OA12403A - Crystalline monohydrate, method for producing the same and the use thereof in the production of a medicament. - Google Patents

Abstract

Crystalline monohydrate (I) of tiotropium bromide ((1alpha ,2beta ,4beta ,5alpha ,7beta )-7-(2-hydroxy-2,2-di(2-thienyl)acetoxy)-9,9-dimethyl-3-oxa-9-azonia-tricyclo[3.3.1.0 2>.4]nonane bromide) is new. An independent claim is also included for the preparation of (I). ACTIVITY : Antiinflammatory; antiasthmatic. MECHANISM OF ACTION : Anticholinergic.

Description

012403

CRYSTALLINE MONOHYDRATE, METHOD FOR MANUFACTURING THE SAME AND USE THEREOF FOR MANUFACTURING A MEDICAMENT. The invention relates to a crystalline monohydrate of 5 (Ια, 2β, 4β, 5α, 7β) 7 - [(hydroxydi-2-thienylacetyl) oxy] -9,9-dimethyl-3-oxa-9-azoniatricyclo [3.3.1. O2,4] nonane bromide, a process for its manufacture and use for the manufacture of a medicament, particularly for the manufacture of a medicament with an anticholinergic effect. 10

BACKGROUND OF THE INVENTION

The compound of Ια, 2β, 4β, 5α, 7β - [(hydroxydi-2-thienylacetyl) oxy] -9,9-dimethyl-3-oxa-9-azoniatricyclo [3.3.1. O2,4] nonane-bromide is known from the European patent application EP 418 716 A1 and has the following chemical structure:

(l) 0124Ù3 - 2 -

The compound has valuable pharmaceutical properties and is known as tiotropium bromide (BA67 9). Tiotropium bromide is a very effective anticholinergic and may be of therapeutic use in the treatment of bronchial asthma or bronchitis COPD (Chronic Obstructive Pulmonary Disease) ). Administration of tiotropium bromide is preferably by inhalation. Appropriate inhalation powders can be used, which fill appropriate capsules (aerosols) and can be administered by means of corresponding powdered inhalers. Alternatively, it is possible to employ inhalation administration with appropriate aerosol inhalers. They may also be aerosols for inhalation of powdered substances which contain, for example, HFA134a, HFA227 or their mixtures as a propellant.

The correct manufacture of the above compositions usable for the administration of a drug to inhale is based ondifferent parameters which are themselves related to the particularity of the drug. Without limitation, examples of such parameters, such as the stability of the activity of the starting material under different environmental conditions, the stability of the preparation of the pharmaceutical preparation, and lastableness in the final composition of the drug can be cited. The medicament used for the manufacture of the above-mentioned drug compositions should be as pure as possible and its long-term storage stability guaranteed under various environmental conditions. It is crucial to avoid the use of drug compositions in which the products of their decomposition are found. In such a case, the active substance content in capsules may be lower than that specified, the moisture absorption decreases the active substance content due to the presence of the active substance itself. Increased weight due to water absorption Drugs which tend to absorb moisture must be protected from moisture during storage, eg by adding appropriate dehydrating agents or by storing the drug in an environment protected from moisture. In addition, the absorption of moisture can decrease the A content of therapeutic substances during manufacture if the drug is exposed to an environment without any protection against moisture.

A homogeneous distribution of the drug in the preparation is a critical factor, especially when a low dose of the drug is needed. To ensure a homogeneous distribution, the particle size of the active substance can be reduced to a suitable value, for example by grinding. Another important aspect, with active substances to be applied by inhalation by means of a powder, is conditioned by the fact that only particles of a certain size reach the lungs by inhalation. The size of these respirable particles (inhalable proportion) is submicron. In order to obtain active substances of the corresponding particle size, a grinding operation (laditemicronisation) is also necessary. In spite of the very severe conditions which are necessary for the progress of the process, it is necessary that the secondary effects of grinding (or micronisation) such as disintegration of the therapeutic substance be mostly avoided; high stability of the active substance is therefore absolutely necessary during the grinding operation. Only a sufficient stability of the active substance during the grinding operation allows the manufacture of a homogeneous drug preparation in which the fixed amount of the active substance is alwaysproducibly present. 012403 - 4 -

