HRP20030276A2 - Crystalline monohydrate, method for producing the same and the use thereof in the production of a medicament - Google Patents

Description

The invention relates to the crystalline monohydrate of the compound (1α, 2β, 4β, 5α, 7β)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-di-methyl-3-oxa-9-azoniatricyclo[3.3. 1.02,4]nonane-bromide, to the process for its production, to its use for the production of a drug, especially for the production of a drug with anticholinergic activity.

Background of the invention

Compound (1α, 2β, 4β, 5α, 7β)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-di-methyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonan- bromide is known from the European patent application EP 418 716 Al and it has the following chemical structure:

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This compound has valuable pharmacological properties and is known as tiotropium bromide (BA679). Tiotropium bromide is a highly effective anticholinergic and can therefore be used in the treatment of asthma or COPD (chronic obstructive pulmonary disease).

Application of tiotropium bromide is primarily done by inhalation. In this case, suitable inhalation powders can be applied, which are filled into suitable capsules (inhalates) and used using suitable powder inhalers. Alternatively, inhalation administration can also be carried out by the application of suitable inhalation aerosols. These also include powdery inhalation aerosols, which contain, for example, HFA134a, HFA227 or their mixtures as propellant gas.

The correct production of the above-mentioned compounds for the production of formulations in which the drug can be administered by inhalation is based on various parameters, which are related to the properties of the active drug itself. Without intending to be limited to the above, examples of these parameters are the stability of the starting materials under different environmental conditions, the stability during the preparation of the pharmaceutical formulation as well as the stability of the final drug formulation. The active substance of the drug, which is used for the production of the above-mentioned drug formulation, must have the highest possible purity and its stability must allow long-term storage under different conditions. This is absolutely necessary to prevent the use of a drug formulation in which, in addition to the actual active substance, there are, for example, its degradation products. In such a case, the content of the active substance found in the capsules could be lower than specified.

Absorption of moisture reduces the content of the active substance of the drug due to the increase in weight caused by the absorption of water. Medicines that tend to absorb moisture should be protected during storage, for example by adding a suitable desiccant or by storing the medicine in an environment that is protected from moisture. In addition, if the drug is exposed to the environment without any protection against moisture, the absorption of moisture can reduce the content of the active substance of the drug during production.

Uniform distribution of the drug in the formulation is a critical factor, especially if a lower dosage of the drug is required. To ensure uniform distribution, the particle size of the active substance can be reduced to a suitable value, for example by grinding. A further point, which is important for inhaled active substances that are applied using powder, is conditioned by the fact that only particles of a certain size enter the lungs during inhalation. The sizes of these particles that enter the lungs (the portion that can be inhaled) are in the sub-micron range. In order to obtain the active substance with the appropriate particle size, grinding (so-called micronization) is also necessary.

Since the breakdown of the active substance of the drug as a side effect of grinding (that is, micronization) should be prevented as much as possible, despite the harsh conditions required during the procedure, high stability of the active substance after grinding is an absolute necessity. Only active substances with sufficiently high stability allow grinding, in a reproducible form and manner, to obtain a homogeneous formulation of the drug, which always contains a determined amount of the active substance.

A further problem that can arise when grinding to produce the desired drug formulation is the energy input with this process and the loading of the crystal surface. Under certain circumstances, this can lead to polymorphic changes, to a change to an amorphous form or to a change in the crystal lattice. Since the same crystalline morphology of the active substance must always be possible for the pharmaceutical quality of the drug formulation, for these reasons, higher requirements are also placed on the stability and properties of crystalline active substances.

The stability of the active substance of the drug in the composition of the drug is also important for determining the shelf life of the type of drug; this duration is the one during which the medicine can be given without any danger. The high stability of the type of medicine in the aforementioned formulations, under different storage conditions, therefore represents a further advantage, both for patients and also for the manufacturer.

In addition to the aforementioned requirements, it should generally be taken into account that any change in the state of the solid substance in the drug, which can improve its physical and chemical stability, towards less stable forms of the same drug represents a significant advantage.

The task of the invention therefore consists in the preparation of a new, stable crystalline form of the tiotropium bromide compound, which meets the aforementioned high requirements set for the active substance of the drug.

Description of the invention in detail

It was found that tiotropium bromide, depending on the choice of conditions that can be applied when cleaning the raw product obtained after technical production, precipitates in different crystalline modifications.

