CN101331128A - Novel forms of tiotropium bromide and processes for preparation thereof - Google Patents

Abstract

This invention relates to novel crystalline forms of tiotropium bromide, processes for preparing them, and their use in pharmaceutical formulations.

Description

New form of tiotropium bromide and preparation method thereof

The cross reference of related application

[0001] the application requires the U.S. Provisional Patent Application submitted on December 19th, 2005 number 60/752,672; The U.S. Provisional Patent Application of submitting on December 27th, 2005 number 60/754,530; The U.S. Provisional Patent Application of submitting on January 23rd, 2006 number 60/761,437; The U.S. Provisional Patent Application of submitting on February 15th, 2006 number 60/774,051; The U.S. Provisional Patent Application of submitting on March 7th, 2006 number 60/780,310; The U.S. Provisional Patent Application of submitting on July 20th, 2006 number 60/832,189; The U.S. Provisional Patent Application of submitting on October 12nd, 2006 number 60/851,223; With the right of priority of applying date of the U.S. Provisional Patent Application of submitting on October 18th, 2006 number 60/852,740, disclosing of they is incorporated herein by reference.

Background of invention

[0002] tiotropium bromide is that M-AChR is had specific anti-smooth alkali energy medicine.Therefore, it is providing the treatment benefit aspect treatment asthma or the chronic obstructive disease of lung (" COPD ").

[0003] chemical name of tiotropium bromide is (1 α; 2 β; 4 β; 5 α, 7 β)-7-[(hydroxyl two-2-thienyl ethanoyl) the oxygen base]-9,9-dimethyl-3-oxa--9-nitrogen three ring [3.3.1.0] nonane bromide or 6 β; 7 beta epoxides-3 beta-hydroxies-8-methyl isophthalic acid α H; 5 α H-tropanium bromides, two-2-thienyl oxyacetate, it has following array structure:

Tiotropium bromide

C ₁₉H ₂₂NO ₄S ₂Br

MW：472.4

[0004] tiotropium bromide can be used as and can derive from Boehringer Ingelheim's

Obtain from commercial channels, wherein it exists as the monohydrate form.

[0005] is disclosed in U.S. Patent number 5,610 from preparation of acetone and methyl alcohol and crystallization tiotropium bromide, in 163, provides the product of fusing point with 217-218 ℃.

[0006] crystalline form of tiotropium bromide also has been reported in each application, for example, the U.S. Patent number 6 of crystalline tiotropium bromide monohydrate is described, 777,423, the U.S. Patent number 6 that tiotropium bromide does not have the hydrate crystalline form is described, 608,055, describe anhydrous tiotropium bromide another crystalline form WO2005/042527 and the publication No. IPCOM000143595D of crystalline tiotropium bromide dichloromethane solvent thing is described.

[0007] different crystal forms (polytropism) occurring is the character of some molecule and molecular complex.Single molecule, the tiotropium bromide in the following formula for example can produce and has different physical properties, for example, the various solids of fusing point, x-ray diffraction pattern, infrared ray absorption finger printing and NMR spectrum.The difference of polymorphic form physical properties aspect comes from the orientation and the molecular interaction of the adjacent molecule (complex compound) in the bulk solid.Therefore, polymorphic form is different solids of sharing the same molecular formula, but compares with other form in the polymorphic form family, and polymorphic form has the different advantages and/or the physical properties of shortcoming.One of most important physical properties of medicine polymorphic form is their solvabilities in the aqueous solution.

[0008] discovery of the new crystalline polymorphic form of medicine has enlarged the inventory of raw material, and formulation science man has utilized these raw material designs to have the pharmaceutical dosage form that target discharges the medicine of trend and/or other required character.Therefore, need to find the other crystalline form of tiotropium bromide.

[0009] similar advantage can also can provide the better approach of other form of generation or solvate from producing other polymorphic form, and the new solvate of processing advantage perhaps can be provided.

Brief summary of the invention

[0010] in one embodiment, the invention provides the tiotropium bromide crystalline form that is called form 1, it is characterized in that, x-ray diffractogram of powder has the peak at about 8.7,15.3,15.5 and 25.3 ± 0.2 degree 2-θ places.

[0011] in another embodiment, the invention provides the preparation method of the tiotropium bromide of form 1, it comprises crystallization tiotropium bromide from comprise methyl alcohol with about 1/3 (volume/volume) ratio and acetone mixture.

[0012] in another embodiment, the invention provides the tiotropium bromide crystalline form that is called form 2, it is characterized in that having the x-ray diffractogram of powder at peak at about 23.1,23.6,24.1,30.1 and 30.3 ± 0.2 degree 2-θ places.

[0013] in one embodiment, the invention provides the preparation method of the tiotropium bromide of form 2, it comprise from by ratio be about 1/1 or the methyl alcohol of about 3/1 (volume/volume) and acetone composition mixture the crystallization tiotropium bromide.

[0014] in another embodiment, the invention provides the tiotropium bromide crystalline form, it is characterized in that, x-ray diffractogram of powder has the peak at about 27.7,27.8,30.3 and 30.5 ± 0.2 degree 2-θ places.This form can be called as form X.

[0015] in another embodiment, the present invention provides the method for the tiotropium bromide of preparation form X by comprising the method for crystallization tiotropium bromide from the mixture that comprises acetate, methyl alcohol and heptane.

[0016] in one embodiment, the invention provides the crystalline form tiotropium bromide that is called form 7, it is characterized in that, x-ray diffractogram of powder has the peak at about 8.8,9.0,11.7 and 17.7 ± 0.2 degree 2-θ places.

[0017] in another embodiment, the present invention provides the preparation method of the tiotropium bromide of form 7 by comprising crystallization tiotropium bromide from the mixture of the anti-solvent that comprises the solvent mixture be made up of acetate and acetonitrile and be made up of diisopropyl ether.

[0018] in another embodiment, the invention provides the crystalline form tiotropium bromide that is called form 8, it is characterized in that x-ray diffractogram of powder has the peak at about 16.2,16.5,28.0 and 28.3 ± 0.2 degree 2-θ places.

[0019] in one embodiment, the invention provides the n-propyl alcohol solvate of tiotropium bromide.

[0020] in another embodiment, the invention provides the crystalline half n-propyl alcohol solvate of the tiotropium bromide that is called form 9, it is characterized in that, calculate x-ray diffractogram of powder as shown in Figure 10.

[0021] in another embodiment, the invention provides the half n-propyl alcohol solvate that is called form 9, it is characterized in that having the monocrystalline XRD of following column data: monoclinic crystalline system; Pc, (No.7) spacer; Unit cell parameters: a, b, c: respectively be 13.4245,12.0419,13.6027 And α, β, γ: respectively be 90,103.818,90[deg], and volume: 2135.3 , formula C _20.5H ₂₆BrNO _4.5S ₂Z be 4; With bulk density D be 1.53[g/cm ³].Described half n-propyl alcohol solvate forms is also substantially determined by the figure that spreads out of the powder X-ray ray shown in the Figure 15 that calculates.

[0022] in another embodiment, the invention provides under isothermal condition from n-propyl alcohol the crystallization tiotropium bromide with the method for the tiotropium bromide of preparation form 9.

[0023] in one embodiment, the invention provides the crystalline tiotropium bromide that is called form 11, it is characterized in that, have the x-ray diffractogram of powder at peak at about 20.2,26.5,28.0 and 31.2 ± 0.2 degree 2-θ places.

[0024] in another embodiment, the invention provides the crystalline half n-propyl alcohol solvate of the tiotropium bromide that is called form 12, it is characterized in that, x-ray diffractogram of powder has the peak at about 20.9,21.1,21.4 and 34.4 ± 0.1 degree 2-θ places.

[0025] in another embodiment, the present invention is by providing the n-propyl alcohol solution of tiotropium bromide, and is cooled to about 55 ℃-Yue 25 ℃ temperature and provides the preparation method of the tiotropium bromide of form 12 to obtain suspension.

[0026] in another embodiment, the invention provides the amorphous tiotropium bromide.

[0027] in another embodiment, the present invention provides the preparation method of amorphous tiotropium bromide by comprising the method for the solution of freeze-drying tiotropium bromide in water, the trimethyl carbinol, methyl alcohol or their mixture.

[0028] in another embodiment, the present invention by comprise the method that the mixture of tiotropium bromide in water is provided, provide it is characterized in that the powder X-ray ray spread out figure 8.9,11.9,13.5,14.8,16.7,17.5,20.3,23.6,24.1 and 26.9 ± there is the preparation method of the tiotropium bromide monohydrate form at peak at degree 2-θ place.

[0029] in another embodiment, the invention provides the tiotropium bromide that is called form 1,2,6,7,8,9,11 and amorphous micronization form.

[0030] in one embodiment, the present invention respectively is the method for crystallization tiotropium bromide the mixture of the methyl alcohol of about 3/1 (volume/volume) and acetone by comprising from comprising ratio, provides to it is characterized in that x-ray diffractogram of powder has the preparation method of the tiotropium bromide that is called form 3 crystalline forms at peak at about 9.82,10.91,13.45,15.34,17.93,19.71,20.90 and 21.45 ± 0.2 degree 2-θ places.

[0031] in another embodiment, the present invention is characterized in that by comprising the method for crystallization tiotropium bromide from ethanol, providing x-ray diffractogram of powder has the preparation method of tiotropium bromide of the crystalline form that is called form 4 at peak at about 9.92,11.03,13.41,15.31,18.10,19.91,20.94 and 21.41 ± 0.2 degree 2-θ places.

[0032] in another embodiment, the present invention is characterized in that by comprising the method for crystallization tiotropium bromide from Virahol, providing the powder X-ray ray figure that spreads out has the preparation method of the crystalline form tiotropium bromide at peak at about 9.86,10.97,13.28,15.28,18.04,19.80,20.71,21.26 ± 0.2 degree 2-θ places.

[0033] in another embodiment, the present invention is by comprising from the method for butanol crystal tiotropium bromide, provide and it is characterized in that x-ray diffractogram of powder is about 9.82,10.88,13.28,15.27,16.39,17.96 there is the preparation method of tiotropium bromide of the crystalline form that is called form 10 at peak at 19.67,20.71 and 21.30 ± 0.2 degree 2-θ places.

[0034] in one embodiment, the invention provides and comprise at least a tiotropium bromide of form 1,2,6,7,8,9,11 or amorphous forms and the pharmaceutical preparation of pharmaceutically acceptable vehicle of being called.

[0035] in another embodiment, the invention provides the preparation method of the pharmaceutical preparation that comprises at least a tiotropium bromide that is called form 1,2,6,7,8,9,11 or amorphous forms and pharmaceutically acceptable vehicle.

[0036] in another embodiment, the invention provides and comprise at least a tiotropium bromide that is called form 1,2,3,4,6,7,8,9,10,11 or amorphous forms prepared according to the methods of the invention and the pharmaceutical preparation of pharmaceutically acceptable vehicle.

[0037] in one embodiment, the invention provides the preparation method of the pharmaceutical preparation of the tiotropium bromide that is called form 1,2,3,4,6,7,8,9,10,11 or amorphous forms prepared according to the methods of the invention that comprises at least a form and pharmaceutically acceptable vehicle.

[0038] in another embodiment, the invention provides comprise at least a form be called 1,2,6,7,8,9,11 or the pharmaceutical preparation of amorphous micronization tiotropium bromide and pharmaceutically acceptable vehicle.

[0039] in another embodiment, the invention provides comprise at least a form be called 1,2,6,7,8,9,11 or the preparation method of the pharmaceutical preparation of amorphous micronization tiotropium bromide and pharmaceutically acceptable vehicle.

[0040] in one embodiment, the invention provides the pharmaceutical preparation that is called form 1,2,3,4,6,7,8,9,10,11 or amorphous micronization tiotropium bromide and pharmaceutically acceptable vehicle prepared according to the methods of the invention that comprises at least a form.

