HRP20040855A2 - Micronized crystalline tiotropium bromide - Google Patents

Description

The invention relates to crystalline micronisate (1α,2β,4β,5α,7β)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo [3.3.1.02,4 ]nonane bromide, a process for its production, as well as its use for the production of drugs, especially for the production of a drug with anticholinergic activity.

Background of the invention

The compound (1α,2β,4β,5α,7β)-7-[(hydroxydi-2-thienylacetyl)-oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo [3.3.1.02,4] nonane bromide is known from the European patent application EP 418 716 A1 and it has the following chemical structure:

[image]

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

Application of tiotropium bromide is primarily by inhalation. In this case, a suitable inhalation powder can be used, which is applied using suitable powder inhalers filled in suitable capsules (inhalates). Alternatively, the inhalation application can also be carried out by the application of a suitable inhalation aerosol. This also includes powder inhalation aerosols, which contain, for example, HFA134a, HFA227 or their mixture as propellant gas.

Regarding the inhalation application of tiotropium bromide, it is necessary to prepare the active substance in the form of finely divided particles (that is, micronized). In this case, the active substance preferably has a mean particle size of 0.5 to 10 μm, preferably of 1 to 6 μm, particularly preferably of 1.5 to 5 μm.

The above-mentioned particle sizes are usually achieved by grinding (so-called micronization) of the active substance. Since, despite the harsh conditions required during the procedure, the breakdown of the active substance of the drug as a side effect of micronization should be avoided as much as possible, the high stability of the active substance after grinding is an absolute necessity. It should be taken into account that during grinding, under certain circumstances, there may be changes in the strength of the active substance, which may have an impact on the pharmacological properties of the form of the medicine that will be spliced by inhalation.

Processes for the micronization of the active substance of the drug are known as such in the state of the art. The task of the proposed invention is now to provide a process that makes available micronized tiotropium bromide in a form that meets the high requirements set for active substances for inhalation application and that the specific properties of tiotropium bromide are taken into account.

Description of the invention in detail

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

It has been found that these various modifications can be obtained to a large extent with the choice of the solvent used for crystallization, as well as with the choice of the procedure conditions in the crystallization process.

For the purpose of the proposed invention for the preparation of tiotropium bromide in micronized form, suitable for inhalation, crystalline tiotropium bromide monohydrate, which can be obtained in crystalline form by choosing specific reaction conditions, proved to be particularly suitable.

For the production of crystalline monohydrate, tiotropium bromide, obtained for example in accordance with the production regulations described in EP 418 716 A1, should be placed in water, heated, cleaned with activated carbon and after separation of the active carbon, with slow cooling, tiotropium bromide-monohydrate slowly crystallizes. According to the invention, preference is given to the process that will be described below.

In a reaction vessel of suitable size, the solvent is mixed with tiotropium bromide, which has been obtained, for example, according to the manufacturing procedure described in EP 418 716 A1. For one mole of tiotropium bromide used, 0.4 to 1.5 kg is used, preferably 0.6 to 1 kg, particularly preferably approx. 0.8 kg of water as solvent. The resulting mixture is heated with stirring to a temperature above 50°C, especially preferably above 60°C. The highest temperature that can be selected depends on the boiling point of the solvent used. The mixture is preferably heated in the range of 80 to 90°C.

Activated charcoal, dry or previously moistened with water, is placed in this solution. For one mole of tiotropium bromide used, preferably 10 to 50 g, particularly advantageously 15 to 35 g, preferably approximately 25 g of activated carbon are added. If necessary, activated carbon is mixed in water before being introduced into the tiotropium bromide solution. For one mole of tiotropium bromide used, 70 to 200 g, preferably 100 to 160 g, preferably approx. 135 g of water. If activated carbon is mixed with water before being introduced into a solution containing tiotropium bromide, then it is recommended to rinse it once more with an equal amount of water.

After the addition of activated carbon, it is stirred at a constant temperature for another 5 to 60 minutes, preferably between 10 and 30 minutes, particularly preferably for approximately 15 minutes, and the resulting mixture is filtered to remove the 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. It is preferably cooled at a 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, once cooled to 20 to 25°C, cooling can be continued further below 20°C, particularly advantageously to 10 to 15°C.

After the cooling is complete, it is stirred for between 20 minutes and 3 hours, preferably between 40 minutes and 2 hours, particularly preferably for approximately one hour, until the crystallization is complete.

The resulting crystals are then isolated by filtration or suction of the solvent. If necessary, the obtained crystals are washed once more, where it is recommended to use water or acetone as a washing solvent. For one mole of tiotropium bromide used, 0.1 to 1.0 1, preferably 0.2 to 0.5 1, particularly preferably approximately 0.3 1 of solvent can be used to wash the resulting crystals of tiotropium bromide monohydrate. If necessary, rinsing can be repeated. The resulting product is dried in a vacuum or with heated circulating air until a water content of 2.5-4.0% is reached.

The thus obtained crystalline tiotropium bromide monohydrate is used for grinding (micronization), which will be described below.

