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WO2013054146A1 - New co crystals useful in the preparation of pharmaceutical compositions - Google Patents

New co crystals useful in the preparation of pharmaceutical compositions Download PDF

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Publication number
WO2013054146A1
WO2013054146A1 PCT/HU2012/000101 HU2012000101W WO2013054146A1 WO 2013054146 A1 WO2013054146 A1 WO 2013054146A1 HU 2012000101 W HU2012000101 W HU 2012000101W WO 2013054146 A1 WO2013054146 A1 WO 2013054146A1
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Prior art keywords
rivaroxaban
crystal
formula
gamma
oxalic acid
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Ceased
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PCT/HU2012/000101
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French (fr)
Inventor
Éva SIPOS
Györgyi KOVÁNYINÉ LAX
Balázs VOLK
József Barkóczy
Mónika MEZÖVÁRI
Zoltán VARGA
András DANCSÓ
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Egis Pharmaceuticals PLC
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Egis Pharmaceuticals PLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the invention relates to new co crystals useful in the preparation of pharmaceutical compositions. More particularly it is concerned with new co crystals of 5 -chloro-N-///5 S/-2-oxo-3 -/4-/3 -oxo-morpholine-4-yl/-phenyl/- 1,3- oxazolidine-5-yl/-methyl/-thiophen-2-carboxamide formed with oxalic acid and gamma-cyclodextrine which can be used as pharmaceutical active ingredient.
  • the invention further relates to preparation of new co crystals.
  • rivaroxaban is an active ingredient of a Xa coagulation factor inhibitor mechanism which can be used for the prevention of thrombus, venous thrombosis and pulmonary embolism derived therefrom in case of patients undergone knee and hip prostesis surgery.
  • Said co crystal is characterized by X-ray powder diffractogram, one-crystals spectrum and Raman spectrum.
  • the compound of the Formula 4 is prepared by dissolving polymorph I of rivaroxaban of the Formula 1 obtained by reproducing the process of the basic patent and malonic acid in an inert solvent /preferably an alcohol or ketone, particularly 2,2,2-trifluoro-ethanol or acetone/ at 50-90°C and thereafter evaporating the solvent or suspending said starting materials in a solvent at 20-25°C and isolating the precipitate.
  • the co crystal /1 :1/ of rivaroxaban and oxalic acid of the Formula 2 having the following characteristic X-ray powder diffraction line measured by CuKa beam: 2 ⁇ ( ⁇ 0,2° 2 ⁇ ): 24,11.
  • the co crystal /1:1/ of rivaroxaban and oxalic acid of the Formula 2 having the following characteristic X-ray powder diffraction lines measured by CuKa beam: 2 ⁇ ( ⁇ 0,2° 2 ⁇ ): 13,91; 20,94; 24,11; 28,05.
  • the co crystal /1:1/ of rivaroxaban and oxalic acid of the Formula 2 having the following characteristic powder diffraction lines measured by CuKa beam: 2 ⁇ ( ⁇ 0,2° 2 ⁇ ): 13,91; 17,43; 19,35; 19,72; 20,94; 24,11; 28,05; 38,95.
  • amorphous or crystalline rivaroxaban or a hydrate, solvate or co crystal of rivaroxaban is dissolved in an organic solvent, water or a mixture of an organic solvent and water, whereupon to the solution oxalic acid is added and the solvent is removed.
  • crystalline rivaroxaban, particularly rivaroxaban polymorph I is used as starting material.
  • organic solvent 2,2,2-trifluoro-ethanol, acetonitrile, a mixture of acetonitrile and water, N-methyl-pyrrolidone, a mixture of N-methyl-pyrrolidone and water or a mixture of 2,2,2-trifluoro-ethanol, methanol and water, particularly advantageously 2,2,2-trifluoro-ethanol is used.
  • the dissolving step is carried out at 20-90°C, preferably at 70-80°C.
  • a 0.9-3.0, preferably 0.75-1.25 molar equivalent amount of oxalic acid in anhydrous or hydrate form is added.
  • the oxalic acid solution or suspension obtained is cooled to a temperature between -20°C and +40°C, preferably between +10°C and + 30°C and the solvent is removed in a known manner.
  • compositions comprising a therapeutically effective amount of the co crystal /1:1/ of rivaroxaban and oxalic acid of the Formula 2 in admixture with at least one pharmaceutically acceptable carrier, diluent or other auxiliary agent.
  • a process for the preparation of the above pharmaceutical compositions which comprises admixing a pharmaceutically effective amount of the co crystal /1 :1/ of rivaroxaban and oxalic acid of the Formula 2 with at least one pharmaceutically acceptable carrier, diluent or other auxiliary agent and converting the mixture into a pharmaceutical composition.
  • the invention also relates to the use of the co crystal /1:1/ of rivaroxaban and oxalic acid of the Formula 2 for the prevention of the formation of thrombus, venous thrombosis and pulmonary embolism derived therefrom in case of patients gone over knee or hip prostesis surgery.
  • the invention also relates to a process for the prevention of the formation of thrombus, venous thrombus and pulmonary embolism derived therefrom in case of patients gone over knee or hip prostesis surgery which comprises administering to the patient in need of such treatment a pharmaceutically active amount of the co crystal /l :1/ of rivaroxaban and oxalic acid having the Formula 2.
  • the invention also relates to the use of the co crystal /1 :1/ of rivaroxaban and oxalic acid of the Formula 2 for the purification of rivaroxaban.
  • the co crystal of rivaroxaban and gamma-cyclodextrin of the Formula 3 /wherein n is 0.9 - 1.1, preferably n l/ having the following X-ray powder diffraction lines measured by CuK beam : /Table 2 contains signals having a relative intensity higher than 6 %/.
  • a process for the preparation of the co crystal of the Formula 3 /wherein n is 0.9-1.1, preferably n l /.
  • amorphous or crystalline rivaroxaban or a hydrate, solvate or co crystal of rivaroxaban is dissolved in an organic solvent, water or a mixture of an organic solvent and water whereupon to the solution gamma-cyclodextrine is added and the solvent is removed.
  • crystalline rivaoxaban particularly advantageously rivaroxaban polymorph I is used.
  • organic solvent 2,2,2-trifluoro- ethanol, aetonitrile, a mixture of acetonitrile and water, N-methyl-pyrrolidone, a mixture of N-methyl-pyrrolidone and water or a mixture of 2,2,2-trifluoro- ethanol, methanol and water, particularly advantageously 2,2,2-trifluoro-ethanol is used.
  • the dissolving step is carried out at 20-90°C, preferably at 70-80°C.
  • a 0.9-3.0 molar equivalent advantageously a 0.9-1.1 molar amount of gamma-cyclodextrine is added.
  • the gamma-cyclodextrine solution or suspension obtained is cooled to a temperature between
  • co crystal of rivaroxaban and gamma-cyclodextrin of the Formula 3 /wherein n is 0.9-1.1, preferably n l/ for the prevention of the formation of thrombus, venous thrombus and pulmonary embolism derived therefrom in case of patients gone over knee or hip prostesis surgery.