[0041] in another embodiment, the invention provides the preparation method of the pharmaceutical preparation that is called form 1,2,3,4,6,7,8,9,10,11 or amorphous micronization tiotropium bromide and pharmaceutically acceptable vehicle prepared according to the methods of the invention that comprises at least a form.

The summary of figure

[0042] Fig. 1 represents the x-ray diffractogram of powder of tiotropium bromide form 1.

[0043] Fig. 2 represents the x-ray diffractogram of powder of tiotropium bromide form 2.

[0044] Fig. 3 represents the TGA curve of tiotropium bromide form 2.

[0045] Fig. 4 represents the x-ray diffractogram of powder of tiotropium bromide form X.

[0046] Fig. 5 represents the TGA curve of tiotropium bromide form X.

[0047] Fig. 6 represents the x-ray diffractogram of powder of tiotropium bromide form 7.

[0048] Fig. 7 represents the TGA curve of tiotropium bromide form 7.

[0049] Fig. 8 represents the x-ray diffractogram of powder of tiotropium bromide form 8.

[0050] Fig. 9 represents the TGA curve of tiotropium bromide form 8.

[0051] Figure 10 represents the x-ray diffractogram of powder of the tiotropium bromide form 9 calculated.

[0052] Figure 11 represents the ORTEP view of tiotropium bromide form 9.

[0053] Figure 12 represents the x-ray diffractogram of powder of tiotropium bromide form 11.

[0054] Figure 13 represents the TGA curve of tiotropium bromide form 11.

[0055] Figure 14 represents the x-ray diffractogram of powder of tiotropium bromide form 12.

[0056] Figure 15 represents the TGA curve of tiotropium bromide form 12.

[0057] Figure 16 represents the x-ray diffractogram of powder of amorphous tiotropium bromide.

Describe in detail

[0058] term " room temperature " for this paper refers between about 18 ℃-Yue 25 ℃, preferably between about 20 ℃-Yue 22 ℃ temperature.

[0059] be disclosed in U.S. Patent number 5,610,163 method for crystallising is not pointed out how crystallization thiophene holder The bromine ammonium is to obtain all the time identical crystalline form. Therefore the present invention not only provide different crystalline and The amorphous Tiotropium Bromide also provides their preparation method.

[0060] term " solvate " that is used for this paper refers to comprise the level that is not water greater than 1% appoint The crystalline material of what solvent.

[0061] the present invention also provides the crystalline Tiotropium Bromide that is called form 1, it is characterized in that powder XRD (" powder x-ray diffraction ") figure is at about 8.7,15.3,15.5 and 25.3 ± 0.2 degree 2-θ There is the peak at the place. The feature of form 1 also is, x-ray diffractogram of powder about 9.9,13.3, 18.0, there is the peak at 20.2 and 24.2 ± 0.2 degree 2-θ places. Form 1 is institute in Fig. 1 basically also The x-ray diffractogram of powder that shows is identified. Those skilled in the art can approve that form 1 can be led to Cross other method, include, but not limited to solid state NMR, FTIR and Raman spectrum and identify.

[0062] form 1 can be the solvation form of Tiotropium Bromide, particular methanol salt (methanolate). As measuring through powder x-ray diffraction, can provide do not occur greater than Any type of Tiotropium Bromide of other of about 10% preferably is not more than other any shape of about 5% The Tiotropium Bromide crystalline form 1 of the relatively pure form of the Tiotropium Bromide of formula. Preferably, penetrate such as powder X-ray It is such that the line diffraction is measured, and Tiotropium Bromide crystalline form 1 can be not more than about 10% thiophene to have Holder bromine ammonium monohydrate preferably is not more than the relatively pure of about 5% tiotropium bromide monohydrate Form provides.

[0063] through comprising that from comprising ratio be the methyl alcohol of about 1/3 (volume/volume) and the mixture of acetone In the method for crystallization Tiotropium Bromide, prepare the Tiotropium Bromide of described form 1.

[0064] is described in the thiophene holder bromine that is used for above crystallization process and following crystallization process of this application Ammonium can obtain through any method known to the skilled. For example, it can pass through U.S. Patent number 5,610, method obtains described in 163.

[0065] provide Tiotropium Bromide containing proportional about 1/3 (volume/volume) methyl alcohol and third that is through comprising Solution in the mixture of ketone also cools off this solution to obtain the method for suspension, carries out crystallization.

[0066] Tiotropium Bromide solution is by merging Tiotropium Bromide and containing proportional about 1/3 (volume/body that is Long-pending) methyl alcohol and mixture and the heating of acetone obtain. Heating is preferably at about 50 ℃-Yue 60 ℃, more preferably to about 57 ℃ temperature, carry out.

[0067] common cooling solution is to bring out the precipitation of crystalline form. Solution preferably is cooled to-6 ℃ approximately To making an appointment with-14 ℃, more preferably to the temperature of making an appointment with-10 ℃. In the most preferred embodiment, cold But carry out gradually so that solution is cooled between about 25 ℃-first Yue 20 ℃ temperature, excellent Select about 21 ℃ temperature, be cooled to subsequently second temperature between about-6 ℃-Yue-14 ℃ Degree. Cooling was preferably finished through about 3 hours gradually. Preferably further be cooled to through about 5 minutes approximately-10 ℃ temperature.

[0068] can keep suspension at least about 3 hours, the yield of the crystalline form that is settled out with increase.

[0069] method for preparing form 1 also can comprise reclaim crystalline form from suspension. Can be through this area Any method of knowing for example, is filtered, and drying under reduced pressure is at least 7 hours subsequently, returns Receive.

[0070] the present invention further provides the crystalline Tiotropium Bromide that is called form 2, it is characterized in that, X-ray diffractogram of powder is at about 23.1,23.6,24.1,30.1 and 30.3 ± 0.2 degree 2-θ places The peak is arranged. The feature of form 2 also be x-ray diffractogram of powder about 9.9,11.0,13.4, 15.3,18.1,19.9,21.4,24.7,25.2,26.0 and 27.2 ± 0.2 degree 2-θ places have The peak. Form 2 also can be identified through the x-ray diffractogram of powder shown in Fig. 2 basically. Form 2 feature also is through thermogravimetry (" TGA ") about 160 ℃ about 0.8%-'s about 2.3% Loss in weight step. Form 2 also can be identified through the TGA curve shown in Fig. 3 basically. The feature of form 2 is that also differential scanning calorimetry (" DSC ") thermal analysis curue has at about 144 ℃ First endothermic peak and in second about 228 ℃ endothermic peak. The spy of Tiotropium Bromide form 2 Levy and also be about 207.6 ℃ fusing point. Those skilled in the art can approve that form 2 can be passed through Other method includes, but not limited to solid state NMR, FTIR and Raman spectrum and identifies.

[0071] form 2 can be the solvate of Tiotropium Bromide, particular methanol salt solvent compound. According to The mensuration of gas chromatography (" GC "), the amount of methyl alcohol is preferably about 4.1%. Can be according to powder X-ray X ray diffraction is measured, is no more than other any type of Tiotropium Bromide of about 10% to contain, Preferably containing the relatively pure form that is no more than other any type of Tiotropium Bromide of about 5% provides The crystalline form 2 of Tiotropium Bromide. Preferably measure according to powder x-ray diffraction, be no more than to contain About 10% tiotropium bromide monohydrate preferably contains and is no more than about 5% Tiotropium Bromide one hydration The relatively pure form of thing provides Tiotropium Bromide crystalline form 2.

[0072] through comprising from comprising about 1/1 or the methyl alcohol of about 3/1 (volume/volume) ratio and acetone The method of crystallization Tiotropium Bromide in the mixture prepares the Tiotropium Bromide of described form 2.

[0073] provides methyl alcohol and the acetone that comprises ratio about 1/1 or about 3/1 (volume/volume) through comprising Tiotropium Bromide solution in the mixture also cools off this solution to obtain the method for suspension, ties Brilliant.

[0074] by merging Tiotropium Bromide and containing the proportional first of about 1/1-about 3/1 (volume/volume) that is The mixture of pure and mild acetone and heating obtain Tiotropium Bromide solution. Heating preferably proceeds to approximately 50 ℃-Yue 70 ℃, more preferably to about 60 ℃ temperature.

[0075] common cooling solution is to bring out crystalline precipitate. Preferably be cooled to about 25 ℃-Yue 20 ℃ Temperature. Preferably reached this temperature range through about 3 hours. It is little at least about 2 to keep suspension The time, the yield of the crystalline form that is settled out with increase.

[0076] method for preparing form 2 also can comprise from suspension and reclaims crystalline form. Can be through known in the art Any method, for example, filter, drying under reduced pressure is at least 7 hours subsequently, returns Receive.

[0077] the present invention further provides crystalline Tiotropium Bromide, it is characterized in that the powder X-ray ray spreads out Penetrate figure and at about 27.7,27.8,30.3 and 30.5 ± 0.2 degree 2-θ places the peak is arranged. This form can be claimed Be form X. The feature of this form can also be x-ray diffractogram of powder about 9.9, 11.0, there is the peak at 13.3,15.3,18.1,19.9 and 21.3 ± 0.2 degree 2-θ places. Form X base Also can identify by the x-ray diffractogram of powder shown in Fig. 4 on the basis. The feature of form X also Be the loss in weight step at about 160 ℃ about 5.3%-about 5.7% through TGA, wherein This level corresponding to the theoretical value of Tiotropium Bromide half acetic acid solvent compound. Form X basically Also can identify through the TGA curve shown in Fig. 5. The feature of form X is that also DSC is poor Show that thermal analysis curue has between about 146 ℃-Yue 150 ℃ first endothermic peak with between approximately 227 ℃-second Yue 228 ℃ endothermic peak. Those skilled in the art can approve, form X Other method be can pass through, solid state NMR, FTIR and Raman spectrum evaluation included but not limited to.

[0078] form X can be the solvation form of Tiotropium Bromide, preferred acetic acid solvent compound, more Preferred half acetic acid solvent compound. The amount of the acetic acid of measuring according to GC is preferably about 5.4%. According to Powder x-ray diffraction is measured, and can contain to be no more than other any type of thiophene of about 10% Holder bromine ammonium preferably contains and is no more than the relatively pure of other any type of Tiotropium Bromide of about 5% Form provides the crystalline form X of Tiotropium Bromide. Measure according to powder x-ray diffraction, preferably with Contain and be no more than about 10% tiotropium bromide monohydrate, preferably contain and be no more than about 5% thiophene holder bromine The relatively pure form of ammonium monohydrate provides the crystalline form X of Tiotropium Bromide.

[0079] through comprising from the mixture that comprises acetic acid, methyl alcohol and heptane crystallization Tiotropium Bromide Method, the form X of preparation Tiotropium Bromide.

[0080] method for crystallising comprises provides the first kind of thiophene holder that is included in acetic acid and the carbinol mixture The bromine ammonium salt solution; Add normal heptane to first kind of solution, obtain second solution, and cool off the Two kinds of solution are to obtain suspension.

[0081] by merging Tiotropium Bromide and comprising the mixture of acetic acid and methyl alcohol and heating obtains the A kind of Tiotropium Bromide solution.

[0082] acetic acid in comprising first kind of solution of acetic acid and methyl alcohol and methyl alcohol is more preferred than each About 7/2 (volume/volume) of about 7/1-.

[0083] first kind of mixture preferably is heated between about 40 ℃-Yue 50 ℃ temperature, and is more excellent Choosing is to about 45 ℃ temperature. Preferably finished heating through about 1.5 hours.

[0084] preferably dropwise adds normal heptane to first kind of solution. Preferably through at least about about 40 minutes of 20-Clock is finished dropwise and is added. Preferably between about 40 ℃-Yue 50 ℃ temperature, more preferably making an appointment with Add under 45 ℃ the temperature. After adding normal heptane, resultant second solution is maintained About-Yue one hour half an hour under the said temperature.

