HK1078871B - Micronized crystalline tiotropium bromide - Google Patents

Description

Crystalline micropowder of tiotropium bromide

Technical Field

The present invention relates to the bromination of (1 alpha, 2 beta, 4 beta, 5 alpha, 7 beta) -7- [ (hydroxydi-2-thienylacetyl) oxy]-9, 9-dimethyl-3-oxa-9-azonia tricyclo [3.3.1.0^2，4]Nonane crystalline micropowder, a process for its preparation and its use in the preparation of pharmaceutical compositions, in particular in the preparation of pharmaceutical compositions having an anticholinergic activity.

Prior Art

Compound bromide (1 alpha, 2 beta, 4 beta, 5 alpha, 7 beta) -7- [ (hydroxy di-2-thienyl acetyl) oxy]-9, 9-dimethyl-3-oxa-9-azonia tricyclo [3.3.1.0^2，4]Nonanes are known from European patent application EP418716A1 and have the following chemical formula:

the compound has valuable pharmacological properties, and the medicine name of the compound is tiotropium bromide (BA 679). Tiotropium bromide is a highly potent anticholinergic substance and thus may show therapeutic benefit in the treatment of asthma or COPD (chronic obstructive pulmonary disease).

Preferably, tiotropium bromide is administered by inhalation. The inhalable powder, suitably filled into suitable capsules, is administered by administration through a suitable powder inhaler. Alternatively, administration may be by inhalation using a suitable inhalable aerosol. This also includes powdered inhalable aerosols containing, for example, HFA134a, HAF227 or mixtures thereof as propellant gas.

For administration of tiotropium bromide by inhalation it is necessary to provide the active substance in finely powdered (micronized) form. Preferably the active substance has an average particle size of 0.5 to 10 μm, more preferably 1 to 6 μm,

the above particle sizes are usually carried out by milling the active substance (known as micronization). Although micronization requires extremely severe conditions during its process, the pharmaceutical active substance should be as protected from being destroyed as possible, and it is therefore absolutely essential to maintain a high stability of the active substance during grinding. It must be taken into account that changes in the solid properties of the active substance occur during the grinding process and thus influence the pharmacological properties of the preparations to be administered by inhalation.

Processes for micronization of pharmaceutically active substances are known in the prior art. The object of the present invention is to provide a process which adapts the micronized form of tiotropium bromide to the high requirements which must be met for the administration of active substances by inhalation, thus providing the specific properties of tiotropium bromide.

Disclosure of Invention

It has been found that the conditions selected after industrial production when purifying the crude tiotropium bromide product lead to different crystalline forms of tiotropium bromide, the so-called polymorphs.

It has also been found that such different crystalline forms can be purposefully produced during crystallization by selection of the solvents used for crystallization and by selection of the appropriate conditions during crystallization.

For the purposes of the present invention (i.e. to provide tiotropium bromide in micronized form for inhalation), it has been demonstrated that it is possible to use crystals of tiotropium bromide monohydrate which can be brought into a particularly suitable crystalline form by the choice of specific reaction conditions.

To prepare this crystalline monohydrate, tiotropium bromide, for example obtained by the manufacturing procedure according to EP418716a1, has to be dissolved in water with heating, purified with activated carbon and slowly crystallized by slow cooling after removal of the activated carbon. The following method is preferably used according to the invention. The solvent is mixed with tiotropium bromide obtained from a process such as that disclosed in EP418716a1 in a suitably sized reaction vessel.

0.4 to 1.5kg, preferably 0.6 to 1kg, and more preferably about 0.8kg of water per mole of tiotropium bromide is used as solvent. The resulting mixture is heated preferably above 50 c and most preferably above 60 c with stirring. The maximum temperature selected depends on the boiling point of the solvent (i.e., water) selected. Preferably the mixture is heated to a temperature in the range of 80-90 ℃.

Dry or wet activated carbon is added to the solution. The amount of activated carbon used per mole of tiotropium bromide is preferably from 10 to 50 grams, more preferably from 15 to 35 grams, and most preferably about 25 grams. If necessary, the activated carbon may be suspended in water prior to addition of the tiotropium bromide-containing solution. The amount of water used to suspend the activated carbon per mole of tiotropium bromide is 70 to 200 grams, preferably 100 to 160 grams, and most preferably about 135 grams. If the activated carbon is suspended in water before being added to the tiotropium bromide solution, it is preferably rinsed again with the same amount of water.

After the addition of the activated carbon, stirring is continued at a constant temperature for 5 to 60 minutes, preferably 10 to 30 minutes, most preferably about 15 minutes, and then the resulting mixture is filtered to remove the activated carbon. The filter was then rinsed with water. The amount of water used for rinsing is 140 to 400 grams, preferably 200 to 320 grams, and optimally about 270 grams per mole of tiotropium bromide.

The filtrate is then slowly cooled, preferably to 20-25 ℃. The cooling rate is preferably reduced by 1 to 10 ℃ every 10 to 30 minutes, preferably 2 to 8 ℃ every 10 to 30 minutes, more preferably 3 to 5 ℃ every 10 to 20 minutes, most preferably about 3 to 5 ℃ every 20 minutes. If necessary, after cooling to 20 to 25 ℃, the mixture can be further cooled to below 20 ℃, and optimally cooled to 10 to 15 ℃.

After the filtrate is cooled, it may be further stirred for 20 minutes to 3 hours, preferably 40 minutes to 2 hours, and most preferably about 1 hour to completely crystallize.

Finally, the crystals formed are isolated by filtration or filtration of the solvent. If necessary, the crystals obtained are subjected to another washing step, and the washing solvent used is preferably water or acetone. The amount of solvent used to wash the resulting crystalline tiotropium bromide monohydrate is from 0.1 to 1.0 liter, preferably from 0.2 to 0.5 liter, optimally about 0.3 liter per mole of tiotropium bromide. This washing step can be repeated if necessary. The resulting product can be dried under vacuum or by heated circulating air until the water content reaches 2.5-4.0%.

