CN101331128B - Novel forms of tiotropium bromide and processes for preparation thereof - Google Patents
Novel forms of tiotropium bromide and processes for preparation thereof Download PDFInfo
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- CN101331128B CN101331128B CN200680047726.4A CN200680047726A CN101331128B CN 101331128 B CN101331128 B CN 101331128B CN 200680047726 A CN200680047726 A CN 200680047726A CN 101331128 B CN101331128 B CN 101331128B
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Abstract
This invention relates to novel crystalline forms of tiotropium bromide, processes for preparing them, and their use in pharmaceutical formulations.
Description
The cross reference of related application
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
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 ").
The 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 lower array structure:
Tiotropium bromide
C
19H
22NO
4S
2Br
MW：472.4
Tiotropium bromide can be used as the SPIRIVA that can derive from Boehringer Ingelheim
HandiHaler
Obtain from commercial channels, wherein it exists as the monohydrate form.
Standby and crystallization tiotropium bromide is disclosed in U.S. Patent number 5,610 from acetone and Methanol, in 163, provides the product of the fusing point with 217-218 ℃.
The 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, tiotropium bromide is described without the U.S. Patent number 6 of hydrate crystalline form, 608,055, describe anhydrous tiotropium bromide another crystalline form WO2005/042527 and the publication No. IPCOM000143595D of crystalline tiotropium bromide dichloromethane solvent compound is described.
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 orientation and the molecular interaction of the adjacent molecule (complex compound) in the bulk solid.Therefore, polymorphic form is the different solids of sharing the same molecular formula, but compares with other form in the polymorphic form family, and polymorphic form has 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.
The 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.
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
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.
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.
In another embodiment, the invention provides the tiotropium bromide crystalline form that is called form 2, it is characterized in that having at about 23.1,23.6,24.1,30.1 and 30.3 ± 0.2 degree 2-θ places the x-ray diffractogram of powder at peak.
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.
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 6.
In another embodiment, the present invention provides the method for the tiotropium bromide of preparation form 6 by comprising the method for crystallization tiotropium bromide from the mixture that comprises acetic acid, methyl alcohol and heptane.
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.
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 that is comprised of acetic acid and acetonitrile and be comprised of diisopropyl ether.
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.
In one embodiment, the invention provides the n-propyl alcohol solvate of tiotropium bromide.
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.
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 lower 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.
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.
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.
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.
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.
In another embodiment, the invention provides the amorphous tiotropium bromide.
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.
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.
In another embodiment, the invention provides and be called form 1,2,6,7,8,9,11 and the tiotropium bromide of amorphous micronization form.
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.
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.
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.
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.
In one embodiment, the invention provides and comprise at least a form 1,2,6,7,8,9,11 or the tiotropium bromide of amorphous forms and the pharmaceutical preparation of pharmaceutically acceptable vehicle that is called.
In another embodiment, the invention provides and comprise at least a form 1,2,6,7,8,9,11 or the preparation method of the pharmaceutical preparation of the tiotropium bromide of amorphous forms and pharmaceutically acceptable vehicle that is called.
In another embodiment, the invention provides and comprise at least a form 1,2,3,4,6,7,8,9,10,11 or the tiotropium bromide of amorphous forms and the pharmaceutical preparation of pharmaceutically acceptable vehicle that is called prepared according to the methods of the invention.
In one embodiment, the invention provides comprise at least a form prepared according to the methods of the invention and be called form 1,2,3,4,6,7,8,9,10,11 or the preparation method of the pharmaceutical preparation of the tiotropium bromide of amorphous forms and pharmaceutically acceptable vehicle.
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.
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.
In one embodiment, the invention provides comprise at least a form prepared according to the methods of the invention and be called form 1,2,3,4,6,7,8,9,10,11 or the pharmaceutical preparation of amorphous micronization tiotropium bromide and pharmaceutically acceptable vehicle.
In another embodiment, the invention provides comprise at least a form prepared according to the methods of the invention and be called form 1,2,3,4,6,7,8,9,10,11 or the preparation method of the pharmaceutical preparation of amorphous micronization tiotropium bromide and pharmaceutically acceptable vehicle.
The summary of figure
Fig. 1 represents the x-ray diffractogram of powder of tiotropium bromide form 1.
Fig. 2 represents the x-ray diffractogram of powder of tiotropium bromide form 2.