  • a process for the prevention of the formation of thrombus, venous thrombus and pulmonary embolism derived therefrom in case of patients gone over knee or hip prostesis surgery which comprises administering to the patient in need of such treatment a pharmaceutiacally effective amount of the co crystal of rivaroxaban and gamma-cyclodextrin of the Formula 3 /wherein n is 0.9-1.1 , preferably n-l/.
  • the X-ray powder diffraction data disclosed in the present patent application are obtained under the following measuring conditions.
  • the X-ray powder diffractogram of the co crystal /1 :1/ of rivaroxaban and oxalic of the Formula 2 and the co crystal /1 :1/ of rivaroxaban and gamma cyclodextrine of the Formula 3 differs from those of the rivaroxaban polymorphs known from prior art /amorphous, polymorph I, polymorph II, polymorph III, polymorph APO-A/ and also from that of gamma- cyclodextrine.
  • the only known co crystal modification of rivaroxaban is the co crystal formed with half an equivalent of malonic acid having the Formula 4 described in WO 2009/149851. Since oxalic acid /HOOC-COOH/ used according to the present invention is analogous to malonic acid /HOOC-CH 2 -COOH/ applied in the known product are neighbours in the homologuous series of dicarboxylic acids, one could have come to the conclusion that said two dicarboxylic acids would be capable of entering into similar interactions with rivaroxaban.
  • the co crystal of the Formula 2 formed with oxalic acid and the co crystal of the Formula 3 formed with gamma-cyclodextrine /where n is 0,9- 1,1, peferably n 1/ have a higher solubility than the active ingredient used in the product of the originator.
  • a further advantage of the co crystal of rivaroxaban formed with oxalic acid l ⁇ : ⁇ l of the Formula 2 resides in the fact that during the formation of the co crystal the chemical purity of the product is improved.
  • the rivaroxaban polymorph I of the Formula 1 used as starting material has a HPLC purity of 99,59 %. After proceeding according to Example 1/A the HPLC of the rivaroxaban - oxalic adid co crystal /l : 1/ of the Formula 2 was found to be 99,90 %.
  • co crystals are an effective purification method on the one hand while the new co crystals can be advantageously used as pharmaceutical active ingredients on the other.
  • the rivaroxaban - oxalic acid co crystal /1:1/ of the Formula 2 is prepared by dissolving amorphous or crystalline rivaroxaban or a hydrate, solvate or co crystal of rivaroxaban, preferably the rivaroxaban polymorph I in an organic solvent, water or a mixture of an organic acid and water, preferably in 2,2,2-trifluoro- ethanol, a mixture of 2,2,2-trifluoro-ethanol and water, acetonitrile, a mixture of acetonitrile and water, N-methyl-pyrrolidone, a mixture of N-methyl-pyrrolidone and water , a mixture of 2,2,2-trifluoro-ethanol, methanol and water, particularly preferably in 2,2,2-trifluoro-ethanol or a mixture of 2,2,2-trifluoro-ethanol and water, if desired under heating the solution, adding a 0.9-3.0 molar equivalent amount of solid oxalic acid, in anhydrous
  • the advantage of the present invention is that both the rivaroxaban - oxalic acid co crystal and the rivaroxaban - gamma cyclodextrin co crystal have a significantly larger solubility than the rivaroxaban polymorph I used in the product of the originator and also than that of the known rivaroxaban - malonic acid co crystal known from prior art, which is very advantageous in the case of particularly poorly soluble rivaroxaban.
  • the advantage of the rivaroxaban - gamma cyclodextrine co crystal is that it is suitable for the preparation of a buccal pharmaceutical composition which can be readily placed under the tongue and is quickly absorbed, namely more rapidly than the drugs acting through the gastrointestinal system.
  • a further advantage of the product according to the present invention is that neither oxalic acid nor gamma-cyclodextrine cause toxicity hazards.
  • a still further advantage of the present invention is that during the formation of the co crystals the HPLC chemical purity of the product is improved.
  • the co crystals of the present invention can be preferably used as pharmaceutical active ingredient.
  • A/ 4.50 g /10.32 millimoles/ of polymorph I of rivaroxaban of the Formula 1 /HPLC purity: 99.59 %/ are dissolved in 9,5 ml of 2,2,2-trifluoro-ethanol at 70- 80°C.
  • To the hot solution 1.29 g /10.15 millimoles/ of oxalic acid dihydrate are added. The solution is stirred at this temperature for 5 minutes. The reaction mixture is allowed to cool to room temperature under stirring. After 4 hours the product is filtered and dried under an infrared lamp.
  • 3.66 g /69 %/ of rivaroxaban - oxalic acid co crystals l ⁇ are obtained in the form of a white solid substance.
  • the IR and NMR spectral data and the X-ray powder diffractogram of the product obtained are identical with those of the product before recrystallization. /Example 1/A/.
  • 1,56 g /3,58 millimoles/ of polymorph I of rivaroxaban of the Formula 1 are dissolved in a mixture of 17,1 ml of 2,2,2-trifluoro-ethanol and 3,6 ml of distilled water at 70-80°C.
  • To the hot solution 4,68 g /3,61 millimoles/ of gamma- cyclodextrin are added.
  • the mixture is stirred at this temperature for 5 minutes whereupon 18 ml of methanol are added dropwise, the mixture is stirred for 10 minutes and allowed to cool to room temperature. After 24 hours the precipitated product is filtered off.
  • the IR and NMR spectral data and the X-ray powder diffractogram of the product obtained are identical with those of the product according to Example 2.
  • the IR and NMR spectral data and the X-ray powder diffractogram of the product obtained are identical with those of the product according to Example 2.

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Abstract

The invention relates to the new co crystals of 5-chloro-N-///5S/-2-oxo-3-/4-/3- oxo-moφholine-4-yl/-phenyl/-l,3-oxazolidine-5-yl/-methyl/-thiophen-2- carboxamide having the INN rivaroxaban formed with oxalic acid and gamma- cyclodextrine. The invention also relates to a process for the preparation of the co crystal of rivaroxaban and oxalic acid of the Formula 2. According to said process amorphous or crystalline rovaroxaban or a hydrate, solvate or co crystal of rivaroxaban is dissolved in an organic solvent, water or a mixture of an organic solvent and water, to the solution oxalic acid is added and the solvent is removed. According to the invention there is also provided a process for the preparation of the co crystal of rivaroxaban and gamma-cyclodextrin of the Formula 3 /wherein n is 0.9-1.1, preferably n=l/. According to said process amorphous or crystalline rivaroxaban or a hydrate, solvate or co crystal of rivaroxaban is dissolved in an organic solvent, water or a mixture of an organic solvent and water, to the solution gamma-cyclodextrine is added and the solvent is removed.