The crystalline tiotropium bromide monohydrate produced was used in the milling step (micronisation) described below. This step can be carried out with a conventional grinding machine. Preferably, the micronization is carried out without water, particularly preferably in the presence of a corresponding inert gas, such as nitrogen. It has proven advantageous to use air jet mills in which the comminution of the ground articles is micronized by impact of the particles with each other and with the walls of the mill vessel. According to the invention, nitrogen is preferably used as the grinding gas. The abrasive is conveyed by means of an abrasive gas under a specific pressure (abrasive pressure). Within the scope of the present invention, the grinding pressure is generally set between about 2 and 8 bar (bar), preferably between about 3 and 7 bar, optimally between about 3.5 and 6.5 bar. The ground material is fed into the air jet mill by a feed gas at a specific pressure (feed pressure). Within the scope of the present invention, it has been found that the feed pressure is set between about 2 and 8 bar (bar), preferably between about 3 and 7 bar, and most preferably between about 3.5 and 6 bar. The feed gas is preferably an inert gas, and more preferably nitrogen is also used. The feed rate of the milled material (crystalline tiotropium bromide monohydrate) is about 5-35g/min, preferably about 10-30 g/min.

For example, without limiting the object of the invention, it has been demonstrated that the following device can be a possible embodiment of an air-jet mill: a 2 inch micronizer manufactured by german Sturtevent inc, 348, Circuit Street, Hanover, MA02239, USA, having a 0.8mm gauge grinding ring. When using such a mill, the milling process is preferably carried out using the following milling parameters: grinding pressure: about 4.5-6.5 bar; feeding pressure: about 4.5-6.5 bar; feed rate of ground material: about 17-21 g/min.

The ground material obtained is then further processed under the following specific conditions. Exposing the micropowder to water vapour having a relative humidity of at least 40% at a temperature of 15-40 deg.C, preferably 20-35 deg.C, most preferably 25-30 deg.C. Preferably, the humidity is set at 50-95% r.h., more preferably 60-90% r.h., most preferably 70-80% r.h. Within the scope of the present invention, the relative humidity (r.h.) is the quotient of the partial vapor pressure and the vapor pressure of water at the relevant temperature. Preferably, the fine powder obtained in the grinding step is fed into the cell condition for at least 6 hours. Preferably, however, the micropowder is fed into the cell conditions for about 12 to 48 hours, more preferably about 18 to 36 hours, and most preferably about 20 to 28 hours.

One aspect of the present invention pertains to tiotropium bromide micropowder obtained by the above-described process.

The fine powder of tiotropium bromide of the present invention obtained by the above method is characterized by the particle size X₅₀A value of between 1.0 μm and 3.5 μm, preferably between 1.1 μm and 3.3 μm, and most preferably between 1.2 μm and 3.0. mu.m, and Q thereof_(5.8)Values are greater than 60%, preferably greater than 70%, optimally greater than 80%. X of the characteristic₅₀Values refer to the average particle size values included below 50% of the particle size by volume distribution of the individual particles. And characteristic Q_(5.8)The value is the amount of particles smaller than 5.8 μm according to the volume distribution of the particles. Within the scope of the invention, the particle size is measured by laser diffractometry (Fraunhofer diffraction). A more detailed description of the process is provided in the examples of the present invention.

Another characteristic of the fine powder of tiotropium bromide according to the invention is its specific surface area (specificsusurf)ace Area) value of 2m²G and 5m²A ratio of 2.5 m/g²G and 4.5m²Between/g, and most preferably at 3.0m²G and 4.0m²Between/g.

Carrying out the process according to the invention makes it possible to obtain micropowder of tiotropium bromide according to the invention, which can be characterized by the specific heat of solution (spezifsche losungswarmen). Preferably it is greater than 65Ws/g, more preferably greater than 71 Ws/g. Most preferably, the solution specific heat value of the micropowder according to the present invention is greater than 74 Ws/g.

Details of measuring the enthalpy of a solution can be found in the description of the embodiments of the present invention.

Tiotropium bromide micropowder obtained using the above process is further characterized by a water content of the micropowder of between about 1% and about 4.5%, preferably between about 1.4% and about 4.2%, more preferably between about 2.4% and 4.1%. Particularly preferred micronized tiotropium bromide according to the present invention has a water content of between about 2.6% and about 4.0%, optimally between about 2.8% and 3.9%, particularly preferably between about 2.9% and 3.8%.

One aspect of the present invention therefore relates to tiotropium bromide micropowder having the above characteristics.

Unless otherwise indicated, tiotropium bromide micropowder mentioned in the context of the present invention refers to tiotropium bromide crystalline micropowder having the above characteristics and being obtained according to the above process of the invention (micronization followed by further processing according to the above parameters).

Another aspect of the invention is directed to the use of tiotropium bromide micropowder of the invention as a pharmaceutical composition based on the pharmaceutical effect of the micropowder of the invention.

Another aspect of the present invention relates to an inhalable powder characterized by containing the fine powder of tiotropium bromide according to the present invention.

In light of the anticholinergic activity of tiotropium bromide, a further aspect of the invention relates to the use of the tiotropium bromide micropowder of the invention for the preparation of a pharmaceutical composition for the treatment of a disease which is therapeutically effective with an anticholinergic agent. Preferably, for the manufacture of a medicament for the treatment of asthma or COPD. Tiotropium bromide micropowder obtained according to the process of the invention is exceptionally suitable for the preparation of pharmaceutical preparations. It finds particular application in the preparation of inhalable powders.

