

3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionic acid ethyl ester-methanesulfonate of the formula A solves the above problem.

It has surprisingly been found that: the salt in crystal modification form I can be prepared by the process described in example 1, and the salt in crystal modification form II can be prepared by the processes described in examples 2 to 4, with selectivity and homogeneity in the preparation in each case.

Furthermore, under certain synthesis conditions as described in example 5, a hydrate form can be obtained whose water content is inferred to be a hemihydrate.

For pharmaceutical use, the active substance contained therein must be in a homogeneous crystalline modification to ensure reliable bioavailability.

The mesylate salt according to the invention is characterized in all three crystal modification forms: good crystallinity and low amorphization during both grinding and compression. Furthermore, it is non-hygroscopic in all three crystal modification forms and is very readily soluble in physiologically acceptable acidic aqueous media.

The compound 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] according to the invention]-methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino]-the crystalline form of the mesylate salt of ethyl propionate is characterized by: its melting point T_m.p..180 ± 3 ℃ (form I), T_m.p..190 ± 3 ℃ (form II) or T_m.p..120 ± 5 ℃ (hemihydrate) (as determined by DSC-differential scanning calorimetry; estimated using the maximum peak; heating rate: 10 ℃/min). The values shown are determined using DSC 821e manufactured by Firma Mettler Toledo.

Accordingly, a first aspect of the present invention relates to 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] amino]-methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino]-ethyl propionate-mesylate in the three above polymorphic forms, characterized by: melting point T_m.p..180 ± 3 ℃ (form I), T_m.p..190 +/-3 ℃ or T_m.p..120 ± 5 ℃ (determined by DSC; estimated using the maximum peak; heating rate: 10 ℃/min). Having a melting point T_m.p..Polymorph I at 180 ± 3 ℃ is preferred.

The invention also relates to a process for selectively preparing the three polymorphic forms, and to the variant forms obtained by this process.

According to the invention, the BIBR1048 MS polymorph I is obtainable by the following steps:

a) a slightly insufficient amount (e.g., 0.98 equivalents) of methanesulfonic acid solution in acetone is slowly added to a solution of BIBR1048 base in acetone at a temperature of about 30 c to 36 c,

b) stirring the mixture at a temperature of about 26 ℃ to 33 ℃ for about 1 hour,

c) cooling it to between about 17 ℃ and 23 ℃ and stirring it at this temperature for a further 40 to 80 minutes,

d) suction filtering the precipitated crystals of form I of BIBR1048 MS, and

e) the product thus obtained is dried under vacuum at a temperature of at most 50 ℃ for at least 4 hours.

According to the invention, the BIBR1048 MS polymorphic form II is obtained by the following steps:

a) a slightly insufficient amount (e.g., 0.98 equivalents) of methanesulfonic acid solution in acetone is slowly added to a solution of BIBR1048 base in acetone at a temperature of about 40 c to 46 c,

b) optionally seeding with BIBR1048 polymorphic form II crystals,

c) stirring the mixture at a temperature of about 40 ℃ to 46 ℃ for about 1 hour

d) It is cooled to between about 17 ℃ and 23 ℃ and stirred at this temperature for a further 40 to 80 minutes,

e) air-suction filtering the precipitated crystals of form II of BIBR1048 MS, and

f) the product thus obtained is dried under vacuum at a temperature of at most 50 ℃ for at least 4 hours.

Or obtained by the following steps:

a) heating the suspension of BIBR1048 MS polymorph I in acetone with stirring at a temperature between 45 ℃ and 50 ℃ for about 4 hours,

b) optionally i) seeding with crystals of BIBR1048 polymorph II, or

II) seeding of BIBR1048 polymorphic form II crystals and additionally adding a small amount of BIBR1048 base,

c) followed by cooling to about 15 c,

d) air-suction filtering the precipitated crystals of form II of BIBR1048 MS, and

e) the product thus obtained is dried under vacuum at a temperature of at most 50 ℃ for at least 4 hours.

Or obtained by the following steps:

a) dissolving BIBR1048 MS polymorph I in acetone, and

b) optionally i) inoculating a small amount of BIBR1048 MS polymorph II, or

II) seeding of BIBR1048 polymorphic form II crystals and additionally adding a small amount of BIBR1048 base,

c) the mixture thus obtained is heated at a temperature of between 40 ℃ and 46 ℃ for at least 1 hour with stirring,

d) followed by cooling to between about 17 ℃ and 23 ℃ and stirring at this temperature for a further 40 to 80 minutes,

e) separating the precipitated crystals of form II of BIBR1048 MS, and

f) the product thus obtained is dried under vacuum at a temperature of at most 50 ℃ for at least 4 hours.

