WO2013079040A1

WO2013079040A1 - Mixed solvate of tiotropium bromide and a method of its preparation

Info

Publication number: WO2013079040A1
Application number: PCT/CZ2012/000121
Authority: WO
Inventors: Igor CERNA; Ludek Ridvan; Vladimir Kral; Josef Hajicek; Ondrej Dammer
Original assignee: Zentiva K.S.
Priority date: 2011-11-28
Filing date: 2012-11-28
Publication date: 2013-06-06
Also published as: CZ304368B6; CZ2011775A3

Abstract

Mixed solvate of propyleneglycol/ethanol solvate of tiotropium bromide of formula V contains ethanol in the range of 3,000 to 40,000 ppm and propyleneglycol in the range of 3,000 to 40,000 ppm. An additional solution provides a method of preparing the solvate of tiotropium bromide, wherein a form of tiotropium bromide, selected from an anhydrous form, hydrate, solvate, or mixed solvate, is dissolved in a mixture of propyleneglycol and ethanol at a temperature in the range of from 40°C to the boiling point of the solvent, the formed solution is cooled down and the precipitated solvate is isolated. The solvate of tiotropium bromide is used in preparing an inhalation therapeutic formulation.

Description

Mixed solvate of tiotropium bromide and a method of its preparation

Technical Field

The invention relates to mixed solvates of tiotropium bromide of structure I and a method of their preparation. The invention includes a new solvate of tiotropium bromide as a combination of two solvents in amounts exceeding 0.1 equivalent of the solvent relatively to the molecule of tiotropium bromide.

(I)

Background Art

Tiotropium bromide of structure II is a trade name for 6-alpha,7-alpha-epoxy-8- methyl-8-azabicyclo(3.2.1 )oct-3-endo-yl-di-2-thienyl) glycolate of methylbromide. Tiotropium bromide, first described in patent EP0418716, is a selective, competitive, reversible antagonist of cholinergic receptors with a long-lasting action. Contrary to the structurally close ipratropium, it selectively blocks muscarinic receptors M1 and M3, whereas M2 receptors are blocked shortly. It has significant bronchodilatation effects. It is in particular used in the therapy of chronic obstructive pulmonary disease (COPD) and in the therapy of asthma. The therapeutical dosing of the active substance is small (in micrograms), in the form of a powder applied by means of an inhalation appliance.

Concerning polymorphy, tiotropium bromide is a very interesting substance with many functional groups (ester group, hydroxyl group, thienyl, quaternary ammonium salt) capable to interact (hydrogen bonds, Van der Waals interactions, ττ-π stacking), which readily forms solvates, co-crystals, and various polymorphic forms.

A process of preparing tiotropium bromide was first published in patent EP0418716. It describes a reaction of scopine di(2-thienyl) glycolate of formula VI with methyl bromide (a 50% solution in anhydrous acetonitrile) in a mixture of the solvents dichloromethane and acetonitrile (Scheme 1 ). Subsequent recrystallization was carried out in an unspecified mixture of methanol and acetone and a white crystalline product with melting point 217 to 218°C was obtained.

Scheme 1

Tiotropium bromide monohydrate (EP 1 326 862) and anhydrous, or desolvated, forms of tiotropium bromide (EP 1 401 445, EP 1 682 542, EP 1 881 980) have been described in the literature. Also known are solvated forms (EP 1 879 888, EP 1 966 196, WO2010101538, WO201 101588), an amorphous form (EP 1 869 035), and a cocrystal with urea (EP 2 084 157). Disclosure of Invention

This invention provides mixed propyleneglycol/ethanol solvate of tiotropium bromide of formula V

(V) and a method of its preparation. This solvate can be used in preparing an inhalation therapeutic formulation for therapy of chronic obstructing pulmonary disease (COPD) and for therapy of asthma.