[0085] usually cools off second solution to bring out crystalline precipitate. Cooling second solution is preferred Extremely between about 30 ℃-Yue 20 ℃ temperature, more preferably extremely between about 30 ℃-Yue 23 ℃ temperature Degree is to obtain suspension. Can keep suspension at least about 3 hours, the crystalline form that is settled out with raising Yield.

[0086] preparation method of form X also can comprise reclaim crystalline form from suspension. Can be through this area Known any method for example, is filtered, and washs filtered form and dry with normal heptane Reclaim.

[0087] the present invention further provides the crystalline Tiotropium Bromide that is called form 7, it is characterized in that, X-ray diffractogram of powder has the peak at about 8.8,9.0,11.7 and 17.7 ± 0.2 degree 2-θ places. Shape The feature of formula 7 also is, x-ray diffractogram of powder about 13.4,15.1,15.3,15.6, 18.1 and there is the peak at 20.2 ± 0.2 degree 2-θ places. Also can spread out through the powder X-ray ray shown in Fig. 6 Penetrate figure and basically determine form 7. The feature of form 7 also is, through about 5.2% of TGA The loss in weight. Also can basically determine form 7 through the TGA curve shown in Fig. 7. Form 7 Feature can be that also the DSC differential thermogram has in first about 136 ℃ endothermic peak With in second about 228.0 ℃ endothermic peak. Those skilled in the art can approve that form 7 can By other method, include, but are not limited to solid state NMR, FTIR and Raman spectrum and identify.

[0088] form 7 can be the solvation form of Tiotropium Bromide, preferred acetic acid solvent compound. According to The amount of the acetic acid that GC measures is preferably about 1.7%. Measure according to powder x-ray diffraction, can Be no more than other any type of Tiotropium Bromide of about 10% to contain, preferably contain and be no more than about 5% The relatively pure form of other any type of Tiotropium Bromide the crystalline form 7 of Tiotropium Bromide is provided. Measure according to powder x-ray diffraction, preferably be no more than about 10% Tiotropium Bromide one water to contain Compound, preferably containing the relatively pure form that is no more than about 5% tiotropium bromide monohydrate provides The crystalline form 7 of Tiotropium Bromide.

[0089] through comprising from comprising the solvent mixture that formed by acetic acid and acetonitrile and by diisopropyl ether The method of crystallization Tiotropium Bromide in the mixture of the anti-solvent that forms prepares the thiophene of described form 7 Holder bromine ammonium.

[0090] crystallization method the tiotropium bromide solution that provides in the described solvent is provided and adds diisopropyl ether to obtain suspension to this solution.

[0091] preferably obtains tiotropium bromide solution by merging tiotropium bromide and described solvent and heating.

[0092] ratio of acetate and acetonitrile preferably respectively is about 1/5 (volume/volume) of about 1/4-in described solvent.

[0093] heating preferably proceeds between about 40 ℃-Yue 50 ℃ temperature.More preferably under about 45 ℃ temperature, heat.Heating was preferably carried out about 1.5 hours.

[0094] preferably dropwise add diisopropyl ether to solution, more preferably warp was at least about 15 minutes.Preferably, more preferably to about 45 ℃ temperature, add between about 40 ℃-Yue 50 ℃ temperature.After adding diisopropyl ether, under said temperature, kept resultant suspension about one hour.

[0095] cools off suspension usually, be settled out the yield of product with raising.Cooling preferably proceeds to about 30 ℃-Yue 20 ℃ temperature, and more preferably cooling solution is to about 30 ℃-Yue 21 ℃ temperature.Cooling was carried out 3 hours at least.

[0096] preparation method of form 7 also can comprise reclaim crystalline form from suspension.Can for example, filter through any method known in the art, wash filtered form with diisopropyl ether subsequently, and drying reclaims.

[0097] the invention provides the crystalline tiotropium bromide that is called form 8, it is characterized in that, x-ray diffractogram of powder has the peak at about 16.2,16.5,28.0 and 28.3 ± 0.2 degree 2-θ places.The feature of form 8 is that also x-ray diffractogram of powder has the peak at about 9.9,11.0,13.4,15.3,17.9,19.7,20.9 and 21.4 ± 0.2 degree 2-θ places.Also can be through the basic form identification 8 of the x-ray diffractogram of powder shown in Fig. 8.The feature of form 8 also is about 5.1% weight loss through TGA.Also can scheme form identification 8 basically through the TGA shown in Fig. 9.The feature of form 8 is that also the DSC differential thermogram has in first about 149 ℃ endotherm(ic)peak with in second about 226 ℃ endotherm(ic)peak.Those skilled in the art can approve that form 8 can be passed through other method, include but not limited to solid state NMR, FTIR and Raman spectrum evaluation.

[0098] form 8 can be the solvation form of tiotropium bromide, preferably alcoholate (alcoholate) and more preferably methylate.Can measure according to powder x-ray diffraction, be no more than other any type of tiotropium bromide of about 10%, preferably contain the crystalline form 8 that the pure relatively form that is no more than other any type of tiotropium bromide of about 5% provides tiotropium bromide to contain.Preferably measure, be no more than about 10% tiotropium bromide monohydrate, preferably contain the crystalline form 8 that the pure relatively form that is no more than about 5% tiotropium bromide monohydrate provides tiotropium bromide to contain by powder x-ray diffraction.

[0099] by comprising the crystalline form 8 for preparing tiotropium bromide from the method for methanol crystallization tiotropium bromide.

[0100] this method comprises the methanol solution that tiotropium bromide is provided and cools off this solution to obtain suspension.

[0101] preferably obtains solution, the methanol solution of tiotropium bromide is provided by merging tiotropium bromide and methyl alcohol and heating.Heating preferably proceeds between about 61 ℃-Yue 65 ℃ temperature.More preferably, under about 63 ℃ temperature, heat.Heating was preferably carried out about 1 hour.

[0102] common cooling solution is to bring out crystalline precipitate.Preferred cooling solution is extremely between about 27 ℃-Yue 22 ℃ temperature.More preferably, cooling solution is to about 22 ℃ temperature.Through at least about reaching above temperature in 2 hours.

[0103] can keep the gained suspension at least about 3.5 hours, the yield of the product that is settled out with raising.

[0104] preparation method of crystalline form 8 also can comprise reclaim crystalline form from suspension.Can for example, filter through any method known in the art, use the filtered form of methanol wash subsequently, and dry, from suspension, reclaim resultant precipitation.

[0105] the present invention also provides the n-propyl alcohol solvate of tiotropium bromide.

[0106] the present invention also provides half n-propyl alcohol solvate of the crystalline tiotropium bromide that is called form 9, it is characterized in that the x-ray diffractogram of powder as calculated shown in Figure 10.Also can identify described half n-propyl alcohol solvate substantially by the x-ray diffractogram of powder of the calculating shown in Figure 10.The feature of crystalline n-propyl alcohol salt (n-propanolate) solvate also is about 5.9% weight loss through TGA, and wherein this level is corresponding to the theoretical value of half n-propyl alcohol solvate of tiotropium bromide.The stoichiometric calculation value of half n-propyl alcohol salt is 5.9%.Measured according to powder x-ray diffraction, can contain and be no more than other any type of tiotropium bromide of about 10%, preferably contain the pure relatively form that is no more than other any type of tiotropium bromide of about 5%, the crystalline half n-propyl alcohol solvate of tiotropium bromide is provided.Preferably measure, can be no more than about 10% tiotropium bromide monohydrate, preferably contain the pure relatively form that is no more than about 5% tiotropium bromide monohydrate, half n-propyl alcohol solvate of tiotropium bromide is provided to contain according to powder x-ray diffraction.Those of skill in the art will recognize that form 9 can pass through other method, include, but not limited to solid state NMR, FTIR and Raman spectrum and identify.

[0107] the invention provides the half n-propyl alcohol solvate that is called form 9, it is characterized in that monocrystalline XRD has following column data: monoclinic crystalline system; Pc, (No.7) spacer; Unit cell parameters: a, b, c: respectively be 13.42,12.04,13.60

With α, β, γ: respectively be 90,103.8,90[deg], and volume: 2135

, formula C _20.5H ₂₆BrNO _4.5S ₂Z be 4; With bulk density D be 1.53[g/cm ³].Also can differentiate described half n-propyl alcohol form basically by the ORTEP view shown in Figure 11.

[0108] by under the isothermal condition from n-propyl alcohol the crystallization tiotropium bromide, the invention provides and it is characterized in that monocrystalline XRD has the preparation method of the tiotropium bromide form 9 of following column data: monoclinic crystalline system; Pc, spacer (No.7); Unit cell parameters: a, b, c: respectively be 13.4245,12.0419,13.6027

And α, β, γ: respectively be 90,103.818,90[deg], and volume: 2135.3

, formula C _20.5H ₂₆BrNO _4.5S ₂Z be 4; With bulk density D be 1.53[g/cm ³].

[0109] general, term " isothermal condition " refers to constant temperature.The isothermal condition of preparation form 9 is temperature of 25 ℃.

[0110] this method comprises provides the n-propyl alcohol of tiotropium bromide solution, cools off the temperature of this solution to 25 ℃, obtaining mixture, keeps mixture about 5 days under 25 ℃.

[0111] preferably provides the n-propyl alcohol solution of tiotropium bromide by merging tiotropium bromide and n-propyl alcohol and heating.Preferably be heated to about 80 ℃-Yue 100 ℃, more preferably to 97 ℃ temperature.

[0112] preferred cooling solution is to bring out single crystal settling.

[0113] preparation method of form 9 also can comprise the recovery crystalline form.Can for example, filter, wash filtered form and dry through any method known in the art, reclaim.

[0114] the invention provides the tiotropium bromide crystalline form that is called form 11, it is characterized in that, x-ray diffractogram of powder has the peak at about 20.2,26.5,28.0 and 31.2 ± 0.2 degree 2-θ places.The feature of form 11 is that also x-ray diffractogram of powder has the peak at about 8.9,15.6,17.7,21.7,23.4 and 24.3 ± 0.2 degree 2-θ places.Form 11 also can be identified through the x-ray diffractogram of powder shown in Figure 12 basically.The feature of form 11 also is the weight loss of pact＜0.1% through TGA.Form 11 also can be identified through the TGA curve shown in Figure 13 basically.The feature of form 11 is that also the DSC differential thermogram has endotherm(ic)peak at about 227 ℃.Those skilled in the art can approve that form 11 can be passed through other method, include, but not limited to solid state NMR, FTIR and Raman spectrum and identify.

[0115] form 11 can be the anhydrous form of tiotropium bromide.Measure as powder x-ray diffraction, can contain and be no more than other any type of tiotropium bromide of about 10%, preferably containing the pure relatively form that is no more than other any type of tiotropium bromide of about 5% provides tiotropium bromide crystalline form 11.Can measure as powder x-ray diffraction, preferably be no more than about 10% tiotropium bromide monohydrate to contain, preferably containing the pure relatively form that is no more than about 5% tiotropium bromide monohydrate provides tiotropium bromide crystalline form 11.

[0116] through comprising that any tiotropium bromide solvate of heating between about 160 ℃-Yue 170 ℃ method of temperature, prepares tiotropium bromide crystalline form 11.

[0117] preferably heats the tiotropium bromide solvate to about 160 ℃ temperature.Preferred heating about 1 hour-Yue 2 hours, more preferably from about 1 hour.

[0118] the invention provides the crystalline half n-propyl alcohol solvate of the tiotropium bromide that is called form 12, it is characterized in that, x-ray diffractogram of powder has the peak at about 20.9,21.1,21.4 and 34.4 ± 0.1 degree 2-θ places.