Accordingly, the present invention relates to inhalable powders containing at least about 0.03%, preferably less than 5%, more preferably less than 3% of tiotropium bromide micropowder obtained as described above, mixed with a physiologically acceptable adjuvant, characterized in that these adjuvants are composed of a mixture of a coarser adjuvant having an average particle size of 15 to 80 μm and a finer adjuvant having an average particle size of 1 to 9 μm, the finer adjuvant constituting 1 to 20% of the total amount of all adjuvants.

The percentages mentioned refer to weight percentages.

In accordance with the present invention, a preferred inhalable powder is one containing from about 0.05% to about 1%, preferably from about 0.1% to about 0.8%, more preferably from about 0.2% to about 0.5% tiotropium bromide micropowder, which can be made as described above and which has the features of the present invention.

Preferably, the inhalable powders according to the invention containing micropowder are characterized in that the auxiliary consists of a mixture of a coarser auxiliary with an average particle size of 17 to 50 μm, preferably 20 to 30 μm, and a finer auxiliary with an average particle size of 2 to 8 μm, preferably 3 to 7 μm. The average particle size referred to herein is therefore the 50% volume distribution value measured with a laser diffractometer using the dry dispersion method. Preferred inhalation powders are those whose finer adjuvant proportion is from 3 to 15%, preferably from 5 to 10%, of the total adjuvant.

When mixtures are concerned within the scope of the present invention, they are obtained by mixing together the above explicitly defined components. Thus, for example, an auxiliary mixture consisting of coarser and finer auxiliary components can only be a mixture of coarser and finer auxiliary components.

The coarser and finer adjuvant components may be composed of chemically identical or chemically different substances, wherein it is preferred that the coarser adjuvant component and the finer adjuvant component of the inhalable powder are composed of the same chemical compound.

Examples of physiologically acceptable adjuvants for the preparation of the inhalable powders containing the micropowder according to the invention include, for example, monosaccharides (such as glucose or arabinose), disaccharides (such as lactose, sucrose, maltose or trehalose), oligo-or polysaccharides (such as dextrin), polyols (such as sorbitol, mannitol or xylitol), salts (such as sodium chloride, calcium carbonate) or mixtures of these adjuvants with one another. Preferably, a monosaccharide or disaccharide is used, although lactose, glucose or trehalose are preferred, more preferably lactose or glucose, particularly (but not limited to) in the form of their hydrates. In the present invention, lactose is a particularly preferred excipient, and lactose monohydrate is preferably used.

The inhalable powders containing the micropowder according to the invention can be administered, for example, by means of an inhaler, the individual doses of which are metered from a reservoir by means of a measuring cell (for example according to US 4570630a) or by means of other apparatus (for example according to DE 3625685 a). It is however preferred that the inhalable powder is filled in capsules (so-called inhalation capsules) which are used in inhalers such as those disclosed in WO 94/28958. If the inhalable powder according to the invention is used in capsules (inhalation capsules) or other packaged form, the individual doses provided by filling the capsules have a filling amount per capsule of 1 to 15mg, preferably 3 to 10mg, most preferably 4 to 6mg of inhalable powder.

Inhalable powders containing micronized tiotropium bromide according to the invention are characterized by a high homogeneity of single dose precision. The range is < 8%, preferably < 6%, most preferably < 4%.

The inhalable powder containing the fine powder of the present invention can be produced as follows.

After all the starting materials have been weighed, an auxiliary mixture is first prepared from the stated proportions of coarser and finer auxiliaries, and the inhalable powders according to the invention are then prepared from the auxiliary mixture and the active substance. If the inhalable powder is administered in inhalation capsules by means of a suitable inhaler, the preparation of the inhalable powder comprises a manufacturing process of capsules containing the powder.

In the following preparation, the weight proportions of the components used are described above for the inhalable powder compositions according to the invention. The inhalable powders according to the invention are produced by mixing the coarser adjuvant component with the finer adjuvant component and mixing the resulting adjuvant mixture with the active substance. When preparing the adjuvant mixture, the coarser and finer adjuvant components are in a suitable mixing vessel. Preferably, the two components are added to the mixing vessel by passing them through a screen granulator having a mesh size of from 0.1 to 2mm, preferably from 0.3 to 1mm, most preferably from 0.3 to 0.6 mm. Preferably, a layer of coarser aid is added first followed by the finer aid, preferably in the mixing step the two components are added in portions, wherein the coarser aid portion is added first, followed by the alternating finer and coarser aid portions. The preparation of the adjuvant mixture is particularly preferably carried out by alternately layering the two adjuvant components. Preferably the two components are alternately sieved through 15 to 45 layers each, most preferably 20 to 40 layers each. When the two components are added, the two adjuvants may be subjected to a mixing process. However, it is preferred that the two components are mixed after being separately sifted in layers.

When the adjuvant mixture has been prepared, the mixture and the active substance (tiotropium bromide micropowder according to the invention) are placed in a suitable mixing vessel. The average particle size of the active substance used is from 0.5 to 10 μm, preferably from 1 to 6 μm, more preferably from 1.5 to 5 μm. The two components are preferably added to the mixing vessel by means of a sieve granulator having a sieve opening of 0.1 to 2mm, preferably 0.3 to 1mm, most preferably 0.3 to 0.6 mm. Preferably, the adjuvant mixture is added first and then the active substance is added to the mixing vessel. During this mixing process, it is preferred that the two components are added in portions. In the preparation of the auxiliary mixture, the two components are each alternately sieved in layers, preferably the sieving of the two components is carried out alternately in 25 to 65 layers, preferably in 30 to 60 layers each. The mixing of the adjuvant mixture with the active substance can be carried out while adding both components. Preferably, however, the two components are mixed after their respective separate layers are screened. If necessary, the obtained powder mixture may be passed through the sieving granulator once or repeatedly several times, and then subjected to the next mixing step.

Another aspect of the invention relates to an inhalable powder comprising tiotropium bromide micropowder according to the invention and obtainable by the process described above.

