WO2013107434A2

WO2013107434A2 - New polymorphous forms of tiotropium iodide and a method of their preparation

Info

Publication number: WO2013107434A2
Application number: PCT/CZ2013/000003
Authority: WO
Inventors: Igor CERNA; Vladimir Kral; Josef Hajicek; Ondrej Dammer
Original assignee: Zentiva, K.S.
Priority date: 2012-01-20
Filing date: 2013-01-09
Publication date: 2013-07-25
Also published as: WO2013107434A3; CZ201241A3

Abstract

The invention relates to new polymorphous forms of tiotropium iodide of formula I and a method of their preparation, wherein a dichloromethane/acetonitrile solvate of tiotropium iodide of formula V is crystallized from water. The solution includes two new polymorphous forms of tiotropium iodide and an amorphous form of tiotropium iodide, including a method of their preparation.

Description

New polymorphous forms of tiotropium iodide and a method of their

preparation

Technical Field

The invention deals with new polymorphous forms of tiotropium iodide of structure I and a method of their preparation. The invention comprises two new polymorphous forms of tiotropium iodide and an amorphous form of tiotropium iodide, including a method of their preparation.

Background Art

Tiotropium bromide of structure II is the commercial name for 6-alpha,7-alpha-Epoxy- 8-methyl-8-azabicyclo(3.2.1 )oct-3-endo-yl-di-2-thienyl) glycolate methyl bromide. Tiotropium bromide, first described in the patent EP0418716, is a selective, competitive, reversible antagonist of cholinergic receptors with a long term effect. Unlike the structurally similar ipratropium it selectively blocks the muscarinic receptors M1 and M3, while it only blocks the receptors M2 for a short time. It has significant bronchodilating effects. It is mainly used to treat the chronic obstructive pulmonary disease (COPD) and asthma. Therapeutic doses of the active substance are small (in micrograms), having the form of powder a lied with the use of an inhaler device.

II

Tiotropium means the free ammonium cation. From the point of view of polymorphism tiotropium represents a very interesting substance with many functional groups (the ester group, hydroxyl group, thienyl, quaternary ammonium salt), capable of an interaction (hydrogen bond, Van der Waals interaction, ττ-π stacking) that readily forms solvates, hydrates, co-crystals and various polymorphous forms.

A preparation method of tiotropium bromide II was first published in the patent EP0418716. It consists in reaction of scopine di(2-thienyl) glycolate (III) with methyl bromide (a 50% solution in anhydrous acetonitrile) in a mixture of the solvents acetonitrile and dichloromethane (Scheme 1 ). Subsequent re-crystallization was performed in a not exactly specified mixture of methanol and acetone and a white crystalline product with the melting point of 217 to 218°C was obtained.

The patent EP0418716 mentions that besides tiotropium bromide the above mentioned quaternization procedure by the action of a reactive mono-derivative of an alkane of formula Z-(alkyl with 1 to 4 carbon atoms), wherein Z is a leaving group, could also be used to prepare other tiotropium salts (bromide II and methanesulfonate are mentioned).

Patent literature (EP2067779, EP2336126) also describes other salts of tiotropium (fluoride, chloride, iodide, d-C₄-alkyl sulphate, sulphate, hydrogen sulphate, phosphate, hydrogen phosphate, dihydrogen phosphate, nitrate, maleate, acetate, trifluoroacetate, citrate, fumarate, tartrate, oxalate, succinate and benzoate, C1-C10- alkyl sulfonate, which can possibly be mono-, di. or tri-substituted with fluorine on the alkyl group, or phenyl sulfonate, which can possibly be mono- or poly-substituted with a CrCio-alkyl on the phenyl group), as well as their indirect preparation method from tiotropium bromide (or possibly methane sulfonate or methyl sulfonate) and a ion pair (where the cation is selected from the group of alkali metals or alkaline earth metals, ammonium cation or tetraalkyl ammonium cation, the anion being selected depending on which salt is being prepared) using anion exchange.

Using tiotropium bicarbonate in the synthesis of various tiotropium salts by the method of ion exchange on an ion exchanger is described in the application EP 1896026.

Forms of tiotropium 10-camphor sulfonate are described in the application WO2010133457.

Disclosure of Invention The invention includes two new crystalline forms and an amorphous form of tiotropium iodide of formula (I)

These forms exhibit suitable physical-chemical characteristics for further use in preparation of a dosage form suitable for filling into an inhaler device. Tiotropium iodide hydrate of chemical formula VI prepared in accordance with this invention manifests the following characteristic reflections in an X-ray powder diffraction pattern measured using CuKa radiation: 14.09; 16.56; 16.91 ; 18.47 and 23.25 +/- 0.2° 2Th.