Detailed Description of Invention

(V)

The mixed solvate prepared according to this invention shows the following characteristic reflections in the powder X-ray record, measured using CuKa radiation: 13.66; 15.55; 18.36; 20.16, 21 .65 +/- 0.2° 2Th. Additionally, the mixed solvate according to this invention shows the following further characteristic reflections in the powder X-ray record: of 10.17; 1 1.30; 16.54; 21 .16; 23.90; 27.30; 29.90, 30.26 +/- 0.2° 2Th.

The solvate of tiotropium bromide prepared according to this invention contains ethanol in the range of 3,000 to 40,000 ppm and propyleneglycol in the range of 3,000 to 40,000 ppm. The contents of residual solvents were determined by gas chromatography.

The mixed solvate according to this invention can be prepared by dissolving the known forms of tiotropium bromide, for instance anhydrous forms, hydrates, and solvates and/or the known mixed solvates in a mixture of ethanol/propyleneglycol at an elevated temperature in the range between 40°C and the boiling point of the solvent; the resulting solution is cooled down and the precipitated solvate is isolated.

In a preferable embodiment of preparing the solvate according to this invention, a solvate of tiotropium bromide selected from the dichloromethane/acetonitrile solvate and/or the methanol/acetone solvate is used, dissolved in a mixture of propyleneglycol and ethanol at temperature in the range of 60 to 80°C; and the formed solution is cooled down to a temperature in the range of -5 to 10°C and the precipitated solvate is isolated.

The separated crude solvate is then dried at normal pressure or under vacuum at temperatures lower than the decomposition temperature of the mixed solvate, typically at temperatures in the range of 20 to 35°C.

Before being used into a medicine form, the obtained solvate is then micronized to a particle size of 0-5 pm (analyzed by SEM - particle size).

Strict rules of registration authorities as regards the type (toxicity) of solvent specify the limits for solvents that can be found in a pharmaceutical product, either in the form of a solvate or as a residual solvent.

One-type solvates described in the patent literature (EP 1 879 888, EP 1 966 196, WO2010101538, WO201 101588) can represent a risk in terms acceptability, due to high amounts of a single solvent in the solvated form of tiotropium bromide, as well as to possible high toxicity of solvents in the described solvates. On the contrary, mixed solvates can be an interesting compromise, wherein, in case of using pharmaceutically acceptable solvents, a lower portion of solvent would be declared since the same number of cavities in the solvate lattice is occupied by the same amount, however, of two or more types of solvents in case of the mixed solvate. Our reproduction of the preparation of tiotropium bromide according to patent EP 0 418 716 by reaction of scopine di(2-thienyl) glycolate with methyl bromide (a 50% solution in anhydrous acetonitrile) in a mixture of the solvents dichloromethane and acetonitrile, followed by subsequent recrystallization in an unspecified mixture of methanol and acetone, resulted in formation of mixed solvates of tiotropium bromide, in particular of dichloromethane/acetonitrile solvate of formula III and methanol- acetone solvate of formula IV.

(Ill (IV) However, the two mixed solvates lack utility in pharmaceutics because the toxic solvents, such as dichloromethane, acetonitrile, methanol, belong to class 2, the amount of which in a pharmaceutical product is limited due to toxicity associated with these solvents.

In a study of preparation of mixed solvates from various solvents, we have selected, as the most appropriate candidate from the prepared mixed solvates, propyleneglycol (propane-1 ,2-diol)-ethanol solvate of formula V, which meets the conditions of both lower amount of the two solvents and low toxicity of the selected solvents for formation of the mixed solvate.

Brief Description of Drawings

Figure 1a. X-ray powder record of dichloromethane/acetonitrile solvate of Example 1 . Figure 1b. DSC thermogram of dichloromethane/acetonitrile solvate of Example 1.

Figure 1c. TGA record of dichloromethane/acetonitrile solvate of Example 1.

Figure 2b. DSC thermogram of dichloromethane/acetonitrile solvate of Example 2.

Figure 2c. TGA record of dichloromethane/acetonitrile solvate of Example 2.

Figure 3a. X-ray powder record of methanol/acetone solvate of Example 3.

Figure 3b. DSC thermogram of methanol/acetone solvate of Example 3.