[0119] feature of form 12 also is, x-ray diffractogram of powder has the peak at about 9.9,11.0,13.5,15.3,18.1,19.9,20.9,21.1,21.4,23.9,25.1,27.1 and 34.4 ± 0.2 degree 2-θ places.Form 12 also can be identified through x-ray diffractogram of powder shown in Figure 14 basically.The feature of form 12 also is about 5.9% the weight loss about 125 ℃-Yue 184 ℃ temperature through TGA, and wherein this level is corresponding to the theoretical value of half n-propyl alcohol solvate of tiotropium bromide.Form 12 also can be identified by the TGA curve shown in Figure 15 basically.The feature of form 12 is that also the DSC differential thermogram has first endotherm(ic)peak of 158 ℃ with in second about 229 ℃ endotherm(ic)peak.Those skilled in the art can approve that form 12 can be passed through other method, include but not limited to solid state NMR, FTIR and Raman spectrum evaluation.

[0120] prepares tiotropium bromide form 12 through comprising the n-propyl alcohol of tiotropium bromide solution being provided and being cooled to about 55 ℃-Yue 25 ℃ temperature to obtain the method for suspension.

[0121] preferably by merging tiotropium bromide and n-propyl alcohol and heating, provides the n-propyl alcohol solution of tiotropium bromide.Preferably be heated to about 80 ℃-Yue 100 ℃, more preferably to 97 ℃ temperature.

[0122] general cooling solution is to bring out the precipitation of described crystalline form.Preferred cooling solution is to about 55 ℃-Yue 25 ℃ temperature.Preferably cooling gradually.Further be cooled to about 25 ℃-Yue 21 ℃ temperature realization cooling gradually again through reaching about 55 ℃ temperature.Preferably reached 55 ℃ through about 4 hours.Preferably reached about 25 ℃-Yue 21 ℃ temperature through about 3 hours.

[0123] preferably further keeps through the about 5-of refrigerative suspension about 18 hours.

[0124] preparation method of form 9 also can comprise reclaim crystalline form from suspension.Can for example filter, wash filtered form and dry through any method known in the art, realize reclaiming.

[0125] the invention provides the tiotropium bromide of amorphous forms.Can identify the amorphous tiotropium bromide through the powder x-ray diffraction shown in Figure 16.Measure as powder x-ray diffraction, the tiotropium bromide of amorphous forms can contain and is no more than other any type of tiotropium bromide of about 10%, preferably contains to be no more than other any type of tiotropium bromide of about 5%.Measure as powder x-ray diffraction, preferably can contain and be no more than about 10% tiotropium bromide monohydrate, preferably contain the pure relatively form that is no more than about 5% tiotropium bromide monohydrate, the tiotropium bromide of amorphous forms is provided.

[0126] by comprising the method for the solution of freeze-drying tiotropium bromide in water, the trimethyl carbinol, methyl alcohol or their mixture, the tiotropium bromide of preparation amorphous forms.

[0127] any type of tiotropium bromide generally can be used as the raw material of freeze-drying process.The tiotropium bromide n-propyl alcohol solvate that is called the tiotropium bromide methyl alcohol form of form 1,2 and 8 and is called form 9 is the preferred feedstock of above method.Preferably, prepare solution by tiotropium bromide is dissolved in water, the trimethyl carbinol, methyl alcohol or their mixture.Preferably under about 20 ℃-Yue 40 ℃ temperature, dissolve.Can before it, filter resulting solution in freeze-drying.Can the about 48 hours freeze-drying of about 24-.

[0128] respectively is the method for crystallization tiotropium bromide the mixture of the methyl alcohol of about 3/1 (volume/volume) and acetone by comprising, the invention provides and be characterised in that x-ray diffractogram of powder has the preparation method of the tiotropium bromide crystalline form that is called form 3 at peak at about 9.82,10.91,13.45,15.34,17.93,19.71,20.90 and 21.45 ± 0.2 degree 2-θ places from comprising ratio.

[0129] crystallisation process comprises, provides tiotropium bromide respectively to be the solution in the mixture of the methyl alcohol of about 3/1 (volume/volume) and acetone comprising ratio, and cools off this solution to obtain suspension.

[0130] respectively be the methyl alcohol of about 3/1 (volume/volume) and the mixture of acetone by merging tiotropium bromide with comprising ratio, and heating, solution is provided.

[0131] preferably is heated to about 50 ℃-Yue 70 ℃ temperature, more preferably to about 60 ℃ temperature.

[0132] common cooling solution is to bring out crystalline precipitate.Preferably be cooled to about room temperature-Yue-5 ℃ temperature.When cooling proceeds to subambient temperature, preferably reached this temperature through about 5 minutes.

[0133] can preferably keep suspension at least about 3 hours, to improve the crystalline form yield.The method for preparing form 3 also can comprise reclaim crystalline form from suspension.

[0134] preparation method of form 3 also can comprise from suspension recovery form 3.Can be through any method known in the art, for example, drying is about 30 minutes under filtration and the nitrogen, and further drying under reduced pressure reclaimed at least about 15 hours subsequently.

[0135] it is characterized in that by comprising from the method for butanol crystal tiotropium bromide, the invention provides x-ray diffractogram of powder has the preparation method of the tiotropium bromide crystalline form that is called form 10 at peak at about 9.82,10.88,13.28,15.27,16.39,17.96,19.67,20.71 and 21.30 ± 0.2 degree 2-θ places.

[0136] this method comprises the butanol solution that tiotropium bromide is provided and cools off this solution to obtain suspension.

[0137] obtains solution by merging tiotropium bromide and propyl carbinol and heating.Heating preferably proceeds between about 90 ℃-Yue 96 ℃ temperature, and heating more preferably proceeds to about 94 ℃ temperature.Preferably, be heated between about 90 ℃-Yue 96 ℃ the about 2.5-3 of temperature hour.Chose wantonly before cooling off it, but filtering heat solution.

[0138] common cooling solution is to bring out the precipitation of crystalline product.Preferred cooling solution is extremely between about 25 ℃-Yue 20 ℃ temperature, and more preferably cooling solution is to about 22 ℃ temperature.Process reaches above temperature at least about 6 hours time.

[0139] keeps the gained suspension to improve the yield of crystalline product.Preferably keep suspension at least about 5 hours.

[0140] preparation method of crystalline form 10 also can comprise from suspension and reclaims it.Can for example, filter, wash filtered form and dry through any method known in the art, reclaim with propyl carbinol.

[0141] it is characterized in that by comprising the method for crystallization tiotropium bromide from ethanol, the invention provides x-ray diffractogram of powder has the preparation method of the tiotropium bromide crystalline form that is called form 4 at peak at about 9.92,11.03,13.41,15.31,18.10,19.91,20.94 and 21.41 ± 0.2 degree 2-θ places.

[0142] this method preferably includes the ethanolic soln that tiotropium bromide is provided and cools off this solution to obtain suspension.

[0143] provides solution by merging tiotropium bromide and ethanol and heating.

[0144] preferred heated solution is extremely between about 70 ℃-Yue 80 ℃ temperature.More preferably, under about 73 ℃-Yue 78 ℃ temperature, heating.

[0145] common cooling solution is to bring out crystalline precipitate.Preferred cooling solution is to room temperature.Preferably be cooled to room temperature through about 5 hours.Keep resulting suspension at least about 3 hours, to increase the yield of the product that crystallization goes out.

[0146] preparation method of above crystalline form also can comprise the method that reclaims described crystalline form from suspension.Can be through any method known in the art, for example, drying is about 30 minutes under filtration and the nitrogen, and further drying under reduced pressure reclaimed at least about 9 hours subsequently.

[0147] is characterised in that by comprising the method for crystallization tiotropium bromide from Virahol, the invention provides x-ray diffractogram of powder has the preparation method of the tiotropium bromide crystalline form at peak at about 9.86,10.97,13.28,15.28,18.04,19.80,20.71,21.26 ± 0.2 degree 2-θ places.

[0148] this method comprises that merging obtains the aqueous isopropanol of tiotropium bromide, and cools off this solution, to obtain suspension.

[0149] through merging tiotropium bromide and Virahol, and heating, this solution is provided.Heating preferably proceeds to about 80 ℃-Yue 100 ℃, more preferably to about 81 ℃ temperature.Preferably heated isopropanol mixture to about 80 ℃-Yue 100 ℃ temperature through about 5 hours.Choosing wantonly can be before cooling off it, filtering heat solution.

[0150] general cooling solution is to bring out crystal settling.Cooling solution, preferably to about 25 ℃-Yue 21 ℃ temperature, more preferably cooling solution is extremely between about 23 ℃-Yue 25 ℃ temperature.Through at least about 4 hours, preferred about 4 hours-Yue 5 hours, reach above temperature.

[0151] keeps the yield of gained suspension with the product that improves crystallization and go out.Preferably keep suspension at least about 5 hours.

[0152] preparation method of described crystalline form also can comprise from suspension and reclaims it.Can for example, filter, wash filtered form and drying through any method known in the art, reclaim.

[0153] it is characterized in that by comprising the method that the mixture of tiotropium bromide in water is provided, the invention provides the powder X-ray ray figure that spreads out has the preparation method of the tiotropium bromide monohydrate form at peak at about 8.9,11.9,13.5,14.8,16.7,17.5,20.3,23.6,24.1 and 26.9 ± 0.2 degree 2-θ places.

[0154] initial tiotropium bromide can be any type of tiotropium bromide.Any type of tiotropium bromide refers to anhydrous and amorphous tiotropium bromide solvate.General tiotropium bromide solvate refers to any solvation form of tiotropium bromide.The solvate forms of tiotropium bromide is preferably from alcoholate and acetic acid solvent thing.Any alcoholate solvate of the preferred tiotropium bromide of alcoholate, more preferably methylate (methanolate), ethylate, n-propyl alcohol solvate, isopropoxide and propyl carbinol salt, most preferably n-propyl alcohol solvate and methylate.

[0155] is preferable under the room temperature mixture is provided.This method can comprise keeps the about 4-8 of mixture hour step under the room temperature.

[0156] preparation method of monohydrate also can comprise reclaim monohydrate from mixture.Can through comprise the filtered precipitation of filtering suspension, washing tiotropium bromide monohydrate form and under nitrogen gas stream the exsiccant method, reclaim.

[0157] being called the tiotropium bromide of form 1,2,6,7,8,9,11 and amorphous new form can be by micronization, the raw material that is suitable for preparing with preparation.The term " be suitable for preparation " that relates to the micronization tiotropium bromide refer generally to tiotropium bromide have at least 90% less than 20 microns particle.[0158] in one embodiment, the invention provides and be called 1,2,6,7,8,9,11 and amorphous micronization form tiotropium bromide.Usually, term " micronization " refers to that at least 90% particle wherein has the material less than 20 microns particle diameter.

[0159] micronization process can be chosen follow-up one wantonly and comprises and expose the micronization form in the method for appropriate solvent with the initial amount of recovering the solvent in the solvate.Term " appropriate solvent " is often referred to the solvent types in initial solvation form.

[0160] the invention provides comprise be called 1,2,6,7,8,9,11 or amorphous forms in the tiotropium bromide of at least a form and the pharmaceutical preparation of pharmaceutically acceptable vehicle.

[0161] the invention provides comprise be called 1,2,6,7,8,9,11 or amorphous forms in the preparation method of pharmaceutical preparation of the tiotropium bromide of at least a form and pharmaceutically acceptable vehicle.

[0162] the invention provides comprise prepared according to the methods of the invention be called 1,2,3,4,6,7,8,9,10,11 or amorphous forms in the tiotropium bromide of at least a form and the pharmaceutical preparation of pharmaceutically acceptable vehicle.

[0163] the invention provides comprise prepared according to the methods of the invention be called 1,2,3,4,6,7,8,9,10,11 or amorphous forms in the preparation method of pharmaceutical preparation of the tiotropium bromide of at least a form and pharmaceutically acceptable vehicle.

[0164] the invention provides comprise be called 1,2,6,7,8,9,11 or amorphous in the micronization tiotropium bromide of at least a form and the pharmaceutical preparation of pharmaceutically acceptable vehicle.