Fig. 3 represents the TGA curve of tiotropium bromide form 2.
Fig. 4 represents the x-ray diffractogram of powder of tiotropium bromide form 6.
Fig. 5 represents the TGA curve of tiotropium bromide form 6.
Fig. 6 represents the x-ray diffractogram of powder of tiotropium bromide form 7.
Fig. 7 represents the TGA curve of tiotropium bromide form 7.
Fig. 8 represents the x-ray diffractogram of powder of tiotropium bromide form 8.
Fig. 9 represents the TGA curve of tiotropium bromide form 8.
Figure 10 represents the x-ray diffractogram of powder of the tiotropium bromide form 9 calculated.
Figure 11 represents the ORTEP view of tiotropium bromide form 9.
Figure 12 represents the x-ray diffractogram of powder of tiotropium bromide form 11.
Figure 13 represents the TGA curve of tiotropium bromide form 11.
Figure 14 represents the x-ray diffractogram of powder of tiotropium bromide form 12.
Figure 15 represents the TGA curve of tiotropium bromide form 12.
Figure 16 represents the x-ray diffractogram of powder of amorphous tiotropium bromide.
Describe in detail
The term " room temperature " that is used for this paper refers between about 18 ℃-Yue 25 ℃, preferably between about 20 ℃-Yue 22 ℃ temperature.
Be disclosed in U.S. Patent number 5,610, how 163 crystallization method does not point out the crystallization tiotropium bromide, to obtain all the time identical crystalline form.Therefore the present invention not only provides different crystalline and amorphous tiotropium bromides, and their preparation method also is provided.
The term " solvate " that is used for this paper refers to comprise the level that is not water greater than the crystalline material of any solvent of 1%.
The present invention also provides the crystalline tiotropium bromide that is called form 1, it is characterized in that, powder X-ray RD (" powder x-ray diffraction ") figure has the peak at about 8.7,15.3,15.5 and 25.3 ± 0.2 degree 2-θ places.The feature of form 1 is 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.Form 1 also can be identified through the x-ray diffractogram of powder shown in Fig. 1 basically.Those skilled in the art can approve that form 1 can be passed through other method, include, but not limited to solid state NMR, FTIR and Raman spectrum and identify.
Form 1 can be the solvation form of tiotropium bromide, particular methanol salt (methanolate).As measuring through powder x-ray diffraction, other any type of tiotropium bromide that does not occur greater than about 10% can be provided, preferably be not more than the tiotropium bromide crystalline form 1 of the relatively pure form of other any type of tiotropium bromide of about 5%.Preferably, as powder x-ray diffraction was measured, tiotropium bromide crystalline form 1 can be not more than about 10% tiotropium bromide monohydrate to have, and the relatively pure form that preferably is not more than about 5% tiotropium bromide monohydrate provides.
Through comprising the method for crystallization tiotropium bromide from the mixture that comprises methyl alcohol that ratio is about 1/3 (volume/volume) and acetone, prepare the tiotropium bromide of described form 1.
The tiotropium bromide that is used for above crystallisation process and following crystallisation process that is described in this application can obtain through any method known to the skilled.For example, it can pass through U.S. Patent number 5,610, and method obtains described in 163.
Through comprising that to provide tiotropium bromide containing proportional for the solution in the mixture of about 1/3 (volume/volume) methyl alcohol and acetone and cool off this solution to obtain the method for suspension, carry out crystallization.
Tiotropium bromide solution obtains by merging tiotropium bromide and containing the mixture of proportional methyl alcohol for about 1/3 (volume/volume) and acetone and heat.Heating is more preferably carried out to about 57 ℃ temperature preferably at about 50 ℃-Yue 60 ℃.
Usually cooling solution is to bring out the precipitation of crystalline form.Solution preferably is cooled to-6 ℃ to-14 ℃ approximately approximately, more preferably to about-10 ℃ temperature.In the most preferred embodiment, cooling is carried out gradually so that solution is cooled between about 25 ℃-first Yue 20 ℃ temperature, and preferred about 21 ℃ temperature is cooled to second temperature between about-6 ℃-Yue-14 ℃ subsequently.Cooling was preferably finished through about 3 hours gradually.Preferably further be cooled to approximately-10 ℃ temperature through about 5 minutes.