The following detailed experimental embodiments are intended to further illustrate the invention and are not intended to limit the scope of the invention by the specific examples described herein below.

Experimental part

A) Preparation of crystalline tiotropium bromide monohydrate

In a suitable reaction vessel, 15.0kg of tiotropium bromide prepared according to the test procedure disclosed in European patent application EP418716A1 was added to 25.7kg of water. The mixture was heated to 80-90 ℃ and stirred at constant temperature until a clear solution formed. Activated carbon (0.8kg) was wetted with water and suspended in 4.4kg of water, poured into a solution containing tiotropium bromide and washed with 4.3kg of water. The resulting mixture was stirred at 80-90 ℃ for at least 15 minutes and then filtered through a heated filter into an external pre-heated to 70 ℃ apparatus. The filter was rinsed with 8.6kg of water. The contents of the apparatus were cooled to a temperature of 20-25 ℃ at a rate of 3-5 ℃ drop every 20 minutes. The apparatus was then further cooled to 10-15 ℃ with cold water and stirring continued for at least 1 hour to complete the crystallization. The crystals were separated by means of a suction filter dryer and the separated crystal slurry was washed with 9 liters of cold water (10-15 ℃ C.) and cold acetone (10-15 ℃ C.). The crystals were dried at 25 ℃ for 2 hours under a stream of nitrogen.

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

B) Characterization of the crystals of tiotropium bromide monohydrate

Tiotropium bromide monohydrate obtained using the above method was analyzed by DSC (differential scanning calorimetry). The DSC graph shows two characteristic signals. The first relatively broad endothermic signal at 50-120 ℃ can be attributed to dehydration of tiotropium bromide monohydrate to the anhydrous form. The second rather sharp endotherm, occurring at 230 + -5 deg.C, can be attributed to melting of the substance. This data was obtained by Mettler DSC 821 and evaluated using the Mettler STAR software package. The data is recorded at a heating rate of 10K/min.

Since the material decomposes upon melting (an uncoordinated melting process), the melting point observed is very dependent on the heating rate. At slower heating rates, the melting/decomposition process clearly occurs at a relatively low temperature, for example, at a heating rate of 3 k/min, which is observed to be 220. + -. 5 ℃. The melting peak may also split. The splitting phenomenon is more pronounced as the heating rate is slower in the DSC test.

The crystalline tiotropium bromide monohydrate can also be characterized using IR spectroscopy. The data were measured using a Nicolet FTIR spectrometer and analyzed by evaluation using the Nicolet software package OMNIC version 3.1. The measurement was carried out with 2.5. mu. mol of tiotropium bromide monohydrate in 300mg of KBr. Table 1 shows the main absorption peaks in the IR spectrum.

Table 1: attribution of specific absorption peaks

Wave number (cm))	Due to the fact that	Type of vibration
			3570，34103105173012601035720	O-H aryl C-HC ═ O epoxy C-O ester C-OC thiophene	Annular vibration of stretching vibration, stretching vibration and stretching vibration

The crystalline tiotropium bromide monohydrate is characterized by X-ray structural analysis. The X-ray diffraction intensity is measured by using monochromatic copper K_αIrradiation was carried out in an AFC 7R-4-circular diffractometer (Rigaku). The structure analysis and the refinement of the crystal structure were performed by the direct method (SHELXS86 program) and FMLQ-refinement (TeXsan program). The details of the test of the crystal structure, the structural analysis and the subdivision are summarized in Table 2.

Table 2: test data of crystal structure analysis of tiotropium bromide monohydrate

A. Crystallization data

Empirical formula [ C₁₉H₂₂NO₄S₂]Br·H₂O

Molecular weight 472.43+18.00

The crystal is colorless in color and shape and is prismatic

Crystal size 0.2X 0.3mm

Monoclinic system of crystallization system

The lattice type being original

Space group P2₁/n

The lattice constant a is 18.0774 Å,

b＝11.9711Å

c＝9.9321Å

β＝102.691°

V＝2096.96ų

number of molecular formula units per unit cell 4

B. Intensity measurement

Diffractometer Rigaku AFC7R

Rigaku RU200 for X-ray generator

Wavelength λ 1.54178 Å (monochromatic copper K)_α-radiation)

Current, voltage 50kV, 100mA

Removing angle of 6 °

Crystallizing assembled vapor saturated capillary

Crystal detection gap 235nm

Detector opening 3.0mm vertical and horizontal

Temperature 18 °

Measuring the lattice constant 25 reflection (50.8 DEG < 2 theta < 56.2 DEG)

Scan type omega-2 theta

Scanning speed 8.032.0 DEG/min in omega

Scanning width (0.58+0.30tan theta) °

2 theta maximum 120 DEG

Number of measurements 5193

Independent reflection 3281 (R)_int＝0.051)

Correcting lorentz polarization absorption

(Transmission factor 0.56-1.00)

10.47 reduction in crystal decay

C. Subdivision into sections

Reflection (I > 3. sigma.I) 1978

Variation 254

Reflection/parameter ratio 7.8

R-value: r, Rw 0.062, 0.066

The X-ray structural analysis carried out showed that the tiotropium bromide monohydrate crystallized as a simple monoclinic lattice, with the following dimensions:

a＝18.0774Å，b＝11.9711Å，c＝9.9321Å，β＝102.691°，V＝2096.96ų。

the atomic coordinates described in Table 3 below were determined by the X-ray structural analysis described above:

table 3: coordinates of the object

Atom(s)	x	y	z	u(eq)
					Br(1)S(1)S(2)O(1)O(2)O(3)O(4)O(5)N(1)C(1)C(2)C(3)C(4)	0.63938(7)0.2807(2)0.4555(3)0.2185(4)0.3162(4)0.3188(4)0.0416(4)0.8185(5)0.0111(4)0.2895(5)0.3330(5)0.3004(5)0.4173(5)	0.0490(1)0.8774(3)0.6370(4)0.7372(6)0.6363(8)0.9012(5)0.9429(6)0.0004(8)0.7607(6)0.7107(9)0.7876(8)0.7672(8)0.7650(8)	0.2651(1)0.1219(3)0.4214(5)0.4365(8)0.5349(9)0.4097(6)0.3390(8)0.2629(9)0.4752(7)0.4632(9)0.3826(8)0.2296(8)0.4148(8)	0.0696(4)0.086(1)0.141(2)0.079(3)0.106(3)0.058(2)0.085(3)0.106(3)0.052(2)0.048(3)0.048(3)0.046(3)0.052(3)