Figure 3c. TGA record of methanol/acetone solvate of Example 3.

Figure 4b. DSC thermogram of methanol/acetone solvate of Example 4.

Figure 4c. TGA record of methanol/acetone solvate of Example 4.

Figure 5a. X-ray powder record of propyleneglycol/ethanol solvate of Example 5. Figure 5b. DSC thermogram of propyleneglycol/ethanol solvate of Example 5.

Figure 5c. TGA record of propyleneglycol/ethanol solvate of Example 5.

Figure 6b. DSC thermogram of propyleneglycol/ethanol solvate of Example 6.

Figure 6c. TGA record of propyleneglycol/ethanol solvate of Example 6.

Examples

Melting points were measured on the Kofler block. The samples in the following Examples were characterized by the methods of X-ray powder diffraction, differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). The amounts of solvents were determined by GC.

Measuring parameters of X-ray powder diffraction: The diffraction patterns were measured on an X^'PERT PRO MPD PANalytical diffractometer with a graphite monochromator, radiation used CuKa (λ = 0.1542 nm (1.542 A)), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 to 40° 2Θ, step size: 0.01 ° 2Θ. The measuring was performed on a flat powder sample, which was placed on a Si plate. The primary optics was adjusted using programmable divergence diaphragms with the irradiated sample area 10 mm, Soller diaphragms 0.02 rad, and a ¼ anti- scattering diaphragm. The secondary optics was adjusted using an X^'Celerator detector with the maximum opening of the detection aperture, the Soller diaphragms 0.02 rad, and a 5.0 mm anti-scattering diaphragm.

Differential scanning calorimetry (DSC) records were measured on a DSC Pyris 1 instrument from Perkin Elmer. Weight of the sample in a standard Al pan was 3 to 4 mg; heating rate 10°C/min. The temperature program used included stabilization at temperature 50°C for 1 minute and heating to 250°C at heating rate 10°C/min. Nitrogen 4.0 N₂ at flow rate 20 ml/min was used as a purge gas.

Thermogravimetric analysis (TGA) records were measured on a TGA 6 instrument from Perkin Elmer. Weight of the sample in a corundum crucible was 15 to 19 mg; heating rate 10°C/min. The temperature program used included stabilization at temperature 20°C for 1 minute and heating to 250°C with heating rate 10°C/min. Nitrogen 4.0 N2 at flow rate 20 ml/min was used as a purge gas. Gas chromatography (GC):

Method A: Monitoring of propyleneqlvcol

Propyleneglycol was determined by gas chromatography on an Agilent 7890 instrument with Fl detection.

Chromatographic conditions: Capilllary column: DB-624 (30 m; 0.53 mm ID; 3.0 μιη df) or equivalent;

Temperature program: 70°C - 2 min, gradient 10°C /min to 170°C - 0 min, Carrier gas: helium for chromatography R; 35 cm/s, constant flow rate

Injection: 1 μΙ

Injector: 200°C, split ratio 5 : 1

Detector: FID, 260°C

Evaluation:

The content of propyleneglycol expressed in ppm was evaluated by the method of external standard according to the formula: x = A x x 5000 , wherein

A^r x / A'"¹" area of the propyleneglycol peak in the chromatogram of the tested sample;

A^r area of the propyleneglycol peak inn the chromatogram of the reference sample; m^r weight of propyleneglycol in a storage solution in mg; m '^sl weight of the tested sample in mg.

Method B: Monitoring of the following solvents: methanol, ethanol, acetonitrile, acetone, dichloromethane.

Determination of these residual solvents was performed by the method of head-space gas chromatography using a PerkinElmer Autosystem XL instrument with Fl detection and a TurboMatrix 40 head-space autosampler.