Another problem that may arise during grinding for the manufacture of the desired pharmaceutical preparation is the energy input caused by this process and the collapse of the surface of the crystals. This may lead, under certain circumstances, to polymorphic modifications, transformation into an amorphous form or modification of the crystal lattice. Since the same crystalline morphology must always be ensured for the pharmaceutical quality of a drug preparation, it is necessary to increase the requirements in terms of the desirability and properties of the crystalline activating substance.

Stability of an active drug substance is also important in the therapeutic compositions to define the duration of validity of the drug; this duration represents the period during which the drug can be administered without any risk. A high stability of the drug in the therapeutic compositions under different storage conditions therefore represents an additional advantage, both for patients and for the manufacturer.

In addition to the aforementioned needs, it should be generally considered that each modification of the state of a drug, which can improve its physical and chemical stability, has a considerable advantage over less stable forms of the same drug.

The object of the invention is therefore to provide a new stable crystalline form of the tiotropium bromide compound, meeting the very strict requirements mentioned above, and which are expected for activemedicamenteuse substance. ° '24 Ο3 5

DETAILED DESCRIPTION OF THE INVENTION

It has been found that the choice of the conditions used for the purification of the crude product obtained during the technical preparation, the tiotropium bromide induces different crystalline modifications of the bromide detiotropium.

It has been found that these various modifications can be obtained in a targeted manner, mainly by the choice of solvent used for the crystallization, as well as by the choice of process conditions, chosen during the crystallization process.

Surprisingly, it has been found that the monohydrated tiotropium bromide, which can be obtained in crystalline form by the choice of specific reaction conditions, meets the above high requirements and thereby achieves the object of the present invention. Accordingly, the present invention relates to a crystalline monohydrate of tiotropium bromide.

Another aspect of the present invention relates to a process for making crystalline hydrates of the detiotropium bromide. This manufacturing process is characterized by the fact that tiotropium bromide, which can for example be obtained according to the indications described in EP 418 716 A1, is put in water, that the mixture obtained is heated and then that the hydrates of bromide of tiotropium are crystallized by slow cooling. The present invention further relates to crystalline hydrates of tiotropium bromide which are obtained by the foregoing procedure.

One aspect of the present invention relates to a process for producing a crystalline monohydrate of tiotropium bromide which will be described in detail in the following. 0) 2403 - 6 -

For the manufacture of the crystalline monohydrate according to the present invention, it is necessary that the bromide detiotropium be put in water, the latter having for example been obtained according to the indications described in the document EP 418 716 Al, to heat it and perform Purification with activated charcoal, and after separation of the active charcoal, slowly crystallize the detiotropium bromide monohydrate by slow cooling.

A preferred embodiment of the invention is described in the following. In a reactor of appropriate size, the solvent is mixed with tiotropium bromide, which is obtained, for example, according to the indications described in document EP 418 716 A1. Per mole of tiotropium bromide used, 0.4 to 1.4 kg, preferably 0 to 1.4 kg are used. , 6 to 1 kg, and more preferably about 0.8 kg of water as a solvent.The resulting mixture is heated with stirring preferably at more than 50 ° C and more preferably at above 60 ° C. The maximum temperature chosen is conditioned by the boiling point of the solvent used, in this case water. Preferably, the mixture is heated to a temperature range of 80 to 90 ° C. Dry or humidified activated carbon is added to this mixture. Preferably, 10 to 50 g, more preferably 15 to 35 g, and more preferably approximately 25 g of charcoal are incorporated per mole of tiotropium bromide. If necessary, the activated carbon is suspended prior to incorporation into the aqueous solution containing the tiotropium bromide. Per mole of tiotropium bromide used, 70 to 200 g, preferably 100 to 160 g, and more preferably about 135 g of water are used for suspending the activated carbon. If activated charcoal is suspended in water before incorporation into the solution containing tiotropium bromide, it is recommended to derive with the same amount of water.

