HK1114856B - Novel crystalline forms of tiotropium bromide - Google Patents
Novel crystalline forms of tiotropium bromide Download PDFInfo
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- HK1114856B HK1114856B HK08110456.8A HK08110456A HK1114856B HK 1114856 B HK1114856 B HK 1114856B HK 08110456 A HK08110456 A HK 08110456A HK 1114856 B HK1114856 B HK 1114856B
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Description
The present invention relates to novel crystalline forms of tiotropium bromide, processes for their preparation and their use for the preparation of pharmaceutical compositions for the treatment of respiratory diseases, in particular for the treatment of COPD (chronic obstructive pulmonary disease) and asthma.
Background
Tiotropium bromide is known from european patent application EP 418716 a1 and has the following chemical structure:
tiotropium bromide is a long-acting, high-efficacy anticholinergic which can be used for the treatment of respiratory diseases, in particular for the treatment of COPD (chronic obstructive pulmonary disease) and asthma. And tiotropium (tiotropium) refers to the free ammonium cation.
Tiotropium bromide is preferably administered by inhalation. Suitable inhalable powders filled in suitable capsules (inhalants) may be used. Alternatively, it may be administered by using a suitable inhalable aerosol. The inhalable aerosols also include powdered inhalable aerosols containing, for example: HFA134a, HFA227 or mixtures thereof as a propellant gas.
The correct preparation of the above-mentioned compositions suitable for the administration of pharmaceutically active substances by inhalation depends on various parameters relating to the nature of the active substance itself. In pharmaceutical compositions using tiotropium bromide in the form of inhalable powders or inhalable aerosols, the formulations are prepared with the crystalline active substance in ground (micronized) form. Since the pharmaceutical properties of pharmaceutical preparations require that the active substance should always have the same crystal modification, the stability and properties of the crystalline active substance are therefore subject to stringent requirements from the standpoint of this point of view.
It is therefore an object of the present invention to provide new crystalline forms of tiotropium bromide compounds which meet the high requirements set forth above for the preparation of any pharmaceutically active substance.
Detailed Description
It is known that different crystalline forms of tiotropium bromide can be obtained, depending on the choice of conditions that can be used during the purification of the crude product obtained after industrial production. It is known that these different crystalline forms can be obtained decisively by the choice of the solvent used for the crystallization and by the choice of the operating conditions during the crystallization.
It was unexpectedly found that starting from the monohydrate of tiotropium bromide (a crystalline form which can be obtained by selecting specific reaction conditions and which was originally described in prior art WO 02/30928), anhydrous crystalline forms of tiotropium bromide meeting the above-mentioned high requirements can be obtained and thus the underlying problem of the present invention is solved.
Thus, in one embodiment, the invention relates to anhydrous crystalline tiotropium bromide. The term anhydrous tiotropium bromide as referred to within the scope of the present invention refers to anhydrous crystals of tiotropium bromide according to the present invention.
The present invention relates to anhydrous crystalline tiotropium bromide, characterized by the structural analysis by X-ray analysis: orthorhombic system (orthorhombic elementary cell) with unit cell parameter a ═ 11.7420(4)，b＝17.7960(7)，c＝19.6280(11)And the unit cell volume is 4101.5(3)3。
In another embodiment, the present invention relates to novel tiotropium bromide solvate crystals. One aspect of the present invention relates to the 1, 4-bis-formation of tiotropium bromideThe alkane solvate crystallized. Another aspect of the present invention relates to the preparation of the novel 1, 4-bis-tiotropium bromideProcess for the crystallization of an alkane solvate, which comprisesThis is explained by way of example in the experimental section below.
The present invention relates to 1, 4-bis (S) -tiotropium bromideAn alkane solvate crystalline characterized by an X-ray structural analysis of: monoclinic electric cell (monoclinic electric cell) with a unit cell parameter of a ═ 13.6650(3)，b＝12.0420(3)，c＝13.7090(3)β 103.8150(13) ° and unit cell volume 2190.61(9)3。
In another embodiment, the present invention relates to crystalline ethanol solvate of tiotropium bromide. Another aspect of the present invention relates to a process for the preparation of the novel crystalline ethanol solvate of tiotropium bromide, which is explained by way of example in the experimental section below.
The present invention relates to crystalline ethanol solvates of tiotropium bromide, characterized by the structural analysis by X-ray: monoclinic system, unit cell parameter a ═ 13.5380(2)，b＝11.9830(2)，c＝26.9410(5)β 105.1990(6) ° and unit cell volume 4217.65(12)3。
In another embodiment, the present invention relates to crystalline methanol solvate of tiotropium bromide. Another aspect of the present invention relates to a process for the preparation of the novel crystalline methanol solvate of tiotropium bromide, which is explained by way of example in the experimental section below.
The present invention relates to crystalline methanol solvate of tiotropium bromide, characterized by the structural analysis by X-ray: monoclinic system, unit cell parameter a ═ 13.4420(2)，b＝37.0890(5)，c＝13.6290(2)β 104.7050(10) ° and unit cell volume 6572.18(16)3。
In another embodiment, the present invention relates to crystalline anisole solvates of tiotropium bromide. Another aspect of the present invention relates to a process for the preparation of the novel crystalline anisole solvate of tiotropium bromide, which is explained by way of example in the experimental section below.
The invention relates to an anisole solvate crystal of tiotropium bromide, which is characterized in that the characteristic value d of the X-ray powder diffraction pattern is 12.99；8.84；7.96；6.84；6.55；5.76；5.40；4.88；4.43；4.21；4.14；3.73；3.58；3.41；3.27；3.18；3.00(ii) a And 2.95And the like.
In another embodiment, the invention relates to crystalline n-butanol solvate of tiotropium bromide. Another aspect of the present invention relates to a process for the preparation of the novel crystalline n-butanol solvate of tiotropium bromide, which is explained by way of example in the experimental section below.
The invention relates to a crystalline n-butanol solvate of tiotropium bromide, characterized in that it has an X-ray powder diffraction pattern with a characteristic value d of 9.83；10.93；13.38；13.54；15.34；17.95；19.77；20.83；21.41；24.15；24.56；25.03；25.66；26.03；26.95(ii) a And 29.87And the like.
In another embodiment, the present invention relates to N, N-dimethylacetamide (═ DMA) solvate crystals of tiotropium bromide. Another aspect of the present invention relates to a process for the preparation of the novel crystalline DMA solvate of tiotropium bromide, which is explained by way of example in the experimental section below.
The invention relates to a DMA solvate crystal of tiotropium bromide, which is characterized in that the characteristic value d of an X-ray powder diffraction pattern is 8.86；7.89；6.50；5.73；5.37；4.89；4.42；4.18；4.10；3.83；3.72；3.55；3.39；3.25；3.16(ii) a And 2.95And the like.
In another embodiment, the present invention relates to crystalline N, N-dimethylformamide (═ DMF) solvate of tiotropium bromide. Another aspect of the present invention relates to a process for the preparation of the novel crystalline DMF solvate of tiotropium bromide, which is explained by way of example in the experimental section below.
The invention relates to a DMF solvate crystal of tiotropium bromide, which is characterized in that the characteristic value d of an X-ray powder diffraction pattern is 8.86；7.95；6.51；5.73；5.36；4.89；4.43；4.19；4.12；3.82；3.68；3.57；3.40；3.25；3.16(ii) a And 2.96And the like.
In another embodiment, the invention relates to an isopropanol solvate of tiotropium bromide. Another aspect of the present invention relates to a process for the preparation of the novel crystalline isopropanol solvate of tiotropium bromide, which is explained by way of example in the experimental section below.
The present invention relates to crystalline isopropanol solvate of tiotropium bromide, characterized by an X-ray powder diffraction patternThe value d is 9.87；11.00；13.31；13.47；15.15；15.35；16.30；18.06；19.80；19.93；20.26；20.77；21.33；23.54；24.02；24.64；25.08；25.85；27.02；27.68；27.93；29.50(ii) a And 29.86And the like.
In another embodiment, the invention relates to a1, 2-propanediol solvate of tiotropium bromide. Another aspect of the present invention relates to a process for the preparation of the novel crystalline 1, 2-propanediol solvate of tiotropium bromide, which is explained by way of example in the experimental section below.
The present invention relates to a crystalline 1, 2-propanediol solvate of tiotropium bromide, characterized in that it has an X-ray powder diffraction pattern with a characteristic value d of 8.89；7.97；6.59；5.77；5.43；4.90；4.44；4.17；3.85；3.73；3.60；3.55；3.42；3.30；3.20And 2.96And the like.
In another embodiment, the present invention relates to a pyridine solvate of tiotropium bromide. Another aspect of the present invention relates to a process for the preparation of the novel crystalline pyridine solvate of tiotropium bromide, which is explained by way of example in the experimental section below.