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

It was surprisingly found that tiotropium bromide monohydrate, which can be obtained in crystalline form by choosing special reaction conditions, meets the high requirements mentioned in the introduction and thus solves the task on which the proposed invention is based. Accordingly, the proposed invention relates to crystalline tiotropium bromide monohydrate.

A further subject of the proposed invention relates to the process for the production of crystalline tiotropium bromide hydrate. This production process is characterized by the fact that tiotropium bromide, which was obtained for example by the process described in publication EP 418 716 A1, is placed in water, the resulting mixture is heated and then tiotropium bromide hydrate crystallizes with slow cooling.

The proposed invention also relates to the crystalline hydrates of tiotropium bromide which can be obtained by the proposed process.

One form of the proposed invention relates to a process for the production of crystalline tiotropium bromide monohydrate, which will be described in detail below. For the production of crystalline monohydrate according to the proposed invention, tiotropium bromide is required, which was obtained, for example, by the process described in EP 418 716 A1, placed in water, heated, cleaned with activated carbon and after separation of activated carbon, tiotropium bromide monohydrate crystallizes with slow cooling.

According to the invention, the procedure is primarily as described below.

In a reaction vessel of appropriate dimensions, the solvent is mixed with tiotropium bromide, which was obtained, for example, by the process described in EP 418 716 A1.

For one mole of added tiotropium bromide, 0.4 to 1.5 kg, preferably 0.6 to 1 kg, is used, especially preferably approx. 0.8 kg of water as solvent.

The resulting mixture is heated with stirring, preferably to a temperature above 50°C, especially preferably to a temperature above 60°C. The highest temperature that can be selected is determined by the boiling point of the water solvent used.

The mixture is preferably heated to a temperature in the range of 80 to 90°C.

Active carbon, dry or moistened with water, is added to this solution. 10 to 50 g, especially preferably 15 to 35 g, most preferably approximately 25 g of activated carbon are added to one mole of added tiotropium bromide. If necessary, activated charcoal is mixed in water before being introduced into the solution containing tiotropium bromide. For the production of activated carbon sludge, 70 to 200 g, preferably 100 to 160 g, preferably approx. 135 g of water. If the activated carbon is slurried in water before being placed in a solution containing tiotropium bromide, it is recommended that it is then rinsed with an equal volume of water.

At a constant temperature and after the addition of active carbon is completed, it is stirred further between 5 and 60 minutes, preferably between 10 and 30 minutes, especially advantageous approx. 15 minutes and the resulting mixture is filtered to remove activated carbon. The filter is then washed with water. For this purpose, 140 to 400 g, preferably 200 to 320 g, preferably approx. 270 g of water.

The filtrate is then slowly cooled, preferably to a temperature of 20-25°C. Cooling is carried out at a cooling rate of 1 to 10°C for 10 to 30 minutes, preferably from 2 to 8°C for 10 to 30 minutes, especially advantageously from 3 to 5°C for 10 to 20 minutes, most preferably from 3 to 5 °C for approx. 20 minutes. If necessary, when it cools down to 20 to 25°C, it can continue to be cooled to below 20°C, especially advantageously to 10 to 15°C.

After complete cooling, which lasts between 20 minutes and 3 hours, preferably between 40 minutes and 2 hours, especially preferably approximately one hour, it can still be stirred for more complete crystallization.

The resulting crystals are then filtered off or sucked off the solvent. It may turn out to be necessary to subject the obtained crystals to another washing, whereby it is recommended to use water or acetone as a washing agent. For one mole of tiotropium bromide used for washing the resulting crystals of tiotropium bromide monohydrate, 0.1 to 1.0 l, preferably 0.2 to 0.5 l, particularly preferably approx. 0.3 l of solvent. Rinsing can be repeated if necessary. The resulting product is dried in a vacuum or with heated air until a water content of 2.5-4.0% is obtained.

One form of the proposed invention relates to crystalline tiotropium bromide monohydrate, which can be obtained in accordance with the process described above.

Tiotropium bromide monohydrate obtained in accordance with the procedure described above was subjected to testing using DSC (Differential Scanning Calorimetry). The DSC diagram shows two characteristic signals. The first, relatively broad, endothermic signal between 50-120°C indicates the removal of water from tiotropium bromide monohydrate and its conversion to the anhydrous form. The second, relatively sharp, endothermic maximum at 230±5°C belongs to the melting point of the substance (Figure 1).