According to the invention, the BIBR1048 MS hemihydrate is obtainable by the following steps:

a) slowly adding one equivalent of methanesulfonic acid in ethyl acetate to a solution of BIBR1048 base in a mixture of 90% aqueous ethanol and ethyl acetate in a volume ratio of about 2:5 at a temperature of about 35 ℃ to 40 ℃,

b) optionally adding ethyl acetate to dilute at the beginning of crystallization of the product,

c) stirring at a temperature of about 35 ℃ to 40 ℃ for about 30 minutes,

d) followed by stirring at ambient temperature for a further 30 minutes,

e) suction filtering the precipitate of the BIBR1048 Ms hemihydrate, and

f) drying at 40 ℃ in a circulating air drying cabinet.

The crystalline form of 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionic acid ethyl ester-methanesulfonate according to the present invention was investigated in more detail by X-ray powder diffraction. The diffraction pattern obtained is shown in figure 1.

The following tables 1 to 3 list the data obtained in this analysis:

table 1: x-ray powder reflectance and intensity (normalized) of 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionic acid ethyl ester-methanesulfonate (form I)

Table 2: x-ray powder reflectance and intensity (normalized) of 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionic acid ethyl ester-methanesulfonate (form II)

Table 3: x-ray powder reflectance and intensity (normalized) of 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionic acid ethyl ester-methanesulfonate (hemihydrate)

In the above tables 1 to 3, the numerical value "2 θ [ ° C °]"diffraction angle in degrees, and numerical valuesSo as to makeIndicating a particular spacing between lattice planes.

In the context of the present invention, the X-ray powder diffractogram is produced using a Cu anode (CuK) equipped with a position-sensitive detector (OED) and as X-ray source_α1The radiation is transmitted to the outside of the container,40kV, 40mA) on a Bruker D8 echelle diffractometer.

The hydrate of the compound 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionic acid ethyl ester-methanesulfonate according to the invention was present in the form of a hemihydrate under standard conditions, from which water would escape while melting at about 120 ℃.

Figure 2 shows thermal analysis of three morphologies.

Experimental part

Example 1

3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionic acid ethyl ester-methanesulfonate salt form I (BIBR 1048MS polymorph I)

52.6 kg of 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionic acid ethyl ester base, which had preferably been purified beforehand by recrystallization from ethyl acetate, were placed in an inertized electric stirring apparatus and 293 kg of acetone were subsequently added. The contents of the apparatus are heated to between 40 and 46 ℃ with stirring. After a clear solution had formed, the contents of the apparatus were filtered through a lens filter into a second electric stirring device and then cooled to between 30 and 36 ℃. 33 kg of acetone pre-cooled to between 0 and 5 ℃, 7.9 kg of 99.5% methanesulfonic acid and a further 9 kg of acetone for rinsing are placed successively in the suspension vessel of the second apparatus. The contents of the suspension vessel are metered in portions to a solution of the ethyl 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionate base at a temperature of 26 to 36 ℃ over 15 to 40 minutes. Subsequently, the mixture is stirred at a temperature of 26 to 33 ℃ for 40 to 60 minutes. It is subsequently cooled to between 17 and 23 ℃ and stirred for a further 40 to 80 minutes. The crystal suspension was filtered through a filter drier and washed with a total of 270 liters of acetone. The product is dried under vacuum at a temperature of maximum 50 ℃ for at least 4 hours.

Yield: 54.5-59.4 kg; the theoretical yield based on 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionic acid ethyl ester base is 90-98%.

Example 2

BIBR1048 MS polymorph II converted from BIBR1048 MS polymorph I

4 g of BIBR1048 MS polymorph I and 35 ml of acetone are placed in a glass flask with stirrer and reflux condenser. The suspension was heated to between 45 and 50 ℃ with stirring and kept at this temperature for 4 hours. It is subsequently cooled to 15 ℃ and the crystals are filtered off with suction via a flat-bottomed (Buchner) funnel, washed with 20ml of acetone and dried at 45 ℃ in vacuo.

Note that: the synthesis can also be performed by seeding with BIBR1048 MS polymorph II. If the conversion rate is slower, it can be accelerated by adding a small amount of BIBR1048 base (e.g. about 50 g of BIBR1048 base to about 90 kg of BIBR1048 MS polymorph I on an industrial scale) in addition to inoculation with BIBR1048 MS polymorph II.

Example 3

3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionic acid ethyl ester-methanesulfonate form II (BIBR 1048MS polymorph form II)

52.6 kg of 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionic acid ethyl ester base, which has preferably previously been purified by recrystallization from ethyl acetate, are placed in an inertized electric stirring apparatus and 293 kg of acetone are subsequently added. The contents of the apparatus are heated to between 40 and 46 ℃ with stirring. After a clear solution is formed, the contents of the apparatus are filtered through a lens filter into a second electrical stirring apparatus. 33 kg of acetone pre-cooled to between 0 and 5 ℃, 7.9 kg of 99.5% methanesulfonic acid and a further 9 kg of propane for rinsing are placed successively in the suspension vessel of the second apparatus. The contents of the suspension vessel were metered in portions to a solution of 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionic acid ethyl ester base and seeded with 10 grams of BIBR1048 MS polymorph form II (e.g. prepared according to example 2) at a temperature of 40 to 46 ℃ over 15 to 40 minutes. Subsequently, the mixture is stirred at a temperature of 40 to 46 ℃ for 40 to 60 minutes. It is subsequently cooled to between 17 and 23 ℃ and stirred for a further 40 to 80 minutes. The crystal suspension was filtered through a filter drier and washed with a total of 270 l of acetone. The product is dried under vacuum at a temperature of maximum 50 ℃ for at least 4 hours.