The present invention relates to pyridine solvate crystals of tiotropium bromide, characterized by an X-ray powder diffraction pattern with a characteristic value d of 13.06；8.89；7.88；6.57；5.76；5.40；4.89；4.45；4.16；3.72；3.55；3.43；3.29；3.19And 2.95And the like.
In another embodiment, the invention relates to a tert-butanol solvate of tiotropium bromide. Another aspect of the present invention relates to a process for the preparation of the novel crystalline tert-butanol solvate of tiotropium bromide, which is explained by way of example in the experimental section below.
The invention relates to crystalline tiotropium bromide tert-butyl alcohol solvate, characterized in that it has an X-ray powder diffraction pattern with a characteristic value d of 13.13；8.81；7.98；6.57；5.76；5.41；4.89；4.44；4.23；4.14；3.73；3.56；3.42；3.29；3.19And 2.95And the like.
In another embodiment, the present invention relates to tetrahydrofuran (═ THF) solvate of tiotropium bromide. Another aspect of the present invention relates to a process for the preparation of the novel crystalline THF solvate of tiotropium bromide, which is explained by way of example in the experimental section below.
The invention relates to a THF solvate crystal of tiotropium bromide, characterized in that the characteristic value d of the X-ray powder diffraction pattern is 8.69；7.84；6.47；5.92；5.70；5.37；4.85；4.41；4.34；4.19；4.09；3.81；3.69；3.58；3.52；3.40；3.27；3.18And 2.94And the like.
In another embodiment, the present invention relates to tetrahydropyran (═ THP) solvates of tiotropium bromide. Another aspect of the present invention relates to a method for preparing the novel crystalline THP solvate of tiotropium bromide, which is explained by way of example in the experimental section below.
The invention relates to a THP solvate crystal of tiotropium bromide, which is characterized in particular by an X-ray powder diffraction pattern with a characteristic value d of 8.94；7.97；6.54；5.75；5.35；4.89；4.44；4.23；4.13；3.89；3.79；3.65；3.60；3.53；3.43；3.24；3.17And 2.98And the like.
The invention also relates to the use of these crystalline forms of tiotropium bromide according to the invention for the preparation of a pharmaceutical composition for the treatment of respiratory diseases, in particular the treatment of COPD and/or asthma.
The present invention also relates to processes for preparing these crystalline forms of tiotropium bromide of the present invention.
Another aspect of the present invention relates to a process for the preparation of the novel anhydrous crystalline forms of tiotropium bromide, characterized in that crystalline tiotropium bromide monohydrate (known from WO 02/30928) is dissolved in a suitable solvent, preferably a solvent mixture comprising N, N-dimethylacetamide, more preferably a solvent mixture comprising dimethylacetamide and water, heated for a period of 10-60 minutes to a temperature in the range of about 30-70 ℃, preferably about 40-60 ℃, and after cooling to a temperature below 15 ℃, preferably below 10 ℃, anhydrous crystalline tiotropium is precipitated from the mixture. Another aspect of the present invention relates to the use of tiotropium bromide monohydrate as starting material for the preparation of anhydrous crystalline tiotropium bromide according to the present invention.
Another aspect of the present invention relates to a process for the preparation of the novel crystalline methanol solvate of tiotropium bromide, characterized in that crystalline tiotropium bromide monohydrate (known from WO 02/30928) is dried at a temperature of 60-90 ℃, preferably 70-85 ℃ for about 10 to 60 minutes, preferably 20-40 minutes, and thereafter dissolved in a methanol containing solvent, preferably a solvent mixture comprising methanol and acetone, and subsequently cooled to a temperature below 0 ℃, preferably to a temperature in the range of-30 to-10 ℃ for at least 10 hours, preferably 12-20 hours, and the thus obtained crystalline methanol solvate is isolated and dried. Another aspect of the present invention relates to the use of tiotropium bromide monohydrate as starting material for the preparation of crystalline methanol solvates of tiotropium bromide according to the invention.
Another aspect of the present invention relates to a process for the preparation of the novel crystalline ethanol solvate of tiotropium bromide, characterized in that crystalline tiotropium bromide monohydrate (known from WO 02/30928) is dried at a temperature of 60-90 ℃, preferably 70-85 ℃ for about 10 to 60 minutes, preferably 20-40 minutes, thereafter redissolved in a solvent comprising ethanol, preferably a solvent mixture comprising ethanol and acetone, and subsequently cooled to a temperature below 0 ℃, preferably to a temperature in the range of-30 to-10 ℃ for at least 10 hours, preferably 12-20 hours, the thus obtained crystals are isolated and dried. Another aspect of the present invention relates to the use of tiotropium bromide monohydrate as starting material for the preparation of crystalline ethanol solvates of tiotropium bromide according to the invention.
Another aspect of the present invention relates to a process for the preparation of the novel crystalline isopropanol solvate of tiotropium bromide, characterized in that crystalline tiotropium bromide monohydrate (known from WO 02/30928) is dried at a temperature of 60-90 ℃, preferably 70-85 ℃ for about 10 to 60 minutes, preferably 20-40 minutes, and thereafter dissolved in a solvent comprising methanol, preferably pure methanol, the solution thus obtained is added to a solvent comprising isopropanol, preferably to pure isopropanol, and subsequently cooled to a temperature below 15 ℃, preferably to a temperature in the range of 0 to 5 ℃ for at least 8 hours, preferably 10-16 hours, the crystals thus obtained are isolated and dried. Another aspect of the present invention relates to the use of tiotropium bromide monohydrate as starting material for the preparation of crystalline isopropanol solvates of tiotropium bromide according to the invention.
Another aspect of the present invention relates to a process for the preparation of the novel crystalline n-butoxide solvate of tiotropium bromide, characterized in that crystalline tiotropium bromide monohydrate (known from WO 02/30928) is dried at a temperature of 60-90 ℃, preferably 70-85 ℃ for about 10 to 60 minutes, preferably 20-40 minutes, thereafter dissolved in a solvent comprising methanol, preferably pure methanol, the solution thus obtained is added to a solvent comprising n-butanol, preferably to pure butanol, and subsequently cooled to a temperature below 15 ℃, preferably to a temperature in the range of 0 to 5 ℃ for at least 8 hours, preferably 10-16 hours, the crystalline thus obtained is isolated and dried. Another aspect of the present invention relates to the use of tiotropium bromide monohydrate as starting material for the preparation of crystalline n-butanol solvate of tiotropium bromide according to the invention.
Another aspect of the present invention relates to a process for the preparation of the novel crystalline THF solvate of tiotropium bromide, characterized in that crystalline tiotropium bromide monohydrate (known from WO 02/30928) is dried at a temperature of 60-90 ℃, preferably 70-85 ℃ for about 10 to 60 minutes, preferably 20-40 minutes, thereafter dissolved in a solvent comprising methanol, preferably pure methanol, the solution thus obtained is added to a solvent comprising THF, preferably to pure THF, and subsequently cooled to a temperature below 15 ℃, preferably to a temperature in the range of 0 to 5 ℃ for at least 8 hours, preferably 10-16 hours, the crystalline thus obtained is isolated and dried. Another aspect of the present invention relates to the use of tiotropium bromide monohydrate as starting material for the THF solvate crystallization of tiotropium bromide according to the present invention.
Another aspect of the present invention relates to the preparation of the novel ditto of tiotropium bromideProcess for the crystallization of an alkane solvate, characterized in that crystalline tiotropium bromide monohydrate (known from WO 02/30928) is dried at a temperature of 60-90 ℃, preferably 70-85 ℃ for about 10 to 60 minutes, preferably 20-40 minutes, and thereafter redissolved in a methanol-containing solvent, preferably pure methanol, and the solution thus obtained is added to a solution containing di-tert-butyl alcoholThe solvent of the alkane is preferably added to the pure diIn an alkane and subsequently cooled to a temperature below 15 ℃, preferably in the range of 0 to 5 ℃ for at least 8 hours, preferably 10-16 hours, the crystals thus obtained being isolated and dried. Another aspect of the present invention relates to tiotropium bromide monohydrate as di-hydrate for the preparation of tiotropium bromide according to the inventionUse of a starting material for the crystallization of an alkane solvate.
Another aspect of the present invention relates to a process for the preparation of the novel crystalline 1, 2-propanediol solvate of tiotropium bromide, characterized in that crystalline tiotropium bromide monohydrate (known from WO 02/30928) is dried at a temperature of 60-90 ℃, preferably 70-85 ℃ for about 10 to 60 minutes, preferably 20-40 minutes, after which it is dissolved in a solvent containing 1, 2-propanediol, preferably in pure 1, 2-propanediol, the solution thus obtained is maintained at a temperature of 30-70 ℃, preferably 40-60 ℃, for about 20-90 minutes, preferably 30-70 minutes, optionally filtered and subsequently cooled to a temperature below 15 ℃, preferably to a temperature in the range of 0-10 ℃ for at least 12 hours, preferably 18-30 hours. The crystals thus obtained are isolated and dried. Another aspect of the present invention relates to the use of tiotropium bromide monohydrate as starting material for the preparation of crystalline 1, 2-propanediol solvates of tiotropium bromide according to the invention.