All available mills can be used to carry out this procedure. At the same time, micronization is preferably carried out with the exclusion of moisture, especially preferably with the use of a suitable inert gas, such as nitrogen. The use of mills with an air jet has proven to be particularly advantageous, in which the comminution of the product is done by smashing the particles together as well as by smashing the particles against the walls of the grinding container. Nitrogen is primarily used as the grinding gas according to the invention.

The ground product is transported under specific pressures (grinding pressure) using the grinding gas. Within the scope of the proposed invention, the grinding pressure is usually set to a value between approximately 2 and approximately 8 bar, preferably between approximately 3 and approximately 7 bar, particularly preferably between approximately 3.5 and approximately 6.5 bar. The introduction of the ground product into the air stream of the mill is carried out by means of a feed gas under specific pressures (feed pressure). In the framework of the proposed invention, the feed pressure is chosen between approximately 2 and approximately 8 bar, preferably between approximately 3 and approximately 7 bar, particularly preferably between approximately 3.5 and approximately 6 bar. An inert gas is also preferably used as the feed gas, particularly preferably nitrogen. Here, the supply of the ground product (crystalline tiotropium bromide monohydrate) to the transport device can be carried out at a rate of approximately 5-35 g/ min, preferably with approximately 10-30 g/min.

For example, but not intended to limit the subject matter of the invention, the following device has been selected as a possible embodiment of an air jet mill: 2-Zoll micronizer with 0.8 mm bore grinding ring from Sturtevant Inc., 348 Circuit Street , Hanover, MA 02239, USA. By using this device, grinding is primarily carried out with the following parameters: grinding pressure: approximately 4.5 - 6.5 bar; supply pressure: approximately 4.5 - 6.5 bar; product feed for grinding: approximately 17 - 21 g/min.

The resulting grinding product is then further processed under specific conditions that will be described below. For this purpose, the micronizate is exposed to water vapor with a relative humidity of at least 40% at a temperature of 15-40°C, preferably 20~35°C, especially preferably at 25-30°C. The humidity is adjusted to a value of 50-95% relative humidity, preferably to 60-90% relative humidity, especially preferably to 70-80% relative humidity.

Within the framework of the proposed invention, relative humidity (r. vi.) means the quotient of the partial pressure of water vapor and the pressure of water vapor at the respective temperature.

The micronizate, obtained by the grinding process described above, is primarily exposed to the above-mentioned spatial conditions during a time period of at least 6 hours. It is advantageous for the micronizate to be exposed to the above-mentioned room conditions in each case for approximately 12 to approximately 48 hours, preferably approximately 18 to approximately 36 hours, particularly preferably approximately 20 to approximately 28 hours.

One aspect of the proposed invention relates to tiotropium bromide micronisate, which can be obtained by the process described above.

The tiotropium bromide micronisate obtainable by the process described above has a characteristic particle size X50 between 1.0 μm and 3.5 μm, preferably between 1/1.μm and 3.3 μm, particularly preferably between 1.2 μm and 3.0 μm and a Q(5,8) value greater than 60%, preferably greater than 70%, particularly advantageously greater than 80%. The characteristic X50 is the mean value of the particle size below which 50% of the amount of particles is located in terms of the volume distribution of individual particles. The characteristic Q(5,8) corresponds to the part of the amount of particles which, in relation to the volume distribution of the particles, is below 5.8 µm. Within the framework of the proposed invention, the size of the particles was determined by laser beam diffraction (Fraunhofer diffraction). Detailed information about this can be found in the experimental part of the description of the invention.

Also, for the micronized tiotropium bromide according to the invention, it is characteristic that it has specific surface values in the range between 2 m2/g and 5 m2/g, to a special extent values between 2.5 m2/g and 4.5 m2/g and to a particularly prominent extent between 3 ,0 m2/year and 4.0 m2/year.

The implementation of the process according to the invention leads to the micronisate of tiotropium bromide according to the invention, which is characterized by a specific heat of dissolution. It has a value that is advantageously greater than 65 Ws/g, preferably greater than 71 Ws/g. It is particularly advantageous that the value of the heat of dissolution of the micronisate according to the invention is greater than 74 Ws/g. Detailed data for determining the enthalpy of dissolution can be found in the description of the experimental part of the invention.

The micronisate of tiotropium bromide, which can be obtained by means of the above process, is further characterized in that the water content of the micronisate is between approximately 1% and approximately 4.5%, preferably between approximately 1.4% and 4.2%, particularly preferably between approximately 2.4% and 4.1%. The tiotropium bromide micronisate according to the invention is particularly advantageously characterized by a water content that is between approximately 2.6% and approximately 4.0%, particularly advantageously between approximately 2.8% and 3.9%, particularly advantageously between approximately 2.9% and 3, 8%.

Accordingly, one aspect of the proposed invention relates to tiotropium bromide micronisate having the above characteristics.

If nothing else is stated, within the scope of the proposed invention, referring to tiotropium bromide micronisate means any crystalline tiotropium bromide micronisate that has the above-mentioned characteristics and that can be obtained by the above-described process according to the invention (micronization and then further processing according to the above-described parameters).