[0165] the invention provides comprise be called 1,2,6,7,8,9,11 or amorphous in the preparation method of pharmaceutical preparation of the micronization tiotropium bromide of at least a form and pharmaceutically acceptable vehicle.

[0166] the invention provides comprise prepared according to the methods of the invention be called 1,2,3,4,6,7,8,9,10,11 or amorphous in the micronization tiotropium bromide of at least a form and the pharmaceutical preparation of pharmaceutically acceptable vehicle.

[0167] the invention provides comprise prepared according to the methods of the invention be called 1,2,3,4,6,7,8,9,10,11 or amorphous in the preparation method of pharmaceutical preparation of the micronization tiotropium bromide of at least a form and pharmaceutically acceptable vehicle.

[0168] present composition comprises and comprises any powder, particle, aggregation and other solids composition that is called the tiotropium bromide of form.

[0169] in addition, the solid preparation that comprises the tiotropium bromide of the present invention of above form also can comprise thinner, for example, the raw material of cellulose-derived is as Solka-floc, Microcrystalline Cellulose, microfine cellulose, methylcellulose gum, ethyl cellulose, Natvosol, hydroxypropylcellulose, Vltra tears, carboxymethyl cellulose salt and other replacement and substituted cellulose not; Starch; Pregelatinized Starch; Known other thinner of inorganic diluents such as lime carbonate and monocalcium phosphate and pharmaceutical industry.Other thinner that is suitable for also comprises paraffin, sugar and sugar alcohol such as N.F,USP MANNITOL and sorbyl alcohol, acrylic ester polymer and multipolymer, and pectin, dextrin and gel.

[0170] be suitable for other vehicle of the present invention and comprise tackiness agent, for example, gum arabic, pregelatinized Starch, sodiun alginate, glucose and be used for wet and dried granulating and direct other tackiness agent of the method for compressed tablets.Also can be present in vehicle in the solid preparation of tiotropium bromide of above form and also comprise the hydroxypropylcellulose of disintegrating agent such as primojel, cross-linked polyvinylpyrrolidone, rudimentary replacement and other.In addition, vehicle can comprise tabletting lubricants such as Magnesium Stearate and calcium stearate and sodium stearyl fumarate; Correctives; Sweetener and sanitas.

[0171] but per os, parenteral (comprising subcutaneous, intramuscular and intravenously), suck and eye gives preparation.Although under any given situation, optimal approach will depend on the character and the seriousness of the disease that will treat, and most preferred approach of the present invention is still oral.Dosage can occur with unit dosage and prepare through any method that pharmaceutical field is known expediently.

[0172] formulation comprises solid dosage, as tablet, powder, capsule, suppository, sachets, tablet and lozenge and liquid suspension and elixir.When not planning to limit this specification sheets, the present invention does not plan to relate to the true solution of tiotropium bromide yet, because its character that is different from the tiotropium bromide solid form can lose.Yet, adopt new form to prepare this class solution (for example,, also giving described solution) and be considered within the scope of the invention according to transmitting solvate with certain ratio of solvate so that except that tiotropium bromide.

[0173] certain, capsule can contain solids composition at the capsule by gelatin or other conventional encapsulated feedstock production.Tablet and powder can be by dressings.And, available casing coated tablet and powder.Enteric coating powder form can have and comprises, but be not limited to, the dressing of the raw materials such as multipolymer of the multipolymer of Cellulose Acetate Phthalate, phthalic acid HYDROXY PROPYL METHYLCELLULOSE, polyvinyl alcohol phthalic acid ester, carboxymethylethylcellulose, vinylbenzene and toxilic acid, methacrylic acid and methyl acrylate, as needs, can adopt suitable softening agent and/or weighting agent to them.Coating tablet can have the dressing on the surface of tablet, or can be and comprise the powder that has casing or the tablet of granule.

[0174] it will be understood by those skilled in the art that existence typically relates to the little analytical error that powder x-ray diffraction is measured, generally have an appointment ± the 0.2 degree 2-θ or the littler order of magnitude in each peak.Therefore, the powder x-ray diffraction peak data of this paper presents with the form of " x-ray diffractogram of powder at peak being arranged at A, B, C etc. ± 0.2 degree 2-θ place ".This shows, for the crystalline form of discussing, in given operating instrument, the summit at A place comes across the somewhere between A ± 0.2 degree 2-θ, and the meeting at the peak at B place appears at B ± 0.2 and spends 2-θ etc.In the discriminating of characteristic peak, this class little, inevitably the property identified can not be converted into the not property identified at the diagnostic characteristics crystalline form, since the particular combinations at these peaks in specified range is not any one specific peak, generally be used for differentiating clearly crystalline form.As selection, the invention provides total figure that also can be used for reporting peak position or peak heights separately.

[0175] describe the present invention with regard to some preferred embodiment, those skilled in the art is from the consideration of this specification sheets, and other embodiment can become apparent.By with reference to the preparation of describing the present composition in detail and the following example of using method, further define the present invention.Many modifications to raw material and method that obviously can not break away from for a person skilled in the art, the scope of the invention.

[0176] used instrument and reagent comprise:

Embodiment

Instrument: Agilent Technologies Mod.6850 gas-chromatography

Post: DB-WAX, 30m, 0.32mm ID, 0.5 μ m df

Detector: FID

300 ℃ of temperature

Hydrogen stream 30.0mL/min

Airflow 300.0mL/min

Replenish helium: 30.0mL/min (total air flow)

Inlet:

Mode indiscrete (Splitless)

140 ℃ of temperature

Pressure 9.00psi

Gas type helium

Gaseous purge stream 60.0mL/min

Purge time 0.10 minute

Total air flow 64.6mL/min

Inject volume 1.0 μ L

Baking box:

40 ℃ of initial temperatures

The initial 5.00 minutes time

Ramp

The numbering ratio (℃/min) outlet temperature (℃) the final time

1 10.00 230 7.00

2 0.0

31.00 minutes working times

Cleaning solvent: methyl-sulphoxide

Veritify:

[0177] diisopropyl ether, normal heptane, acetone, methyl alcohol, methylene dichloride, ethanol, acetonitrile, acetate.

Internal standard solution:

[0178] 250 μ L dioxane → 250mL methyl-sulphoxide.

Raw material standard solution:

[0179] the 1mL all kinds of SOLVENTS adds to 100.0mL internal standard solution.

Working standard solution:

[0180] 1mL raw material standard solution adds to 100.0mL internal standard solution (0.1 μ L/mL all kinds of SOLVENTS).

Sample solution:

[0181] in the 100mg sample, adds 1mL internal standard solution.

Powder x-ray diffraction:

[0182] powder x-ray diffraction (" PXRD ") analysis is adopted the ARLX-ray powder diffraction meter XTRA-030 type that the Peltier detector is housed, Cu K alpha-ray X-ray source, wavelength: 1.54178

Adopt the circular standard aluminum sample holder of the circular zero background quartz disk of band to introduce sample.Sweep parameter: scope: 2-40deg.2 θ, continuous sweep, speed: 3deg./min.Because experimental differences, as instrument, specimen preparation etc., the accuracy of peak position is defined+/-0.2 degree.

Analyze the monocrystalline XRD method of tiotropium bromide n-propyl alcohol solvate:

[0183] employing merges

With ω scanning, through Xcalibur PX, Cu K α collects data.Anisotropically selected all non-hydrogen atoms, the selected hydrogen atom of laying by the geometric position of hope, location OH hydrogen atom from Fourier figure.Data gathering: CrysAlis RED (Oxford diffraction, 2002); Structure cell is purified (cell refinement): CrysAlis RED; Reduction of data (data reduction): CrysAlis RED; Be used for dissolving the program of structure: SIR92 (Altomare etc., 1994); Be used for the program of refining structure: crystallization (Betteridge etc., 2003) Thermogravimetric analysis (" TGA ")

[0184] TGA/SDTA 851, Mettler Toledo, example weight 7-15mg.

Rate of heating: at flow velocity is the N of 50ml/min ₂In the air-flow 10 ℃/minute.

Sweep limit: 30-250 ℃.

Dsc (" DSC ")

[0185] DSC 822 ^e/ 700, Mettler Toledo, example weight: 3-5mg.

Rate of heating: 10 ℃/min., the hole count of crucible: 3

At N ₂In the air-flow: flow velocity=40ml/min, sweep limit: 30-250 ℃, 10 ℃ of/minute rate of heating.

Embodiment 1: the preparation of tiotropium bromide form 1

Under [0186] 57 ℃, with mixture (55ml) the dissolving tiotropium bromide (2.50g) of the methanol/acetone of 1/3 (volume/volume).Through about 30 minutes heated solutions to 57 ℃.Then, at least 3 hours internal cooling to 21 ℃ (not observing solid forms), in about 5 minutes, be quickly cooled to-10 ℃.Kept the gained suspension under-10 ℃ at least 3 hours, and filtered, with 1.0mL mixture washing solid through sintered glass funnel.21 ℃, at N ₂Air-flow dry 30 minutes down then in 111 ℃, decompression (40mbar) dry 7 hours down, generates 0.01g tiotropium bromide form 1.

Embodiment 2: the preparation of tiotropium bromide form 2

Under [0187] 60 ℃, with methanol/acetone mixture (13ml) the dissolving tiotropium bromide (2.50g) of 3/1 (volume/volume).Through about 30 minutes heated solutions to 60 ℃, then at least 3 hours internal cooling to 22 ℃.Kept the gained suspension under 22 ℃ at least 2 hours, and filtered, wash solid twice with the 1.5mL mixture through sintered glass funnel.22 ℃, N ₂Under the air-flow, dry 30 minutes, again in 111 ℃, decompression (40mbar) dry 7 hours down generated 1.19g tiotropium bromide form 2.TGA weight loss: 2.3%.

Embodiment 3: the preparation of tiotropium bromide form 2

Under [0188] 60 ℃, with 1/1 (volume/volume) methanol/acetone mixture (8.5ml) dissolving tiotropium bromide (1.00g).Through about 30 minutes heated solutions to 60 ℃, then at least 3 hours internal cooling in 21 ℃.Kept the gained suspension under 21 ℃ at least 3 hours, and filtered, wash solid three times with the 1.0mL mixture through sintered glass funnel.21 ℃, N ₂Air-flow dry 30 minutes down, again in 111 ℃, decompression (40mbar) dry 7 hours down generates 0.154g tiotropium bromide form 2.TGA weight loss: 0.8%.

Embodiment 4: be characterised in that x-ray diffractogram of powder about 9.82,10.91,13.45, 15.34, there is the tiotropium bromide at peak at 17.93,19.71,20.90 and 21.45 ± 0.2 degree 2-θ places Preparation

Under [0189] 60 ℃, dissolve thick tiotropium bromide (2.50g) with 3/1 (volume/volume) methanol/acetone mixture (13ml).Through about 30 minutes heated solutions to 60 ℃, then at least 3 hours internal cooling in 22 ℃.Kept the gained suspension under 22 ℃ at least 2 hours, and used through sintered glass funnel and filter, wash solid twice with the 1.5mL mixture.22 ℃, N ₂Under the air-flow, dry 30 minutes, generate 1.40g tiotropium bromide form 3.TGA weight loss: 5.1%.

Embodiment 5: be characterised in that x-ray diffractogram of powder about 9.82,10.91,13.45, 15.34, there is the tiotropium bromide at peak at 17.93,19.71,20.90 and 21.45 ± 0.2 degree 2-θ places The preparation method

Under [0190] 60 ℃, dissolve thick tiotropium bromide (2.50g) with the mixture (13ml) of 3/1 (volume/volume) methanol/acetone.Through about 30 minutes heated solutions to 60 ℃, then at least 3 hours internal cooling to 22 ℃.Kept the gained suspension under 22 ℃ at least 2 hours, and filtered, wash solid twice with the 1.5mL mixture through sintered glass funnel.22 ℃, N ₂Air-flow dry 30 minutes down, 60 ℃, reduced pressure down dry 15 hours again, generate 1.33g tiotropium bromide form 3.TGA weight loss: 4.3%.