C(5)C(6)

0.1635(5)0.1435(5)

0.6746(9)0.7488(9)

0.497(1)0.6085(9)

0.062(3)0.057(3)

Table 3 continues: coordinates of the object

C(7)C(8)C(9)C(10)C(11)C(12)C(13)C(14)C(15)C(16)C(17)C(18)C(19)H(1)H(2)H(3)H(4)H(5)H(6)H(7)H(8)H(9)H(10)H(11)H(12)H(13)H(14)H(15)H(16)H(17)H(18)H(19)H(20)H(21)

0.0989(6)0.0382(5)0.0761(6)0.1014(6)0.0785(5)-0.0632(6)-0.0063(6)0.4747(4)0.2839(5)0.528(2)0.5445(5)0.2552(6)0.2507(6)-0.0767-0.0572-0.1021-0.0210-0.04630.03770.13000.18730.11900.07620.1873-0.00250.10840.14980.06580.29060.24060.23280.46490.57290.5930

0.6415(8)0.7325(9)0.840(1)0.8974(8)0.8286(8)0.826(1)0.6595(9)0.8652(9)0.6644(9)0.818(2)0.702(2)0.684(1)0.792(1)0.84530.89190.78100.68260.61780.61340.70260.79150.62840.57500.60820.71160.83830.93290.87340.59270.62580.81910.94430.86560.6651

0.378(1)0.3439(9)0.315(1)0.443(1)0.5540(9)0.444(1)0.554(1)0.430(1)0.1629(9)0.445(2)0.441(1)0.019(1)-0.016(1)0.52860.39490.39060.63590.49820.57810.67700.64900.29850.40160.53930.26990.25060.46260.62500.2065-0.0469-0.10750.42540.46600.4477

0.059(3)0.056(3)0.064(3)0.060(3)0.053(3)0.086(4)0.062(3)0.030(2)0.055(3)0.22(1)0.144(6)0.079(4)0.080(4)0.1020.1020.1020.0730.0730.0730.0690.0690.0690.0690.0730.0660.0750.0710.0630.0650.0940.0970.0370.2680.165

H(22)H(23)

0.81920.7603

-0.06100.0105

0.16190.2412

0.0840.084

x, y, z: component coordinates;

u (eq) means the square amplitude of atomic motion in the crystal

C) Preparation of the Tiotropium Bromide micropowder of the invention

Tiotropium bromide monohydrate prepared as described above was obtained using a 2 inch micronizing mill with a 0.8mm aperture in the grinding ring, manufactured by Firma Sturtevant inc., 348, circit Street, Hanover, MA02239, USA. The polishing was carried out using nitrogen as polishing gas and setting the following polishing parameters: grinding pressure: about 5.5 bar; feeding pressure: about 5.5 bar; feed (monohydrate crystallization) rate: 19 g/min.

The resulting ground material was then spread on a metal plate having a thickness of about 1cm and placed under the following ambient conditions for 24-24.5 hours: 25-30 ℃; the relative humidity is 70-80%.

D) Measurement technology for characterizing tiotropium bromide micropowder

The parameters mentioned in the description that characterize the tiotropium bromide micropowder of the invention are obtained using the following measurement techniques and methods:

d.1) measurement of the water content (tiotropium bromide) according to Karl-Fischer:

titrator: mettler DL18 type

Correction substance: disodium tartrate dihydrate

Titration solution: Hydranal-Tirtrant 5(Riedel-deHaen)

Solvent: hydranal solvent (Riedel-deHaen)

The measuring method comprises the following steps:

sample amount: 50-100mg

Stirring time: 60 seconds

The stirring time before titration was used to ensure that the sample had completely dissolved. The water content of the sample is expressed as a percentage calculated by the apparatus.

D.2) measurement of the particle size by laser diffraction (Fraunhofer diffraction)

The measuring method comprises the following steps:

the powder was sent to a laser diffraction spectrometer in a dispersion unit to measure particle size.

The measuring equipment comprises: laser diffraction spectrometer (HELOS), fa

Software: WINDOX version 3.3/REL 1

A dispersing unit: RODOS/dispersion pressure: 3 bar

Equipment parameters:

a detector: multielement detector (31 semi-circle ring)

The method comprises the following steps: air dispersion

Focal length: 100mm

Measurement range: RS 0.5/0.9-175 μm

Evaluation mode: HRLD-mode

Rodos dry disperser:

an injector: 4mm

Pressure: 3 bar

Vacuum of an injector: maximum (100 mbar)

Air extraction: nilfisk (advance 5s)

A metering device: vibri

Feeding rate: 40% (manually increase to 100%)

Height of the bed: 2mm

Rotation speed: 0

D.3) measurement of specific surface area (1-bundle b.e.t. method):

the measuring method comprises the following steps:

the specific surface area was measured by exposing the powder samples to an atmosphere of nitrogen/helium at different pressures. Nitrogen gas can be condensed on the particle surface by sample cooling. The amount of nitrogen condensed is determined by the change in thermal conductivity of the nitrogen/helium mixture, and the surface of the sample is calculated from the surface nitrogen required. From this value and the weight of the sample, the specific surface area can be calculated.