Due to the pharmaceutical action of the micronisate according to the invention, a further aspect of the proposed invention relates to the use of the tiotropium bromide micronisate according to the invention as a medicine.

A further aspect of the proposed invention relates to an inhalation powder characterized by the content of micronized tiotropium bromide according to the invention.

Due to the anticholinergic effect of tiotropium bromide, a further aspect of the proposed invention relates to the use of micronized tiotropium bromide according to the invention for the production of a medicine for the treatment of diseases in which the application of anticholinergics can be used therapeutically. A suitable use for the manufacture of a medicament for the treatment of asthma or COPD is preferred.

Micronized tiotropium bromide, which can be obtained by the process according to the invention, is particularly suitable for the preparation of pharmaceutical formulations. It can be particularly advantageously used for the production of inhalation powder.

Accordingly, the proposed invention relates to an inhalation powder containing at least approximately 0.03%, preferably below 5%, particularly preferably below 3% of micronized tiotropium bromide obtained by the process described above in a mixture with a physiologically unquestionable excipient, which is characterized in that the auxiliary substance consists of a mixture of the auxiliary substance with larger particles with a size of 15 to 80 μm and a smaller auxiliary substance with an average particle size of 1 to 9 μm, whereby the proportion of the smaller auxiliary substance in the total amount of the auxiliary substance is 1 to 20%.

The above data on percentages are mass percentages.

According to the invention, preference is given to an inhalation powder containing approximately 0.05 to approximately 1%, preferably approximately 0.1 to approximately 0.8%, particularly preferably approximately 0.2 to approximately 0.5% of the micronized tiotropium bromide obtained above by the described process and which has the characteristic values of the micronisate obtained according to the invention.

The inhalation powder containing the micronisate according to the invention is characterized by the fact that the auxiliary substance consists of a mixture of a larger auxiliary substance with an average particle size of 17 to 50 μm, especially preferably from 20 to 30 μm, and a smaller auxiliary substance with an average particle size of 2 to 8 um, especially favorable from 3 to 7 um. At the same time, in the sense used here, the average particle size means a 50% value from the volume distribution measured by laser beam diffraction using dry dispersion.

According to the invention, preference is given to inhalation powder in which the proportion of finer excipients in the total amount of excipients is 3 to 15%, particularly preferably 5 to 10%.

When a mixture is mentioned within the framework of the proposed invention, it always means a mixture obtained by mixing previously clearly defined components, accordingly, a mixture of coarse and fine auxiliary substances is understood, for example, only such a mixture obtained by mixing a coarse auxiliary component substances with a smaller component of excipients.

The proportions of coarser and finer excipients can consist of chemically identical or chemically different substances, whereby preference is given to inhalation powder in which the proportion of coarser excipients and the proportion of finer excipients consist of the same chemical compound.

As physiologically unquestionable excipients, which can be used for the preparation of the inhalation powder containing the micronisate according to the invention, the following can be mentioned for example: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, sucrose, maltose or trehalose), oligo- and polysaccharides (eg dextran), polyalcohols (eg sorbitol, mannitol, xylitol), salts (eg sodium chloride, calcium carbonate) or mutual mixtures of these excipients. Primarily mono- or disaccharides are used, whereby preference is given to the use of lactose, glucose or trehalose, preferably lactose or glucose, especially, but not exclusively, in the form of their hydrate. Lactose, preferably lactose monohydrate, is particularly advantageously used as an auxiliary substance in terms of the invention.

The inhalation powder containing the micronisate according to the invention can be applied, for example, by means of an inhaler, which dispenses a single dose from a container by means of a metering chamber (e.g. according to US 4570630A) or by means of another device built into the apparatus (e.g. according to DE 36 25 685 A ). In any case, the inhalation powder can conveniently be filled into capsules (so-called inhalates), which are placed in inhalers for use, as described for example in WO 94/28958.

If the inhalable powder according to the invention, in terms of the above-mentioned preferred application, is to be filled into capsules (inhalates) as a usual form of packaging for single doses, filling amounts of 1 to 15 mg, preferably 3 to 10 mg, are possible 4 to 6 mg inhalation powder per capsule.

The inhalation powder containing micronized tiotropium bromide according to the invention is characterized by a high degree of homogeneity in terms of the precision of individual dosing. It is in the range of <8%, preferably <6%, especially preferably <4%.

The inhalation powder containing micronized tiotropium bromide according to the invention can be obtained by the process described below.

When the starting materials are weighed, the preparation of the auxiliary substance mixture is first carried out from the defined fractions of the larger auxiliary substance and the smaller auxiliary substance. Then, the inhalation powder according to the invention is prepared from the mixture of auxiliary substance and active substance. If the inhalation powder is to be applied by inhalation in inhalers suitable for this purpose, the production of the inhalation powder ends with the preparation of capsules containing the powder.

In the production process, which is described below, the listed components are placed in mass fractions, as they were described in the previously described inhalation powder formulations.