Description

New co crystals useful in the preparation of pharmaceutical compositions
The technical field of the invention
The invention relates to new co crystals useful in the preparation of pharmaceutical compositions. More particularly it is concerned with new co crystals of 5 -chloro-N-///5 S/-2-oxo-3 -/4-/3 -oxo-morpholine-4-yl/-phenyl/- 1,3- oxazolidine-5-yl/-methyl/-thiophen-2-carboxamide formed with oxalic acid and gamma-cyclodextrine which can be used as pharmaceutical active ingredient. The invention further relates to preparation of new co crystals.
The state of the art
It is known that rivaroxaban is an active ingredient of a Xa coagulation factor inhibitor mechanism which can be used for the prevention of thrombus, venous thrombosis and pulmonary embolism derived therefrom in case of patients undergone knee and hip prostesis surgery.
Rivaroxaban of the Formula
Figure imgf000002_0001
and the preparation thereof were first described by Straub et al in EP 1,261,606.
In EP 1,583,761 a further synthesis route was described for the preparation of rivaroxaban.
In WO 2007/039132 a new polymorph II of rivaroxaban of the Formula 1 is protected. According to said international patent publication the processes disclosed in the basic patent /EP 1,261,606/ and EP 1,583,761 lead to the formation of the polymorph I modification.
In WO 2009/149851 the co crystals of rivaroxaban of the Formula 1 formed with half equivalent of malonic acid, the preparation and therapeutical use thereof are disclosed; said co crystal corresponds to the Formula
Figure imgf000003_0001
Said co crystal is characterized by X-ray powder diffractogram, one-crystals spectrum and Raman spectrum. The compound of the Formula 4 is prepared by dissolving polymorph I of rivaroxaban of the Formula 1 obtained by reproducing the process of the basic patent and malonic acid in an inert solvent /preferably an alcohol or ketone, particularly 2,2,2-trifluoro-ethanol or acetone/ at 50-90°C and thereafter evaporating the solvent or suspending said starting materials in a solvent at 20-25°C and isolating the precipitate.
According to WO 2010/075631 a new polymorph of rivaroxaban of the Formula 1 - namely the modification APO-A - is prepared from polymorph I.
Object of the invention
Recently in pharmaceutical industry substantial need has appeared for the reproducible manufacture of pure morphologically uniform active ingredients. This is a basic pre-condition of the suitability of the active ingredient for the requirements of the formulation of medicines. It is namely well-known that various salts and polymorphs differ from each other in significant properties, e.g. solubility, chemical stability, polymorph stability, speed of dissolution, bioavailability, filtering, drying and tabletting characteristics. In order to meet the economical reqirements of the manufacturing process it is highly important that said process should be readily feasible on industrial scale and provide a morphologically uniform product free of impurities.
It is the object of the present invention to provide highly pure morphologically uniform new rivaroxaban modifications which have more preferable physico- chemical properties -particularly solubility - than the known forms, possess a chemical stability at least as high than that of the known polymorphs and can be prepared by a process feasible on industrial scale.
In course of the preparation of the co crystals according to the present invention it has been surprisingly found that the object of the present invention can be achieved with the aid of the co crystal /1:1/ of rivaroxaban and oxalic acid of the Formula
Figure imgf000004_0001
and the co crystal of rivaroxaban and gamma-cyclodextrine of the Formula
Figure imgf000004_0002
/wherein n is 0,9-1,1, preferably n=l/. Detailed description of the invention
According to the present invention there are provided the co crystal /1 :1/ of rivaroxaban and oxalic acid of the Formula 2 and the co crystal of rivaroxaban and gamma-cyclodextrine of the Formula 3 /wherein n is 0.9-1.1, preferably n=l/.
According to the present invention there is provided the co crystal /1 :1/ of rrivaroxaban and oxalic acid of the Formula 2.
According to the present invention there is also provided the co crystal /1 :1/ of rivaroxaban and oxalic acid of the Formula 2 having the following characteristic X-ray powder diffraction line measured by CuKa beam: 2 Θ (±0,2° 2 Θ): 24,11.
According to the present invention there is provided the co crystal /1:1/ of rivaroxaban and oxalic acid of the Formula 2 having the following characteristic X-ray powder diffraction lines measured by CuKa beam: 2 Θ (±0,2° 2 Θ): 13,91; 20,94; 24,11; 28,05.
According to the present invention there is also provided the co crystal /1:1/ of rivaroxaban and oxalic acid of the Formula 2 having the following characteristic powder diffraction lines measured by CuKa beam: 2 Θ (±0,2° 2 Θ): 13,91; 17,43; 19,35; 19,72; 20,94; 24,11; 28,05; 38,95.
Acccording to the present invention there is also provided the co crystal /1:1/ of rivaroxaban and oxalic acid of the Formula 2 having the following powder diffraction lines measured by CuKa beam: Im' Table 1 signals having a relative intensity larger than 6 % are shown/.
Table 1
Position and relative intensities /larger than 6 %/ in compound of the Formula 2
Peak 2 Θ d (A) Relative intensity
1 13,91 6,362 73,6
2 14,81 5,978 11,7
3 16,50 5,367 13,1
4 17,43 5,084 53,4
5 19,35 4,583 49,4
6 19,72 4,499 53,5
7 20,43 4,344 27,2
8 20,94 4,239 79,6
9 22,48 3,953 6,5
10 24,11 3,688 100,0
11 25,51 3,489 26,6
12 25,78 3,453 14,0
13 27,09 3,289 16,8
14 28,05 3,178 76,5
15 29,07 3,069 7,4
16 30,45 3,933 24,0
17 30,88 2,894 16,2
18 31,43 2,844 12,5
19 32,59 2,745 21,0
20 33,38 2,682 21,9
21 33,89 2,643 28,3
22 34,47 2,600 10,3
23 36,04 2,490 9,5
24 36,75 2,444 8,9
25 37,46 2,399 7,4
26 38,95 2,310 39,5
27 39,91 2,257 22,8
28 40,96 2,202 31,2
29 42,74 2,114 10,4
30 46,85 1,938 14,7
31 48,28 1,884 8,1 According to a further aspect of the present invention there is provided a process for the preparation of the co crystal of the Formula 2. According to the process of the present invention amorphous or crystalline rivaroxaban or a hydrate, solvate or co crystal of rivaroxaban is dissolved in an organic solvent, water or a mixture of an organic solvent and water, whereupon to the solution oxalic acid is added and the solvent is removed.
According to a preferred form of realization of the process of the present invention crystalline rivaroxaban, particularly rivaroxaban polymorph I is used as starting material.
According to an other preferred form of realization of the process of the present invention as organic solvent 2,2,2-trifluoro-ethanol, acetonitrile, a mixture of acetonitrile and water, N-methyl-pyrrolidone, a mixture of N-methyl-pyrrolidone and water or a mixture of 2,2,2-trifluoro-ethanol, methanol and water, particularly advantageously 2,2,2-trifluoro-ethanol is used.
According to a preferred form of realization of the process of the present invention the dissolving step is carried out at 20-90°C, preferably at 70-80°C.