Chromatographic conditions:

Capillary column: CP Sil 5 CB (30 m * 0.32 mm χ 3.0 μηη) or equivalent;

Temperature program: 40°C - 3 min, gradient 20°C /min to 160°C - 2 min; Carrier gas: helium for chromatography R; 1.6 ml/min Injector: split flow rate 4.0 ml/min, 165°C Detector: FID, 300°C, Range: 1 , Attn: -3

Evaluation:

The content of residual solvents expressed in % was evaluated by the method of external standard according to the formula: x x 0,2 , wherein

A'"" ... peak area of an individual residual solvent in the chromatogram of the tested sample;

A ... peak area of an individual residual solvent in the chromatogram of the reference sample; m ...weight of an individual residual solvent in the basic solution in mg; ...weight of the tested sample in mg.

Reference examples according to the procedure of patent EP0418716: Preparation of dichloromethane/acetonitriie solvate of tiotropium bromide (III) Example 1

15.0 g of scopine di(2-thienyl)glycolate (39.7 mmol) was dissolved in 150 ml of a mixture of dichloromethane (60 ml) and acetonitrile (90 ml) at 55°C; the solution was cooled to 33°C and 35.0 g of 55% MeBr in acetonitrile (5.1 equivalent) was added. The solution was stirred and left to cool down freely without stirring still for 24 hours. The formed crystalline product was filtered, washed with 60 ml of dichloromethane, and dried in a vacuum oven at 35°C for 6 hours. 20.3 g of white crystals were obtained, HPLC purity 99.55%. The content of solvents (determined by GC): dichloromethane 61 ,000 ppm, acetonitrile 9,700 ppm.

X-ray powder diffraction - Diffraction peaks of dichloromethane/acetonitriie solvate

Pos. d Rel.

[°2Th.] [A] = 0.1 nm Int. [%]

9.90 8.925 55.5 11.05 8.002 9.8

13.36 6.621 53.2

15.24 5.809 72.3

16.1 1 5.496 61.1

18.06 4.908 66.2

19.89 4.460 100.0

21.04 4.220 35.6

21.46 4.138 59.9

23.17 3.835 39.8

23.60 3.767 61.7

23.79 3.737 35.4

24.64 3.611 38.3

24.98 3.563 53.9

26.12 3.409 15.4

30.15 2.962 60.3

32.60 2.745 97.8

The thermogram of differential scanning calorimetry (DSC) contains a minor endotherm of T_onSeti = 160.2°C, T_peaki = 169.8°C, and a major endotherm of T_onSet2 = 226.3°C, T_Peak2 = 228.4°C; the thermogravimetric analysis (TGA) record shows 9.2% of the solvent.

The X-ray powder record is shown in the Annex in Figure 1a, the DSC thermogram is in Figure 1 b, and the TGA record is in Figure 1c.

Example 2 2.0 g of scopine di(2-thienyl)glycolate (5.3 mmol) was dissolved in 20 ml of a mixture of dichloromethane (8 ml) and acetonitrile (12 ml) at 55°C. The solution was cooled down to 33°C and 5.46 g of 55% MeBr in acetonitrile (5.1 equivalents) was added. The solution was stirred and left to cool freely without stirring still for 48 hours. The formed crystalline product was filtered, washed with 30 ml of dichloromethane, and dried in a vacuum oven at 35°C for 6 hours. 2.65 g of white crystals were obtained, HPLC purity 99.60%. The content of solvents (determined by GC): dichloromethane 69,000 ppm, acetonitrile 8,200 ppm.

The X-ray record was identical to the X-ray diffraction pattern from Example 1.

The DSC thermogram contains a minor endotherm of T_onseti = 157.9°C, T_peaki = 164.8°C, and a major endotherm of T_onSet2 = 227.4°C, T_peak2 = 228.9 ; the scan of the thermogravimetric analysis (TGA) shows 8.6 % of the solvent.

DSC thermogram is shown in the Annex in Figure 2b and TGA scan is in Figure 2c.