The production of inhalation powder according to the invention is carried out by mixing a part of a larger excipient with a part of a finer excipient and then mixing the resulting mixture of excipients with the active substance.

For the production of the auxiliary substance mixture, the coarser and finer parts of the auxiliary substance are placed in a suitable container of the mixer. The addition of the two components is preferably done via a sieve granulator with a mesh size of 0.1 to 2 mm, especially preferably 0.3 to 1 mm, preferably 0.3 to 0.6 mm. First, a larger auxiliary substance is placed and then a part of the smaller auxiliary substance is introduced into the mixing bowl. In this procedure, the mixing is done primarily by adding two components in portions, where a part of the coarser auxiliary substance is first placed and then a finer and larger auxiliary substance is added alternately.

In the production of the auxiliary substance mixture, alternating, layered heating of the two components is especially advantageous. The two components are heated alternately in 15 to 45, particularly advantageously in 20 to 40 layers of each component. The mixing of the two auxiliary substances is already done during the addition of the two components. In any case, it is mixed preferably after the layered heating of the two ingredients.

After preparation of the auxiliary substance mixture, this mixture and the active substance, micronized tiotropium bromide according to the invention, are placed in a suitable container of the mixer. The active substance used has an average particle size of from 0.5 to 10 µm, preferably from 1 to 6 µm, particularly preferably from 1.5 to 5 µm. The addition of the two components is preferably done through a sieve granulator with a mesh size of 0.1 to 2 mm, especially preferably 0.3 to 1 mm, preferably 0.3 to 0.6 mm. First, a mixture of auxiliary substances is placed in the mixing bowl, and then the active substance is introduced.

In this mixing process, it is advantageous to add the two components in portions. During the production of the auxiliary substance mixture, alternating, layered heating of the two components is especially advantageous. The heating of the two components is preferably carried out alternately in 25 to 65, especially advantageously in 30 to 60 layers of each component. The mixing of the excipient mixture with the active substance can already be carried out during the addition of the two components. In any case, it is mixed preferably only after the two ingredients have been heated in layers.

The powdery mixture obtained in this way can, if necessary, be added again, one or more times, through the sieve granulator and then subjected to further mixing each time.

A further aspect of the proposed invention relates to an inhalation powder containing micronized tiotropium bromide and obtained by the process described above.

The following detailed experimental implementations serve to further explain the proposed invention, but the scope of the invention is by no means limited to the following examples of the implementation form.

EXPERIMENTAL PART

A) Preparation of crystalline tiotropium bromide monohydrate

In a suitable reaction vessel with 25.7 kg of water, 15.0 kg of tiotropium bromide, obtained for example by the process described in the experimental part of the European patent application EP 418 716 Al, is placed. The mixture is heated to 80-90°C and heated at a constant temperature until a clear solution is formed.

Activated carbon {0.8 kg) moistened with water is mixed in 4.4 kg of water, this mixture is added to a solution containing tiotropium bromide and washed with 4.3 kg of water. The resulting mixture is stirred for at least 15 min at 80-90°C and then filtered through a hot filter into an apparatus preheated to a jacket temperature of 70°C. The filter is washed with 8.6 kg of water. The contents of the device are cooled at a rate of 3-5°C in 20 minutes to a temperature of 20-25°C. The apparatus is further cooled to 10-15°C using cooling water and crystallization is assisted by stirring for at least another hour. The crystallisate is isolated over a nut drier, the isolated crystal slurry is 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 theoretical).

B) Characterization of crystalline tiotropium bromide monohydrate

Tiotropium bromide monohydrate, obtained by the process described above, was examined using DSC (Differential Scanning Calorimetry). The DSC diagram has two characteristic signals. The first, relatively broad, endothermic signal is between 50-120°C and it belongs to the removal of water from tiotropium bomide monohydrate and its transition to the anhydrous form. The second, relatively sharp endothermic maximum is at 230±5°C and it belongs to the melting point of the substance. These data were obtained using a Mettler DSC 821 device and were processed using Mettler's STAR software package. Data were recorded at a heating rate of 10 K/min.

As this substance melts with decomposition (= incongruent melting), the observed melting point is highly dependent on the rate of heating. At lower heating rates, melting/decomposition is observed at significantly lower temperatures. So, for example, with a heating rate of 3 K/min, it is seen at 220±5°C. In addition, it may happen that a split melting point peak is obtained. The appearance of splitting is all the stronger, which is the lower heating rate in the DSC experiment.

Crystalline tiotropium bromide monohydrate was characterized by IR spectroscopy. Data were recorded using a Nicolet FTIR spectrometer and numerically processed with the Nicolet OMNIC software package, version 3.1. The measurement was performed with 2.5 μmol of tiotropium bromide monohydrate in 300 mg of KBr.

Table 1 includes several important bands of the IR spectrum.