Can keep suspension at least about 3 hours, the yield of the crystalline form that is settled out with increase.
The method for preparing form 1 also can comprise reclaim crystalline form from suspension.Can for example, filter through any method known in the art, drying under reduced pressure is at least 7 hours subsequently, reclaims.
The present invention further provides the crystalline tiotropium bromide that is called form 2, it 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.The feature of form 2 is 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.Form 2 also can be identified through the x-ray diffractogram of powder shown in Fig. 2 basically.The feature of form 2 also is through the weight loss step of thermogravimetric analysis (" TGA ") at about 160 ℃ about 0.8%-about 2.3%.Form 2 also can be identified through the TGA curve shown in Fig. 3 basically.The feature of form 2 is that also dsc (" DSC ") thermogram has in first about 144 ℃ endotherm(ic)peak with in second about 228 ℃ endotherm(ic)peak.The feature of tiotropium bromide form 2 also is about 207.6 ℃ fusing point.Those skilled in the art can approve that form 2 can be passed through other method, include, but not limited to solid state NMR, FTIR and Raman spectrum and identify.
Through comprise from comprise about 1/1 or the mixture of the methyl alcohol of about 3/1 (volume/volume) ratio and acetone the method for crystallization tiotropium bromide, prepare the tiotropium bromide of described form 2.
Methyl alcohol and the tiotropium bromide solution in the acetone mixture that comprises ratio about 1/1 or about 3/1 (volume/volume) is provided and cools off this solution to obtain the method for suspension through comprising, carry out crystallization.
Obtain tiotropium bromide solution by merging tiotropium bromide and containing proportional mixture for the methyl alcohol of about 1/1-about 3/1 (volume/volume) and acetone and heat.Heating preferably proceeds to about 50 ℃-Yue 70 ℃, more preferably to about 60 ℃ temperature.
Usually 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.Can keep suspension at least about 2 hours, the yield of the crystalline form that is settled out with increase.
The method for preparing form 2 also can comprise from suspension recovery crystalline form.Can for example, filter through any method known in the art, drying under reduced pressure is at least 7 hours subsequently, reclaims.
The present invention further provides crystalline tiotropium bromide, 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 6.The feature of this form can be also that 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.Form 6 also can be identified by the x-ray diffractogram of powder shown in Fig. 4 basically.The feature of form 6 also is the weight loss step at about 160 ℃ about 5.3%-about 5.7% through TGA, and this level wherein is corresponding to the theoretical value of tiotropium bromide half acetic acid solvent compound.Form 6 also can be identified through the TGA curve shown in Fig. 5 basically.The feature of form 6 is that also the DSC differential thermogram has between about 146 ℃-Yue 150 ℃ first endotherm(ic)peak with between about 227 ℃-second Yue 228 ℃ endotherm(ic)peak.Those skilled in the art can approve that form 6 can be passed through other method, include but not limited to solid state NMR, FTIR and Raman spectrum evaluation.
Through comprising the method for crystallization tiotropium bromide from the mixture that comprises acetic acid, methyl alcohol and heptane, the form 6 of preparation tiotropium bromide.
Crystallization method comprises provides the first tiotropium bromide that is included in acetic acid and carbinol mixture solution; Add normal heptane to the first solution, obtain the second solution, and cooling the second solution, to obtain suspension.
Obtain the first tiotropium bromide solution by merging tiotropium bromide and comprising the mixture of acetic acid and methyl alcohol and heat.
Acetic acid in comprising the first solution of acetic acid and methyl alcohol and methyl alcohol than each preferred about 7/2 (volume/volume) of about 7/1-.
The first mixture preferably is heated between about 40 ℃-Yue 50 ℃ temperature, more preferably to about 45 ℃ temperature.Preferably finished heating through about 1.5 hours.
Preferably dropwise add normal heptane to the first solution.Preferably add through finishing in about 40 minutes dropwise at least about 20-.Preferably between about 40 ℃-Yue 50 ℃ temperature, more preferably under about 45 ℃ temperature, add.After adding normal heptane, make resulting the second solution maintain about-Yue one hour half hour under the said temperature.
Usually cooling the second solution is to bring out crystalline precipitate.Cooling the second solution is preferably extremely between about 30 ℃-Yue 20 ℃ temperature, more preferably extremely between about 30 ℃-Yue 23 ℃ temperature, to obtain suspension.Can keep suspension at least about 3 hours, the yield of the crystalline form that is settled out with raising.