Equipment and materials:

the measuring equipment comprises: monosorb, Fa

A heater: monotektor, Fa

Measuring and drying gas: nitrogen (5.0)/helium (4.6)70/30, Fa

Adsorbent: helium with 30% nitrogen

Cooling agent: liquid nitrogen

A measuring chamber: using capillary tubes, Fa.W. Pabisch GmbH & Co.KG

Correcting the peak: 100 μ l, Fa.

And (3) analyzing the scale: R160P, fa

Calculating the specific surface area:

the value displayed by the measuring device is m²]Expressed and usually converted to [ cm ] by adding weight (dry weight)²/g]：

A_spezSpecific surface area [ cm ]²/g]

Measured value of MW ═ m²]

m_trDry weight [ g]

10000 ═ conversion factor [ cm ═ cm²/m²]

D.4) measurement of the Heat of solution (enthalpy of dissolution) E_c：

Enthalpy of solution is determined using a solution calorimeter 2225 precision solution calorimeter manufactured by fa.

The solution heat is calculated from the temperature change due to the dissolution process and the temperature change associated with the system conditions calculated from the baseline.

Before and after the ampoule is broken, an electronic calibration must be made with an integrated heating resistor whose power is precisely known. A known thermal power is input into the system for a set period and the temperature thereof is measured for a jump.

Method and device parameters:

a solution calorimeter: 2225 Precision Solution calorimeters, Fa

A reaction chamber: 100ml of

Thermal resistance: 30.0 k.OMEGA. (25 ℃ C.)

Stirring speed: 600U/min

A thermostat: 2277 Thermal Activity Monitor, Fa

Temperature: 25 ℃ plus or minus 0.0001 ℃ (24 hours)

Measuring an ampoule: crushed ampoule 1ml, Fa

And (3) sealing: silicon plugs and beeswax, Fa

Weight: 40-50mg

Solvent: chemical pure water

Volume of solvent: 100ml of

Bath temperature: 25 deg.C

Dissolution temperature: height of

Initial temperature: -40mK (+ -10 mK) temperature excursion

Interface: 2280 + 002TAM auxiliary interface, 50Hz, Fa

Software: solcal V1.1 for WINDOWS

Evaluation: the evaluation is automatically performed by clicking on CALCULATION/ANALYSE EXPERIMENT with a menu. (dynamic baseline: correction after ampoule Break)

Electronic correction:

electronic corrections are required during the measurement, once before and once after the ampoule breaks. The results of the correction after ampoule breaking were used for evaluation.

Heat quantity: 2.5Ws

Thermal power: 250mW

Heating time: 10s

Baseline interval: 5 minutes (before and after heating)

Evaluation of tiotropium bromide micropowder:

since the weight of the tiotropium bromide micropowder weighed is corrected for the moisture content of the material, an unsealed ampoule containing about 1g of the test material is left open for at least 4 hours. After the equilibration time, the ampoules were sealed with a silicon plug and the water content of the feedstock samples was measured by Karl-Fischer titration.

The filled and sealed ampoule was weighed once more. The weight of the sample was then corrected according to the following formula:

wherein: m is_cIs the corrected weight

m_wIs weighed into the ampoule

x is the percentage of water content (determined by Karl-Fischer titration in parallel)

The weight m corrected by the calculation formula_cAs input value for the calculation of the enthalpy of the measured solution (═ weight).

E) Preparation of powder preparation containing tiotropium bromide micropowder

In the examples below, lactose monohydrate (200M) is used as the coarser auxiliary. This is obtained, for example, under the product name Pharmatose 200M from Firom DMV International, 5460 Veghel/NL.

In the examples below, lactose monohydrate (5 μ) was used as a finer aid. It can be obtained by preparing lactose monohydrate 200M by a conventional method (micronization). Lactose monohydrate 200M is available, for example, under the product name Pharmatose 200M from Firma DMV International, 5460 Veghel/NL.

Device for measuring the position of a moving object

The inhalable powders containing tiotropium bromide micropowder of the present invention can be prepared using, for example, the following machines and equipment:

mixing vessel or powder mixer:rhonrad mixer 200L; the model is as follows: DFW 80N-4; the manufacturer: firma Engelsmann, D-67059 Ludwigshafen.

Granulating and screening:quadro Comil; the model is as follows: 197-S; the manufacturer: firma Joisten& Kettenbaum，D-51429 Bergisch-Gladbach。

E.1) preparation of the adjuvant mixture:

31.82kg of lactose monohydrate (200M) for inhalation were used as the coarser auxiliary component. 1.68kg of lactose monohydrate (5 μm) was used as the finer auxiliary component. The proportion of the finer auxiliary components in the resulting auxiliary mixture is 5%.

About 0.8 to 1.2kg of lactose monohydrate (200M) for inhalation is fed through a suitable granulating sieve having a mesh size of 0.5mm into a suitable mixing vessel. About 0.05 to 0.07kg of lactose monohydrate (5 μ M) are then sieved alternately with about 0.8 to 1.2kg of lactose monohydrate for inhalation (200M) in portions and placed in a mixing vessel. Lactose monohydrate (200M) and lactose monohydrate (5 μ M) were added to 31 and 30 layers, respectively (tolerance. + -. 6 layers), for inhalation.

Subsequently, the respective sieved components were mixed (mixed at 900 rpm).

E.2) preparation of the final mixture

The final mixture was prepared using 32.87kg of the adjuvant mixture (1: 1) and about 0.13kg of the microparticles of tiotropium bromide according to the invention. The content of active substance in the 33.0kg of inhalable powder obtained was 0.4%.

Approximately 1.1 to 1.7kg of the auxiliary mixture (E.1) are introduced into a suitable mixing vessel through a suitable granulating sieve having a sieve opening of 0.5 mm. A batch of about 0.003kg of tiotropium bromide microparticles in a layer and a batch of about 0.6 to 0.8kg of the adjuvant mixture (e.1) in a layer are then alternately screened into a mixing vessel. The adjuvant mixture and the active substance were added in 46 and 45 layers (tolerance. + -. 9 layers), respectively.