Preparation of methanol/acetone solvate of tiotropium bromide (IV)

(recrystallization according to the procedure of patent EP 0 418 716)

Example 3

5.0 g of tiotropium bromide (dichloromethane/acetonitrile solvate) was dissolved in 42 ml of a mixture methanol (24 ml) /acetone (18 ml) = 4/3 (57 % MeOH) at 60°C. The solution was cooled to -10 °C within 90 min and further stirred at this temperature for 3.5 hours. The recrystallized product was filtered, washed with a minimum amount of ice-cold acetone, and dried under vacuum at 87°C for 17 hours. 3.46 g of white crystals were obtained; yield 69%, HPLC purity 99.90%. The content of solvents (determined by GC): methanol 23,000 ppm, acetone 4,500 ppm.

X-ray powder diffraction - Diffraction peaks of methanol/acetone solvate

Pos. d Rel. Int.

[°2Th.] [A] = 0.1 nm [%]

6.88 12.831 25.2

10.04 8.806 33.9

11.14 7.937 27.5

13.54 6.536 62.7

13.65 6.481 95.6

15.47 5.724 66.8

18.20 4.870 67.5

20.04 4.427 75.6

21.55 4.121 100.0 23.70 3.751 12.6

24.24 3.668 27.2

24.78 3.590 17.6

25.25 3.524 27.5

26.10 3.411 17.1

27.33 3.261 34.0

28.13 3.170 18.3

30.96 2.886 14.5

32.14 2.783 20.0

33.33 2.686 13.9

The thermogram of differential scanning calorimetry (DSC) contains a minor endotherm of T_onseti = 134.6°C, T_peaki = 139.2°C, and a major endotherm of T_onset2 = 227.0°C, T_Peak2 = 230.3°C; the record of the thermogravimetric analysis (TGA) shows 4.1 % of the solvent.

The X-ray powder record is shown in the Annex in Figure 3a, DSC record is in Figure 3b, and TGA scan is in Figure 3c.

Example 4 490 mg of tiotropium bromide (dichloromethane/acetonitrile solvate) was dissolved in 5 ml of a mixture methanol (2 ml) /acetone (3 ml) = 4/3 (40 % MeOH) at 75°C. The solution was cooled to 0°C within 60 min and further stirred at this temperature for 1 .5 hour. The crystalline product was filtered, washed with a minimum amount of acetone, and dried at 1 11 °C for 22 hours. 160 mg of white crystals were obtained; yield 33%, HPLC purity 99.80%. The content of solvents (determined by GC): methanol 15,900 ppm, acetone 12,000 ppm.

The X-ray record of the sample from Example 4 was similar to the diffraction pattern from Example 3.

The thermogram of the differential scanning calorimetry (DSC) for Example 4 contains a minor endotherm of T_onseti = 1 13.8°C, T_peaki = 122.2°C, and a major endotherm of T₀nset2 = 228.5°C, T_Peak2 = 231.7°C; the record of the thermogravimetric analysis (TGA) shows 3.8% of the solvent.

The DSC records are shown in the Annex in Figures 4b, TGA scans are in Figures 4c.

Working examples according to the invention

Preparation of propyleneglycol/ethanol solvate of tiotropium bromide (V)

Example 5

5.0 g of tiotropium bromide (dichloromethane/acetonitrile solvate) was dissolved in 100 ml of a mixture propyleneglycol (40 ml) /ethanol (60 ml) = 2/3 at 80°C. The solution was cooled to 5°C within 90 minutes and further stirred at this temperature for 18 hours. The crystals were filtered, washed with a minimum amount of ethanol, and dried in a vacuum oven at 0.04 MPa (400 mbar) at laboratory temperature for 0.5 hour; then dried freely. 4.09 g of white crystals were obtained; yield 82%, HPLC purity 99.84%. The content of solvents (determined by GC): ethanol 35,000 ppm, propyleneglycol 14,000 ppm.

The X-ray powder diffraction - diffraction peaks of propyleneglycol/ethanol solvate

Pos. d Rel. Int.