The preparation method of form 6 also can comprise reclaim crystalline form from suspension.Can be through any method known in the art, for example, filter, wash filtered form and drying reclaims with normal heptane.
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.The feature of form 7 is 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.Also can basically determine form 7 through the x-ray diffractogram of powder shown in Fig. 6.The feature of form 7 also is, through about 5.2% the weight loss of TGA.Also can basically determine form 7 through the TGA curve shown in Fig. 7.The feature of form 7 can be that also the DSC differential thermogram has in first about 136 ℃ endotherm(ic)peak with in second about 228.0 ℃ endotherm(ic)peak.Those skilled in the art can approve that form 7 can be passed through other method, include, but are not limited to solid state NMR, FTIR and Raman spectrum and identify.
Form 7 can be the solvation form of tiotropium bromide, preferred acetic acid solvent compound.The amount of the acetic acid of measuring according to GC is preferably about 1.7%.Measure 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 crystalline form 7 that the relatively pure form that is no more than other any type of tiotropium bromide of about 5% provides tiotropium bromide.Measure according to powder x-ray diffraction, preferably be no more than about 10% tiotropium bromide monohydrate to contain, preferably contain the crystalline form 7 that the relatively pure form that is no more than about 5% tiotropium bromide monohydrate provides tiotropium bromide.
Through comprising the method for crystallization tiotropium bromide from comprise the solvent mixture that is formed by acetic acid and acetonitrile and the mixture of the anti-solvent that is formed by diisopropyl ether, prepare the tiotropium bromide of described form 7.
Crystallization method the tiotropium bromide solution that provides in the described solvent is provided and adds diisopropyl ether to obtain suspension to this solution.
Preferably obtain tiotropium bromide solution by merging tiotropium bromide and described solvent and heating.
The ratio of acetic acid and acetonitrile preferably respectively is about 1/5 (volume/volume) of about 1/4-in described solvent.
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.
Preferably dropwise add diisopropyl ether to solution, more preferably warp was at least about 15 minutes.Preferably between about 40 ℃-Yue 50 ℃ temperature, more preferably to about 45 ℃ temperature, add.After adding diisopropyl ether, under said temperature, kept resulting suspension about one hour.
Usually cool off suspension, 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.
The 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.
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 basically form identification 8 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.
By comprising the crystalline form 8 for preparing tiotropium bromide from the method for methanol crystallization tiotropium bromide.
The method comprises the methanol solution that tiotropium bromide is provided and cools off this solution to obtain suspension.
Preferably obtain solution by merging tiotropium bromide and methyl alcohol and heating, the methanol solution of tiotropium bromide is provided.Heating preferably proceeds between about 61 ℃-Yue 65 ℃ temperature.More preferably, under about 63 ℃ temperature, heat.Heating was preferably carried out about 1 hour.
Usually 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.
Can keep the gained suspension at least about 3.5 hours, the yield of the product that is settled out with raising.
The 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 subsequently the filtered form of methanol wash, and dry, from suspension, reclaim resulting precipitation.
The present invention also provides the n-propyl alcohol solvate of tiotropium bromide.
The present invention also provides the crystalline tiotropium bromide of substantially identifying by the x-ray diffractogram of powder of the calculating shown in Figure 10 half n-propyl alcohol solvate.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 relatively pure 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 according to powder x-ray diffraction, can be no more than about 10% tiotropium bromide monohydrate to contain, preferably contain the relatively pure form that is no more than about 5% tiotropium bromide monohydrate, half n-propyl alcohol solvate of tiotropium bromide is provided.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.
The invention provides the half n-propyl alcohol solvate that is called form 9, it is characterized in that monocrystalline XRD has lower 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 basically differentiate described half n-propyl alcohol form by the ORTEP view shown in Figure 11.
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 lower 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].
Generally, term " isothermal condition " refers to constant temperature.The isothermal condition of preparation form 9 is temperature of 25 ℃.
The 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 ℃.
The n-propyl alcohol solution of tiotropium bromide preferably is provided by merging tiotropium bromide and n-propyl alcohol and heating.Preferably be heated to about 80 ℃-Yue 100 ℃, more preferably to 97 ℃ temperature.
Preferred cooling solution is to bring out single crystal settling.
The 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.