Table 1. Membership of specific bands

[image]

Crystalline tiotropium bromide monohydrate was characterized by X-ray structural analysis. X-ray diffraction intensity measurements were performed on a circular diffractometer AFC7R-4 (Rigaku) using monochromatized copper α-radiation. Structure solution and crystal structure refinement were performed using the direct method (SHELXS8 6 program) and FMLQ refinement (TeXsan program). Experimental details for the crystal structure, structure solution, and refinement are listed 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

color and shape of crystals: colorless, prismatic

crystal dimensions: 0.2 x 0.3 x 0.3 mm

crystal system: monoclinic

lattice 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 unit formulas 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,

crystal detector spacing; 235 mm,

detector opening: 3.0 mm vertically and horizontally,

temperature: 18°C,

determination of lattice constants: 25 reflexes

(50.8°<2Θ<56.2°),

search type: ω - 2Θ,

search speed: 8.0 32.0°/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 factor 0.56-1.00),

crystal decay: 10.47% waste.

C. Refinement

reflexes (I > 3σI): 1978

variables: 254

reflex ratio/parameter: 7.8

R value R, Rw: 0.062, 0.066.

Based on the X-ray analysis of the structure, it was determined 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, p = 102.691, V = 2096.96 Å3.

The above X-ray analysis of the structure determined the coordinates of the atoms listed in Table 3.

Table 3: Coordinates

[image] x, y, z: fractional coordinates.

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

C) Preparation of micronized thiopropium bromide according to the invention

The thiopropium bromide monohydrate obtained by the process described above is micronized in a 2-Zoll type air jet micronizer mill with a 0.8 mm diameter grinding ring from Sturtevant Inc., 348 Circuit Street, Hanover, MA 02239, USA. In doing so, with the use of nitrogen as a grinding gas, the following grinding parameters are set:

grinding pressure: 5.5 bar,

supply pressure: 5.5 bar

feed (crystalline monohydrate) or feed rate: 19 g/min.

The resulting grinding product is then spread on a sheet for shrinking to a layer thickness of approximately 1 cm and subjected to the following climatic conditions for 24 - 24.5 hours:

temperature: 25 - 30°C,

relative humidity: 70-80%.

D) Measuring techniques for the characterization of micronized tiotropium bromide according to the invention

The parameters characterizing the micronized tiotropium bromide according to the invention, which are mentioned in the description, were obtained using the measuring technique and methods described below.

D.1) Determination of water content according to Karl-Fischer (tiotropium bromide):

Titration device: type Mettler DL 18 s, calibration substance: disodium tartrate hydrate, titration agent: Hvdranal-Totrant (Riedel-deHaen), solvent: Hvđranal Solvent (Riedel-deHaen).

Measuring method:

amount of sample: 50 - 100 mg,

mixing time: 60 s.

The mixing time before starting the titration serves to achieve complete dissolution of the sample.

The device calculates the water content in the sample in percentage.

D.2) Determination of particle size using laser beam diffraction (Fraunhofer diffraction) Measurement method: To determine the particle size, the powder was brought to the laser beam diffraction spectrometer using a dispersing device.

Measuring device: laser diffraction spectrometer

(HELOS), a Sympatec company.

Software package: WIND0X version 3.3/REL 1. Dispersing device: RODOS/pressure

dispersing: 3 bars,

Device parameters:

Detector: multi-element detector (31 semicircular rings),

method: air dispersing,

focal length: 100 mm,

measuring range: RS 0.5/0.9-175 μm,

mode of expression: HRLD-Mode.

Rhodes dry dispersing device:

Injector: 4 mm,

pressure: 3 bar,

injector pressure: maximum (~100 mbar),

extraction: Nilfilsk (idle stroke 5 s),

dosing device: Vibri,

transport ratio: 40% (manual lifting up to 100%),

layer height: 2 mm, number of revolutions: 0.

D.3) Determination of specific surface area (l-Pkt.-B.E.T. method)

Measuring method

The specific surface area is determined by exposing the powder sample to a nitrogen/helium atmosphere under different pressures. By cooling the sample, condensation of nitrogen molecules occurs on the surface of the particles. The amount of condensed nitrogen is determined by changing the thermal conductivity of the mixture of nitrogen and helium, and the surface of the sample is determined by the surface consumption of nitrogen. The specific surface area is calculated from this value.

Devices and materials:

Measuring device: Monosorb, Quantachrome company,

heating device: Monotektor, Quantachrome company,

measuring and drying gas: nitrogen (5.0)/helium (4.6) 70/30, Messer Griesheim,

absorbate: nitrogen 30% in helium,

coolant: liquid nitrogen,

measuring cell: with capillary tube, company W. Pabisch GmbH & Co. KG,

calibration syringe: 1000 μl, Precision Sampling Corp.,

analytical balance: R 160 P, company Satorius.

Calculation of specific surface area

The device shows measured values in [m ] and i.d.R. in [cm /g] converted to weight (dry mass):

[image]

Aspec = specific surface area [cm2/g],

MW = measured value [m2],

mtr = dry mass [g],

10000 = conversion factor [cm2/m2].