According to a further preferred form of realization of the process of the present invention to the solution a 0.9-3.0, preferably 0.75-1.25 molar equivalent amount of oxalic acid in anhydrous or hydrate form is added.
According to a further preferred form of realization of the process of the present invention the oxalic acid solution or suspension obtained is cooled to a temperature between -20°C and +40°C, preferably between +10°C and + 30°C and the solvent is removed in a known manner.
According to a further aspect of the present invention there are provided pharmaceutical compositions comprising a therapeutically effective amount of the co crystal /1:1/ of rivaroxaban and oxalic acid of the Formula 2 in admixture with at least one pharmaceutically acceptable carrier, diluent or other auxiliary agent.
According to a further aspect of the present invention there is provided a process for the preparation of the above pharmaceutical compositions which comprises admixing a pharmaceutically effective amount of the co crystal /1 :1/ of rivaroxaban and oxalic acid of the Formula 2 with at least one pharmaceutically acceptable carrier, diluent or other auxiliary agent and converting the mixture into a pharmaceutical composition.
According to a further aspect of the present invention there is provided the use of the co crystal of rivaroxaban and oxalic acid of the Formula 2 for therapeutical purposes.
The invention also relates to the use of the co crystal /1:1/ of rivaroxaban and oxalic acid of the Formula 2 for the prevention of the formation of thrombus, venous thrombosis and pulmonary embolism derived therefrom in case of patients gone over knee or hip prostesis surgery.
The invention also relates to a process for the prevention of the formation of thrombus, venous thrombus and pulmonary embolism derived therefrom in case of patients gone over knee or hip prostesis surgery which comprises administering to the patient in need of such treatment a pharmaceutically active amount of the co crystal /l :1/ of rivaroxaban and oxalic acid having the Formula 2.
The invention also relates to the use of the co crystal /1 :1/ of rivaroxaban and oxalic acid of the Formula 2 for the purification of rivaroxaban.
According to the present invention there is also provided the co crystal of rivaroxaban and gamma-cyclodextrin having the Formula 3 /wherein n is 0.9 - 1.1, preferably n=l/.
According to the present invention there is also provided the co crystal of rivaroxaban and gamma-cyclodextrin of the Formula 3 /wherein n is 0.9 - 1.1, preferably n=l/ having the following characteristic X-ray powder diffraction line measured by CuKa beam: 2 Θ (±0,2° 2 Θ): 7,49.
According to the present invention there is also provided the co crystal of rivaroxaban and gamma-cyclodextrine of the Formula 3 /wherein n is 0.9 - 1.1, preferably n=l/ having the following characteristic X-ray powder diffraction lines measured by CuKa beam : 2 Θ (±0,2° 2 Θ): 7,49; 16,61; 22,53.
According to the present invention there is also provided the co crystal of rivaroxaban and gamma-cyclodextrin of the Formula 3 /wherein n is 0.9 - 1.1, preferably n=l/ having the following X-ray powder diffraction lines measured by CuKa beam: 2 Θ (±0,2° 2 Θ): 5,34; 7,49; 14,94; 15,86.
According to the present invention there is also provided the co crystal of rivaroxaban and gamma-cyclodextrin of the Formula 3 /wherein n is 0.9 - 1.1, preferably n=l/ having the following X-ray powder diffraction lines measured by CuKa beam: 2 Θ (±0,2° 2 Θ): 5,34; 7,49; 14,26; 14,94; 15,86; 16,61; 19,56; 19,96; 21,76; 22,53; 25,65; 26,70.
According to the present invention there is also provided the co crystal of rivaroxaban and gamma-cyclodextrin of the Formula 3 /wherein n is 0.9 - 1.1, preferably n=l/ having the following X-ray powder diffraction lines measured by CuK beam : /Table 2 contains signals having a relative intensity higher than 6 %/.
Table 2
The position of the diffraction lines and the relative intensities in the compound of the Formula 3 /larger than 6 %/
Figure imgf000009_0001
Figure imgf000010_0001
According to a further aspect of the present invention there is provided a process for the preparation of the co crystal of the Formula 3 /wherein n is 0.9-1.1, preferably n=l /.According to the process of the present invention amorphous or crystalline rivaroxaban or a hydrate, solvate or co crystal of rivaroxaban is dissolved in an organic solvent, water or a mixture of an organic solvent and water whereupon to the solution gamma-cyclodextrine is added and the solvent is removed.
According to a preferred form of realization of the process of the invention crystalline rivaoxaban, particularly advantageously rivaroxaban polymorph I is used.
In course of the process of the present invention as organic solvent 2,2,2-trifluoro- ethanol, aetonitrile, a mixture of acetonitrile and water, N-methyl-pyrrolidone, a mixture of N-methyl-pyrrolidone and water or a mixture of 2,2,2-trifluoro- ethanol, methanol and water, particularly advantageously 2,2,2-trifluoro-ethanol is used.
According to a preferred form of realization of the process of the present invention the dissolving step is carried out at 20-90°C, preferably at 70-80°C.
According to a preferred form of realization of the process of the present invention to the solution a 0.9-3.0 molar equivalent, advantageously a 0.9-1.1 molar amount of gamma-cyclodextrine is added.
According to a preferred form of realization of the process of the present invention the gamma-cyclodextrine solution or suspension obtained is cooled to a temperature between
-20°C and +40°C, advantageously to +10-30°C whereupon the solvent is removed in a known manner.
According to a further aspect of the present invention there are provided pharmaceutical compositions ccomprising the co crystal of rivaroxaban and gamma-cyclodextrin of the Formula 3 /wherein n is 0.9-1.1, preferably n=l/ in admixture with at least one pharmaceutically acceptable carrier, diluent or other auxiliary agents.
According to a further aspect of the present invention there is provided a process for the preparation of said pharmaceutical compositions which comprises admixing the co crystal of rivaroxaban and gamma-cyclodextrin of the Formula 3 /wherein n is 0.9-1.1, preferably n=l/ with at least one pharmaceutically acceptable carrier, diluent or other auxiliary agent and converting the mixture into a pharmaceutical composition.
According to a further aspexct of the present invention there is provided the use of the co crystal of rivaroxaban and gamma-cyclodextrin of the Formula 3 /wherein n is 0.9-1.1, preferably n=l/ for pharmaceutical purposes. According to a further aspect of the present invention there is provided the use of the co crystal of rivaroxaban and gamma-cyclodextrin of the Formula 3 /wherein n is 0.9-1.1, preferably n=l/ for the prevention of the formation of thrombus, venous thrombus and pulmonary embolism derived therefrom in case of patients gone over knee or hip prostesis surgery.
According to a further aspect of the present invention there is provided a process for the prevention of the formation of thrombus, venous thrombus and pulmonary embolism derived therefrom in case of patients gone over knee or hip prostesis surgery which comprises administering to the patient in need of such treatment a pharmaceutiacally effective amount of the co crystal of rivaroxaban and gamma-cyclodextrin of the Formula 3 /wherein n is 0.9-1.1 , preferably n-l/.