In the presence of a constant temperature, after adding the activated charcoal, stirring is continued for 5 to 60 minutes, preferably 10 to 30 minutes, and more preferably for about 15 minutes, after which the mixture obtained is filtered off. to remove the activated carbon. The filter is then washed with water. To do this, 140 to 400 g, preferably 200 to 320 g, and more preferably approximately 270 g of water are used per mole of tiotropium bromide.

The filtrate is then cooled slowly preferably to a temperature of 20 and 25 ° C. Cooling is preferably carried out at a rate of 1 to 10 ° C every 10 to 30 minutes, preferably 2 to 8 ° C every 10 to 30 minutes, more preferably 3 to 5 ° C every 10 to 20 minutes, plus preferably still 3 to 5 ° C every 20 minutes or so. If appropriate, after cooling to a temperature of 20 to 25 ° C, the cooling may continue to a temperature below 20 ° C, preferably 10 to 15 ° C.

When the cooling is complete, stirring is continued for 20 minutes at 3 hours, preferably between 40 minutes and 2 hours, more preferably for approximately one hour to complete the crystallization.

The crystals produced are then isolated by filtration or aspiration of the solvent. If it is necessary to subject the crystals obtained to another washing step, it is recommended to use water or acetone as a washing solution. For washing the crystals obtained from monohydrated tiotropium bromide, 0.1 to 1.0 liter, preferably 0.2 to 0.5 liter, and more preferably about 0.3 liter of solvent, may be used per mole of tiotropium bromide. If necessary, the washing step can be repeated. The product obtained is dried under vacuum or by means of hot air circulation until a water content of 2.5 to 4.0% is obtained. 01 24 0 3 - 8 -

One aspect of the present invention relates to a crystalline monohydrate of tiotropium bromide produced according to the previously described procedure.

The tiotropium bromide monohydrate, obtainable by the procedure described, was subjected to a differential scanning calorimetry (DSC) test. The diagramDSC has two characteristic signals. The first relatively broad heatwave, between 50 and 120 ° C, comes from the dehydration of tiotropium bromide monohydrate in an anhydrous form. The second maximum endothermic relatively bright at 230 ° ± 5 ° C is attributable to the melting of the substance (Figure 1). This data was obtained using a Mettler DCS 821 instrument and analyzed using STAR Mettler software. The data were recorded at a heating rate of 10 K / min.

Since the substance melts when decomposing (= incongruous melting procedure), the melting point observed is much dependent on the heating rate. In case of low heating conditions, the decomposition / melting operation is observed at lower temperatures, for example at a heating rate of 3 K / min at 220 ± 5 ° C. In addition, it may occur that the melting peak is divided. The split occurs as much as the heating rate in the DSC experiment is low.

Therefore, the present invention is directed to a crystalline monohydrate of tiotropium bromide which is characterized in accordance with Figure 1, by an endothermic maximum at 230 ° C (± 5 ° C) at a heating rate of 10 k / min.

The tiotropium bromide monohydrate according to the invention has been characterized by infrared spectroscopy.

Data were collected using a spectrometer

Nicolet FTIR and Nicolet OMNIC software, version 3.1. The 012403 9

Measurement was carried out with 2.5 pmol of tiotropium bromide monohydrate in 300 mg of KBr. The spectrum IRobtained is reproduced in FIG. 2. Table 1 brings together some of the essential bands of the IR spectrum.

Table 1: Distribution of specific bands

Number of waves (cm'1) Assignment Type of oscillations 3570, 3410 O-H Stretched oscillation 3105 Aryl C-H Stretched oscillation 1730 C = O Stretched oscillation 1260 Epoxy C-0 Stretched oscillation 1035 Ester C-OC Stretched oscillation 720 Thiophene Annular oscillation

Therefore, the present invention relates to a crystalline monohydrate of tiotropium bromide which is characterized in accordance with FIG. 2 by an IR spectrum which, inter alia, has bands at wave numbers of 3570, 3410, 3105, 1730, 1260, 1035 and 720 cm. "1.