D.4) Determination of heat of dissolution (enthalpy of dissolution) EC

The heat of dissolution is determined using the 2225 Precision Solution Calorimeter

by Thermometric.

The heat of dissolution is calculated from the temperature change caused by dissolution and the temperature change calculated from the base value that is conditioned by the system.

Before and after breaking the ampoule, an electrical calibration with an integrated heating resistor of exactly known power is performed in each case. In doing so, a known heating power is connected to the system during a determined period of time and the temperature jump is determined. Method and apparatus parameters

Solution calorimeter: 2225 Precision Solution Calorimeter, Thermometric,

reaction cell: 100 ml,

thermistor resistor: 30.0 kΏ (at 25°C),

mixing speed: 600 rpm,

thermostat: device thermostat 2277 Thermal Activitv Monitor TAM, company Thermometric,

temperature: 25°C±0.0001°C (during 24h),

measuring ampoules: fragile ampoules of 1 ml, Thermometric company,

seals: silicone plugs and beeswax, Thermometric company,

scales: 40 to 50 mg,

solvent: water, chemically pure,

solvent volume: 100 ml,

bath temperature: 25°C,

melting temperature: high,

initial temperature: -40 mK (±10 mK) temperature offset,

interface: 2280-002 TAM accessorv interface 50 Hz, Thermometric company,

software support: SolCal V 1.1 for WINDOWS,

display mode: automatic display with the menu item CALCULATION/ANALYSE EXPERIMENT (dynamics of the basic value; calibration after breaking the ampoule).

Electric calibration

Electrical calibration is performed during the measurement, once before and once after breaking the ampoule. To display the results, calibration is taken after breaking the ampoule.

Amount of heat: 2.5 Ws,

heater power: 250 mW,

heating duration: 10 s,

duration of basic value: 5 min (before and after heating).

Presentation of results for micronized tiotropium bromide

Since the mass of weighed micronized tiotropium bromide must be corrected for the water content of the material, unstoppered, open ampoules are allowed to stand for at least 4 h together with approx. 1 g of test substance. After this equilibration period, the ampoules are closed with silicone stoppers and the water content in the loose sample is determined by Karl-Fischer titration.

Full and stoppered ampoules are weighed again on the scale. The correction of the mass of the sample is made according to the following formula:

[image]

Thereby:

mc is the corrected mass,

mw is the mass of the sample weighed in the ampoule,

x is the water content in percent (determined by parallel Karl-Fischer titration).

The corrected mass mc, determined after this conversion, is used as an input value (= weight) to calculate the measured enthalpy of dissolution.

E) Preparation of burst formulation containing micronized tiotropium bromide according to the invention

In the following examples, lactose monohydrate (200 M) is used as a larger excipient. It can be obtained for example from the company DMV International, 54 60 Veghel/ The Netherlands under the product name Pharmatose 200M.

In the following examples, lactose monohydrate (5 μ) is used as an excipient. It can be obtained by the usual process (micronization) from lactose monohydrate 200M. Lactose monohydrate 200M can be obtained, for example, from the company DMV International, 5460 Veghel/ The Netherlands under the product name Pharmatose 200M.

Devices

The following machines and devices can be used for the production of inhalation powder containing micronized tiotropium bromide according to the invention:

Mixing vessel or powder mixer: RhSnradmischer 200 L; type DFVJ80N-4; manufacturer Engelsmann, D-67059 Ludwigshafen.

Sieve granulator: Quadro Comil; type 197-S; manufacturer company Joisten & Kettenbaum, D-51429 Bergisch-Gladbach.

E.1) Production of excipient mixture

31.82 kg of lactose monohydrate for inhalation purposes (200M) is taken as a larger component of the auxiliary substance. 1.68 kg of lactose monohydrate (5 μm) is taken as a smaller component of the excipient. In 33.5 kg of the auxiliary substance mixture, which is obtained from it, the proportion of the smaller component of the auxiliary substance is 5%.

Through a suitable sieve granulator with a mesh size of 0.5 mm, put approx. 0.8 to 1.2 kg of lactose monohydrate for inhalation purposes (200M). Then lactose monohydrate (5 μm) is heated alternately and in layers in portions of approx. 0.05 to 0.07 kg and lactose monohydrate for inhalation purposes (200M) in portions of 0.8 to 1.2 kg. Lactose monohydrate for inhalation purposes (200M) and lactose monohydrate (5 um) are added in 31 and 30 layers respectively (tolerance: 6 layers).

Then the heated ingredients are mixed (mixing: 900 revolutions).

E.2) Production of the final mixture

For the production of the final mixture, 32.87 kg of the auxiliary substance mixture (1.1) and approximately 0.13 kg of micronized tiotropium bromide according to the invention are used. This yields 33.0 kg of inhalation powder containing 0.4% of the active substance.

Through a suitable sieve granulator with a mesh size of 0.5 mm, put approx. 1.1 to 1.7 kg of excipient mixture (E.1). Then alternately in layers, in portions of approx. 0.003 kg, sprinkles micronized tiotropium bromide and the excipient mixture (E.1) in portions of 0.8 to 0.8 kg. The mixture of excipients and active substance is added in 4 6 or 45 layers (tolerance: ±9 layers).