According to a further aspect of the present invention there is provided the use of the co crystal of rivaroxaban and gamma-cyclodextrin of the Formula 3 /wherein n is 0.9-1.1, preferably n=l/ for the purifation of rivaroxaban.
The X-ray powder diffraction data disclosed in the present patent application are obtained under the following measuring conditions.
Apparatus: Rigaku Corporation, Miniflex II. powder- diffractometer
Radiation: CuKoc (λ=1,54184 A)
Accelerating voltage: 30 kV
Anode current: 15 mA
Uptake speed: 1,5 °/minute
Stepwise interval: 0,01 °
Measuring range: 3,0-50,0° 2Θ (continous Θ-Θ, reflection) Sample holder: zero background, Si one-crystal
Rotation speed of sample holder: 1 rotation sec
Type of detector: MiniFlex2
Soller: 2,5°
Apertures: 1,25° (divergence, scattered); 0,3 mm
(receiving) Sample preparatory process: without pulverization, at room temperature
Reference standard: RSRP-43275 Si sheet
It is well-known in the field of pharmaceutical compositions that the person skilled in the art can identify the crystalline form on the basis of the peaks appearing on the X-ray powder diffractogram.
It can be seen from the above data that the X-ray powder diffractogram of the co crystal /1 :1/ of rivaroxaban and oxalic of the Formula 2 and the co crystal /1 :1/ of rivaroxaban and gamma cyclodextrine of the Formula 3 differs from those of the rivaroxaban polymorphs known from prior art /amorphous, polymorph I, polymorph II, polymorph III, polymorph APO-A/ and also from that of gamma- cyclodextrine.
The only known co crystal modification of rivaroxaban is the co crystal formed with half an equivalent of malonic acid having the Formula 4 described in WO 2009/149851. Since oxalic acid /HOOC-COOH/ used according to the present invention is analogous to malonic acid /HOOC-CH2-COOH/ applied in the known product are neighbours in the homologuous series of dicarboxylic acids, one could have come to the conclusion that said two dicarboxylic acids would be capable of entering into similar interactions with rivaroxaban. However we have found in a surprising manner that in the rivaroxaban - oxalic acid co crystal of the Formula 2 prepared in our laboratory the molar ratio of rivaroxaban and oxalic acid is 1 :1, as it is proved by the result of elemental analysis. Similarly in the co crystal of the Formula 3 formed with gamma-cyclodextrin have a molecural ratio of 1 :0,9-1,1, preferably 1 :1.
It follows from prior art toxicological data that the maximal daily dose to be introduced with 10 mg of rivaroxaban amounts to 2.07 mg of oxalic acid. The normal daily introduced oxalic acid dose is 5-500 mg. It is to be mentioned that oxalic acid is an endogenous material formed in human organism. For this reason no toxicity problems occur. Similarly in such amounts gamma-cyclodextrin does not exhibit any detrimental toxical effect so much the less that it is used in feed additives and foodstuff in quantities higher by orders of magnitude. We have compared the solubility of polymorph I of rivaroxaban of the Formula 1, the co-crystal of rivaroxaban formed with oxalic acid /1:1/ of the Formula 2, the co crystal of rivaroxaban and gamma-cyclodextrin of the Formula 3 /wherein n is 0.9-1.1, preferably n=l/ and the known co crystal of rivaroxaban formed with malonic acid /l :0.5/ of the Formula 4 at room temperature in saturated solutions. The results are determined by HPLC and summarized in Table 3.
Table 3
Solubility of rivaroxaban polymorph I and the co crystals
Figure imgf000014_0001
As it appears from Table 3 the solubility of the co crystal of rivaroxaban and oxalic acid of the Formula 2 in both biologically relevant media /water and 0.1 molar hydrochloric acid/ and in 1 % acetic acid is surprisingly more than twice larger than that of the polymorph I used in the product of the originator, Bayer Schering Pharma AG XARELTOR. Similarly such a more than two-fold difference is found in course of the comparison with the co crystal of rivaroxaban and malonic acid /1:0.5/ of the Formula 4. This is so much surprising as oxalic acid and malonic acid are chemically related compounds. The co crystal of rivaroxaban and gamma-cyclodextrin of the Formula 3 /wherein n is 0.9-1.1, preferably n=l/ gives still more favourable results because the solubility thereof in various media is 6-10 times larger than that of rivaroxaban polymorph I or of that of the rivaroxaban - malonic acid co crystal known from prior art. Rivaroxaban is an active ingredient of low solubility and therefore the achievement of a suitable dissolution from the tablet constitutes a serious problem. From this practical point of view it is a very valuable recognition of the present invention that the co crystal of the Formula 2 formed with oxalic acid and the co crystal of the Formula 3 formed with gamma-cyclodextrine /where n is 0,9- 1,1, peferably n = 1/ have a higher solubility than the active ingredient used in the product of the originator.
A further advantage of the co crystal of rivaroxaban formed with oxalic acid l\ :\l of the Formula 2 resides in the fact that during the formation of the co crystal the chemical purity of the product is improved. The rivaroxaban polymorph I of the Formula 1 used as starting material has a HPLC purity of 99,59 %. After proceeding according to Example 1/A the HPLC of the rivaroxaban - oxalic adid co crystal /l : 1/ of the Formula 2 was found to be 99,90 %.
The formation of co crystals is an effective purification method on the one hand while the new co crystals can be advantageously used as pharmaceutical active ingredients on the other.
According to a further aspect of the present invention there is provided a process for the preparation of the rivaroxaban - oxalic acid co crystal /l :1/ of the Formula 2.
The rivaroxaban - oxalic acid co crystal /1:1/ of the Formula 2 is prepared by dissolving amorphous or crystalline rivaroxaban or a hydrate, solvate or co crystal of rivaroxaban, preferably the rivaroxaban polymorph I in an organic solvent, water or a mixture of an organic acid and water, preferably in 2,2,2-trifluoro- ethanol, a mixture of 2,2,2-trifluoro-ethanol and water, acetonitrile, a mixture of acetonitrile and water, N-methyl-pyrrolidone, a mixture of N-methyl-pyrrolidone and water , a mixture of 2,2,2-trifluoro-ethanol, methanol and water, particularly preferably in 2,2,2-trifluoro-ethanol or a mixture of 2,2,2-trifluoro-ethanol and water, if desired under heating the solution, adding a 0.9-3.0 molar equivalent amount of solid oxalic acid, in anhydrous form or as a solvate, or adding a solution contaning an identical amount of oxalic acid, cooling the solution or suspension, if desired adding a precipitating solvent or evaporating the solvent and isolating the product.
According to a further aspect of the present invention there is provided a process for the preparation of the rivaroxaban - gamma-cyclodextrin co crystal of the Formula 3 /wherein n is 0.9-1.1, preferably n=l/.