Another aspect of the present invention relates to a process for the preparation of the novel crystalline anisole solvate of tiotropium bromide, characterized in that crystalline tiotropium bromide monohydrate (known from WO 02/30928) is dried at a temperature of 60-90℃, preferably 70-85℃, for about 10 to 60 minutes, preferably 20-40 minutes, after which it is dissolved in a anisole containing solvent, preferably pure anisole. The solution thus obtained is maintained at a temperature of 30-70 ℃, preferably 40-60 ℃ for about 20-90 minutes, preferably 30-70 minutes, optionally filtered and subsequently cooled to a temperature below 15 ℃, preferably in the temperature range of 0 to 10 ℃ for at least 12 hours, preferably 18-30 hours. The crystals thus obtained are isolated and dried. Another aspect of the present invention relates to the use of tiotropium bromide monohydrate as starting material for the preparation of the crystalline anisole solvate of tiotropium bromide according to the present invention.
Another aspect of the present invention relates to a process for the preparation of the novel crystalline THP solvate of tiotropium bromide, characterized in that crystalline tiotropium bromide monohydrate (known from WO 02/30928) is dried at a temperature of 60-90 ℃, preferably 70-85 ℃ for about 10 to 60 minutes, preferably 20-40 minutes, after which it is dissolved in a solvent containing THP, preferably in pure THP, the solution thus obtained is maintained at a temperature of 30-70 ℃, preferably 40-60 ℃ for about 20-90 minutes, preferably 30-70 minutes, optionally filtered and subsequently cooled to a temperature below 15 ℃, preferably to a temperature in the range of 0 to 10 ℃ for at least 12 hours, preferably 18-30 hours. The crystals thus obtained are isolated and dried. Another aspect of the present invention relates to the use of tiotropium bromide monohydrate as starting material for the preparation of the crystalline THP solvate of tiotropium bromide according to the present invention.
Another aspect of the present invention relates to a process for the preparation of the novel crystalline DMF solvate of tiotropium bromide, characterized in that crystalline tiotropium bromide monohydrate (known from WO 02/30928) is dried at a temperature of 60-90 ℃, preferably 70-85 ℃ for about 10 to 60 minutes, preferably 20-40 minutes, after which it is suspended in a DMF containing solvent, preferably dissolved in pure DMF, to the solution thus obtained an anti-solvent (anti solvent), preferably dichloromethane, is added, the crystalline thus obtained is isolated and dried. Another aspect of the present invention relates to the use of tiotropium bromide monohydrate as starting material for the preparation of the DMF solvate crystals of tiotropium bromide according to the present invention.
Another aspect of the present invention relates to a process for the preparation of the novel crystalline DMA solvate of tiotropium bromide, characterized in that crystalline tiotropium bromide monohydrate (known from WO 02/30928) is dried at a temperature of 60-90 ℃, preferably 70-85 ℃ for about 10 to 60 minutes, preferably 20-40 minutes, after which it is suspended in a DMA containing solvent, preferably dissolved in pure DMA, to the solution thus obtained an anti-solvent, preferably dichloromethane, is added, and the crystalline thus obtained is isolated and dried. Another aspect of the present invention relates to the use of tiotropium bromide monohydrate as starting material for the preparation of DMA solvate crystals of tiotropium bromide according to the present invention.
Another aspect of the present invention relates to a process for the preparation of the novel crystalline THF solvate of tiotropium bromide, characterized in that crystalline tiotropium bromide monohydrate (known from WO 02/30928) is dissolved in an acetone-containing solvent, preferably a solvent mixture comprising acetone and water, the solvent is slowly evaporated and the remaining solid is treated with a THF-containing solvent, preferably a solvent comprising THF and water, the solution thus obtained is maintained at a temperature of 30-70 ℃, preferably 40-60 ℃, for about 10 to 60 minutes, preferably 20-40 minutes, and subsequently cooled to a temperature below 15 ℃, preferably in the temperature range of 0 to 10 ℃, for at least 12 hours, preferably 18-30 hours. The crystals thus obtained are isolated and dried. Another aspect of the present invention relates to the use of tiotropium bromide monohydrate as starting material for the preparation of THF solvate crystals of tiotropium bromide according to the present invention.
Another aspect of the present invention relates to a process for the preparation of the novel crystalline tert-butyl alcohol solvate of tiotropium bromide, characterized in that crystalline tiotropium bromide monohydrate (known from WO 02/30928) is dissolved in a solvent comprising acetone, preferably a solvent comprising acetone and water, the solvent is slowly evaporated and the remaining solid is treated with a solvent comprising tert-butyl alcohol, preferably a solvent comprising tert-butyl alcohol and water, the solution thus obtained is maintained at a temperature of 30-70 ℃, preferably 40-60 ℃, for about 10 to 60 minutes, preferably 20-40 minutes, and subsequently cooled to a temperature below 15 ℃, preferably in the temperature range of 0 to 10 ℃, for at least 12 hours, preferably 18-30 hours. The crystals thus obtained are isolated and dried. Another aspect of the present invention relates to the use of tiotropium bromide monohydrate as starting material for the preparation of crystalline tert-butanol solvates of tiotropium bromide according to the invention.
Another aspect of the present invention relates to a process for the preparation of the novel pyridine solvate crystals of tiotropium bromide, characterized in that the tiotropium bromide monohydrate crystals (known from WO 02/30928) are dissolved in a solvent comprising acetone, preferably a solvent comprising acetone and water, the solvent is slowly evaporated and the remaining solid is treated with a solvent comprising pyridine, preferably a solvent comprising pyridine and water, the solution thus obtained is maintained at a temperature of 30-70 ℃, preferably 40-60 ℃, for about 10 to 60 minutes, preferably 20-40 minutes, and subsequently cooled to a temperature below 15 ℃, preferably in the temperature range of 0 to 10 ℃, for at least 12 hours, preferably 18-30 hours. The crystals thus obtained are isolated and dried. Another aspect of the present invention relates to the use of tiotropium bromide monohydrate as starting material for the preparation of the pyridine solvate crystals of tiotropium bromide according to the present invention.
The following examples serve to further illustrate the invention and do not limit the scope of the invention to the polymer embodiments of the following examples.
Examples of syntheses according to the invention
Example 1: anhydrous crystals of tiotropium bromide
600mg of tiotropium bromide monohydrate crystals (according to WO 02/30928) are dissolved in 10ml of a 1: 1 mixture of N, N-dimethylacetamide and water. The solution was stirred at 50 ℃ for 30 minutes. Thereafter, the solvent was slowly evaporated under vacuum (about 1kPa) at room temperature. After about 24 hours a first anhydrous crystalline tiotropium bromide was formed, which was obtained by filtration and drying at ambient conditions.
Example 2: crystalline methanol solvate of tiotropium bromide
1.0g of tiotropium bromide monohydrate (according to WO 02/30928) was dried in vacuo at 80 ℃ for 30 minutes. The anhydrous form obtained in this step is then dissolved with stirring in 10ml of a 2: 1 mixture of methanol/acetone. The solution was stored in a refrigerator at-20 ℃ for 16 hours. When the solution is stirred and slowly warmed to room temperature, tiotropium bromide methanol solvate crystallizes out. The crystals were filtered off and dried at ambient conditions.
Example 3: crystalline ethanol solvate of tiotropium bromide
1.0g of tiotropium bromide monohydrate (according to WO 02/30928) was dried in vacuo at 80 ℃ for 30 minutes. The anhydrous form obtained in this step is then dissolved with stirring in 10ml of a 2: 1 mixture of ethanol/acetone. The solution was stored in a refrigerator at-20 ℃ for 16 hours. When the solution is stirred and slowly warmed to room temperature, tiotropium bromide ethanol solvate is crystallized and precipitated. The crystals were filtered off and dried at ambient conditions.
Example 4: crystalline isopropanol solvate of tiotropium bromide
2.0g of tiotropium bromide monohydrate (according to WO 02/30928) were dried in vacuo at 80 ℃ for 30 minutes. The anhydrous form obtained in this step is then dissolved in 50ml of methanol with stirring. This methanol solution of tiotropium bromide was added slowly to 50ml of isopropanol at room temperature with stirring. The mixture was stirred at room temperature for a further 30 minutes and stored in a refrigerator at 4 ℃ overnight. The resulting crystals were filtered and dried at ambient conditions.