These data were obtained using a Mettler DSC 821 and were quantified using the STAR software package. These data were recorded at a heating rate of 10 K/min.

Since this substance melts with decomposition ( = incongruent melting process), the observed melting point depends on the heating rate. At lower heating rates, the melting/decomposition process can be observed at significantly lower temperatures. So, for example, at a heating rate of 3 K/min it is seen at 220±5°C. In addition, it may happen that the melting point is split. This splitting is all the stronger the lower the heating rate during the DSC experiment.

Accordingly, the proposed invention relates to crystalline tiotropium bromide monohydrate, which, according to Figure 1, is characterized by an endothermic maximum at 230°C (±5°C) at a heating rate of 10K/min.

Tiotropium bromide monohydrate was examined using IR spectroscopy. Data were recorded using a Nicolet FT IR spectrometer and quantified using the Nicolet OMNIC software package, version 3.1. Measurements were made with 2.5, fimol tiotropium bromide monohydrate in 300 mg KBr. The obtained IR spectrum is shown in Figure 2. Table 1 lists several of the most important bands of the IR spectrum.

Table 1: Affiliation of certain bands

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Accordingly, the proposed invention relates to crystalline tiotropium bromide monohydrate, which is characterized by the IR spectrum shown in Figure 2, which has bands, among others, at wave numbers 3570, 3410, 3105, 1730, 1260, 1035 and 720 cm-1.

Tiotropium bromide monohydrate according to the invention was characterized by X-ray structural analysis. X-ray diffraction intensity measurements were performed on a circular diffractometer AFC7R-4 (Rigaku) using monochromatic copper Kα radiation. The solution of the structure and refinement of the crystal structure was performed by the direct method (SHELKS86 program) and FMLQ refinement (TeKsan program). Experimental details for the crystal structure, solution, and structure refinement are summarized in Table 2 .

Table 2; Experimental data for the analysis of the crystal structure of tiotropium bromide monohydrate.

A. Crystal data

Empirical formula: [C19H22NO4S2]Br•H2O

Molecular weight: 472.43 + 18.00

Crystal color, shape: colorless, prismatic

Crystal dimensions: 0.2 x 0.3 x 0.3 mm

Crystal system: monoclinic

Grid type: primitive

Spatial group: P 21/n

Lattice constants a = 18.0774 A

b = 11.9711 A

c = 9.9321 A

β = 102, 691°

V = 2096, 96 A3

Number of groups of the above formula per elementary cell: 4

B. Intensity measurements

Diffractometer: Rigaku AFC7R

X-ray generator: Rigaku RU200

Wavelength: λ, = 1.54178 A (monochromatized copper Kα radiation)

Current, voltage: 50 kV, 100 mA

Shooting angle: 6

Crystal assembly: capillary saturated with water vapor

Spacing of the crystal detector: 235 mm

Detector aperture: 3.0 mm vertically and horizontally

Temperature: 18

Determination of lattice constant: 25 reflexes

(50.8<2Θ<56.2°)

Search device type: ω - 2 Θ

Search speed: 8.0 32, O/min in ω

Search width: (0.58 + 0.30 tan Θ)

2 Θ max.: 120

Measurements: 5193

Independent reflexes: 3281 (Rint = 0.051)

Corrections: Lorentz polarization absorption

(transmission factors 0.56-1.00)

crystal reduction: 10.47% decrease

C. Refinement

Reflexes (I > 3σI): 1978

Variable: 254

Ratio reflexes/parameter: 7.8

R values, R, Rw: 0.062, 0.066

Based on the X-ray analysis, it was found that crystalline tiotropium bromide hydrate has a simple monoclinic cell with the following dimensions: 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 crystalline tiotropium bromide monohydrate, which is characterized by the unit cell described above.

Using the X-ray analysis of the structure described above, the coordinates of the atoms listed in Table 3 were determined.

Table 3: Coordinates

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x, y, z: fractional coordinates;

U(eq) mean square amplitude of movement of atoms in the crystal.

A further form of the proposed invention relates to the use of tiotropium bromide monohydrate as a medicine due to the pharmaceutical efficiency of the hydrate according to the invention.