The rivaroxaban - gamma cyclodextrin co crystal of the Formula 3 /wherein n is 0.9-1.1, preferably n=l/ is prepared by dissolving amorphous or crystalline rivaroxaban or a hydrate, solvate or co crystal of rivaroxaban, preferably the rivaroxaban polymorph I in an organic solvent, water or a mixture of an organic solvent and water, preferably in 2,2,2-trifluoro-ethanol, a mixture of 2,2,2- trifluoro-ethanol and water, acetonitrile, a mixture of acetonitrile and water, N- methyl-pyrrolidone, a mixture of N.methyl-pyrrolidone and water, a mixture of 2,2,2-trifluoro-ethanol, methanol and water, particularly in 2,2,2-trifluoro-ethanol or a mixture of 2,2,2-trifluoro-ethanol and water, if desired under heating the solution, thereafter adding a 0.9-3.0 molar equivalent amount of gamma- cyclodextrin in the form of the solid substance or as a solution, thereafter if desired cooling the solution or suspension, if desired adding a precipitating solvent or evaporating the solvent and isolating the product.
The advantage of the present invention is that both the rivaroxaban - oxalic acid co crystal and the rivaroxaban - gamma cyclodextrin co crystal have a significantly larger solubility than the rivaroxaban polymorph I used in the product of the originator and also than that of the known rivaroxaban - malonic acid co crystal known from prior art, which is very advantageous in the case of particularly poorly soluble rivaroxaban.
The advantage of the rivaroxaban - gamma cyclodextrine co crystal is that it is suitable for the preparation of a buccal pharmaceutical composition which can be readily placed under the tongue and is quickly absorbed, namely more rapidly than the drugs acting through the gastrointestinal system. A further advantage of the product according to the present invention is that neither oxalic acid nor gamma-cyclodextrine cause toxicity hazards.
A still further advantage of the present invention is that during the formation of the co crystals the HPLC chemical purity of the product is improved.
Consequently the co crystals of the present invention can be preferably used as pharmaceutical active ingredient.
Further details of the present invention are to be found in the following Examples without limiting the scope of protection to said Examples.
Example 1
Preparation of rivaroxaban - oxalic acid (1:1) co crystal of the Formula 2
A/ 4.50 g /10.32 millimoles/ of polymorph I of rivaroxaban of the Formula 1 /HPLC purity: 99.59 %/ are dissolved in 9,5 ml of 2,2,2-trifluoro-ethanol at 70- 80°C. To the hot solution 1.29 g /10.15 millimoles/ of oxalic acid dihydrate are added. The solution is stirred at this temperature for 5 minutes. The reaction mixture is allowed to cool to room temperature under stirring. After 4 hours the product is filtered and dried under an infrared lamp. Thus 3.66 g /69 %/ of rivaroxaban - oxalic acid co crystals l\
Figure imgf000017_0001
are obtained in the form of a white solid substance. HPLC purity 99,90 %..
Mp.: 168-169°C.
IR (KBr): 3347, 1788, 1737, 1630, 1557, 1520 cm'1.
1H-NMR (DMSO-d6, 500 MHz): 13.96 (br s, 1H), 8.94 (t, J=5.8 Hz, 1H), 7.68 (d, J=4.1 Hz, 1H), 7.56 (~d, J=9.0 Hz, 2H), 7.41 (~d, J=9.0 Hz, 2H), 7.18 (d, J=4.0 Hz, 1H), 4.84 (m, 1H), 4.19 (m, 1H), 4.19 (s, 2H), 3.97 (m, 2H), 3.86 (m, 1H), 3.72 (m, 2H), 3.61 (~t, J=5.6 Hz, 2H).
l3C-NMR (DMSO-d6, 125 MHz): 166.12, 161.08, 160.97, 154.25, 138.61, 137.26, 136.66, 133.42, 128.60, 128.26, 126.08, 118.54, 71.48, 67.90, 63.64, 49.18, 47.62, 42.38. Elemantary analysis for the Formula C21H20ClN3O9S (M: 435,89): calc: C 47,96; H 3,83; N 7,99; S 6,10; CI 6,74 %. Found: C 47,80; H 3,84; N 7,95; S 6,18; CI 6,77 %.
The X-ray powder diffractogram of the rivaroxaban - gamma cyclodextrine co crystal /1:1/ of the Formula 2 is shown on Figure 1. The characteristic peaks are summarized in Table 1.
B/ 0,75 g /1,72 millimoles/ of the above product are dissolved in 4 ml of hot 2,2,2- trifluoro-ethanol, the solution is stirred for 10 minutes and allowed to cool to room temperature. The product is filtered off. Thus 0.50 g /67 %/ of rivaroxaban - oxalic acid co crystal /l : 1/ is obtained.
Elementary analysis for the Formula C21H20ClN3O9S (M: 435,89): calc. C 47,96; H 3,83; N 7,99; S 6,10; CI 6,74 %. Found: C 47,64; H 3,73; N 7,96; S 6,17; CI 6,80 %.
DSC: 169,85 °C.
The IR and NMR spectral data and the X-ray powder diffractogram of the product obtained are identical with those of the product before recrystallization. /Example 1/A/.
Example 2
Preparation of rivaroxaban - gamma cyclodextrin co crystal of the Formula
3
1,56 g /3,58 millimoles/ of polymorph I of rivaroxaban of the Formula 1 are dissolved in a mixture of 17,1 ml of 2,2,2-trifluoro-ethanol and 3,6 ml of distilled water at 70-80°C. To the hot solution 4,68 g /3,61 millimoles/ of gamma- cyclodextrin are added. The mixture is stirred at this temperature for 5 minutes whereupon 18 ml of methanol are added dropwise, the mixture is stirred for 10 minutes and allowed to cool to room temperature. After 24 hours the precipitated product is filtered off. IR (KBr): 3417, 1737, 1646, 1159, 1079, 1026 cm"1.
1H-NMR (DMSO-d6, 500 MHz): 8.94 (t, J=5.9 Hz, 1H), 7.68 (d, J=4.0 Hz, 1H), 7.56 (~d, J-9.0 Hz, 2H), 7.40 (~d, J=9.0 Hz, 2H), 7.18 (d, J=4.0 Hz, 1H), 5.72 (m, 16H), 4.89 (d, J=3.5 Hz, 8H), 4.84 (m, 1H), 4.50 (~t, J=5.6 Hz, 8H), 4.19 (m, 1H), 4.19 (s, 2H), 3.97 (m, 2H), 3.88 (m, 1H), 3.85 (m, 2H), 3.71 (m, 2H), 3.62 (m, 32H), 3.32 (m).
I3C-NMR (DMSO-d6, 125 MHz): 166.16, 161.00, 154.28, 138.60, 137.27, 136.67, 133.45, 128.63, 128.30, 126.13, 118.56, 101.86, 81.12, 73.08, 72.77, 72.35, 71.50, 67.91, 63.65, 60.17, 49.20, 47.63, 42.39.