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 the 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.
Through comprising any tiotropium bromide solvate of heating to the method between about 160 ℃-Yue 170 ℃ temperature, preparation tiotropium bromide crystalline form 11.
Preferred heating tiotropium bromide solvate is to about 160 ℃ temperature.Preferred heating about 1 hour-Yue 2 hours, more preferably from about 1 hour.
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.
The feature of form 12 is 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 ± 0.2 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.
Prepare 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.
Preferably by merging tiotropium bromide and n-propyl alcohol and heating, provide the n-propyl alcohol solution of tiotropium bromide.Preferably be heated to about 80 ℃-Yue 100 ℃, more preferably to 97 ℃ temperature.
General cooling solution is to bring out the precipitation of described crystalline form.Preferred cooling solution is to about 55 ℃-Yue 25 ℃ temperature.Preferably gradually cooling.Further be cooled to again about 25 ℃-Yue 21 ℃ gradually cooling of temperature realization through reaching about 55 ℃ temperature.Preferably reached 55 ℃ through about 4 hours.Preferably reached about 25 ℃-Yue 21 ℃ temperature through about 3 hours.
Preferred further keeping through about 18 hours of the about 5-of suspension of cooling.
The 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.
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 such 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 such as powder x-ray diffraction, preferably can contain and be no more than about 10% tiotropium bromide monohydrate, preferably contain the relatively pure form that is no more than about 5% tiotropium bromide monohydrate, the tiotropium bromide of amorphous forms is provided.
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.
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 form 1,2 and 8 tiotropium bromide methyl alcohol form and is called form 9 is the preferred feedstock of above method.Preferably by tiotropium bromide is dissolved in water, the trimethyl carbinol, methyl alcohol or their mixture, prepare solution.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-.
Respectively be 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, 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.
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.
Respectively be the methyl alcohol of about 3/1 (volume/volume) and the mixture of acetone by merging tiotropium bromide and comprising ratio, and heating, solution is provided.
Preferably be heated to about 50 ℃-Yue 70 ℃ temperature, more preferably to about 60 ℃ temperature.
Usually cooling solution is to bring out crystalline precipitate.Preferably be cooled to about room temperature-Yue-5 ℃ temperature.When cooling proceeds to the temperature that is lower than room temperature, preferably reached this temperature through about 5 minutes.
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.
The 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.
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.
The method comprises the butanol solution that tiotropium bromide is provided and cools off this solution to obtain suspension.
Obtain 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.
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.
Keep the gained suspension with the yield of the product of raising crystallization.Preferably keep suspension at least about 5 hours.
The preparation method of crystalline form 10 also can comprise from suspension and reclaims it.Can for example, filter, wash filtered form and dry with propyl carbinol through any method known in the art, reclaim.
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.
The method preferably includes the ethanolic soln that tiotropium bromide is provided and cools off this solution to obtain suspension.
Provide solution by merging tiotropium bromide and ethanol and heating.
Preferred heated solution is extremely between about 70 ℃-Yue 80 ℃ temperature.More preferably, under about 73 ℃-Yue 78 ℃ temperature, heating.
Usually 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.
The 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.
Be 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.
The method comprises that merging obtains the aqueous isopropanol of tiotropium bromide, and cools off this solution, to obtain suspension.
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.
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.
Keep the gained suspension with the yield of the product that improves crystallization and go out.Preferably keep suspension at least about 5 hours.
The 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.
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.
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 compound.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.
Be preferable under the room temperature mixture is provided.The method can comprise keeps the about 4-8 of mixture hour step under the room temperature.
The 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 dry method, reclaim.
Be called form 1,2,6,7,8,9,11 and the tiotropium bromide of 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.
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.
Micronization process can be chosen follow-up one wantonly and comprise that exposure micronization form is in the method for appropriate solvent with the initial amount of the solvent in the recovery solvate.Term " suitable solvent " is often referred to the kind of the solvent in initial solvation form.
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.
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.
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.
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.
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.
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.
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.
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.
The present composition comprises and comprises any powder, particle, aggregation and other solids composition that is called the tiotropium bromide of form.
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 such 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; Other thinner that inorganic diluents such as calcium carbonate and monocalcium phosphate and pharmaceutical industry are known.Other applicable thinner also comprises paraffin, Saccharide and saccharide alcohols such as N.F,USP MANNITOL and sorbyl alcohol, acrylic ester polymer and multipolymer, and pectin, dextrin and gel.