For the production of a medicine that can be administered by inhalation, especially an inhalation powder containing crystalline tiotropium bromide monohydrate described in the proposed invention, crystalline tiotropium bromide monohydrate can be produced by a process known from the state of the art. In this connection, reference is made, for example, to the description in DE-A-179 22 07. Accordingly, a further object of the proposed invention is an inhalation powder characterized by the content of tiotropium bromide monohydrate.

Due to the anticholinergic effect of tiotropium bromide monohydrate, a further object of the proposed invention is the use of tiotropium bromide monohydrate for the production of a medicine for the treatment of diseases in which an anticholinergic can be used therapeutically. A suitable use for the manufacture of a medicament for the treatment of asthma or COPD is preferred.

The following synthesis example serves to illustrate the implementation of the production process of crystalline tiotropium bromide monohydrate. The presented procedure should be understood only as a possible example of the procedure presentation and its purpose is not to limit the invention.

An example of synthesis

25.7 kg of water is placed in a suitable reaction vessel and 15.0 kg of tiotropium bromide is added. The mixture is heated to 80-90°C and stirred at a constant temperature until a clear solution is obtained. Activated carbon (0.8 kg), moistened with water, is mixed in 4.4 kg of water and this mixture is added to the solution containing tiotropium bromide and supplemented with 4.3 kg of water. The mixture obtained in this way is stirred for at least 15 minutes at 80-90°C and then filtered through a filter into an apparatus whose jacket is preheated to 70°C. The filter is washed with 8.6 kg of water. The contents of the apparatus are cooled to a temperature of 20-25°C at a cooling rate of 3-5°C in 20 minutes. The apparatus is further cooled to 10-15°C by cooling with cold water and crystallization is assisted by stirring for another hour. The crystallisate is isolated by suction, the isolated crystals are washed with 9 l of cold water (10-15°C) and with cold acetone (10-15°C). The obtained crystals are dried for 2 hours at 25°C in a stream of nitrogen.

Yield: 13.4 kg of tiotropium bromide monohydrate (86% of the theoretical).

Claims (12)

1. A compound, characterized in that it is crystalline tiotropium bromide monohydrate. 2. Crystalline tiotropium bromide monohydrate according to claim 1, characterized in that in the thermal analysis by DSC at a heating rate of 10 K/min, the endothermic maximum appears at 230±5°C. 3. Crystalline tiotropium bromide monohydrate according to claim 1 or 2, characterized in that its IR spectrum has bands, among others, at wave numbers 3570, 3410, 3105, 1730, 1260, 1035 and 720 cm-1. 4. Crystalline tiotropium bromide monohydrate according to any one of claims 1, 2 or 3, characterized in that it has a simple monoclinic cell with the following dimensions: a = 18.0774 Å, b = 11.9711 Å, c = 9.9321 Å, β = 102.691°, V = 2096.96 Å3. 5. Process for the production of crystalline tiotropium bromide monohydrate according to any claim 1, 2, 3 or 4, characterized in that a) tiotropium bromide is placed in water, b) the resulting mixture is heated, c) active carbon is added, i d) after separating the activated carbon, tiotropium bromide monohydrate crystallizes with slow cooling of the aqueous solution. 6. The method according to claim 5, characterized in that a) 0.4 to 1.5 kg of water is used per mole of added tiotropium bromide, b) the resulting mixture is heated to a temperature above 50°C, c) 10 to 50 g of activated carbon is added per mole of added tiotropium bromide, and after the addition of active carbon is complete, the mixture is continued for another 5 to 60 minutes, d) the resulting mixture is filtered, the resulting filtrate is cooled to a temperature of 20-25°C in 10 to 30 minutes at a cooling rate of 1 to 10°C and tiotropium bromide monohydrate crystallizes. 7. Medicine, characterized in that it contains crystalline tiotropium bromide monohydrate according to any of claims 1 to 4. 8. Medicine according to claim 6, characterized in that it is an inhalation powder. 9. The use of crystalline tiotropium bromide monohydrate according to any one of claims 1 to 4, characterized in that it is used for the production of a drug for the treatment of diseases in which an anticholinergic can be therapeutically administered. 10. Use according to claim 9, characterized in that the disease is asthma or COPD. 11. Process for the production of crystalline tiotropium bromide hydrate, characterized in that tiotropium bromide is placed in water, the resulting mixture is heated and then the tiotropium bromide hydrate crystallizes with slow cooling. 12. Crystalline hydrate of tiotropium bromide, characterized in that it can be obtained by the process according to claim 11.