The crystalline monohydrate of tiotropium bromide according to the invention has been characterized by X-ray structural analysis. Radiation measurements of diffraction intensity were made on a 4 circles AFC7R diffractometer (Rigaku) using the monochromatized radiation of copper Ka line. The structural solution and the refinement of the crystalline structure were carried out by means of direct methods (ProgramSHELXS86) and refinement FMLQ (TeXsan program). Experimental details concerning the crystalline structure, the refinement and the structural solution are shown in Table 2.

Table 2: Experimental data relating to the crystalline structural analysis of crystalline monohydrate of tiotropium bromide. 012403 10 A. Crystalline data

Empirical formula

Weight of the formulaForm and color of the crystalDimension of the crystalCrystalline systemType of network

Space Group

Network constants

Units of formulas elementary cell B. Intensity measurementsDiffractometerX-ray generatorWavelength

Voltage, current

Call angle

Crystal assembly

Crystal Detector DistanceDetector OpeningTemperature Definition of Network Constants

Scan type

Sweep speed

Scanning width 2 Omax

Measures

[C19H22NO4S2] Br. H2O 472.43 + 18.00

Colorless, prismatic0.2 x 0.3 x 0.3 mmMonoclinicPrimitive P2i / nA = 18.0774A, B = 11.9711A C = 9.9321A β = 102.691) V = 2096, 96A3 4

Rigaku AFC7R

Rigaku RU200 λ = 1.54178Â (monochromatic radiation of copper Kodu line)

50 kV, 100 mA 6

Capillaries saturated with water vapor235 mm 3.0 mm vertical and horizontal18 25 reflexes (50.8 <2Θ <56.2 °) ω - 2 Θ 8.0 32.0 / min in ω (0.58 + 0, 30 tan Θ) 120 5193 012403 11 Independent reflexesCorrections C. Refinement Reflexes (i> 3ol)

Variable

Reflex / Parameters Report R: R, Rw 3281 (Rint = 0.051)

Polarization of LorentzAbsorption (Transmission Factors0,56 - 1,00)

Crystalline corrosion 10.47% waste 1978 254 7.8 0.062; 0.066 Structural X-ray analysis showed that crystalline lemonohydrate of tiotropium bromide exhibited a single monoclinic cell with the following dimensions: 5 a = 18.0774 Å, b = 11.9711 Å, c = 9.9321 Å, β = 102.691 ° ), V = 2096.96 Å3.

Accordingly, the present invention relates to a crystalline monohydrate of tiotropium bromide which is characterized by the elementary cell described above.

The atom coordinates described in Table 3 were defined by the present X-ray structural analysis: Table 3: Coordinates

Atom XYZ u (eq) Br (1) 0.63938 (7) 0, 0490 (1) 0.2651 (1) 0.0696 (4) S (1) 0.2807 (2) 0.8774 (3) 0.129 (3) 0.086 (1) S (2) 0.4555 (3) 0.6670 (4) 0.4214 (5) 0.141 (2) O (1) 0.2185 (4) O, 7372 (4) 6) 0.4365 (8) 0.079 (3) O (2) 0.3162 (4) 0.663 (8) 0.5349 (9) 0.106 (3) O (3) 0.3188 (4) 0, 9012 (5) 0.4097 (6) 0.058 (2) 0 (4) 0.0416 (4) 0.9429 (6) 0.3390 (8) 0.085 (3) 012403 - 12 -