VI

The hydrate in accordance with this invention further manifests the following other characteristic reflections in an X-ray powder diffraction pattern: 8.94; 15.54; 20,08; 24,06; 25,99; 28, 26 and 29,32 +/- 0,2° 2Th. The hydrate of this invention is further characterized by a water content in the range of 1 .5 to 4% by weight.

Another object of this invention consists in a mixed dichloromethane/acetonitrile solvate of chemical formula V,

v which shows the following characteristic reflections in an X-ray powder diffraction pattern measured using CuKa radiation: 15.14;19.50;21.15 and 29,79 +/- 0,2° 2Th.

This solvate further exhibits the following other characteristic reflections in an X-ray powder diffraction pattern 17.77; 20.51 ; 23.16; 23.74 and 25,51 +/- 0,2° 2Th.

The tiotropium iodide solvate prepared according to this invention contains dichloromethane in a range of 5000 - 50000 ppm and acetonitrile in a range of 1500- 30000 ppm. The contents of residual solvents were determined by gas chromatography. Still another object of this invention consists in an amorphous tiotropium iodide of chemical formula VII,

Amorphous form

VII

which is characterized by the X-ray diffraction pattern shown in Fig. 4a. Preparation of new forms and salts of tiotropium represents an important part of the development from the point of view of a higher chance of having a pharmaceutically acceptable substance complying with the formulation requirements. The use of tiotropium in inhaler devices is preceded by grinding (micronization) of the substance to the required particle size (1-5 μιη). Thus, micronization may represent a major intervention into the structure of the given crystalline form of the pharmaceutical product. Therefore as many forms and salts of the particular pharmaceutical substances as possible need to be available.

This invention also provides a new method of obtaining the above mentioned forms of tiotropium iodide.

Anhydrous tiotropium iodide IV was prepared in accordance with EP2336126 in an indirect way from tiotropium bromide by reacting it with a saturated aqueous solution of ammonium iodide; re-crystallization was performed from methanol (Schema 2). Schema 2

Anhydrous form

This method of preparation involves a high risk of contamination of the prepared iodide by the not completely reacted tiotropium bromide II.

Our preparation method is based on direct synthesis of tiotropium iodide, namely by quaternization of scopine di(2-thienyl)glycolate III by means of methyl iodide (Scheme 3 .

Scopine di(2-thienyl)glycolate III was dissolved in a mixture of acetonitrile and dichloromethane and methyl iodide is added. Conveniently, a solution of methyl iodide (1 to 10 equivalents) in acetonitrile is added and the reaction mixture is reacted at a temperature of from -20°C to the room temperature for 2-12 hours. The product crystallized from the reaction mixture is separated by filtration and washed with dichloromethane. This way a dichloromethane/acetonitrile solvate of tiotropium iodide V was prepared. Re-crystallization of tiotropium iodide prepared this way from an aqueous solution produced the hydrate of formula VI with the water content in the range of 1.5 to 4%. Crystallization of the dichloromethane/acetonitrile solvate is conveniently carried out in such a way that the solvate is dissolved in water at a temperature in the range of 60-100°C and then cooled to a temperature between -10°C and 0°C, which makes it gradually crystallize.

Amorphous tiotropium iodide of formula VII is obtained by dissolution of the dichloromethane/acetonitrile solvate of tiotropium iodide prepared using the above mentioned method in water. The aqueous solution is then frozen, conveniently by submerging in an acetone/dry ice bath and the frozen solution is then lyophilized. A modification of the lyophilization conditions also resulted in achieving the required size of particles. Lyophilization under a pressure in the range of 1 to 2 MPa provided particles with a size smaller than 5 μπι, measured by the SEM method. Examples

The melting points were measured using a Kofler bench.

Samples in the examples below were characterized using the methods of X-ray Powder Diffraction, Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA). The amounts of solvents were determined by gas chromatography (GC). The size of particles of the amorphous form of tiotropium iodide was determined using the SEM method. The lyophilization was carried out using a Christ, ALPHA 2-4 LSC device.

Measurement parameters of X-ray powder diffraction: The diffraction patterns were produced with an XPERT PRO MPD PANalytical diffractometer with a graphite monochromator, CuKa radiation used (λ=1.542 A), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40° 2Θ, increment: 0.01 ° 2Θ. The measurement was performed with a flat powder sample that was placed on a Si plate. For the primary optic setting programmable divergence diaphragms with the irradiated area of the sample of 10 mm, Soller diaphragms 0.02 rad and a 1/4 anti-dispersion diaphragm were used. For the secondary optic setting an X^'Celerator detector with the maximum opening of the detection slot, a Soller diaphragm 0.02 rad and an anti- dispersion diaphragm 5.0 mm were used. The records of the Differential Scanning Calorimetry (DSC) were measured using a DSC Pyris 1 device from Perkin Elmer. The charge of the sample in a standard Al pot was between 3-4 mg and the heating rate was 10°C/min. The temperature program used consists of one stabilization minute at 50°C, and then of heating up to 250°C at the heating rate of 10°C/min. 4.0 N₂ was used as the carrier gas at the flow rate of 20 ml/min.