Example 5: crystalline n-butanol solvate of tiotropium bromide
2.0g of tiotropium bromide monohydrate (according to WO 02/30928) were dried in vacuo at 80 ℃ for 30 minutes. The anhydrous form obtained in this step is then dissolved in 50ml of methanol with stirring. This methanol solution of tiotropium bromide was slowly added to 50ml of n-butanol at room temperature with stirring. The mixture was stirred at room temperature for a further 30 minutes and stored in a refrigerator at 4 ℃ overnight. The resulting crystals were filtered and dried at ambient conditions.
Example 6: crystalline THF solvate of tiotropium bromide
2.0g of tiotropium bromide monohydrate (according to WO 02/30928) were dried in vacuo at 80 ℃ for 30 minutes. The anhydrous form obtained in this step is then dissolved in 50ml of methanol with stirring. This methanol solution of tiotropium bromide was added slowly to 50ml of tetrahydrofuran at room temperature with stirring. The mixture was stirred at room temperature for a further 30 minutes and stored in a refrigerator at 4 ℃ overnight. The resulting crystals were filtered and dried at ambient conditions.
Example 7: 1, 4-bis-of tiotropium bromideCrystals of alkane solvate
2.0g of tiotropium bromide monohydrate (according to formula I) are added under vacuum at 80 deg.CWO 02/30928) for 30 minutes. The anhydrous form obtained in this step is then dissolved in 50ml of methanol with stirring. This methanol solution of tiotropium bromide was slowly added to 50ml of bis (bromoxymethyl) at room temperature with stirringIn an alkane. The mixture was stirred at room temperature for a further 30 minutes and stored in a refrigerator at 4 ℃ overnight. The resulting crystals were filtered and dried at ambient conditions.
Example 8: crystalline 1, 2-propanediol solvate of tiotropium bromide
2.0g of tiotropium bromide monohydrate (according to WO 02/30928) were dried in vacuo at 80 ℃ for 30 minutes. The anhydrous form obtained in this step was suspended in 10ml of 1, 2-propanediol at 50 ℃ for 20 minutes and then filtered to give a saturated solution of tiotropium bromide in 1, 2-propanediol. The concentration was determined by HPLC and it was determined that about 100mg/ml tiotropium bromide was dissolved in 1, 2-propanediol. After filtering the slurry at 50 ℃, a small portion was transferred to a 1.8ml glass vial and placed in a temperature control device. The solution was held at 50 ℃ for a further 30 minutes and subsequently cooled at a rate of 30 ℃/hour to a final temperature of 5 ℃. At this temperature, the solid was kept in solution for 24 hours. After this cooling crystallization step, a dry solid was obtained by filtration and drying at ambient conditions.
Example 9: crystalline anisole solvate of tiotropium bromide
At 50 ℃, 1.0g of tiotropium bromide monohydrate (according to WO 02/30928) was suspended in 5ml of a 60: 40 mixture of anisole (═ methoxybenzene)/water for 20 minutes and subsequently filtered to give a saturated solution of tiotropium bromide in this solvent mixture. The concentration was determined by HPLC and it was determined that about 90mg/ml tiotropium bromide in the mixture was dissolved in anisole/water 60: 40. After filtering the slurry at 50 ℃, a small portion was transferred to a 1.8ml glass vial and placed in a temperature control device. The solution was held at 50 ℃ for a further 30 minutes and subsequently cooled at a rate of 30 ℃/hour to a final temperature of 5 ℃. At this temperature, the solid was kept in solution for 24 hours. After this cooling crystallization step, a dry solid was obtained by filtration and drying at ambient conditions.
Example 10: crystalline THP solvate of tiotropium bromide
At 50 ℃, 1.0g of tiotropium bromide monohydrate (according to WO 02/30928) was suspended in 5ml of a 60: 40 THP/water mixture for 20 minutes and subsequently filtered to give a saturated solution of tiotropium bromide in this solvent mixture. The concentration was determined by HPLC and it was determined that about 35mg/ml tiotropium bromide in the mixture was dissolved in THP/water 60: 40. After filtering the slurry at 50 ℃, a small portion was transferred to a 1.8ml glass vial and placed in a temperature control device. The solution was held at 50 ℃ for a further 30 minutes and subsequently cooled at a rate of 30 ℃/hour to a final temperature of 5 ℃. At this temperature, the solid was kept in solution for 24 hours. After this cooling crystallization step, a dry solid was obtained by filtration and drying at ambient conditions.
Example 11: crystalline DMF solvate of tiotropium bromide
1.0g of tiotropium bromide monohydrate (according to WO 02/30928) was dried in vacuo at 80 ℃ for 30 minutes. The anhydrous form obtained in this step was suspended in 10ml of DMF at room temperature for 2 hours and then filtered to give a saturated solution of tiotropium bromide in DMF. The concentration was determined by HPLC and it was determined that about 75mg/ml tiotropium bromide was dissolved in DMF. After the slurry was filtered at room temperature, a small portion was transferred to a 1.8ml glass vial. Dichloromethane was added as an anti-solvent in a ratio of solvent to anti-solvent of 1: 2. A precipitated solid was obtained by filtration and dried at ambient conditions.
Example 12: DMA solvate crystals of tiotropium bromide
1.0g of tiotropium bromide monohydrate (according to WO 02/30928) was dried in vacuo at 80 ℃ for 30 minutes. The anhydrous form obtained in this step was suspended in 10ml of DMA at room temperature for 2 hours and then filtered to give a saturated solution of tiotropium bromide in DMA. The concentration was determined by HPLC and it was determined that about 40mg/ml tiotropium bromide was dissolved in DMA. After the slurry was filtered at room temperature, a small portion was transferred to a 1.8ml glass vial. Dichloromethane was added as an anti-solvent in a ratio of solvent to anti-solvent of 1: 2. A precipitated solid was obtained by filtration and dried at ambient conditions.
Example 13: crystalline THF solvate of tiotropium bromide
600mg of tiotropium bromide crystals (according to WO 02/30928) are dissolved in 10ml of an 80: 20 acetone/water mixture. Transfer 40. mu.l of this stock solution to one of the wells of a 96-well plate. The tray containing the mother liquor was placed in a vacuum chamber (1.3kPa) at room temperature for 40 hours. After evaporation of the mother liquor solvent, 40. mu.l of a 60: 40 THF/water mixture was added to the well. The entire 96-well plate was then sealed and heated to 50 ℃ at a rate of 5 ℃/min and the plate was allowed to sit at this temperature for an additional 30 minutes. The disk was then cooled to a final temperature of 5 ℃ at a cooling rate of 5 ℃/hour. The pan was left at this temperature for a further 24 hours. The pan was then opened and the solid obtained by evaporating the solvent at room temperature in a vacuum chamber (13 kPa).
Example 14: crystalline tert-butanol solvate of tiotropium bromide
600mg of tiotropium bromide crystals (according to WO 02/30928) are dissolved in 10ml of an 80: 20 acetone/water mixture. Transfer 40. mu.l of this stock solution to one of the wells of a 96-well plate. The tray containing the mother liquor was placed in a vacuum chamber (1.3kPa) at room temperature for 40 hours. After evaporation of the mother liquor solvent, 40. mu.l of a 20: 80 tert-butanol/water mixture was added to the wells. The entire 96-well plate was then sealed and heated to 50 ℃ at a rate of 5 ℃/min and the plate was allowed to sit at this temperature for an additional 30 minutes. The disk was then cooled to a final temperature of 5 ℃ at a cooling rate of 5 ℃/hour. The pan was left at this temperature for a further 24 hours. The pan was then opened and the solid obtained by evaporating the solvent at room temperature in a vacuum chamber (13 kPa).
Example 15: crystalline pyridine solvate of tiotropium bromide
600mg of tiotropium bromide crystals (according to WO 02/30928) are dissolved in 10ml of an 80: 20 acetone/water mixture. Transfer 40. mu.l of this stock solution to one of the wells of a 96-well plate. The tray containing the mother liquor was placed in a vacuum chamber (1.3kPa) at room temperature for 40 hours. After evaporation of the mother liquor solvent, 40. mu.l of a 50: 50 mixture of pyridine/water was added to the well. The entire 96-well plate was then sealed and heated to 50 ℃ at a rate of 5 ℃/min and the plate was allowed to sit at this temperature for an additional 30 minutes. The disk was then cooled to a final temperature of 5 ℃ at a cooling rate of 5 ℃/hour. The pan was left at this temperature for a further 24 hours. The pan was then opened and the solid obtained by evaporating the solvent at room temperature in a vacuum chamber (13 kPa).
Characterization of the crystalline forms of tiotropium bromide according to the invention
The method comprises the following steps:
single crystal X-ray diffraction
The appropriate single crystals selected after the crystallization experiment were stuck to a glass fiber and fixed on an X-ray diffraction goniometer. X-ray diffraction data of these crystals were collected using a KappaCCD system and MoK α radiation generated by a FR 590X-ray generator (Delft, Bruker Nonius, Netherlands) at a temperature of 233K.