Atom XYZ u (eq) 0 (5) 0.8185 (5) 0.0004 (8) 0.2629 (9) 0.106 (3) N (1) 0.0111 (4) 0.7607 (6) 0, 4752 (7) 0.052 (2) C (1) 0.2895 (5) 0.7107 (9) 0.4632 (9) 0.048 (3) C (2) 0.3330 (5) 0.87876 (8) 0.3826 (8) 0.048 (3) C (3) 0.3004 (5) 0.7672 (8) 0.2296 (8) 0.046 (3) C (4) 0.4173 (5) 0.7650 (5) 8) 0.4148 (8) 0.052 (3) C (5) 0.1635 (5) 0.66746 (9) 0.497 (1) 0.062 (3) C (6) 0.1455 (5) 0.7488 (5) 9) 0.6085 (9) 0.057 (3) C (7) 0.0989 (6) 0.6415 (8) 0.378 (1) 0.059 (3) C (8) 0.0382 (5) O, 7325 (6) 9) 0.3439 (9) 0.056 (3) C (9) 0.0761 (6) 0.840 (1) 0.315 (1) 0.064 (3) C (10) 0.1014 (6) 0.8874 (8) 0.443 (1) 0.060 (3) 0 (11) 0.0785 (5) 0.828 (8) 0.5540 (9) 0.053 (3) C (12) -0.0632 (6) 0.826 (1) 0 , 444 (1) 0.086 (4) C (13) -0.0063 (6) 0.6595 (9) 0.554 (1) 0.062 (3) C (14) 0.4747 (4) 0.8552 (9) 0.430 (1) 0.030 (2) C (15) 0.2839 (5) 0.664 (9) 0.1629 (9) 0.055 (3) C (16) 0.528 (2) 0.818 (2) 0.445 (2) 0.22 (1) C (17) 0.5445 (5) 0.702 (2) 0.441 (1) 0.144 (6) C (18) 0.2552 (6) 0.684 (1) 0.019 (1) 0.079 (1) 4) C (19) 0.2507 (6) 0.792 (1) -0.016 (1) 0.080 (4) H (1) -0.0767 0 , 8453 0.5286 0.102 H (2) -0.0572 0.8919 0.3949 0.102 H (3) -0.1021 0.7810 0.3906 0.102 H (4) -0.0210 0.6826 0.6359 0.073 H (5) -0, 0463 0.6178 0.4982 0.073 H (6) 0.0377 0.6134 0.5787 0.073 H (7) 0.1300 0.7026 0.6770 0.069 H (8) 0, 1873 0.7915 0.6490 0.069 H (9) 0.1190 0.6284 0.2985 0.069 H (10) 0.0762 0.5750 0.4016 0.069 H (ll) 0.183 73.6082 0.5393 0.073 H (12) -0.0025 0.7116 0.2699 0.066 H (13) 0.1084 0.8383 0.2506 0.075 H (14) 0.14898.9329 0.4626 0.071 012403 13

Atom XYZ u (eq) H (15) 0.0658 0.8734 0.6250 0.063 H (16) 0.2906 0.5927 0.2065 0.065 H (17) 0.2406 0.6258 -0.0469 0.094 H (18) 0.2328 0.8191 -0.1075 0.097 H (19) 0.4649 0.9443 0.4254 0.037 H (20) 0.5729 0.8656 0.4660 0.268 H (21) 0.5930 0 , 6651 0.4477 0.165 H (22) 0.8192 -0.0610 0.1619 0.084 H {23) 0.7603 0.0105 0.24x12 0.084 X, Y, Z: Fractional Coordinates ü (eq) Mean Square Amplitude atomic movement in the crystal

Another aspect of the present invention relates, in consideration of the pharmaceutical efficacy of the hydrate according to the invention, the use of the crystalline monohydrate of tiotropium bromide as a medicament.

For the manufacture of a medicament administered by inhalation, in particular an inhalation powder which contains the crystalline monohydrate of tiotropium bromide according to the present invention, can be carried out according to the process known in the prior art. Reference is hereby made to the teaching of DE-A-179 22 07. Accordingly, another aspect of the present invention is an inhalable powder which is characterized by a content of tiotropium bromide monohydrate.