Then the heated ingredients are mixed (mixing: 900 revolutions). Then the final mixture is passed through the sieve granulator two more times and mixed each time (mixing: 900 revolutions).

E.3) Inhalation capsules

Inhalation capsules (inhaletes) with the following composition are made with the mixture obtained according to E.2:

micronized tiotropium bromide: 0.0225 mg

lactose monohydrate (200 M): 5.2025 mg

lactose monohydrate (5 um): 0.2750 mg

hard gelatin capsule: 49.0 mg

total: 54.5 mg

In an analogous process as described under E.2, inhalation capsules (inhaletes) with the following composition were obtained:

And)

micronized tiotropium bromide: 0.0225 mg

lactose monohydrate (200 M): 4.9275 mg

lactose monohydrate (5 μm): 0.5500 mg

hard crelatin capsule:______ 49.0 mg

total: 54.5 mg

b)

micronized tiotropium bromide: 0.0225 mg

lactose monohydrate (200 M): 5.2025 mg

lactose monohydrate (5 μm): 0.2750 mg

polyethylene capsule:_________ 100.0 mg

total: 105.50 mg

F) Measuring techniques for determining the particle size of auxiliary substance components used in E)

The following describes the way in which the determination of the average particle size of the various excipient ingredients contained in the micronized tiotropium bromide according to the invention and in the formulation produced according to E) can be carried out.

F.1) Determination of particle size of smaller lactose

Measuring device and adjustment

The device is handled in accordance with the manufacturer's instructions.

Measuring device: HELOS spectrometer for laser diffraction, (SympaTec).

dispersing device: RODOS dry dispersing device with suction funnel, (SympaTec),

sample amount: from 100 mg,

product supply: oscillating groove Vibri by Sympatec,

vibration groove frequency: 40 to 100%, increasing,

duration of sample supply: 1 to 15 sec (in the case of 100 mg),

focal length: 100 mm (measuring range: 0.9-175 μm),

measurement time: approx. 15 s (in the case of 100 mg),

cycle time: 20 ms,

Start/Stop at: 1 % on channel 28,

dispersing gas: compressed air,

pressure: 3 bar,

pressure: maximum,

method of expression of results: HRLD.

Sample preparation/product supply

At least 100 mg of the test substance is weighed on a sheet of paper. Any larger clumps are broken up with another piece of paper. The finely divided powder is then sprinkled on the front half of the vibration groove (approx. 1 cm from the front edge). After starting the measurement, the frequency of the vibrating groove is changed from approx. 4 0% to 100% (towards the end of the measurement). The time it takes to bring the entire sample is 10 to 15 seconds.

F.2) Determination of the particle size of lactose 200M

Measuring device and adjustment

The device is handled in accordance with the manufacturer's instructions.

Measuring device: HELOS spectrometer for laser diffraction, (SympaTec),

dispersing device: RODOS dry dispersing device with suction funnel, (SympaTec),

sample amount: from 500 mg,

product supply: oscillating chute Vibri by Sympatec,

vibration groove frequency: 18 to 100%, increasing,

focal length (1): 200 mm (measuring range: 1.8-350 μm),

focal length (2): 500 mm (measuring range: 4.5-875 μm),

measurement time/waiting time: 10 s,

cycle time: 10 ras,

Start/Stop at: 1 % on channel 19,

pressure: 3 bar, underpressure: maximum,

method of expression of results: HRLD.

Sample preparation/product supply

At least 500 mg of the test substance is weighed on a sheet of paper. Any larger clumps are broken up with another piece of paper. The powder is transferred to the funnel of the vibrating chute. A distance of 1/2 to 1/4 mm is set between the vibrating groove and the funnel. After starting the measurement, the amplitude of the vibration trough is increased from 0% to 40% while the continuous flow of the product is set. After that, the amplitude is reduced to approx. 18%. Towards the end of the measurement, the amplitude is increased to 100%.

Claims (26)