The sieved components are mixed after addition.

The final mixture was passed through the granulation screen again and then mixed again (mixing at 900 rpm).

E.3) inhalation capsules

Inhalation capsules having the following composition were prepared using the mixture obtained according to example 2:

tiotropium bromide micropowder: 0.0225mg

Lactose monohydrate (200M): 5.2025mg

Lactose monohydrate (5 μm): 0.2750mg

Hard capsules: 49.0mg

Total weight: 54.5mg

Inhalation capsules (inhalettes) having the following composition can be obtained according to the process described in e.2:

a)

tiotropium bromide micropowder: 0.0225mg

Lactose monohydrate (200M): 4.9275mg

Lactose monohydrate (5 μm): 0.5500mg

Hard capsules: 49.0mg

Total weight: 54.5mg

b)

Tiotropium bromide micropowder: 0.0225mg

Lactose monohydrate (200M): 5.2025mg

Lactose monohydrate (5 μm): 0.2750mg

Polyethylene capsule: 100.0mg

Total weight: 105.50mg

F) Measurement of particle size of the auxiliary Components used in E)

The average particle size of the various auxiliary components of the formulations containing tiotropium bromide micropowder according to the invention prepared according to the formulation specified in E) can be measured according to the following method:

f.1) measurement of micronized lactose particle size:

measuring equipment and adjustment thereof:

the device is operated according to the manufacturer's instructions and operational guidelines.

The measuring equipment comprises: HELOS laser diffraction spectrometer (SympaTec)

A dispersing unit: RODOS Dry disperser with suction funnel, (SympaTec)

Sample amount: 100mg of

Feeding a sample: vibri vibrating pipe, fa

Frequency of vibrating the pipe: 40 to 100 percent

Sample feed time: 1 to 15 seconds (sample size 100 mg)

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

Measuring time: about 15s (sample size 100 mg)

Cycle time: 20ms

Start/stop at: 1% in the pipe 28

Dispersing gas: compressed air

Pressure: 3 bar

Vacuum: maximum of

The evaluation method comprises the following steps: HRLD

Sample preparation/feed:

at least 100mg of the test substance is weighed out onto a card. All large lumps are broken up with another cardboard. The powder was then lightly dusted onto the front half of the vibrating tube (about 1cm from the leading edge). After the start of the measurement, the frequency of the vibrating tube was adjusted from 40% to 100% (to the end of the measurement). The total sample feed time was 10 to 15 seconds.

F.2) measurement of the particle size of lactose 200M:

measuring equipment and adjustment thereof:

the equipment is operated according to the manufacturer's instructions and operation guidance.

The measuring equipment comprises: HELOS laser diffraction spectrometer (Sympatec)

A dispersing unit: RODOS Dry disperser with suction funnel, (Sympatec)

Sample amount: 500mg of

Feeding a sample: VIBRI type vibrating conduit, fa. sympatec

Frequency of vibrating the pipe: 18 is increased to 100 percent

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

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

Measuring time: 10s

Cycle time: 10ms

Start/stop at: 1% in the pipeline 19

Pressure: 3 bar

Vacuum: maximum of

The evaluation method comprises the following steps: HRLD

Sample preparation/feed:

at least 500mg of the test substance is weighed out onto a card. All large clumps were broken up with another piece of cardboard. The powder was then transferred into the funnel of a vibrating tube. The gap between the vibrating tube and the funnel is set between 1.2 and 1.4 mm. After the start of the measurement, the amplitude of the vibrating tube was adjusted from 0% to 40% until the flow of the sample was continuous. The amplitude was then adjusted to about 18%. The amplitude adjustment of the measurement is increased to 10 o% by the end of the measurement.

Claims (32)

1. A crystalline tiotropium bromide micropowder characterized by a particle size X₅₀Between 1.0 μm and 3.5 μm, Q_(5.8)The value is greater than 60%, the value of the specific surface is 2m²G and 5m²Between/g, the specific heat of the solution is greater than 65Ws/g and the water content is from 1% to 4.5%.

2. Fine crystalline tiotropium bromide powder according to claim 1, characterized by a particle size X₅₀A value between 1.1 μm and 3.3 μm, and Q thereof_(5.8)The value is greater than 70%.

3. Fine crystalline tiotropium bromide powder according to claim 1, characterized by a specific surface area value of 2.5m²G and 4.5m²Between/g.

4. Fine crystalline tiotropium bromide powder according to claim 2, characterized by a specific surface area value of 2.5m²G and 4.5m²Between/g.

5. Fine crystalline tiotropium bromide powder according to one of claims 1 to 4, characterized in that the specific heat of the solution is greater than 71 Ws/g.

6. Crystalline tiotropium bromide micropowder according to one of claims 1 to 4, characterized by a water content of from 1.4% to 4.2%.

7. Fine crystalline tiotropium bromide powder according to claim 5, characterized by a water content of 1.4% to 4.2%.

8. A process for the preparation of crystalline tiotropium bromide micropowder according to one of claims 1 to 7, characterized in that

a) Micronizing crystalline tiotropium bromide monohydrate,

wherein the compound has an endotherm 230 + -5 deg.C measured at a heating rate of 10K/min by DSC thermal analysis, and is characterized by IR spectrum, which shows absorption peaks at wavelengths 3570, 3410, 3105, 1730, 1260, 1035 and 720cm^-1And it is a simple monoclinic crystal with a size of a-18.0774 Å, b-11.9711 Å, c-9.9321 Å, β -102.691 °, V-2096.96 ų；

b) And then exposed to water vapor having a relative humidity of at least 40% at a temperature of 15-40 deg.C for at least 6 hours.