The cell parameters and crystal structure were determined and refined using the maXus software package (Mackay et al, 1997). The theoretical pattern of X-ray powder diffraction was calculated from the crystalline structure using Powdercell (Kraus et al, 1999) version 2.3 of Windows.
Powder X-ray diffraction
X-ray powder diffraction patterns were taken using an Avantium's T2 high throughput XRPD instrument. The sample plate was fixed on a Bruker GADDS diffractometer equipped with a Hi-Star area detector. The long d-spacings of the XRPD platform were corrected using SilverBehenate and the short d-spacings were corrected using Corundum.
Data collection was performed at room temperature using monochromatic CuK α radiation in the region of 2 θ between 1.5 and 41.5 °. The exposure time for each pass is 90 to 180 seconds, and the diffraction patterns for each hole are collected over two 2 theta ranges (1.5 ≦ 2 theta ≦ 19.5 for the first pass and 21.5 ≦ 2 theta ≦ 41.5 for the second pass). No background subtraction or curve smoothing was performed on the XRPD pattern.
Characterization of Anhydrous Crystal of Tiotropium Bromide
The anhydrous crystals of tiotropium bromide were orthorhombic (see table 1).
Table 1 crystallization and structure accuracy data for form C.
Empirical formula C19H22NO4S2 +·Br-
Fw 472.41
T[K] 293(2)
λ[] 0.71073
Crystal system orthorhombic system
Space group Pbca
Cell parameters
a[] a＝11.7420(4)
b[] b＝17.7960(7)
c[] c＝19.6280(11)
β[°]
V[3] 4101.5(3)
Z 8
Dm[g/cm3] 1.530
F(000) 1936
Crystal size [ mm ]3] 0.4×0.4×0.1
Theta range [ ° ] 2 → 27.5
Collected diffraction points 20542
Independent diffraction Point 4648
[Rint＝0.0442]
Data/limits/parameters 4648/0/350
S 1.038
R[I＞2σ(I)] R1＝0.0445，
wR2＝0.0814
The R factor (all data) R1 ═ 0.0732,
wR2＝0.0918
extinction coefficient 0.0006(2)
Highly crystalline anhydrous tiotropium bromide is obtained by the above process. Further determined by X-ray powder diffraction. The anhydrous tiotropium bromide according to the invention has an X-ray powder diffraction pattern as shown in figure 1.
Characteristic peaks and normalized intensities are listed in table 2 below.
Table 2: x-ray powder diffraction (maximum 2 theta 30 °) and intensity (normalized) of an anhydrous crystalline form of tiotropium bromide
| 2θ[°] | d[] | I/I0[％] |
| 9.80 | 9.02 | 17 |
| 8.90 | 9.93 | 36 |
| 8.10 | 10.91 | 32 |
| 7.53 | 11.75 | 32 |
| 6.60 | 13.41 | 7 |
| 5.87 | 15.08 | 89 |
| 5.57 | 15.89 | 4 |
| 5.44 | 16.28 | 11 |
| 5.36 | 16.53 | 5 |
| 5.11 | 17.33 | 5 |
| 4.91 | 18.07 | 56 |
| 4.85 | 18.29 | 41 |
| 4.81 | 18.44 | 38 |
| 4.66 | 19.03 | 10 |
| 4.53 | 19.58 | 2 |
| 4.45 | 19.94 | 4 |
| 4.39 | 20.23 | 11 |
| 4.34 | 20.45 | 15 |
| 4.30 | 20.65 | 11 |
| 4.24 | 20.91 | 29 |
| 4.17 | 21.27 | 27 |
| 4.11 | 21.59 | 9 |
| 4.05 | 21.91 | 100 |
| 3.84 | 23.14 | 52 |
| 3.75 | 23.68 | 17 |
| 3.68 | 24.14 | 23 |
| 3.60 | 24.73 | 17 |
| 3.52 | 25.31 | 18 |
| 3.44 | 25.91 | 28 |
| 3.36 | 26.50 | 5 |
| 3.30 | 27.01 | 7 |
| 3.22 | 27.65 | 16 |
| 3.18 | 28.07 | 6 |
| 3.15 | 28.35 | 10 |
| 3.10 | 28.74 | 10 |
| 3.06 | 29.12 | 13 |
| 2.97 | 30.05 | 11 |
"2 θ [ ° in the above list]"value represents the number of diffraction angles, and" dhk1[]"value representsIs the specific interplanar spacing in units.
1, 4-bis-of tiotropium bromideCharacterization of alkane solvate crystals
1, 4-bis-of tiotropium bromideThe alkane solvate crystals were crystallized in the monoclinic system (see table 3).
Table 3.
Empirical formula 2 (C)19H22NO4S2 +·Br-)·C4H8O2
Fw 516.47
T[K] 293(2)
λ[] 0.71073
Monoclinic system of crystal system
Space group P21/c
Cell parameters
a[] 13.6650(3)
b[] 12.0420(3)
c[] 13.7090(3)
β[°] 103.8150(13)
V[3] 2190.61(9)
Z 4
Dm[g/cm3] 1.566
F(000) 1064
Theta range [ ° ] 1.5 → 29
Total diffraction point 15269
Independent diffraction spots 5034
[Rint＝0.043]
Data/limits/parameters 5034/0/285
S 1.039
R[I＞2σ(I)] R1＝0.071，
wR2＝0.193
The R factor (all data) R1 ═ 0.095,
wR2＝0.220
1, 4-bis-of tiotropium bromideThe X-ray powder diffraction pattern of the alkane solvate crystals is shown in fig. 2. Characteristic peaks and normalized intensities are listed in table 4 below.
Table 4: contains twoAlkyl and tiotropium bromideX-ray powder diffraction (maximum 2 theta 30 °) and intensity (normalized) of solvated crystalline forms of tiotropium bromide with an alkane stoichiometry close to 2: 1
| 2θ[°] | d[] | I/I0[％] |
| 8.91 | 9.92 | 11 |
| 8.02 | 11.03 | 12 |
| 6.61 | 13.38 | 32 |
| 6.01 | 14.72 | 3 |
| 5.80 | 15.27 | 49 |
| 5.45 | 16.24 | 17 |
| 4.90 | 18.09 | 68 |
| 4.46 | 19.88 | 46 |
| 4.25 | 20.88 | 44 |
| 4.16 | 21.33 | 100 |
| 3.94 | 22.54 | 3 |
| 3.84 | 23.12 | 11 |
| 3.76 | 23.64 | 18 |
| 3.73 | 23.85 | 29 |
| 3.62 | 24.58 | 16 |
| 3.56 | 24.99 | 18 |
| 3.43 | 25.95 | 31 |
| 3.30 | 26.98 | 20 |
| 3.21 | 27.77 | 21 |
| 3.07 | 29.05 | 2 |
| 3.01 | 29.64 | 9 |
| 2.97 | 30.05 | 24 |
Characterization of the crystalline ethanol solvate of tiotropium bromide
The ethanol solvate of tiotropium bromide crystallized as a monoclinic system (see table 5).
Table 5.
Empirical formula 2 (C)19H22NO4S2 +·Br-)·C2H6O
Fw 990.90
T[K] 120(2)
λ[] 0.71073
Monoclinic system of crystal system
Space group P21/c
Cell parameters
a[] 13.5380(2)
b[] 11.9830(2)
c[] 26.9410(5)
β[°] 105.1990(6)
V[3] 4217.65(12)
Z 8
Dm[g/cm3] 1.561
F(000) 2040
Theta range [ ° ] 2.3 → 30.5
Total diffraction point 18368
Independent diffraction Point 12282
[Rint＝0.048]
Data/limits/parameters 12282/0/714
S 1.04
R[I＞2σ(I)] R1＝0.0556，
wR2＝0.1239
The R factor (all data) R1 is 0.0812,
wR2＝0.1395
the X-ray powder diffraction pattern of the crystalline ethanol solvate of tiotropium bromide is shown in fig. 3. Characteristic peaks and normalized intensities are listed in table 6 below.