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 other tackiness agent of the method for wet and dried granulating and direct pressing tablet.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.
But per os, parenteral (comprising subcutaneous, intramuscular and intravenously), suck and eye gives preparation.Although in any given situation, optimal approach will depend on 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.
Formulation comprises solid dosage, such 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, so that except tiotropium bromide, also according to transmitting solvate to described solution with certain ratio of solvate) and be considered within the scope of the invention.
Certainly, capsule can contain solids composition at the capsule by gelatin or other conventional encapsulated raw material preparation.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, such 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 with the powder of casing or the tablet of granule.
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 ± 0.2 degree 2-θ or the less 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 for 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 separately reporting peak position or peak heights.
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.The following example by with reference to the preparation and application of describing the present composition in detail further defines 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.
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)
Entrance:
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:
Diisopropyl ether, normal heptane, acetone, methyl alcohol, methylene dichloride, ethanol, acetonitrile, acetic acid.
Internal standard solution:
250 μ L dioxane → 250mL methyl-sulphoxides.
Raw material standard solution:
The 1mL all kinds of SOLVENTS adds to 100.0mL internal standard solution.
Working standard solution:
1mL raw material standard solution adds to 100.0mL internal standard solution (0.1 μ L/mL all kinds of SOLVENTS).
Sample solution:
In the 100mg sample, add 1mL internal standard solution.
Powder x-ray diffraction:
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, such as instrument, sample preparation etc., the accuracy of peak position is defined+/-0.2 degree.
Analyze the monocrystalline XRD method of tiotropium bromide n-propyl alcohol solvate:
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 ")
TGA/SDTA 851, Mettler Toledo, example weight 7-15mg.Rate of heating: be the N of 50ml/min at flow velocity
2In the air-flow 10 ℃/minute.Sweep limit: 30-250 ℃.
Dsc (" DSC ")
DSC 822e/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 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, be cooled 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 through sintered glass funnel, with 1.0mL mixture washing solid.21 ℃, at N
2Drying is 30 minutes under the air-flow, and then in 111 ℃, drying is 7 hours under decompression (40mbar), generates 0.01g tiotropium bromide form 1.
Embodiment 2: the preparation of tiotropium bromide form 2
Under 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, be cooled to 22 ℃.Keep the gained suspension under 22 ℃ at least 2 hours, and filtered through sintered glass funnel, wash solid twice with the 1.5mL mixture.22 ℃, N
2Under the air-flow, dry 30 minutes, again in 111 ℃, lower dry 7 hours of decompression (40mbar) generated 1.19g tiotropium bromide form 2.TGA weight loss: 2.3%.
Embodiment 3: the preparation of tiotropium bromide form 2
Under 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, cool off in 21 ℃.Keep the gained suspension under 21 ℃ at least 3 hours, and filtered through sintered glass funnel, wash solid three times with the 1.0mL mixture.21 ℃, N
2Drying is 30 minutes under the air-flow, and again in 111 ℃, lower dry 7 hours of decompression (40mbar) generates 0.154g tiotropium bromide form 2.TGA weight loss: 0.8%.
Embodiment 4: be characterised in that x-ray diffractogram of powder has the preparation of the tiotropium bromide 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
Under 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, cool off in 22 ℃.Keep 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 has the preparation method of the tiotropium bromide 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
Under 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, be cooled to 22 ℃.Keep the gained suspension under 22 ℃ at least 2 hours, and filtered through sintered glass funnel, wash solid twice with the 1.5mL mixture.22 ℃, N
2Drying is 30 minutes under the air-flow, and 60 ℃, lower dry 15 hours again of decompression generates 1.33g tiotropium bromide form 3.TGA weight loss: 4.3%.
Embodiment 6: be characterised in that x-ray diffractogram of powder has the preparation of the tiotropium bromide 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 placesUnder [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
2Drying is 30 minutes under the air-flow, generates 1.31g tiotropium bromide form 3.TGA weight loss: 4.5%.