The records of the Thermogravimetric Analysis (TGA) were measured with a TGA 6 device from Perkin Elmer. The charge of the sample in a corundum pot was between 15-19 mg and the heating rate was 10°C/min. The temperature program used consists of one stabilization minute at 20°C and then of heating up to 250°C at the heating rate of 10°C/min. 4.0 N2 was used as the carrier gas at the flow of 20 ml/min. Gas Chromatography (GC):

The following solvents are monitored: acetonitrile, dichloromethane.

These residual solvents were determined using the headspace gas chromatography method in a PerkinElmer Autosystem XL device with Fl detection with the use of a TurboMatrix 40 headspace autosampler.

Chromatographic conditions:

Capillary column: CP Sil 5 CB (30 m ^χ 0.32 mm ^χ 3.0 μιη) or equivalent

Temperature program: 40 °C - 0 min, gradient 15 °C /min to 60 °C - 0 min, gradient 30 °C /min to 160 °C - 1 min

Carrier gas: helium for chromatography R; 2,0 ml/min

Injector: splitting flow 4.0 ml/min, 165 °C

Detector: FID, 300 °C, Range: 1 , Attn: -3

SEM particle size A Mira/LMU scanning electron microscope was used for the analysis. The image was taken by means of a detector of back scattered electrons (BSE) at the acceleration voltage of 7 kV. The particle size was determined based on the scale included in the image.

Brief Description of Drawings Figure 1a. X-ray powder diffraction pattern of a dichloromethane/acetonitrile solvate of tiotropium iodide (br. TIO-IC-101 )

Figure 1 b. DSC record of a dichloromethane/acetonitrile solvate of tiotropium iodide Figure 1c. TGA record of a dichloromethane/acetonitrile solvate of tiotropium iodide Figure 2b. DSC record of a dichloromethane/acetonitrile solvate of tiotropium iodide Figure 2c. TGA record of a dichloromethane/acetonitrile solvate of tiotropium iodide Figure 3a. X-ray powder diffraction pattern of a tiotropium iodide hydrate

Figure 3b. DSC record of a tiotropium iodide hydrate

Figure 3c. TGA record of a tiotropium iodide hydrate

Figure 4a. X-ray powder diffraction pattern of an amorphous form of tiotropium iodide Figure 4b. DSC record of an amorphous form of tiotropium iodide

Figure 4c. Tg record of an amorphous form of tiotropium iodide

Figure 4d. TGA record of an amorphous form of tiotropium iodide

Figure 4e. SEM record of an amorphous form of tiotropium iodide

Examples of working of the invention

Preparation of a dichloromethane/acetonitrile solvate of tiotropium iodide (V) by direct synthesis

Example 1

5 g of scopine di(2-thienyl) glycolate (13.26 mmol) was dissolved in 50 ml of a mixture of dichloromethane (20ml) and acetonitrile (30ml) at 50°C, then the solution was cooled to 25°C and 34.2 g of 55% CH₃I in acetonitrile (10 equivalents) were added. The solution was stirred-up, filtered through kieselguhr and crystallized without stirring at -20°C for 5h. The resulting crystalline product was filtered, washed with 60 ml of dichloromethane and dried in a vacuum drier at 25°C for 20h. 6.59 g of greyish white crystals were obtained, HPLC purity 99.1 %. Solvent content (determined by GC): dichloromethane 47100ppm, acetonitrile 3200ppm. X-ray powder diffraction - Diffraction peaks of the dichloromethane/acetonitrile solvate of tiotropium iodide

The record of Differential Scanning Calorimetry (DSC) contains three endotherms at Tpeaki = 151.1 °C and

and the record of Thermogravimetric Analysis (TGA) contains 10.6% of solvents.

The X-ray powder diffraction pattern is included in the Annex in figure 1a, the DSC record is in figure 1 b, and TGA 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 (8ml) and acetonitrile (12ml) at 50°C, then the solution was cooled to 25°C and 13.68 g of 55% CH₃I in acetonitrile (10 equivalents) were added. The solution was stirred-up and then crystallized at -20°C for 3h. The resulting crystalline product was filtered, washed with 50 ml of dichloromethane and dried in a vacuum drier at 25°C for 20h. 2.74 g of white crystals were obtained, HPLC purity 98.9%. Content of solvents (determined with GC): dichloromethane 31900ppm, acetonitrile 9000ppm. The X-ray diffraction pattern was the same as that of Example 1.