9. The process according to claim 8, wherein in step a) the micronization is carried out under an inert gas.

10. The process according to claim 8, wherein in step a) the micronization is carried out under nitrogen.

11. The method according to claim 8, wherein step a) is carried out with an air jet mill using the following milling parameters:

grinding pressure: 2-8 bar;

feeding pressure: 2-8 bar;

grinding/feed gas: nitrogen gas;

feeding: 5-35 g/min.

12. The method according to claim 9, characterized in that step a) is carried out with an air-jet mill using the following milling parameters:

grinding pressure: 2-8 bar;

feeding pressure: 2-8 bar;

grinding/feed gas: nitrogen gas;

feeding: 5-35 g/min.

13. A process according to any one of claims 8-12, characterized in that in step b) the product obtained in step a) is exposed to water vapour having a relative humidity of 50-95% at a temperature of 20-35 ℃ for 12 to 48 hours.

14. A process according to any one of claims 8 to 12, characterized in that the crystalline tiotropium bromide monohydrate as starting material is obtained by the following steps:

a) adding tiotropium bromide to water;

b) heating the resulting mixture;

c) adding activated carbon and

d) after removal of the activated carbon, the aqueous solution was slowly cooled to slowly crystallize tiotropium bromide monohydrate.

15. A process according to claim 13, characterized in that the crystalline tiotropium bromide monohydrate as starting material is obtained by the following steps:

a) adding tiotropium bromide to water;

b) heating the resulting mixture;

c) adding activated carbon and

d) after removal of the activated carbon, the aqueous solution was slowly cooled to slowly crystallize tiotropium bromide monohydrate.

16. The method of claim 14, wherein the method further comprises removing the substrate from the container

a) 0.4 to 1.5kg of water per mole of tiotropium bromide is used,

b) the resulting mixture is heated to greater than 50 c,

c) 10 to 50g of activated carbon per mole of tiotropium bromide is used, and the mixture is stirred for a further 5 to 60 minutes after the addition of activated carbon,

d) the resulting mixture was filtered, and the resulting filtrate was cooled to 20-25 ℃ at a cooling rate of 1 to 10 ℃ per 10 to 30 minutes to crystallize the tiotropium bromide monohydrate.

17. The method of claim 15, wherein the step of removing comprises removing the substrate from the container

a) 0.4 to 1.5kg of water per mole of tiotropium bromide is used,

b) the resulting mixture is heated to greater than 50 c,

c) 10 to 50g of activated carbon per mole of tiotropium bromide is used, and the mixture is stirred for a further 5 to 60 minutes after the addition of activated carbon,

d) the resulting mixture was filtered, and the resulting filtrate was cooled to 20-25 ℃ at a cooling rate of 1 to 10 ℃ per 10 to 30 minutes to crystallize the tiotropium bromide monohydrate.

18. Use of crystalline tiotropium bromide micropowder according to any one of claims 1 to 7 for the preparation of a pharmaceutical composition for the treatment of asthma or chronic obstructive pulmonary disease.

19. The use according to claim 18, the pharmaceutical composition being an inhalable pharmaceutical composition.

20. Use of crystalline tiotropium bromide micropowder according to any one of claims 1 to 7 for the preparation of a pharmaceutical composition for the treatment of a disease which can be effectively treated by administration of an anticholinergic agent.

21. A pharmaceutical composition characterized by containing a fine crystalline tiotropium bromide powder according to any one of claims 1-7.

22. Pharmaceutical composition according to claim 21, characterized in that the composition is an inhalable powder.

23. Pharmaceutical composition according to claim 22, characterized in that the inhalable powder contains at least 0.03% of fine crystalline tiotropium bromide powder according to any one of claims 1 to 7 mixed with a physiologically acceptable adjuvant, said composition being further characterized in that the adjuvant is constituted by a coarser adjuvant having an average particle size of 15 to 80 μm mixed with a finer adjuvant having an average particle size of 1 to 9 μm, wherein the finer adjuvant is in a proportion of 1 to 20% of the total amount of adjuvant.

24. Pharmaceutical composition according to claim 23, characterized in that the inhalable powder contains 0.05% to 1% of micronized crystalline tiotropium bromide according to any one of claims 1-7.

25. Pharmaceutical composition according to claim 23, characterized in that the inhalable powder contains 0.1% to 0.8% of crystalline tiotropium bromide micropowder according to any one of claims 1-7.

26. Pharmaceutical composition according to any of claims 23-25, characterized in that the auxiliary is constituted by a coarser auxiliary with an average particle size of 17 to 50 μm mixed with a finer auxiliary with an average particle size of 2 to 8 μm.

27. A pharmaceutical composition according to any one of claims 23 to 25, characterised in that the relatively fine auxiliary accounts for a proportion of 3 to 15% of the total amount of auxiliary.

28. Pharmaceutical composition according to one of claims 23 to 25, characterized in that monosaccharides, disaccharides, oligosaccharides and polysaccharides, polyols, salts or mixtures of these auxiliaries with one another are used as auxiliaries.

29. Pharmaceutical composition according to claim 28, characterized in that glucose, arabinose, lactose, sucrose, maltose, trehalose, dextrin, sorbitol, mannitol, xylitol, sodium chloride, calcium carbonate or mixtures of these auxiliaries with one another are used as auxiliaries.

30. Pharmaceutical composition according to claim 29, characterized in that glucose or lactose or a mixture of these auxiliaries with one another is used as an auxiliary.

31. A process for the preparation of a pharmaceutical composition according to one of claims 23 to 30, characterized in that in a first step a coarser auxiliary fraction is mixed with a finer auxiliary fraction and in a subsequent step the obtained auxiliary mixture is mixed with tiotropium bromide micropowder according to any one of claims 1 to 7.

32. A capsule characterized by containing a pharmaceutical composition according to one of claims 22 to 30.