Embodiment 6: be characterised in that x-ray diffractogram of powder about 9.82,10.91,13.45, 15.34, there is the tiotropium bromide at peak at 17.93,19.71,20.90 and 21.45 ± 0.2 degree 2-θ places PreparationUnder [0191] 60 ℃, dissolve thick tiotropium bromide (2.50g) with 3/1 (volume/volume) methanol/acetone mixture (13ml).Through about 30 minutes heated solutions to 60 ℃, be quickly cooled to-5 ℃ (5 minutes) and be maintained at-5 ℃ at least 3 hours.The gained suspension filters through sintered glass funnel, with 1.0mL mixture washing solid.21 ℃, N ₂Air-flow dry 30 minutes down generates 1.31g tiotropium bromide form 3.TGA weight loss: 4.5%.

Embodiment 7: be characterised in that x-ray diffractogram of powder about 9.92,11.03,13.41, 15.31, there is the tiotropium bromide at peak at 18.10,19.91,20.94 and 21.41 ± 0.2 degree 2-θ places Preparation

Under 78 ℃, make thick tiotropium bromide (1.00g) be dissolved in dehydrated alcohol (65ml).Through about 30 minutes heated solutions to 78 ℃, then at least 6 hours internal cooling to 22 ℃.Kept the gained suspension under 22 ℃ at least 3 hours, and filtered, with dehydrated alcohol (twice of 2 * 1.0ml) washing solid through sintered glass funnel.22 ℃, N ₂Air-flow dry 30 minutes down, then in 60 ℃, the pressure of minimizing (17mbar) dry 9 hours down generates 0.66g tiotropium bromide form 4.TGA weight loss: 4.8%.The stoichiometric calculation value of half ethylate: 4.64%.

Embodiment 8: be characterised in that x-ray diffractogram of powder about 9.92,11.03,13.4l, 15.31, there is the tiotropium bromide at peak at 18.10,19.91,20.94 and 21.41 ± 0.2 degree 2-θ places SystemBe equipped with

Under [0192] 73 ℃, make thick tiotropium bromide (0.80g) be dissolved in ethanol 96% (18.4ml).Through about 1 hour heated solution to 73 ℃, then at least 5 hours internal cooling to 23 ℃.Kept the gained suspension under 23 ℃ at least 3 hours, and filtered, with ethanol 96% (twice of 2 * 1.5ml) washing solid through sintered glass funnel.23 ℃, N ₂Air-flow dry 1.5 hours down, again in 60 ℃, the pressure of minimizing (18mbar) dry 5 hours down generates 0.39g tiotropium bromide form 4.TGA weight loss: 4.7%.The stoichiometric calculation value of half ethylate: 4.64%.

Embodiment 9: the preparation of tiotropium bromide form X

Under [0193] 45 ℃, with 7/2 (volume/volume) acetate/carbinol mixture (11ml) dissolving tiotropium bromide (1.00g), through 1.5 hours heated solutions to 45 ℃, again with dropwise adding normal heptane (2.75ml) at least 20 minutes.Heated resulting solution to 45 ℃ (not observing solid forms) through 1 hour, be cooled to 23.5 ℃, kept the gained suspension at least 3 hours under 23.5 ℃ through at least 3 hours.After filtering, wash solid three times with the 3.0mL normal heptane through sintered glass funnel.At 60 ℃, under the pressure of minimizing (18mbar), dry 16 hours, generate 0.67g tiotropium bromide form X.TGA weight loss: 5.4%.

Embodiment 10: the preparation of tiotropium bromide form X

Under [0194] 45 ℃,,, dropwise added normal heptane (2.5ml) again through at least 15 minutes through 1.5 hours heated solutions to 45 ℃ with 7/1 (volume/volume) acetate/carbinol mixture (10ml) dissolving tiotropium bromide (0.50g).Through the 0.5 hour solution to 45 that obtains of heating ℃ (not observing solid forms), be cooled to 28 ℃ through at least 3 hours, kept the gained suspension at least 3 hours under 28 ℃.After filtering, wash solid three times with the 2.0mL normal heptane through sintered glass funnel.At 60 ℃, under the pressure of minimizing (19mbar), dry 18 hours, or at 90-100 ℃, 18mbar pressure dry 7 hours down generates 0.29g tiotropium bromide form X.TGA weight loss: 5.7%.

Embodiment 11: the preparation of tiotropium bromide form 7

Under [0195] 45 ℃,,, dropwise added diisopropyl ether (DIPE) through at least 15 minutes (6.75ml) again through 1 hour heated solution to 45 ℃ with 1/4 (volume/volume) acetate/acetonitrile mixture (6.75ml) dissolving tiotropium bromide (0.60g).Through at least 1 hour suspension to 45 of obtaining of heating ℃, be cooled to 21.5 ℃ through at least 3 hours, kept at least 3 hours under 21.5 ℃.After filtering, wash solid three times with 1.8mL diisopropyl ether (DIPE) through sintered glass funnel.At 21 ℃, N ₂Air-flow dry 1 hour down generates 0.40g tiotropium bromide form 7.

Embodiment 12: the preparation of tiotropium bromide form 8

Under [0196] 63 ℃, make tiotropium bromide (0.80g) be dissolved in methyl alcohol (3.4ml).Through about 1 hour heated solution to 63 ℃, be cooled to 22 ℃ through at least 2 hours again.Kept the gained suspension under 22 ℃ at least 3.5 hours, and filtered through sintered glass funnel.With methyl alcohol (2 * 0.8ml) washing solids twice, at 22 ℃, N ₂Air-flow dry 1 hour down generates 0.49g tiotropium bromide form 8.TGA weight loss: 5.1%.

Embodiment 13: the preparation of tiotropium bromide form 9

Make tiotropium bromide (45mg) be dissolved in n-propyl alcohol (4ml) under [0197] 97 ℃.The n-propyl alcohol solution of thermotropism tiotropium bromide adds pentyl acetate (4ml) then.25 ℃, under the isothermal condition, crystallization 5 days obtains the monocrystalline of tiotropium bromide form 9.Capture monocrystalline through the viscose glue technology from the mother liquor on the top of the glass needle of goniometer assembly, and measure in 298K.

Embodiment 14: the preparation of tiotropium bromide

Under [0198] 81 ℃, make tiotropium bromide (0.40g) be dissolved in Virahol (160ml).Through about 5 hours heated solutions to 81 ℃, filter through sintered glass funnel, be cooled to 23 ℃ through at least 4 hours again.Kept the gained suspension under 23 ℃ at least 5 hours, and filtered through sintered glass funnel.With Virahol (2 * 1.0ml) washing solids twice, at 23 ℃, N ₂Air-flow dry 1 hour down, then at 60 ℃, decompression (18mbar) dry 5 hours down generates the 0.23g tiotropium bromide.TGA weight loss: 6.0%.

Embodiment 15: the preparation of tiotropium bromide form 9

Under [0199] 97 ℃, make tiotropium bromide (4g) be dissolved in n-propyl alcohol (348ml), be cooled to 55 ℃ through 4 hours again, reduced to 25 ℃ from 55 ℃ through 3 hours.Under 20-25 ℃, stirred 12 hours, filter suspension, at 45 ℃, decompression dry 20 hours down obtains tiotropium bromide form 9 (3g).

Embodiment 16: the preparation of tiotropium bromide form 9

Under [0200] 83 ℃, the n-propyl alcohol (60ml) that tiotropium bromide (2g) is dissolved in contain 5%w/w water was cooled to 25 ℃ through 4 hours again.Under 20-25 ℃, stir after 12 hours, filter suspension, at 45 ℃, decompression dry 20 hours down obtains tiotropium bromide form 9 (1.3g).

Embodiment 17: the preparation of tiotropium bromide form 9

Under [0201] 85 ℃, the n-propyl alcohol (58.5ml) that tiotropium bromide (2g) is dissolved in contain 2%w/w water was cooled to 25 ℃ through 5 hours again.Under 20-25 ℃, stir 12 hours after-filtration suspensions, at 45 ℃, decompression dry 20 hours down obtains tiotropium bromide form 9 (1.8g).

Embodiment 18: be characterised in that x-ray diffractogram of powder has the preparation of the tiotropium bromide at peak at about 9.82,10.88,13.28,15.27,16.39,17.96,19.67,20.71 and 21.30 ± 0.2 degree 2-θ places

Under [0202] 94 ℃, make thick tiotropium bromide (0.40g) be dissolved in propyl carbinol (70ml).Through about 2.5 hours heated solutions to 94 ℃, filter through sintered glass funnel, be cooled to 22 ℃ through at least 6 hours again.Kept the gained suspension under 22 ℃ at least 5 hours, and filtered through sintered glass funnel.With propyl carbinol (2 * 1.0ml) washing solids twice, at 22 ℃, N ₂Air-flow dry 3 hours down, again in 65 ℃, decompression (18mbar) dry 16.5 hours down generates 0.133g tiotropium bromide form 10.TGA weight loss: 6.9%.

Embodiment 19: the preparation of tiotropium bromide form 11

[0203] in baking box, in 160 ℃, heating tiotropium bromide methylate, half propyl carbinol salt and half acetic acid solvent thing are 1 hour in independent Glass Containers, measure various materials through XRD.

Embodiment 20: the preparation of tiotropium bromide amorphous forms

[0204] under the room temperature, make the 1g tiotropium bromide be dissolved in 50ml water, subsequent filtration (to remove undissolved small-particle), freeze-drying 24 hours.

Vacuum chamber:＜20 μ m Hg, 2

Chambers temp during 4 hours :-40 ℃-22 ℃.

Embodiment 21: the universal method of preparation tiotropium bromide monohydrate

[0205] tiotropium bromide is mixed with 80.7mL water, stirred the mixture under the room temperature 4 hours.Filtering mixt is used the 10mL water washing.Room temperature, under vacuum and the nitrogen, the thing of buying property obtained the monohydrate form strainer last 15 minute.

Embodiment 19: the preparation of tiotropium bromide monohydrate

[0206] tiotropium bromide is suspended in water, 22-25 ℃ was stirred suspension 4 hours down.After the filtration, with 10mL water washing solid.20 °-25 ℃, under vacuum and the nitrogen, product is placed strainer last 15 minute.Water-content in the sample is 4.3% (TGA analysis).

Embodiment 20: prepare tiotropium bromide monohydrate from the tiotropium bromide ethylate

[0207] the dried tiotropium bromide ethylate of 13.45g is suspended in the 80.7mL water, stirred suspension 4 hours under the room temperature.After the filtration, use the 10mL water washing.Room temperature under vacuum and the nitrogen places product strainer last 15 minute, obtains the 11.66g monohydrate.Water-content in the sample is 4.3% (TGA analysis).

Embodiment 21: the tiotropium bromide micronization

[0208] tiotropium bromide is obtained following P.S.D target by micronization:

Minimum 80%＜5.84 μ m

Minimum 70% between the 0.6-10 micron

Used pulverizer is micronizer mill (Jet-mill) MC 50 (Micro-Macinazionne manufacturing).The nozzle at 32 ° of 05 ' angles is housed.

Nitrogen is used as micronization gas.

Micronization air pressure is 10 crust.

Input speed is 0.2kg/hr.

The PSD value of the micronization tiotropium bromide that obtains through above method is:

80％＜5.84μm

93.76% between the 0.6-10 micron.

Claims (148)

1. a crystalline tiotropium bromide is characterized in that, x-ray diffractogram of powder has the peak at about 8.7,15.3,15.5 and 25.3 ± 0.2 degree 2-θ places.

2. the crystalline tiotropium bromide of claim 1, its feature are that also x-ray diffractogram of powder has the peak at about 9.9,13.3,18.0,20.2 and 24.2 ± 0.2 degree 2-θ places.