The X-ray powder diffractogram of the product - i.e. the co crystal of rivaroxaban and gamma-cyclodextrin of the Formula 3 - is shown on Figure 2 and the characteristic peaks are summarized in Table 2.
Example 3
Preparation of the co crystal of rivaroxaban and gamma-cyclodextrine of the
Formula 3
87 mg /0,20 millimoles/ of polymorph I of rivaroxaban of the Formula 1 are dissolved in 0,95 ml of 2,2,2-trifluoro-ethanol at 70-80°C. To the hot solution 260 mg /0,20 millimoles/ of gamma-cyclodextrine are added. The mixture is stirred at this temperature for 10 minutes, wheeupon 2 ml of methanol are added dropwise, the mixture is stirred for 10 minutes and allowed to stand to room temperature. After 6 days the mixture is evaporated to dryness and the white crystals are collected.
The IR and NMR spectral data and the X-ray powder diffractogram of the product obtained are identical with those of the product according to Example 2.
Example 4
Preparation of the co crystal of rivaroxaban and gamma-cyclodextrine of the
Formula 3. 87 mg /0,20 millimole/ of polymorph I of rivaroxaban of the Formula 1 are dissolved in 0,95 ml of 2,2,2-trifluoro-ethanol at 70-80°C. To the hot solution 260 mg /0.20 millimoles/ of gamma-cyclodextrin and 0,5 ml of water are added. After stirring for 10 minutes /during this stirring step no conversion was observed the mixture is allowed to cool to room temperature. After 6 days the mixture is evaporated to dryness and the white crystals obtained are collected.
The IR and NMR spectral data and the X-ray powder diffractogram of the product obtained are identical with those of the product according to Example 2.

Claims

What we claim is,
1/ Co crystal /l :1/ of rivaroxaban and oxalic acid of the Formula
Figure imgf000021_0001
21 Co crystal of rivaroxaban and oxalic acid of the Formula 2 having the following X-ray powder diffraction line measured by CuK beam: 2 Θ (±0,2° 2 Θ): 24,11.
3/ Co crystal /1 : 1/ of rivaroxaban and oxalic acid of the Formula 2 having the following powder diffraction lines measured by CuKa beam: 2 Θ (±0,2° 2 Θ): 13,91 ; 20,94; 24,11; 28,05.
4/ Co crystal of rivaroxaban and oxalic acid of the Formula 2 having the following powder diffraction lines measured by CuKa beam: 2 Θ (±0,2° 2 Θ): 13,91 ; 17,43; 19,35; 19,72; 20,94; 24,11; 28,05; 38,95.
5/ Co crystal /1 :1/ of rivaroxaban and oxalic acid of the Formula 2 according to the X-ray powder diffractogram shown on the Figure 1 having the following powder diffraction lines measured by CuKa beam:
Peak 2 Θ d (A) Relative
intensity
1 13,91 6,362 73,6
2 14,81 5,978 11,7
3 16,50 5,367 13,1
4 17,43 5,084 53,4
5 19,35 4,583 49,4
6 19,72 4,499 53,5
7 20,43 4,344 27,2
8 20,94 4,239 79,6
Figure imgf000022_0001
6/ Process for the preparation of the co crystal of the Formula 2 according to any of Claims 1-5 which comprises dissolving amorphous or crystalline rivaroxaban or a hydrate, solvate or co crystal of rivaroxaban in an organic solvent, water or a mixture of an organic solvent and water, adding oxalic acid to the solution and removing the solvent.
7/ Process according to Claim 6 which comprises using in the process crystalline rivaroxaban, advantageously polymorph I of rivaroxaban.
8/ Process according to Claim 6 or 7 which comprises using as organic solvent 2,2,2-trifluoro-ethanol, acetonitrile, a mixture of acetonitrile and water, N-methyl- pyrrolidone, a mixture of N-methyl-pyrrolidone and water or a mixture 2,2,2- trifluoro-ethanol, methanol and water, preferably 2,2,2-trifluoro-ethanol.
9/ Process aaccording to any of Claims 6-8 which comprises carrying out the dissolving step at 20-90°C, preferably at 70-80°C. 10/ Process according to any of Claims 6-9 which comprises adding to the solution a 0,9-3,0, preferably 0,75-1,25 equivalent amount of oxalic acid, in anhydrous form or as a hydrate.
11/ Process according to any of Claims 6-10 which comprises cooling the oxalic acid solution or suspension to a temperature between -20°C and +40°C, preferably to a temperature between +10°C and +30°C and removing the solvent in a known manner.
12/ Pharmaceutical composition comprising a pharmaceutically effective amount of the co crystal /1 :1/ of rivaroxaban and oxalic acid of the Formula 2 according to any of Claims 1-5 in admixture with at least one pharmaceutically acceptable carrier, diluent or other auxiliary agent.
13/ Process for the preparation of the pharmaceutical compositions according to Claim 12 which comprises admixing the co crystal l\ : 1/ of rivaroxaban and oxalic acid of the Formula 2 with at least one pharmaceutically acceptable carrier, diluent or other auxiliary agent and converting the mixture into a pharmaceutical composition.
14/ Use of the co crystal of rivaroxaban and oxalic acid of the Formula 2 according to any of Claims 1-5 for pharmaceutical purposes.
15/ Use of the co crystal /1 : 1/ of rivaroxaban and oxalic acid of the Formula 2 according to any of Claims 1-5 for the prevention of the formation of thrombus, venous thrombus and pulmonary embolism derived therefrom in case of patients gone over knee or hip prostesis surgery.
16/ Process for the the prevention of the formation of thrombus, venous thrombus and pulmonary embolism derived therefrom in case of patients gone over knee or hip prostesis surgery which comprises administering to the patient in need of such treatment a pharmaceutically effective amount of the co crystal /1 :1/ of rivaroxaban and oxalic acid of the Formula 2 according to any of Claims 1-5. 17/ Use of the co crystal /1:1/ of rivaroxaban and oxalic acid of the Formula 2 according to any of Claims 1-5 for the purification of rivaroxaban.
18/ The co crystal of rivaroxaban and gamma-cyclodextrin of the Formula
Figure imgf000024_0001
/wherein n is 0.9-1.1, preferably n=l/.
19/ The co crystal of rivaroxaban and gamma-cyclodextrin of the Formula 3 /wherein n is 0.9-1.1 , preferably n=l/ of the Formula 3 having the following X-ray powder diffraction line measured by CuKa beam: 2 Θ (±0,2° 2 Θ): 7,49.
20/ The co crystal of rivaroxaban and gamma-cyclodextrin of the Formula 3 /wherein n is 0.9-1.1, preferably n=l/ having the following powder diffraction lines measured by CuKa beam: 2 Θ (±0,2° 2 Θ): 7,49; 16,61; 22,53.
21/ The co crystal of rivaroxaban and gamma-cyclodextrin of the Formula 3 /wherein n is 0.9-1.1, preferably n=l/ having the following powder diffraction lines measured by CuKa beam: 2 Θ (±0,2° 2 Θ): 5,34; 7,49; 14,94; 15,86.