Embodiment 7: be characterised in that x-ray diffractogram of powder has the preparation of the tiotropium bromide 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
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, be cooled to 22 ℃.Keep the gained suspension under 22 ℃ at least 3 hours, and filtered through sintered glass funnel, wash solid twice with dehydrated alcohol (2x1.0ml).22 ℃, N
2Drying is 30 minutes under the air-flow, and then in 60 ℃, lower dry 9 hours of the pressure of minimizing (17mbar) 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 has the preparation of the tiotropium bromide 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
Under 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, be cooled to 23 ℃.Keep the gained suspension under 23 ℃ at least 3 hours, and filtered through sintered glass funnel, wash solid twice with ethanol 96% (2x 1.5ml).23 ℃, N
2Drying is 1.5 hours under the air-flow, and again in 60 ℃, lower dry 5 hours of the pressure of minimizing (18mbar) 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 6
Under 45 ℃, with 7/2 (volume/volume) acetic acid/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.Heat resulting solution to 45 ℃ (not observing solid forms) through 1 hour, be cooled to 23.5 ℃ through at least 3 hours, kept the gained suspension at least 3 hours under 23.5 ℃.After filtering through sintered glass funnel, wash solid three times with the 3.0mL normal heptane.At 60 ℃, under the pressure of minimizing (18mbar), dry 16 hours, generate 0.67g tiotropium bromide form 6.TGA weight loss: 5.4%.
Embodiment 10: the preparation of tiotropium bromide form 6
Under 45 ℃, with 7/1 (volume/volume) acetic acid/carbinol mixture (10ml) dissolving tiotropium bromide (0.50g), through 1.5 hours heated solutions to 45 ℃, dropwise added again normal heptane (2.5ml) through at least 15 minutes.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 through sintered glass funnel, wash solid three times with the 2.0mL normal heptane.At 60 ℃, under the pressure of minimizing (19mbar), dry 18 hours, or at 90-100 ℃, drying is 7 hours under the 18mbar pressure, generates 0.29g tiotropium bromide form 6.TGA weight loss: 5.7%.
Embodiment 11: the preparation of tiotropium bromide form 7
Under 45 ℃, with 1/4 (volume/volume) acetic acid/acetonitrile mixture (6.75ml) dissolving tiotropium bromide (0.60g), through 1 hour heated solution to 45 ℃, dropwise added diisopropyl ether (DIPE) through at least 15 minutes (6.75ml) again.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 through sintered glass funnel, wash solid three times with 1.8mL diisopropyl ether (DIPE).At 21 ℃, N
2Drying is 1 hour under the air-flow, generates 0.40g tiotropium bromide form 7.
Embodiment 12: the preparation of tiotropium bromide form 8
Under 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 (2x0.8ml) washing solid twice, at 22 ℃, N
2Drying is 1 hour under the air-flow, 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 97 ℃.Then the n-propyl alcohol solution of thermotropism tiotropium bromide adds pentyl acetate (4ml).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 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 (2x1.0ml) washing solid twice, at 23 ℃, N
2Drying is 1 hour under the air-flow, and then at 60 ℃, lower dry 5 hours of decompression (18mbar) generates the 0.23g tiotropium bromide.TGA weight loss: 6.0%.
Embodiment 15: the preparation of tiotropium bromide form 9
Under 97 ℃, make tiotropium bromide (4g) be dissolved in n-propyl alcohol (348ml), be cooled to 55 ℃ through 4 hours again, be down to 25 ℃ through 3 hours from 55 ℃.Under 20-25 ℃, stirred 12 hours, filter suspension, at 45 ℃, lower dry 20 hours of decompression obtains tiotropium bromide form 9 (3g).
Embodiment 16: the preparation of tiotropium bromide form 9
Under 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 ℃, lower dry 20 hours of decompression obtains tiotropium bromide form 9 (1.3g).
Embodiment 17: the preparation of tiotropium bromide form 9
Under 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 and filter suspension after 12 hours, at 45 ℃, lower dry 20 hours of decompression 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 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 (2x1.0ml) washing solid twice, at 22 ℃, N
2Drying is 3 hours under the air-flow, and again in 65 ℃, lower dry 16.5 hours of decompression (18mbar) generates 0.133g tiotropium bromide form 10.TGA weight loss: 6.9%.
Embodiment 19: the preparation of tiotropium bromide form 11
In baking box, in 160 ℃, heating tiotropium bromide methylate, half propyl carbinol salt and half acetic acid solvent compound are 1 hour in independent Glass Containers, measure various materials through XRD.