3. the crystalline tiotropium bromide of claim 2, its feature also is x-ray diffractogram of powder as shown in Figure 1.

4. the crystalline tiotropium bromide of claim 1, wherein said crystalline form is the methanol solvate thing of tiotropium bromide.

5. one kind prepares and is characterised in that x-ray diffractogram of powder has the method for the crystalline tiotropium bromide at peak at about 8.7,15.3,15.5 and 25.3 ± 0.2 degree 2-θ places, and it comprises that from containing proportional respectively be crystallization tiotropium bromide the mixture of the methyl alcohol of about 1: 3 (volume/volume) and acetone.

6. the method for claim 5, wherein said crystallization may further comprise the steps:

A) provide tiotropium bromide containing the proportional solution in about 1/3 (volume/volume) methyl alcohol and the acetone mixture that is; And b) cools off this solution to obtain suspension.

7. the method for claim 6, wherein tiotropium bromide solution proportionally obtains for the methyl alcohol of about 1/3 (volume/volume) and the mixture and the heating of acetone by merging tiotropium bromide and containing.

8. the method for claim 7, heating wherein proceeds to about 50 ℃-Yue 60 ℃ temperature.

9. the method for claim 6, cooling wherein reach approximately-6 ℃ to-14 ℃ temperature approximately.

10. the method for claim 9, cooling is wherein carried out gradually so that solution is cooled between about 25 ℃-first Yue 20 ℃ temperature, be cooled to subsequently between approximately-6 ℃ to second temperature of-14 ℃ approximately.

11. a crystalline tiotropium bromide is characterized in that, x-ray diffractogram of powder has the peak at about 23.1,23.6,24.1,30.1 and 30.3 ± 0.2 degree 2-θ places.

12. the crystalline tiotropium bromide of claim 11, its feature are that also x-ray diffractogram of powder has the peak at about 9.9,11.0,13.4,15.3,18.1,19.9,21.4,24.7,25.2,26.0 and 27.2 ± 0.2 degree 2-θ places.

13. the crystalline tiotropium bromide of claim 11, its feature also is x-ray diffractogram of powder as shown in Figure 2.

14. the crystalline tiotropium bromide of claim 11, its feature also are through the weight loss step of thermogravimetric analysis at about 160 ℃ about 0.8%-about 2.3%.

15. the crystalline tiotropium bromide of claim 14, its feature also are TGA curve as shown in Figure 3.

16. the crystalline tiotropium bromide of claim 11, its feature are that also the DSC differential thermogram has in first about 144 ℃ endotherm(ic)peak with in second about 228 ℃ endotherm(ic)peak.

17. the crystalline tiotropium bromide of claim 11, its feature also is about 207.6 ℃ fusing point.

18. the crystalline tiotropium bromide of claim 11, wherein said crystalline form are the methanol solvate things of tiotropium bromide.

19. one kind prepares and it is characterized in that x-ray diffractogram of powder has the method for the crystalline tiotropium bromide at peak at about 23.1,23.6,24.1,30.1 and 30.3 ± 0.2 degree 2-θ places, it comprises from comprising ratio between about 1: crystallization tiotropium bromide the methyl alcohol of 1-about 3: 1 (volume/volume) and the mixture of acetone.

20. the method for claim 19, wherein said crystallization may further comprise the steps: a) provide tiotropium bromide comprise about 1/1 or the mixture of the methyl alcohol of about 3/1 (volume/volume) ratio and acetone in solution, and b) cool off this solution to obtain suspension.

21. the method for claim 20, wherein tiotropium bromide solution obtains by merging tiotropium bromide and containing proportional mixture and heating for the methyl alcohol of about 1/1-about 3/1 (volume/volume) and acetone.

22. the method for claim 21, heating wherein proceed to about 50 ℃-Yue 70 ℃ temperature.

23. the method for claim 20, cooling wherein reach about 25 ℃-Yue 20 ℃ temperature.

24. a crystalline tiotropium bromide is characterized in that, x-ray diffractogram of powder has the peak at about 27.7,27.8,30.3 and 30.5 ± 0.2 degree 2-θ places.

25. the crystalline tiotropium bromide of claim 24, its feature are that also x-ray diffractogram of powder has the peak at about 9.9,11.0,13.3,15.3,18.1,19.9 and 21.3 ± 0.2 degree 2-θ places.

26. the crystalline tiotropium bromide of claim 25, its feature also is x-ray diffractogram of powder as shown in Figure 4.

27. the crystalline tiotropium bromide of claim 24, its feature also are, through the weight loss step of TGA at about 160 ℃ about 5.3%-about 5.7%.

28. the crystalline tiotropium bromide of claim 27, its feature also are TGA curve as shown in Figure 5.

29. the crystalline tiotropium bromide of claim 24, its feature also be, the DSC differential thermogram has between about 146 ℃-Yue 150 ℃ first endotherm(ic)peak with between about 227 ℃-second Yue 228 ℃ endotherm(ic)peak.

30. the crystalline tiotropium bromide of claim 24, wherein said crystalline form are the acetic acid solvent things of tiotropium bromide.

31. one kind prepares and it is characterized in that x-ray diffractogram of powder has the method for the crystalline tiotropium bromide at peak at about 27.7,27.8,30.3 and 30.5 ± 0.2 degree 2-θ places, it comprises crystallization tiotropium bromide from the mixture that comprises acetate, methyl alcohol and heptane.

32. the method for claim 31, wherein said crystallization may further comprise the steps: the first kind of tiotropium bromide solution that is included in acetate and the carbinol mixture a) is provided; B) add normal heptane to first kind of solution, obtain second kind of solution, and c) second kind of solution of cooling, suspension obtained.

33. the method for claim 32, wherein first kind of tiotropium bromide solution obtains with comprising acetate and methanol mixture and heating by merging tiotropium bromide.

34. the method for claim 32, wherein the acetate in comprising first kind of solution of acetate and methyl alcohol and the ratio of methyl alcohol are about 7/2 (volume/volume) of about 7/1-.

35. the method for claim 32, the heating of wherein said first kind of solution is carried out under about 40 ℃-Yue 50 ℃ temperature.

36. the method for claim 32, normal heptane wherein carries out in the mode that drips to the adding of first kind of solution.

37. the method for claim 36, being added under about 40 ℃-Yue 50 ℃ temperature wherein carried out.

38. the method for claim 32, wherein second kind of solution is cooled between about 30 ℃-Yue 20 ℃ temperature.

39. a crystalline tiotropium bromide is characterized in that, x-ray diffractogram of powder has the peak at about 8.8,9.0,11.7 and 17.7 ± 0.2 degree 2-θ places.

40. the crystalline tiotropium bromide of claim 39, its feature are that also x-ray diffractogram of powder has the peak at about 13.4,15.1,15.3,15.6,18.1 and 20.2 ± 0.2 degree 2-θ places.

41. the crystalline tiotropium bromide of claim 40, its feature also is x-ray diffractogram of powder as shown in Figure 6.

42. the crystalline tiotropium bromide of claim 39, its feature are that also the weight loss through TGA is about 5.2%.

43. the crystalline tiotropium bromide of claim 42, its feature also are TGA curve as shown in Figure 7.

44. the crystalline tiotropium bromide of claim 39, its feature are that also the DSC differential thermogram has in first about 136 ℃ endotherm(ic)peak with in second about 228 ℃ endotherm(ic)peak.

45. the crystalline tiotropium bromide of claim 39, wherein said crystalline form are the acetic acid solvent things of tiotropium bromide.

46. one kind prepares and it is characterized in that x-ray diffractogram of powder has the method for the crystalline tiotropium bromide at peak at about 8.8,9.0,11.7 and 17.7 ± 0.2 degree 2-θ places, it comprises crystallization tiotropium bromide from the mixture of the anti-solvent that comprises the solvent mixture be made up of acetate and acetonitrile and be made up of diisopropyl ether.

47. the method for claim 46, wherein said crystallization may further comprise the steps: a) be provided at the tiotropium bromide solution in the described solvent, b) and to this solution add diisopropyl ether to obtain suspension.

48. the method for claim 46, tiotropium bromide solution wherein obtains by merging tiotropium bromide and described solvent and heating.

49. the method for claim 47, wherein the ratio of acetate in described solvent mixture and acetonitrile respectively is about 1/5 (volume/volume) of about 1/4-.

50. the method for claim 48, heating wherein proceed between about 40 ℃-Yue 50 ℃ temperature.

51. the method for claim 47 wherein adds diisopropyl ether and carries out in the dropping mode in described solution.

52. the method for claim 51, being added under about 40 ℃-Yue 50 ℃ temperature wherein carried out.

53. the method for claim 47, cooling wherein proceed to about 30 ℃-Yue 20 ℃ temperature.

54. a crystalline tiotropium bromide is characterized in that, x-ray diffractogram of powder has the peak at about 16.2,16.5,28.0 and 28.3 ± 0.2 degree 2-θ places.

55. the crystalline tiotropium bromide of claim 54, its feature are that also x-ray diffractogram of powder has the peak at about 9.9,11.0,13.4,15.3,17.9,19.7,20.9 and 21.4 ± 0.2 degree 2-θ places.

56. the crystalline tiotropium bromide of claim 55, its feature also is x-ray diffractogram of powder as shown in Figure 8.

57. the crystalline tiotropium bromide of claim 54, its feature also are through the weight loss of TGA about 5.1%.

58. the crystalline tiotropium bromide of claim 57, its feature also are TGA curve as shown in Figure 9.

59. the crystalline tiotropium bromide of claim 54, its feature are that also the DSC differential thermogram has in first about 149 ℃ endotherm(ic)peak with in second about 226 ℃ endotherm(ic)peak.

60. the crystalline tiotropium bromide of claim 54, wherein said crystalline form are the methanol solvate things of tiotropium bromide.

61. a method for preparing according to the crystalline tiotropium bromide of claim 54, it comprises crystallization from methyl alcohol.

62. the method for claim 61, wherein said crystallization may further comprise the steps: the methanol solution of tiotropium bromide a) is provided, and b) cool off this solution to obtain suspension.

63. the method for claim 62, wherein the methanol solution of tiotropium bromide provides by merging tiotropium bromide and methyl alcohol, and obtains this solution through heating.

64. the method for claim 63, heating wherein proceed between about 61 ℃-Yue 65 ℃ temperature.

65. the method for claim 62, solution wherein are cooled between about 27 ℃-Yue 22 ℃ temperature.

66. tiotropium bromide crystalline n-propyl alcohol solvate.

67. a tiotropium bromide crystalline n-propyl alcohol solvate is characterized in that the x-ray diffractogram of powder as calculated shown in Figure 10.

68. the crystalline n-propyl alcohol solvate of the tiotropium bromide of claim 67, wherein said crystalline form are half n-propyl alcohol solvates of tiotropium bromide.

69. the crystalline half n-propyl alcohol salt form of a tiotropium bromide is characterized in that having the monocrystalline XRD of following column data: monoclinic crystalline system; Pc, (No.7) spacer; Unit cell parameters: a, b, c: be respectively 13.42,12.04,13.60

With α, β, γ: be respectively 90,103.8,90[deg], and volume: 2135

Formula C ₂₀₅H ₂₆BrNO _4.5S ₂Z be 4; With bulk density D be 1.53[g/cm ³].

70. the tiotropium bromide half n-propyl alcohol salt form of claim 69 is characterized in that ORTEP view as shown in Figure 11.

71. one kind prepares and is characterised in that monocrystalline XRD has the method for the crystalline tiotropium bromide n-propyl alcohol solvate of following column data: monoclinic crystalline system; Pc, (No.7) spacer; Unit cell parameters: a, b, c: respectively be 13.42,12.04,13.60

With α, β, γ: respectively be 90,103.8,90[deg], and volume: 2135

Formula C ₂₀₅H ₂₆BrNO _4.5S ₂Z be 4; With bulk density D be 1.53[g/cm ³], it is included under the isothermal condition method of crystallization tiotropium bromide from n-propyl alcohol.