The record of Differential Scanning Calorimetry (DSC) contains three endotherms at

Tpeak3⁼197.3°C and the record of Thermogravimetric Analysis (TGA) contains 12% of solvents. The DSC record is included in the Annex in figure 2b, and TGA is in figure 2c.

Preparation of a tiotropium iodide hydrate (VI)

Example 3

1 g of tiotropium iodide (dichloromethane/acetonitrile solvate) was dissolved in 9ml of H₂0 at 75°C. The solution was cooled down to -5°C during 40 min and further stirred at this temperature for 2h. The re-crystallized product was filtered and dried at the room temperature and pressure for 17h. 0.77 g of white powder was obtained; yield 77%, HPLC purity 99.4%. Water content 1.7%.

X-ray powder diffraction - Diffraction peaks of the tiotropium iodide hydrate

Interplanar distance [A] =

Pos. [°2Th.] 0.1 nm Rel. Int. [%]

8.94 9.883 31.7

1 1.90 7.432 30.9

13.38 6.610 25.9

14.09 6.280 55.9 14.70 6.020 28,9

15.54 5.698 36.0

16.56 5.350 92.5

16.81 5.269 90.4

17.43 5.083 51.7

18.47 4.799 80.1

19.10 4.643 36.1

20.08 4.419 57.6

21.48 4.134 36.2

22.20 4.001 32.1

23.25 3.823 100.0

24.06 3.696 40.3

24.99 3.560 85.1

26.43 3.369 34.4

27.82 3.204 25.1

28.56 3.123 33.0

29.32 3.043 42.7

29.99 2.978 26.3

30.88 2.894 22.0

31.72 2.819 14.9

36.35 2.470 22.5

The record of Differential Scanning Calorimetry (DSC) contains two endotherms at

and the record of Thermogravimetric analysis (TGA) contains 2% by weight of water. The X-ray powder diffraction pattern is included in the Annex in figure 3a, DSC record is in figure 3b, and TGA is in figure 3c.

Preparation of an amorphous form of tiotropium iodide (VII)

Example 4

1 g of tiotropium iodide (dichloromethane/acetonitrile solvate) was dissolved in 25ml of H₂0 at 55°C. After cooling to the room temperature the clear solution was frozen (bath with a dry ice and ethanol mixture, -70°C) and subjected to lyophilization (1.8 Pa vacuum for 72h). 1 g of white amorphous matter was obtained, HPLC purity 99.2%. Ball-shaped particles were obtained with a smaller size than 5pm and the water content of 1.0% by weight. X-ray powder diffraction - amorphous form

The record of Differential Scanning Calorimetry (DSC) contains a vitreous transition at Tg=104.4°C and an endotherm at

and the record of Gravimetric Analysis (TGA) contains 0% of water or solvent. The X-ray powder diffraction pattern is included in the Annex in figure 4a, DSC record is in figure 4b, Tg is in figure 4c, TGA is in figure 4d and SEM is in figure 4e.

Claims

1. A tiotropium iodide hydrate of formula VI

VI exhibiting the following characteristic peaks in an X-ray powder diffraction pattern, measured using CuKa radiation: 14.09; 16.56; 16.91 ; 18.47 and 23.25 +/- 0,2° 2Th.

2. The tiotropium iodide hydrate according to claim 1 , exhibiting the following

further characteristic reflections in an X-ray powder diffraction pattern: 8.94; 15.54; 20.08; 24.06; 25.99; 28.26 and 29.32 +/- 0.2° 2Th.

3. The tiotropium iodide hydrate according to claim 1 , containing water in the

range of 1.5 to 4% by weight.

4. A method for obtaining the tiotropium iodide hydrate according to claim 1 ,

characterized in that a dichloromethane/acetonitrile solvate of tiotropium iodide of formula V

V is crystallized from water.

5. A dichloromethane/acetonitrile solvate of tiotropium iodide of formula V, exhibiting the following characteristic peaks in an X-ray powder diffraction pattern, measured using CuKa radiation: 15.14; 19.50;2 .15 and 29.79 +/- 0,2° 2Th.

6. The dichloromethane/acetonitrile solvate of tiotropium iodide according to claim 5, exhibiting the following further characteristic reflections in an X-ray powder diffraction pattern: 17.77, 23.16, 23.74, 25.51 and 29,44 +/- 0,2° 2Th.

7. The dichloromethane/acetonitrile solvate of tiotropium iodide according to claim 5, characterized in that it contains dichloromethane in the range of 5000 - 50000 ppm and acetonitrile in the range of 1500-30000 ppm.

8. A method of obtaining amorphous tiotropium iodide, characterized in that the solvate according to claim 5 is dissolved in water and lyophilized.

9. Amorphous tiotropium solvate prepared by the method of claim 8,

characterized in that the size of its particles is smaller than δμηι, as measured by the SEM method.

10. Tiotropium iodide in the amorphous form.