Embodiment 20: the preparation of tiotropium bromide amorphous forms
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 mHg, 2
Chambers temp during 4 hours :-40 ℃-22 ℃.
Embodiment 21: the universal method of preparation tiotropium bromide monohydrate
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 upper 15 minute.
Embodiment 19: the preparation of tiotropium bromide monohydrate
Tiotropium bromide is suspended in water, and 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 upper 15 minute.Water-content in the sample is 4.3% (TGA analysis).
Embodiment 20: prepare tiotropium bromide monohydrate from the tiotropium bromide ethylate
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 upper 15 minute, obtains the 11.66g monohydrate.Water-content in the sample is 4.3% (TGA analysis).
Embodiment 21: the tiotropium bromide micronization
Tiotropium bromide is obtained following P.S.D target by micronization:
Minimum 70% between the 0.6-10 micron
Used pulverizer is micronizer mill (Jet-mill) MC 50 (Micro-Macinazionne systems
Make).The nozzle at 32 ° of 05 ' angles is housed.
Nitrogen is used as micronization gas.
Micronization air pressure is 10 bar.
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 (5)
1. a crystalline tiotropium bromide is characterized in that, its x-ray diffractogram of powder as shown in Figure 12.
2. method for preparing crystalline tiotropium bromide according to claim 1, it comprises that heating tiotropium bromide solvate is to the temperature between 160 ℃-170 ℃.
3. the micronization form of the tiotropium bromide of claim 1.
4. pharmaceutical preparation, it comprises tiotropium bromide and the pharmaceutically acceptable vehicle of claim 1.
5. pharmaceutical preparation, it comprises tiotropium bromide and the pharmaceutically acceptable vehicle of claim 1, and described tiotropium bromide is the micronization form.
Applications Claiming Priority (17)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US75267205P | 2005-12-19 | 2005-12-19 | |
| US60/752,672 | 2005-12-19 | ||
| US75453005P | 2005-12-27 | 2005-12-27 | |
| US60/754,530 | 2005-12-27 | ||
| US76143706P | 2006-01-23 | 2006-01-23 | |
| US60/761,437 | 2006-01-23 | ||
| US77405106P | 2006-02-15 | 2006-02-15 | |
| US60/774,051 | 2006-02-15 | ||
| US78031006P | 2006-03-07 | 2006-03-07 | |
| US60/780,310 | 2006-03-07 | ||
| US83218906P | 2006-07-20 | 2006-07-20 | |
| US60/832,189 | 2006-07-20 | ||
| US85122306P | 2006-10-12 | 2006-10-12 | |
| US60/851,223 | 2006-10-12 | ||
| US85274006P | 2006-10-18 | 2006-10-18 | |
| US60/852,740 | 2006-10-18 | ||
| PCT/US2006/048734 WO2007075858A2 (en) | 2005-12-19 | 2006-12-19 | Novel forms of tiotropium bromide and processes for preparation thereof |
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| CN102731494A (en) * | 2005-12-19 | 2012-10-17 | 西科尔公司 | Novel forms of tiotropium bromide and processes for preparation thereof |
| PT106142A (en) * | 2012-02-10 | 2013-08-12 | Hovione Farmaciencia S A | PROCESS FOR THE PREPARATION OF TIOTROPE BROMIDE |
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| CN103130798B (en) * | 2011-11-30 | 2015-12-02 | 连云港润众制药有限公司 | The crystallization of tiotropium bromide |
| JP6158939B2 (en) * | 2012-11-05 | 2017-07-05 | ゼンティーバ，カー．エス． | Stabilization of tiotropium solvates. |
| CN103965178B (en) * | 2013-02-06 | 2018-03-02 | 中国药科大学 | Purposes as the pyrrolidin derivatives of M3 muscarinic receptor antagonists and its in pharmacy |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102731494A (en) * | 2005-12-19 | 2012-10-17 | 西科尔公司 | Novel forms of tiotropium bromide and processes for preparation thereof |
| PT106142A (en) * | 2012-02-10 | 2013-08-12 | Hovione Farmaciencia S A | PROCESS FOR THE PREPARATION OF TIOTROPE BROMIDE |
| PT106142B (en) * | 2012-02-10 | 2014-07-18 | Hovione Farmaci Ncia S A | PROCESS FOR THE PREPARATION OF TIOTROPE BROMIDE |
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