72. the method for claim 71, wherein said crystallization may further comprise the steps: the n-propyl alcohol solution of tiotropium bromide a) is provided, b) cools off the temperature of this solution to 25 ℃, obtaining mixture, with c) kept this mixture about 5 days under 25 ℃.

73. the method for claim 72, wherein the n-propyl alcohol solution of tiotropium bromide obtains by merging tiotropium bromide and n-propyl alcohol and heating.

74. the method for claim 73, heating wherein proceed to about 80 ℃-Yue 100 ℃ temperature.

75. a crystalline tiotropium bromide is characterized in that, x-ray diffractogram of powder has the peak at about 20.2,26.5,28.0 and 31.2 ± 0.2 degree 2-θ places.

76. the crystalline tiotropium bromide of claim 75, its feature are that also x-ray diffractogram of powder has the peak at about 8.9,15.6,17.7,21.7,23.4 and 24.3 ± 0.2 degree 2-θ places.

77. the crystalline tiotropium bromide of claim 76, its feature also is x-ray diffractogram of powder as shown in Figure 12.

78. the crystalline tiotropium bromide of claim 75, its feature also are the weight loss about＜0.1% through TGA.

79. the crystalline tiotropium bromide of claim 78, its feature also are TGA curve as shown in Figure 13.

80. the crystalline tiotropium bromide of claim 75, its feature are that also the DSC differential thermogram has endotherm(ic)peak at about 227 ℃.

81. a method for preparing according to the crystalline tiotropium bromide of claim 75, it comprises that heating tiotropium bromide solvate is extremely between about 160 ℃-Yue 170 ℃ temperature.

82. the crystalline n-propyl alcohol solvate of a tiotropium bromide is characterized in that, x-ray diffractogram of powder has the peak at about 20.9,21.1,21.4 and 34.4 ± 0.2 degree 2-θ places.

83. the crystalline tiotropium bromide of claim 82, its feature are that also x-ray diffractogram of powder has the peak at about 9.9,11.0,13.5,15.3,18.1,19.9,20.9,21.1,21.4,23.9,25.1,27.1 and 34.4 ± 0.1 degree 2-θ places.

84. the crystalline tiotropium bromide of claim 83, its feature also is the x-ray diffractogram of powder shown in Figure 14.

85. the crystalline tiotropium bromide of claim 82, its feature are that also the weight loss through TGA is about 5.9% under the about 125 ℃-Yue 184 ℃ temperature.

86. the crystalline tiotropium bromide of claim 85, its feature also is the x-ray diffractogram of powder shown in Figure 15.

87. the crystalline tiotropium bromide of claim 86, its feature are that also the DSC differential thermogram has first endotherm(ic)peak of 158 ℃ with in second about 229 ℃ endotherm(ic)peak.

88. the crystalline tiotropium bromide n-propyl alcohol solvate of claim 82, wherein said crystalline form are half n-propyl alcohol solvates of tiotropium bromide.

89. one kind prepares and it is characterized in that x-ray diffractogram of powder has the method for the crystalline n-propyl alcohol salt solvent of the tiotropium bromide thing at peak at about 20.9,21.1,21.4 and 34.4 ± 0.1 degree 2-θ places, it comprises provides the n-propyl alcohol of tiotropium bromide solution and is cooled to about 55 ℃-Yue 25 ℃ temperature to obtain suspension.

90. the method for claim 89, wherein the n-propyl alcohol solution of tiotropium bromide obtains by merging tiotropium bromide and n-propyl alcohol and heating.

91. the method for claim 90, wherein heating proceeds to about 80 ℃-Yue 100 ℃, more preferably to 97 ℃ temperature.

92. the method for claim 89, solution wherein are cooled to about 55 ℃-Yue 25 ℃ temperature.

93. the method for claim 92, cooling is wherein carried out gradually.

94. the amorphous forms of a tiotropium bromide.

95. the amorphous tiotropium bromide of claim 94 is characterized in that, x-ray diffractogram of powder as shown in Figure 16.

96. a method for preparing the amorphous tiotropium bromide, it comprises the tiotropium bromide solution of freeze-drying in water, the trimethyl carbinol, methyl alcohol or their mixture.

97. the method for claim 96, wherein any type of tiotropium bromide is used as the raw material of freeze-drying process.

98. the method for claim 97, raw material wherein are claim 1,2 and 8 tiotropium bromide methylate.

99. the method for claim 97, raw material wherein are claim 67,71 and 84 tiotropium bromide n-propyl alcohol salt.

100. the method for claim 96, solution wherein prepares by tiotropium bromide is dissolved in water, the trimethyl carbinol, methyl alcohol or their mixture.

101. the method for claim 100, being dissolved under the about 20 ℃-Yue 40 ℃ temperature wherein carried out.

102. one kind prepares and it is characterized in that x-ray diffractogram of powder has the method for the tiotropium bromide crystalline form at peak at about 9.82,10.91,13.45,15.34,17.93,19.71,20.90 and 21.45 ± 0.2 degree 2-θ places, it comprises that from containing proportional be crystallization tiotropium bromide the mixture of the methyl alcohol of about 3/1 (volume/volume) and acetone.

103. the method for claim 102, wherein said crystallization comprises: a) be provided at contain proportional for about 3/1 (volume/volume) methyl alcohol and the tiotropium bromide solution in the mixture of acetone; And b) through cooling off this solution to obtain suspension.

104. the method for claim 103, solution wherein is by merging tiotropium bromide and comprising the methyl alcohol that ratio is about 3/1 (volume/volume) and the mixture and the heating of acetone and obtain.

105. the method for claim 104, heating wherein proceed to about 50 ℃-Yue 70 ℃ temperature.

106. reaching about room temperature, the method for claim 103, cooling wherein arrive-5 ℃ temperature approximately.

107. one kind prepares and it is characterized in that x-ray diffractogram of powder has the method for the tiotropium bromide crystalline form at peak at about 9.82,10.88,13.28,15.27,16.39,17.96,19.67,20.71 and 21.30 ± 0.2 degree 2-θ places, it comprises crystallization tiotropium bromide from propyl carbinol.

108. the method for claim 107, crystallization wherein comprises the butanol solution that tiotropium bromide is provided, and cools off this solution to obtain suspension.

109. the method for claim 108, solution wherein obtains through merging tiotropium bromide and propyl carbinol and heating.

110. the method for claim 109, heating wherein proceed between about 90 ℃-Yue 96 ℃ temperature.

111. the method for claim 108, solution wherein are cooled between about 25 ℃-Yue 20 ℃ temperature.

112. one kind prepares and it is characterized in that x-ray diffractogram of powder has the method for the tiotropium bromide crystalline form at peak at about 9.92,11.03,13.41,15.31,18.10,19.91,20.94 and 21.41 ± 0.2 degree 2-θ places, it comprises crystallization tiotropium bromide from ethanol.

113. the method for claim 112, wherein said crystallization comprise the ethanolic soln that tiotropium bromide is provided and cool off this solution to obtain suspension.

114. the method for claim 113, solution wherein obtains by merging tiotropium bromide and ethanol and heating.

115. the method for claim 114, solution wherein are heated between about 70 ℃-Yue 80 ℃ temperature.

116. the method for claim 113, solution wherein is cooled to room temperature.

117. one kind prepares and it is characterized in that the powder X-ray ray figure that spreads out has the method for the tiotropium bromide crystalline form at peak at about 9.86,10.97,13.28,15.28,18.04,19.80,20.71,21.26 ± 0.2 degree 2-θ places, it comprises crystallization tiotropium bromide from Virahol.

118. the method for claim 117, wherein said crystallization comprise the aqueous isopropanol that tiotropium bromide is provided and cool off this solution to obtain suspension.

119. the method for claim 118, solution wherein obtains by merging tiotropium bromide and Virahol and heating.

120. the method for claim 119, heating wherein proceed to about 80 ℃-Yue 100 ℃ temperature.

121. the method for claim 118, solution wherein are cooled to about 25 ℃-Yue 21 ℃ temperature.

122. one kind prepares and it is characterized in that the powder X-ray ray figure that spreads out has the method for the tiotropium bromide monohydrate form at peak at 8,9,11.9,13.5,14.8,16.7,17.5,20.3,23.6,24.1 and 26.9 ± 0.2 degree 2-θ places, it comprises provides the mixture of tiotropium bromide in water.

123. the method for claim 122, initial tiotropium bromide wherein can be any type of tiotropium bromide.

124. the method for claim 123, initial tiotropium bromide wherein is solvate, anhydrous form or amorphous forms.

125. the method for claim 124, tiotropium bromide solvate forms wherein is selected from alcoholate and acetic acid solvent thing.

126. the method for claim 125, alcoholate wherein are selected from methylate, ethylate, n-propyl alcohol salt, isopropoxide or propyl carbinol salt.

127. the method for claim 126, alcoholate wherein is selected from n-propyl alcohol salt or methylate.

128. in the claim 1,11,24,39,54,66,67,69,75,82 and 94 each the tiotropium bromide crystalline form, wherein the tiotropium bromide of any described form has the tiotropium bromide that is no more than about 10% any other described form.

129. the tiotropium bromide of claim 128, wherein the tiotropium bromide of any described form has the tiotropium bromide of about 5% any other the described form of being no more than.

130. the tiotropium bromide of claim 128, wherein the tiotropium bromide of any described form has and is no more than about 10% tiotropium bromide monohydrate.

131. the tiotropium bromide of claim 130, wherein the tiotropium bromide of any described form has and is no more than about 5% tiotropium bromide monohydrate.

132. claim 1,11,24,39,54,66,67,69,75,82 and 94 tiotropium bromide particulate form.

133. a pharmaceutical preparation, it comprises the claim 1,11,24,39,54,66,67,69,75 of at least a form, 82 and 94 tiotropium bromide and pharmaceutically acceptable vehicle.

134. method for preparing the pharmaceutical preparation of the claim 1,11,24,39,54,66,67,69,75 that comprises at least a form, 82 and 94 tiotropium bromide and pharmaceutically acceptable vehicle.

135. a pharmaceutical preparation, it comprises the claim 1 prepared according to the methods of the invention, 11,24,39,54,66,67,69,75 of at least a form, 82 and 94 tiotropium bromide and pharmaceutically acceptable vehicle.

136. method for preparing the pharmaceutical preparation of the claim 1 prepared according to the methods of the invention, 11,24,39,54,66,67,69,75 that comprises at least a form, 82 and 94 tiotropium bromide and pharmaceutically acceptable vehicle.

137. a pharmaceutical preparation, it comprises the claim 1,11,24,39,54,66,67,69,75 of at least a form, 82 and 94 micronization tiotropium bromide and pharmaceutically acceptable vehicle.

138. method for preparing the pharmaceutical preparation of the claim 1,11,24,39,54,66,67,69,75 that comprises at least a form, 82 and 94 micronization tiotropium bromide and pharmaceutically acceptable vehicle.

139. a pharmaceutical preparation, it comprises the claim 1 prepared according to the methods of the invention, 11,24,39,54,66,67,69,75 of at least a form, 82 and 94 micronization tiotropium bromide and pharmaceutically acceptable vehicle.

140. method for preparing the pharmaceutical preparation of the claim 1 prepared according to the methods of the invention, 11,24,39,54,66,67,69,75 that comprises at least a form, 82 and 94 micronization tiotropium bromide and pharmaceutically acceptable vehicle.

141. tiotropium bromide crystalline form 1.

142. tiotropium bromide crystalline form 2.

143. tiotropium bromide crystalline form 6.

144. tiotropium bromide crystalline form 7.

145. tiotropium bromide crystalline form 8.

146. tiotropium bromide is crystalline half n-propyl alcohol salt form.

147. tiotropium bromide crystalline form 11.

148. tiotropium bromide crystalline form 12.

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