Table 6: x-ray powder diffraction (maximum 2 theta 30 °) and intensity (normalized) of solvated crystalline forms of tiotropium bromide with ethanol and a stoichiometry of tiotropium bromide to ethanol close to 2: 1
| 2θ[°] | d[] | I/I0[％] |
| 13.16 | 6.71 | 6 |
| 8.91 | 9.92 | 29 |
| 8.00 | 11.05 | 30 |
| 6.88 | 12.86 | 7 |
| 6.60 | 13.41 | 63 |
| 6.02 | 14.71 | 3 |
| 5.77 | 15.34 | 61 |
| 5.43 | 16.31 | 13 |
| 4.94 | 17.93 | 13 |
| 4.89 | 18.12 | 85 |
| 4.46 | 19.91 | 76 |
| 4.39 | 20.22 | 12 |
| 4.25 | 20.90 | 38 |
| 4.21 | 21.11 | 11 |
| 4.15 | 21.39 | 100 |
| 3.97 | 22.39 | 3 |
| 3.84 | 23.13 | 12 |
| 3.76 | 23.65 | 27 |
| 3.71 | 23.96 | 25 |
| 3.61 | 24.67 | 23 |
| 3.55 | 25.08 | 28 |
| 3.42 | 26.00 | 37 |
| 3.29 | 27.07 | 25 |
| 3.20 | 27.85 | 21 |
| 3.08 | 29.00 | 4 |
| 3.06 | 29.20 | 4 |
| 3.01 | 29.66 | 13 |
| 2.97 | 30.02 | 14 |
Characterization of the crystalline methanol solvate of tiotropium bromide
The methanol solvate of tiotropium bromide crystallized as a monoclinic system (see table 7).
Table 7.
Empirical formula (C)19H22NO4S2 +·Br-)·CH4O
Fw 500.43
T[K] 293(2)
λ[] 0.71073
Monoclinic system of crystal system
Space group P21/c
Cell parameters
a[] 13.4420(2)
b[] 37.0890(5)
c[] 13.6290(2)
β[°] 104.7050(10)
V[3] 6572.18(16)
Z 12
Dm[g/cm3] 1.529
F(000) 3120
Theta range [ ° ] 1.6 → 30.0
Total diffraction Point 41043
Independent diffraction points 17392
[Rint＝0.065]
Data/limits/parameters 17392/12/851
S 1.06
R[I＞2σ(I)] R1＝0.0924，
wR2＝0.2766
The R factor (all data) R1 ═ 0.1441,
wR2＝0.2364
the X-ray powder diffraction pattern of the crystalline methanol solvate of tiotropium bromide is shown in fig. 4. Characteristic peaks and normalized intensities are listed in table 8 below.
Table 8: x-ray powder diffraction (maximum 2 theta 30 °) and intensity (normalized) of solvated crystalline forms of tiotropium bromide with methanol and with a stoichiometry of tiotropium bromide to methanol close to 1: 1
| 2θ[°] | d] | I/I0[％] |
| 13.00 | 6.79 | 5 |
| 8.98 | 9.84 | 38 |
| 8.09 | 10.93 | 24 |
| 6.86 | 12.89 | 7 |
| 6.59 | 13.43 | 60 |
| 6.50 | 13.61 | 14 |
| 5.81 | 15.25 | 26 |
| 5.76 | 15.38 | 43 |
| 5.35 | 16.55 | 11 |
| 4.94 | 17.94 | 53 |
| 4.50 | 19.70 | 100 |
| 4.34 | 20.45 | 6 |
| 4.25 | 20.88 | 26 |
| 4.21 | 21.11 | 8 |
| 4.14 | 21.44 | 92 |
| 3.93 | 22.63 | 12 |
| 3.84 | 23.14 | 10 |
| 3.67 | 24.25 | 20 |
| 3.62 | 24.55 | 23 |
| 3.55 | 25.05 | 13 |
| 3.49 | 25.52 | 12 |
| 3.45 | 25.78 | 10 |
| 3.41 | 26.12 | 11 |
| 3.30 | 27.01 | 9 |
| 3.28 | 27.17 | 14 |
| 3.26 | 27.33 | 13 |
| 3.18 | 27.99 | 15 |
| 3.15 | 28.27 | 8 |
| 3.09 | 28.85 | 5 |
| 3.05 | 29.30 | 16 |
| 3.01 | 29.71 | 30 |
Characterization of the anisole solvate Crystal of tiotropium Bromide
The X-ray powder diffraction pattern of the anisole solvate crystals of tiotropium bromide is shown in fig. 5. Characteristic peaks and normalized intensities are listed in table 9 below.
Table 9: x-ray powder diffraction (maximum 2 theta 30 °) and intensity (normalized) of solvate crystalline forms of tiotropium bromide with anisole
| 2θ[°] | d] | I/I0[％] |
| 6.80 | 12.99 | 7 |
| 10.00 | 8.84 | 28 |
| 11.11 | 7.96 | 26 |
| 12.93 | 6.84 | 6 |
| 13.51 | 6.55 | 75 |
| 15.38 | 5.76 | 64 |
| 16.40 | 5.40 | 13 |
| 18.16 | 4.88 | 80 |
| 20.01 | 4.43 | 73 |
| 21.07 | 4.21 | 42 |
| 21.47 | 4.14 | 100 |
| 23.85 | 3.73 | 22 |
| 24.88 | 3.58 | 23 |
| 26.11 | 3.41 | 32 |
| 27.23 | 3.27 | 27 |
| 28.02 | 3.18 | 21 |
| 29.79 | 3.00 | 18 |
| 30.29 | 2.95 | 27 |
Characterization of crystalline n-butanol solvate of tiotropium bromide
The X-ray powder diffraction pattern of the n-butanol solvate crystals of tiotropium bromide is shown in fig. 6. Characteristic peaks and normalized intensities are listed in table 10 below.
Table 10: x-ray powder diffraction (maximum 2 theta 30 °) and intensity (normalized) of a solvate crystalline form of tiotropium bromide containing n-butanol with a stoichiometry of tiotropium bromide to n-butanol close to 2: 1
| 2θ[°] | d] | I/I0[％] |
| 13.08 | 6.75 | 4 |
| 8.99 | 9.83 | 21 |
| 8.09 | 10.93 | 21 |
| 6.89 | 12.84 | 5 |
| 6.61 | 13.38 | 70 |
| 6.53 | 13.54 | 13 |
| 5.77 | 15.34 | 37 |
| 5.38 | 16.46 | 11 |
| 4.94 | 17.95 | 85 |
| 4.49 | 19.77 | 38 |
| 4.36 | 20.36 | 3 |
| 4.26 | 20.83 | 24 |
| 4.15 | 21.41 | 100 |
| 3.91 | 22.71 | 8 |
| 3.82 | 23.27 | 9 |
| 3.68 | 24.15 | 23 |
| 3.62 | 24.56 | 16 |
| 3.55 | 25.03 | 15 |
| 3.47 | 25.66 | 13 |
| 3.42 | 26.03 | 16 |
| 3.31 | 26.95 | 14 |
| 3.27 | 27.27 | 9 |
| 3.20 | 27.89 | 10 |
| 3.17 | 28.12 | 6 |
| 3.03 | 29.48 | 11 |
| 2.99 | 29.87 | 16 |
Characterization of the DMA solvate Crystal of tiotropium Bromide
The X-ray powder diffraction pattern of the DMA solvate crystals of tiotropium bromide is shown in fig. 7. Characteristic peaks and normalized intensities are listed in table 11 below.
Table 11: x-ray powder diffraction (maximum 2 theta of 30 °) and intensity (normalized) of a solvate crystalline form of tiotropium bromide with N, N-dimethylacetamide (═ DMA)
| 2θ[°] | d] | I/I0[％] |
| 9.98 | 8.86 | 16 |
| 11.20 | 7.89 | 17 |
| 13.62 | 6.50 | 62 |
| 15.46 | 5.73 | 49 |
| 16.50 | 5.37 | 13 |
| 18.14 | 4.89 | 67 |
| 20.06 | 4.42 | 77 |
| 21.26 | 4.18 | 62 |
| 21.65 | 4.10 | 100 |
| 23.22 | 3.83 | 9 |
| 23.90 | 3.72 | 23 |
| 25.03 | 3.55 | 21 |
| 26.23 | 3.39 | 22 |
| 27.38 | 3.25 | 34 |
| 28.26 | 3.16 | 15 |
| 30.24 | 2.95 | 32 |
Characterization of the DMF solvate Crystal of tiotropium Bromide
The X-ray powder diffraction pattern of the DMF solvate crystals of tiotropium bromide is shown in fig. 8. Characteristic peaks and normalized intensities are listed in table 12 below.
Table 12: x-ray powder diffraction (maximum 2 theta of 30 °) and intensity (normalized) of a solvate crystalline form of tiotropium bromide with N, N-dimethylformamide (═ DMF)
| 2θ[°] | d] | I/I0[％] |
| 6.84 | 12.91 | 6 |
| 9.97 | 8.86 | 18 |
| 11.12 | 7.95 | 15 |
| 13.58 | 6.51 | 64 |
| 15.46 | 5.73 | 63 |
| 16.51 | 5.36 | 12 |
| 18.14 | 4.89 | 73 |
| 20.01 | 4.43 | 76 |
| 21.20 | 4.19 | 54 |
| 21.56 | 4.12 | 100 |
| 23.26 | 3.82 | 12 |
| 24.14 | 3.68 | 14 |
| 24.95 | 3.57 | 19 |
| 26.19 | 3.40 | 19 |
| 27.39 | 3.25 | 32 |
| 28.18 | 3.16 | 15 |
| 30.21 | 2.96 | 26 |
Characterization of the crystalline Isopropanol solvate of tiotropium Bromide
The X-ray powder diffraction pattern of the crystalline isopropanol solvate of tiotropium bromide is shown in figure 9. Characteristic peaks and normalized intensities are listed in table 13 below.