22/ The co crystal of rivaroxaban and gamma-cyclodextrin of the Formula 3 /wherein n 0,9-1,1, preferably n=l/ having the following powder diffraction lines measured by CuKa beam: 2 Θ (±0,2° 2 Θ): 5,34; 7,49; 14,26; 14,94; 15,86; 16,61; 19,56; 19,96; 21,76; 22,53; 25,65; 26,70.
23/ The co crystal of rivaroxaban and gamma-cyclodextrin of the Formula 3 /wherein n is 0.9-1.1, preferably n=l/ having the following powder diffraction lines measured by CuKa beam:
Figure imgf000025_0001
24/ Process for the preparation of the co crystal of rivaroxaban and gamma- cyclodextrin of the Formula 3 /wherein n is 0.9-1.1, preferably n=l/ according to any of Claims 18-23 which comprises dissolving amorphous or crystalline rivaroxaban or a hydrate, solvent or co crystal of rivaroxaban in an organic solvent, water or a mixture of an organic solvent and water, adding gamma- cyclodextrine to the solution and removing the solvent.
25/ Process according to Claim 24 which comprises using crystalline rivaroxaban, particularly advantageously polymorph I of rivaroxaban in the procedure.
26/ Process according to Claim 24 or 25 which comprises using as organic solvent 2,2,2-trifluoro-ethanol, acetonitrile, a mixture of acetonitrile and water, N-methyl- pyrrolidone, a mixture of N-methyl-pyrrolidone and water or a mixture of 2,2,2- triofiuoro-ethanol, methanol and water, preferably 2,2,2-trifluoro-ethanol.
27/ Process according to any of Claims 24-26 which comprises carrying out the dissolving step at 20-90°, preferably at 70-80°C.
28/ Process according to any of Claims 24-27 which comprises adding to the solution a 0,9-3,0, preferably 0,9-1,1 molar equivalent mount of gamma- cyclodextrine.
29/ Process according to any of Claims 24-28 which comprises cooling the gamma-cyclodextrine solution or suspension to a temperature between -20°C and 40°C, preferably between +10°C and +30°C and removing the solvent in a known manner.
30/ Pharmaceutical composition comprising a pharmaceutically effective amount the co crystal of rivaroxaban and gamma-cyclodextrin of the Formula 3 /wherein n is 0.9-1.1, preferably n=l/ according to any of Claims 18-23 in admixture with at least one pharmaceutically acceptable carrier, diluent or other auxiliary agent.
31/ Process for the preparation of pharmaceutical compositions according to Claim 30 which comprises admixing the co crystal of rivaroxaban and gamma- cyclodextrin of the Formula 3 /wherein n is 0.9-1.1, preferably n=l/ according to any of Claims 18-23 with at least one pharmaceutically acceptable carrier, diluent or other auxiliary agent and converting the mixture into a pharmaceutical composition. 32/ Use of the co crystal of rivaroxaban and gamma-cyclodextrin of the Formula 3 /wherein n is 0.9-1.1, preferably n=l/ according to any of Claims 18-23 for pharmaceutical purposes.
33/ Use of the co crystal of rivaroxaban and gamma-cyclodextrin of the Formula 3 /wherein n is 0.9-1.1, preferably n=l/ according to any of Claims 18-23 for the prevention of the formation of thrombus, venous thrombus and pulmonary embolism derived therefrom in case of patients gone over knee or hip prosthesis surgery.
34/ Process for the prevention of the formation of thrombus, venous thrombus and pulmonary embolism derived therefrom in case of patients gone over knee or hip prosthesis surgery which comprises administering to the patient in need of such treatment a pharmaceutically efficient amount of the co crystal of rivaroxaban and gamma-cyclodextrin of the Formula 3 /wherein n is 0.9-1.1, preferably n=l/ according to any of Claims 18-23.
35/ Use of the co crystal of rivaroxaban and gamma-cyclodextrin of the Formula 3 /wherein n is 0.9-1.1, preferably n=l/ according to any of Claims 18-23 for the purification of rivaroxaban.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1261606A1 (en) 1999-12-24 2002-12-04 Bayer Aktiengesellschaft Substituted oxazolidinones and their use in the field of blood coagulation
EP1583761A1 (en) 2003-01-07 2005-10-12 Bayer HealthCare AG METHOD FOR PRODUCING 5-CHLORO- i N /i -({5 i S /i )-2-OXO-3- 4-(3-OXO-4-MORPHOLINYL)-PHENYL -1,3-OXAZOLIDIN-5-YL&rc ub;-METHYL)-2-THIOPHENE CARBOXAMIDE
WO2007039132A1 (en) 2005-10-04 2007-04-12 Bayer Healthcare Ag Novel polymorphous form and the amorphous form of 5-chloro-n-({ (5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidine-5-yl}-methyl)-2-thiophene carboxamide
WO2009149851A1 (en) 2008-06-12 2009-12-17 Bayer Schering Pharma Aktiengesellschaft New co-crystal compound of rivaroxaban and malonic acid
WO2010075631A1 (en) 2008-12-31 2010-07-08 Apotex Pharmachem Inc Polymorphic form of 5-chloro-n-{[(5s)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxa-zolidin-5-yl]-methyl}thiophene-2-carboxamide

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1261606A1 (en) 1999-12-24 2002-12-04 Bayer Aktiengesellschaft Substituted oxazolidinones and their use in the field of blood coagulation
EP1583761A1 (en) 2003-01-07 2005-10-12 Bayer HealthCare AG METHOD FOR PRODUCING 5-CHLORO- i N /i -({5 i S /i )-2-OXO-3- 4-(3-OXO-4-MORPHOLINYL)-PHENYL -1,3-OXAZOLIDIN-5-YL&rc ub;-METHYL)-2-THIOPHENE CARBOXAMIDE
WO2007039132A1 (en) 2005-10-04 2007-04-12 Bayer Healthcare Ag Novel polymorphous form and the amorphous form of 5-chloro-n-({ (5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidine-5-yl}-methyl)-2-thiophene carboxamide
WO2009149851A1 (en) 2008-06-12 2009-12-17 Bayer Schering Pharma Aktiengesellschaft New co-crystal compound of rivaroxaban and malonic acid
WO2010075631A1 (en) 2008-12-31 2010-07-08 Apotex Pharmachem Inc Polymorphic form of 5-chloro-n-{[(5s)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxa-zolidin-5-yl]-methyl}thiophene-2-carboxamide

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LOFTSSON ET AL: "Cyclodextrins and their pharmaceutical applications", INTERNATIONAL JOURNAL OF PHARMACEUTICS, ELSEVIER BV, NL, vol. 329, no. 1-2, 20 December 2006 (2006-12-20), pages 1 - 11, XP005809167, ISSN: 0378-5173, DOI: 10.1016/J.IJPHARM.2006.10.044 *

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