Due to the anticholinergic efficacy of tiotropium bromide monohydrate, another aspect of the present invention relates to the use of the detiotropium bromide monohydrate for the manufacture of a medicament for the treatment of conditions in which the application of ananticholinergic develop a therapeutic effect. A preferred use is the manufacture of a medicament for the treatment of COPD asthma or bronchitis. The following example of synthesis serves to illustrate a manufacturing process carried out, for example, for a crystal monohydrate of tiotropium bromide. This possible procedure is given as an example and is not intended to limit the invention to its content.

Sample summary

In a suitable reactor, 15.0 kg of detiotropium bromide is added in 25.7 kg of water. The mixture is heated to 80-90 ° C and is mixed at constant temperature until a clear solution is obtained. Wet activated carbon (0.8 kg) is suspended in 4.4 kg, this mixture is added to the solution containing tiotropium bromide and rinsed with 4.3 kg of water. The mixture thus obtained was stirred for at least 15 minutes at 80-90 ° C and then filtered through a heated filter in an apparatus preheated to a jacket temperature of 70 ° C. The filter is rinsed with 8.6 kg of water. The contents of the apparatus are cooled by 3-5 ° C in 20 minutes steps to reach a temperature of 20-25 ° C. The apparatus is further cooled to 10-15 ° C by cooling with cold water and the crystallization is completed by stirring for at least one hour. The crystallizate is isolated by a suction apparatus, the isolated crystalline product is washed with 9 l of cold water (10-15 ° C.) and cold acetone (10-15 ° C.). The crystals obtained are dried at 25 ° C. for 2 hours in a stream of nitrogen. Product obtained; 13.4 kg of tiotropium bromide monohydrate (86% of theory).

Claims (11)

072403 CLAIMS 1. Crystalline monohydrate of tiotropium bromide. 2. Crystalline monohydrate of tiotropium bromide according to claim 1, characterized by an endothermic maximum at 230 ° ± 5 ° C during the thermal analysis by the DSC at a heating rate of 10 K / min. Crystalline monohydrate of tiotropium bromide according to claim 1 or 2, characterized by an IR spectrum which inter alia includes bands for wave numbers of 3570, 3410, 3105, 1730, 1260, 1035 and 720 cm -1. Crystalline monohydrate of tiotropium bromide according to one of claims 1, 2 or 3, characterized by a single monoclinic cell having the following dimensions: a = 18.0774 A, b = 11.9711 A, c = 9, 9321 A, β = 102.691 °, V = 2096.96 Å. 5. Process for the production of a crystalline monohydrate tiotropium bromide according to one of claims 1, 2, 3 or 4, characterized in that a) the tiotropium bromide is put in water, b) the mixture obtained is heated, c) activated charcoal is added and d) after removing the activated charcoal, the monohydrated tiotropium bromide is crystallized slowly by slow cooling of the aqueous solution. Process according to Claim 5, characterized in that (a) 0.4 to 1.5 kg of water are used per mole of tiotropium bromide used (b) the mixture obtained is heated to above 50 ° C. (c) 10 to 50 g of activated charcoal are added per mole of tiotropium bromide used, and after the addition of the activated carbon, stirring is continued for 5 to 60 minutes; d) the mixture obtained is filtered, the filtrate obtained is cooled at a rate; from 1 to -10 ° C every 10 to 30 minutes at a temperature of 20 to 25 ° C and the tiotropium bromide monohydrate crystallizes during this operation. 7. A medicinal product characterized by a content of crystalline monohydrate of tiotropium bromide according to one of Claims 1 to 4. 8. Medicament according to claim 6, characterized in that it is a powder to inhale. 9. Use of the crystalline monohydrate of bromide detiotropium according to one of claims 1 to 4 for the manufacture of a medicament for the treatment of affections, in which the application of unanticholinergic can develop a therapeutic action. 10. Use according to claim 9, characterized in that it is diseases such as asthma or labronchite COUD. 012403 - 17 - 11. Process for the production of crystalline hydrates of tiotropium bromide, characterized in that the tiotropium bromide is put in water, the mixture obtained is heated and then the hydrates of tiotropium bromide are crystallized by slow cooling. 12. Crystalline hydrates of tiotropium bromide, obtainable by the process according to claim 11.