Table 13: x-ray powder diffraction (maximum 2 theta 30 °) and intensity (normalized) of solvate crystalline forms of tiotropium bromide containing isopropanol and having a stoichiometry of tiotropium bromide: isopropanol close to 2: 1
| 2θ[°] | d] | I/I0[％] |
| 13.10 | 6.74 | 9 |
| 8.95 | 9.87 | 27 |
| 8.04 | 11.00 | 24 |
| 6.89 | 12.84 | 5 |
| 6.65 | 13.31 | 50 |
| 6.57 | 13.47 | 20 |
| 5.84 | 15.15 | 30 |
| 5.77 | 15.35 | 68 |
| 5.43 | 16.30 | 15 |
| 4.96 | 17.88 | 11 |
| 4.91 | 18.06 | 100 |
| 4.48 | 19.80 | 71 |
| 4.45 | 19.93 | 24 |
| 4.38 | 20.26 | 12 |
| 4.27 | 20.77 | 44 |
| 4.22 | 21.05 | 12 |
| 4.16 | 21.33 | 89 |
| 4.11 | 21.58 | 8 |
| 3.86 | 23.02 | 12 |
| 3.78 | 23.54 | 24 |
| 3.70 | 24.02 | 30 |
| 3.61 | 24.64 | 30 |
| 3.55 | 25.08 | 32 |
| 3.44 | 25.85 | 34 |
| 3.33 | 26.79 | 7 |
| 3.30 | 27.02 | 20 |
| 3.22 | 27.68 | 16 |
| 3.19 | 27.93 | 15 |
| 3.03 | 29.50 | 15 |
| 2.99 | 29.86 | 18 |
Characterization of crystalline 1, 2-propanediol solvate of tiotropium bromide
The crystalline 1, 2-propanediol solvate of tiotropium bromide with an X-ray powder diffraction pattern is shown in fig. 10. Characteristic peaks and normalized intensities are listed in table 14 below.
Table 14: x-ray powder diffraction (maximum 2 theta 30 °) and intensity (normalized) of a solvate crystalline form of tiotropium bromide with 1, 2-propanediol
| 2θ[°] | d] | I/I0[％] |
| 6.82 | 12.95 | 5 |
| 9.94 | 8.89 | 15 |
| 11.10 | 7.97 | 17 |
| 13.43 | 6.59 | 48 |
| 15.34 | 5.77 | 71 |
| 16.32 | 5.43 | 19 |
| 18.10 | 4.90 | 83 |
| 19.97 | 4.44 | 65 |
| 21.31 | 4.17 | 100 |
| 23.11 | 3.85 | 8 |
| 23.86 | 3.73 | 42 |
| 24.71 | 3.60 | 22 |
| 25.07 | 3.5 5 | 24 |
| 26.05 | 3.42 | 29 |
| 27.03 | 3.30 | 34 |
| 27.88 | 3.20 | 28 |
| 30.16 | 2.96 | 25 |
Characterization of the pyridine solvate Crystal of tiotropium Bromide
An X-ray powder diffraction pattern of the pyridine solvate crystals of tiotropium bromide is shown in fig. 11. Characteristic peaks and normalized intensities are listed in table 15 below.
Table 15: x-ray powder diffraction (maximum 2 theta 30 °) and intensity (normalized) of solvate crystalline forms of tiotropium bromide with pyridine
| 2θ[°] | d] | I/I0[％] |
| 6.76 | 13.06 | 44 |
| 9.94 | 8.89 | 24 |
| 11.22 | 7.88 | 7 |
| 13.48 | 6.57 | 46 |
| 15.38 | 5.76 | 69 |
| 16.40 | 5.40 | 24 |
| 18.13 | 4.89 | 100 |
| 19.94 | 4.45 | 62 |
| 21.36 | 4.16 | 79 |
| 23.92 | 3.72 | 30 |
| 25.08 | 3.55 | 31 |
| 25.97 | 3.43 | 31 |
| 27.11 | 3.29 | 34 |
| 27.96 | 3.19 | 30 |
| 30.27 | 2.95 | 29 |
Characterization of the crystalline tert-butanol solvate of tiotropium bromide
The X-ray powder diffraction pattern of the crystalline t-butanol solvate of tiotropium bromide is shown in fig. 12. Characteristic peaks and normalized intensities are listed in table 16 below.
Table 16: x-ray powder diffraction (maximum 2 theta 30 °) and intensity (normalized) of tiotropium bromide solvate crystalline form with tert-butanol
| 2θ[°] | d] | I/I0[％] |
| 6.73 | 13.13 | 23 |
| 10.03 | 8.81 | 21 |
| 11.08 | 7.98 | 19 |
| 13.46 | 6.57 | 58 |
| 15.38 | 5.76 | 77 |
| 16.36 | 5.41 | 17 |
| 18.13 | 4.89 | 86 |
| 19.96 | 4.44 | 64 |
| 20.97 | 4.23 | 29 |
| 21.46 | 4.14 | 100 |
| 23.86 | 3.73 | 25 |
| 24.98 | 3.56 | 19 |
| 26.04 | 3.42 | 30 |
| 27.10 | 3.29 | 36 |
| 27.95 | 3.19 | 24 |
| 30.28 | 2.95 | 22 |
Characterization of the THF solvate Crystal of tiotropium Bromide
The crystalline THF solvate of tiotropium bromide has an X-ray powder diffraction pattern as shown in figure 13. Characteristic peaks and normalized intensities are listed in table 17 below.
Table 17: x-ray powder diffraction (30. max. 2. theta.) and intensity (normalized) of a solvate crystalline form of tiotropium bromide containing tetrahydrofuran (═ THF) and a stoichiometry of tiotropium bromide: THF of approximately 2: 1
| 2θ[°] | d] | I/I0[％] |
| 6.98 | 12.65 | 4 |
| 10.17 | 8.69 | 10 |
| 11.28 | 7.84 | 13 |
| 13.68 | 6.47 | 58 |
| 14.95 | 5.92 | 10 |
| 15.53 | 5.70 | 65 |
| 16.48 | 5.37 | 20 |
| 18.30 | 4.85 | 95 |
| 20.11 | 4.41 | 54 |
| 20.45 | 4.34 | 29 |
| 21.19 | 4.19 | 41 |
| 21.69 | 4.09 | 100 |
| 23.31 | 3.81 | 10 |
| 24.10 | 3.69 | 79 |
| 24.89 | 3.58 | 18 |
| 25.28 | 3.52 | 39 |
| 26.20 | 3.40 | 28 |
| 27.29 | 3.27 | 60 |
| 28.02 | 3.18 | 36 |
| 29.44 | 3.03 | 7 |
| 29.92 | 2.98 | 9 |
| 30.34 | 2.94 | 26 |
Characterization of the THP solvate Crystal of tiotropium Bromide
The X-ray powder diffraction pattern of the crystalline THP solvate of tiotropium bromide is shown in fig. 14. Characteristic peaks and normalized intensities are listed in table 18 below.
Table 18: x-ray powder diffraction (maximum 2 theta 30 °) and intensity (normalized) of a solvate crystalline form of tiotropium bromide containing tetrahydropyran (═ THP) and a stoichiometry of tiotropium bromide: THP close to 2: 1
| 2θ[°] | d] | I/I0[％] |
| 6.95 | 12.71 | 5 |
| 9.89 | 8.94 | 28 |
| 11.10 | 7.97 | 23 |
| 13.54 | 6.54 | 67 |
| 15.41 | 5.75 | 57 |
| 16.56 | 5.35 | 10 |
| 18.13 | 4.89 | 71 |
| 19.97 | 4.44 | 76 |
| 20.97 | 4.23 | 41 |
| 21.52 | 4.13 | 100 |
| 22.86 | 3.89 | 8 |
| 23.45 | 3.79 | 14 |
| 24.37 | 3.65 | 19 |
| 24.69 | 3.60 | 22 |
| 25.18 | 3.53 | 13 |
| 25.98 | 3.43 | 22 |
| 27.48 | 3.24 | 21 |
| 28.12 | 3.17 | 18 |
| 30.00 | 2.98 | 23 |
Formulations containing the crystalline forms of tiotropium bromide of the present invention
The crystalline forms of tiotropium bromide according to the invention are particularly suitable for the preparation of pharmaceutical formulations for administration, for example by inhalation, such as inhalable powders or, for example, aerosol formulations containing a propellant, in particular inhalable powders and aerosol suspensions containing a propellant. These pharmaceutical preparations or compositions may contain the crystalline tiotropium according to the invention and one or more further active ingredients selected from the group consisting of: betamimetics, EGFR inhibitors, PDEIV-inhibitors, steroids and LTD4 antagonists, optionally in combination with a pharmaceutically acceptable excipient.