1. Micronized crystalline tiotropium bromide, characterized in that it has an X50 particle size value between 1.0 μm and 3.5 μm and a Q(5.8) value greater than 60%, a specific surface area value in the range between 2 m2/g and 5 m2/g, a specific heat of dissolution greater than 65 Ws/g, and a water content of approximately 1% to approximately 4.5%. 2. Micronized crystalline tiotropium bromide according to claim 1, characterized in that it has an X50 particle size value of 1.1 (m to 3.3 p and a Q(5.8) value greater than 70%). 3. Micronized crystalline tiotropium bromide according to either claim 1 or 2, characterized in that it has a specific surface area value in the range of 2.5 m2/g to 4.5 m2/g. 4. Micronized crystalline tiotropium bromide according to any one of claims 1, 2 or 3, characterized in that it has a specific heat of dissolution greater than 71 Ws/g. 5. Micronized crystalline tiotropium bromide according to any one of claims 1 to 4, characterized in that it has a water content of about 1.4% to about 4.2%. 6. Process for the production of micronized tiotropium bromide according to any of claims 1 to 5, characterized in that a) crystalline tiotropium bromide monohydrate, which according to thermal analysis, using DSC at a heating rate of 10 K/min, has an endothermic maximum at 230±+5°C, and is characterized by an IR spectrum that, among others, has bands at wave numbers 3570 , 3410, 3105, 1730, 1260, 1035 and 720 cm-1 and which is characterized by a simple monoclinic cell with the following dimensions: a = 18.0774 Å, b = 11.9711 Å, c = 9.9321 Å, p = 102.691, V = 2096.96 Å3, micronizes and b) then, at a temperature of 15-40°C, it is exposed to a relative humidity of at least 40% for a period of time of at least 6 hours. 7. The method according to claim 6, characterized in that stage a) of micronization is carried out under an inert gas, preferably nitrogen. 8. The method according to claim 6 or 7, characterized in that step a) micronization is carried out using an air jet mill with the following grinding parameters: grinding pressure: approximately 2-8 bar; supply pressure: approximately 2-8 bar; grinding/feed gas: nitrogen; product feed: approximately 5-35 g/min. 9. The process according to any claim 6, 7 or 8, characterized in that for the implementation of step b) the product obtained in step a) is exposed for approximately 12 to approximately 48 hours to a relative humidity of 50-95% at a water vapor temperature of 20- 35°C. 10. The process according to any of claims 6 to 9, characterized in that it is used as a starting product crystalline tiotropium bromide monohydrate obtained in the following grades: 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 slowly crystallizes with slow cooling of the aqueous solution. 11. The method according to claim 10, characterized in that a) add 0.4 to 1.5 kg of water per mole of tiotropium bromide used, b) the obtained mixture is heated above 50°C, c) per mole of tiotropium bromide used, 10 to 50 g of activated charcoal is added and after the addition of activated charcoal is finished, the mixture is continued for between 5 and 60 minutes, d) the resulting mixture is filtered, the resulting filtrate is cooled at a rate of 1 to 10°C for 10 to 30 minutes to a temperature of 20-25°C and tiotropium bromide monohydrate crystallizes. 12. Crystalline tiotropium bromide micronisate, characterized in that it is obtained by the process according to any of claims 6 to 11. 13. The use of micronized crystalline tiotropium bromide according to any of claims 1-5 or 12, characterized in that it is used for the production of a pharmaceutical preparation, preferably an inhalation pharmaceutical preparation. 14. The use of micronized crystalline tiotropium bromide according to any one of claims 1-5 or 12, characterized in that it is used for the production of a drug for the treatment of diseases in which an anticholinergic can be therapeutically useful. 15. Use according to claim 14, characterized in that the disease is asthma or COPD. 16. Medicine, characterized in that it contains micronized crystalline tiotropium bromide according to any of claims 1-5 or 12. 17. Medicine according to claim 16, characterized in that the medicine is an inhalation powder. 18. Inhalation powder according to claim 17, characterized in that it contains at least approximately 0.03% micronized tiotropium bromide according to any of claims 1-5 or 12 in admixture with a physiologically unquestionable excipient, and further characterized in that the auxiliary the substance consists of a mixture of larger excipients with an average particle size of 15 to 80 μm and smaller excipients with an average particle size of 1 to 9 μm, whereby the proportion of the smaller excipient in the total amount of excipients is 1 to 20%. 19. Inhalation powder according to claim 18, characterized in that it contains between approximately 0.05 and approximately 1%, preferably between approximately 0.1 and approximately 0.8% of micronized tiotropium bromide according to any of claims 1-5 or 12. 20. Inhalation powder according to any claim 18 or 19, characterized in that the auxiliary substance consists of a mixture of a larger auxiliary substance with an average particle size of 17 to 50 μm and a smaller auxiliary substance with an average particle size of 2 to 8 μm. 21. Inhalation powder according to any claim 18, 19 or 20, characterized in that the proportion of smaller excipients in the total amount of excipients is 3 to 15%. 22. Inhalation powder according to any of claims 18 to 21, characterized in that monosaccharides, disaccharides, oligo- and polysaccharides, polyalcohols, salts or mutual mixtures of these auxiliary substances are used as excipients. 23. Inhalation powder according to claim 22, characterized in that glucose, arabinose, lactose, sucrose, maltose, trehalose, dextran, sorbitol, mannitol, xylitol, sodium chloride, calcium carbonate or mutual mixtures of these auxiliary substances are used as excipients. 24. Inhalation powder according to claim 23, characterized in that glucose or lactose or mutual mixtures of these auxiliary substances are used as excipients. 25. The method for the production of inhalation powder according to any of claims 18 to 24, characterized by the fact that in the first stage the proportion of a larger excipient is mixed with the proportion of a finer excipient, and in the next stage the resulting mixture of excipients is mixed with micronized tiotropium bromide according to any which request 1-5 or 12. 26. A capsule (inhaler), characterized in that it contains inhalation powder obtained according to any of claims 17-25.