Yield: 54.5-59.4 kg; is 90-98% of the theoretical yield based on ethyl 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionate base.

Note that: the synthesis can also be performed without seeding with BIBR1048 MS polymorph II. However, it is preferred to use a method of inoculation.

Example 4

BIBR1048 MS polymorph II converted from BIBR1048 MS polymorph I

30.7 kg of BIBR1048 MS polymorph I are placed in an inertized electric stirring apparatus and 199 kg of acetone are subsequently added. The contents of the apparatus were inoculated with 10 grams of BIBR1048 MS polymorph form II (e.g. prepared according to example 2), heated to between 40 and 46 ℃ with stirring, and kept at this temperature for at least 1 hour. The mixture is then cooled to between 17 and 23 ℃ and stirred for a further 40 to 80 minutes.

The crystal suspension was separated by using a barrier centrifuge (stulpzentrifuge) and washed with a total amount of 45 kg of acetone. The product is dried in a vacuum drying oven at a temperature of maximum 50 ℃ for at least 4 hours.

Yield: 27.7-30.1 kg; 90-98% of the theoretical yield.

Note that: the synthesis can also be performed without seeding with BIBR1048 MS polymorph II. However, it is preferred to use a method of inoculation. If the conversion rate is slower, a small amount of BIBR1048 base may be added in addition to seeding with BIBR1048 MS polymorph II (e.g., about 50 grams of BIBR1048 base in about 90 kilograms of BIBR1048 MS polymorph I).

Example 5

3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionic acid ethyl ester methanesulfonate-hemihydrate

A solution of 1.53 g (15.93 mmol) methanesulfonic acid in 15 ml ethyl acetate is added dropwise with stirring to a solution of 10.0 g (15.93 mmol) 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionic acid ethyl ester base (prepared as described in WO 98/37075) in 16.5 ml 90% aqueous ethanol and 40 ml ethyl acetate at 35 to 40 ℃. After a few minutes, the product started to crystallize and was diluted with 30 ml of ethyl acetate. It is stirred for a further 30 minutes at 35 to 40 ℃ and for a further 30 minutes at ambient temperature, after which the precipitate is filtered off with suction, washed with about 20ml of ethyl acetate and dried at 40 ℃ in a circulating air drying cabinet.

Yield: 99% of the theoretical yield.

Drawings

Figure 1 shows X-ray powder diffraction patterns of three crystalline forms of ethyl 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionate mesylate.

Figure 2 shows the thermal analysis and melting point measurement (DSC) of three crystalline forms of ethyl 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionate mesylate.

Claims (5)

1. 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] form in crystal form]-methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino]-ethyl propionate mesylate, characterized by: it is a hemihydrate, melting point T_m.p.=120 ± 5 ℃, wherein the melting point is determined by DSC; evaluating with the maximum peak value; heating rate: 10 ℃/min and which has the following d in the X-ray powder diffraction diagram_hk1The value:and

2. a pharmaceutical composition comprising the ethyl 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionate-methanesulfonate of claim 1, in combination with one or more inert carriers and/or diluents.

3. A process for preparing a pharmaceutical composition according to claim 2, characterized in that: non-chemically adding the ethyl 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionate-methanesulfonate of claim 1 to one or more inert carriers and/or diluents.

4. A process for the preparation of 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionic acid ethyl ester methanesulfonate of claim 1, characterized by:

a) slowly adding one equivalent of methanesulfonic acid solution in ethyl acetate to a solution of ethyl 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionate dissolved in a mixture of 90% aqueous ethanol and ethyl acetate in a volume ratio of 2:5 at a temperature of 35 ℃ to 40 ℃,

b) when the product begins to crystallize, ethyl acetate is optionally added for dilution,

c) stirring the mixture at a temperature of 35 ℃ to 40 ℃ for a further 30 minutes,

d) followed by stirring at ambient temperature for a further 30 minutes,

e) vacuum filtering the precipitate of 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionic acid ethyl ester methanesulfonate hemihydrate, and

f) drying at 40 ℃ in a circulating air drying cabinet.

5. Use of 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionic acid ethyl ester-methanesulfonate according to claim 1 for the preparation of a pharmaceutical composition suitable for the prevention of deep vein thrombosis and stroke after surgery.