[°2Th.] [A] = 0.1 nm [%]

10.17 8.695 16.8

1 1.30 7.821 19.7

13.66 6.478 50.2

15.55 5.694 50.3

16.54 5.356 15.2

18.36 4.829 100.0

20.16 4.401 78.5

21.16 4.196 55.4

21.65 4.102 90.0

23.38 3.803 16.0

23.90 3.720 32.0 24.20 3.675 37.4

24.93 3.569 31 .0

25.33 3.513 36.3

26.24 3.393 42.1

27.30 3.264 38.1

28.07 3.177 27.5

29.90 2.986 18.1

30.26 2.951 21.0

32.19 2.779 24.0

34.53 2.596 12.3

The thermogram of the differential scanning calorimetry (DSC) contains a minor endotherm of T_onseti = 150.0°C, T_peaki = 152.6°C, and a major endotherm of T_onSet2 = 227.2°C, T_Peak2 = 230.2°C; the record of the thermogravimetric analysis (TGA) shows 6.2% of the solvent.

The X-ray powder record is shown in the Annex in Figure 5a, DSC record is in Figure 5b, and TGA scan is in Figure 5c.

Example 6 2.0 g of tiotropium bromide (dichloromethane solvate) was dissolved in 40 ml of a mixture propyleneglycol (16 ml) / ethanol (24 ml) = 2/3 at 80°C. The solution was cooled to 5°C within 90 minutes and stirred at this temperature for 2 hours. The reaction mixture was cooled to 0°C and stirred at this temperature for 2 hours. The crystals were filtered, washed with a minimum amount of ethanol, dried in a vacuum oven at 0.03 to 0.04 MPa (300 to 400 mbar) at laboratory temperature for 0.5 hour and then dried freely. 1.61 g of white crystals were obtained, yield 81 %, HPLC purity 99.6%. The content of solvents (determined by GC): ethanol 30,000 ppm, propyleneglycol 35,000 ppm.

The X-ray record was identical to the X-ray diffraction pattern from Example 5. The thermogram of the differential scanning calorimetry (DSC) contains a minor endotherm of T_onseti = 154.3°C, T_peaki = 162.6°C, and a major endotherm of T_onSet2_. = 222.3°C, T_Peak2 = 225.3°C; the record of the thermogravimetric analysis (TGA) shows 7.6 % of the solvent.

The DSC record is shown in the Annex in Figure 6b, and TGA scan is in Figure 6c.

Claims

1) Mixed propyleneglycol/ethanol solvate of tiotropium bromide of formula V

V

2) The solvate of tiotropium bromide according to claim 1 , showing the following characteristic peaks in the powder X-ray record, measured using radiation CuKa: 13.66; 15.55; 18.36; 20.16, 21.65 +/- 0.2° 2Th.

3) The solvate of tiotropium bromide according to claims 1 or 2, showing the following additional characteristic peaks in the powder X-ray record, measured using radiation CuKa: 10.17; 1 1.30; 16.54; 21.16; 23.90; 27.30; 29.90, 30.26 +/- 0.2° 2Th.

4) The solvate of tiotropium bromide according to claims 1 , 2 or 3, characterized in that it contains ethanol in the range of 3,000 to 40,000 ppm.

5) The solvate of tiotropium bromide according to any one of the preceding claims, characterized in that it contains propyleneglycol in the range of 3,000 to 40,000 ppm.

6) A method of preparing the solvate of tiotropium bromide according to claims 1 to 5, characterized in that a form of tiotropium bromide, selected from an anhydrous form, hydrate, solvate, or mixed solvate, is dissolved in a mixture of propyleneglycol and ethanol at a temperature in the range of from 40°C to the boiling point of the solvent, and the formed solution is cooled down and the precipitated solvate is isolated.

7) The method according to claim 6, characterized in that a solvate of tiotropium bromide selected from dichloromethane/acetonitrile solvate and/or methanol/acetone solvate is dissolved in a mixture of propyleneglycol and ethanol at a temperature in the range of from 60 to 80°C, the formed solution is cooled down and the precipitated solvate is isolated.

8) The method according to claim 6, characterized in that the solution is cooled down to a temperature in the range of from -5 to 10°C. 9) Use of the solvate of tiotropium bromide according to claims 1 to 5 for preparing an inhalation therapeutic formulation.