Inhalable powders
The invention also relates to an inhalable powder containing 0.001 to 3% tiotropium in crystalline form of tiotropium bromide according to the invention and a physiologically acceptable excipient. And tiotropium refers to the ammonium cation.
Preferred inhalable powders according to the invention contain 0.01 to 2% tiotropium. Particularly preferred inhalable powders have a tiotropium content of about 0.03 to 1%, preferably 0.05 to 0.6%, particularly preferably 0.06 to 0.3%. Of particular importance according to the invention is the final inhalable powder containing about 0.08 to 0.22% tiotropium.
The amount of tiotropium specified above is based on the amount of tiotropium cation contained.
The excipients used for the purposes of the present invention are prepared by suitable grinding and/or sieving in a manner known in the art. The excipient used according to the invention may also be a mixture of excipients, obtained by mixing excipients of different average particle sizes.
Examples of physiologically acceptable excipients which can be used for the preparation of the inhalable powders for inhalation according to the invention include: monosaccharides (e.g., glucose, fructose, or arabinose), disaccharides (e.g., lactose, sucrose, maltose, trehalose), oligo-and polysaccharides (e.g., dextran, dextrin, maltodextrin, starch, cellulose), polyols (e.g., sorbitol, mannitol, xylitol), cyclodextrins (e.g., α -cyclodextrin, β -cyclodextrin, γ -cyclodextrin, methyl- β -cyclodextrin, hydroxypropyl- β -cyclodextrin), amino acids (e.g., arginine hydrochloride), or salts (e.g., sodium chloride, calcium carbonate), or mixtures thereof. Preferably, mono-or disaccharides are used, and preferably lactose or glucose, particularly but not exclusively in the form of their hydrates. Lactose is a particularly preferred excipient for the purposes of the present invention.
Within the scope of the inhalable powders according to the invention, the maximum average particle size of the excipient may be up to 250 μm, preferably between 10 and 150 μm, most preferably between 15 and 80 μm. It sometimes seems appropriate to add to the above excipients a finer excipient fraction having an average particle size of 1 to 9 μm. These finer excipients may also be selected from the above-mentioned available excipients. The average particle diameter can be determined by methods known in the art (see, for example, WO02/30389, paragraphs A and C). Finally, to prepare the inhalable powders according to the invention, anhydrous crystals of micronized tiotropium bromide, which are preferably characterized by a mean particle size of 0.5 to 10 μm, particularly preferably 1 to 5 μm, are added to the excipient mixture (cf. e.g. WO02/30389, paragraph B). Methods for grinding and micronizing active substances are known in the prior art.
If no specially prepared excipient mixture is used as excipient, it is especially preferred to use an excipient having an average particle diameter of 10-50 μm and a fine particle content of 10% of 0.5 to 6 μm.
The average particle diameter herein means a value of 50% volume distribution measured by a laser diffractometer using a dry dispersion method. The average particle diameter can be determined using methods known in the art (see, e.g., WO02/30389, paragraphs A and C). Similarly, a fine particle content of 10% here refers to a 10% value of the volume distribution measured using a laser diffractometer. In other words, for the purposes of the present invention, a 10% fines content represents a 10% number of particles (based on volume distribution) at this particle size.
All percentages used within the scope of the present invention are by weight unless otherwise indicated.
In particularly preferred inhalable powders, the excipient is characterized in that its mean particle size is between 12 and 35 μm, particularly preferably between 13 and 30 μm.
Also particularly preferred are inhalable powders in which the content of 10% of fine particles is about 1 to 4 μm, preferably about 1.5 to 3 μm.
Based on the problem of the present invention, the inhalable powders according to the invention are characterized by a high uniformity of the single dose precision. The range is < 8%, preferably < 6%, most preferably < 4%.
After weighing out the starting materials, inhalable powders are prepared from excipients and the active substance using methods known in the art. For example, reference may be made to the disclosure of, for example, WO 02/30390. The inhalable powders according to the invention can thus be obtained by the process described below, for example. In the preparation process described hereinafter, these ingredients are used in the weight proportions of the composition of inhalable powder described above.
First, the excipients and the active substance are placed in a suitable mixing vessel. The average particle size of the active substance used is from 0.5 to 10 μm, preferably from 1 to 6 μm, most preferably from 2 to 5 μm. The excipients and the active substance are preferably added using a sieve or granulation sieve with a mesh size of 0.1 to 2mm, preferably 0.3 to 1mm, most preferably 0.3 to 0.6 mm. Preferably, the excipients are added and the active substance is added to the mixing vessel. During the mixing process, the two ingredients are preferably added in portions. It is particularly preferred to sieve the two components in alternating layers. Excipients may be mixed with the active while the two ingredients are still being added. However, it is preferred that the mixing is only carried out after the two components have been sifted in layers.
The invention also relates to the use of the inhalable powder according to the invention for the preparation of a pharmaceutical composition for the treatment of respiratory diseases, in particular for the treatment of COPD and/or asthma.
Inhalable powders according to the invention are for example: an inhaler may be used which can dose a single dose from a reservoir via a metering chamber (e.g. according to US4570630A) or by other means (e.g. according to DE 3625685 a). However, the inhalable powders according to the invention are preferably filled in capsules (to make so-called inhalants), which can be used in inhalers as described in, for example, WO 94/28958.
Most preferably, the capsule containing the inhalable powder according to the invention is administered using an inhaler as shown in fig. 15. The inhaler is characterized in that the housing 1 has two windows 2, a cover plate 3, a screen plate 5 which has an air inlet and is fixed by a screen plate housing 4, an inhalation chamber 6 which is connected to the cover plate 3, a button 9 which is provided with two pointed plugs 7 and a spring (movable to a spring) 8 which can move in the opposite direction, and a connector 12 which is connected to the housing 1, the cover plate 3 and an outer cover 11 through a shaft 10 so as to be capable of bouncing or closing and adjusting the air hole 13 of the flow resistance.
The invention also relates to the use of an inhalable powder containing one or several, preferably one, crystalline form of tiotropium bromide according to the invention for the preparation of a pharmaceutical composition for the treatment of respiratory diseases, in particular for the treatment of COPD and/or asthma, characterized in that an inhaler as described above and shown in fig. 15 is used.
For administering inhalable powders containing the crystalline form of tiotropium bromide according to the invention using powder filled capsules, it is especially preferred to use capsules selected from synthetic plastics, most preferably from polyethylene, polycarbonate, polyester, polypropylene and polyethylene terephthalate materials. Particularly preferred synthetic plastics materials are polyethylene, polycarbonate or polyethylene terephthalate. If polyethylene is used as a particularly preferred capsule material according to the invention, it is preferred to use a density of from 900 to 1000kg/m3Preferably 940-3More preferably about 960-3Polyethylene (high density polyethylene). The synthetic plastics according to the invention can be processed in various ways using manufacturing methods known in the art. Injection molding of plastics is preferred according to the invention. Particularly preferred is an injection molding method without using a mold release agent. The production process has been described in detail and is characterized by particular reproducibility.
Another aspect of the invention relates to a capsule as described above containing an inhalable powder as described above according to the invention. These capsules may contain about 1 to 20mg, preferably about 3 to 15mg, more preferably about 4 to 12mg of inhalable powder. Preferred formulations of the invention contain 4 to 6mg of inhalable powder. Equally important to the invention are capsules for inhalation which contain the formulation according to the invention in an amount of 8 to 12 mg.
The invention also relates to an inhalation device consisting of one or more capsules as described above, characterised in that the content is an inhalable powder according to the invention, and an inhaler as shown in figure 15.
The invention also relates to the use of the above-described capsules characterized by the content of inhalable powders according to the invention for the preparation of a pharmaceutical composition for the treatment of respiratory diseases, in particular for the treatment of COPD and/or asthma.
Filled capsules containing the inhalable powder according to the invention are produced by filling empty capsules with the inhalable powder according to the invention in a method known in the art.
Examples of inhalable powders according to the invention
The following examples serve to illustrate the invention in more detail, without limiting the scope of the invention by the following exemplary embodiments.
Active substance
The crystalline tiotropium bromide according to the invention is used for producing the inhalable powders according to the invention. The micronization of these crystals can be carried out analogously to the methods known in the art (cf. for example WO 03/078429A 1). Wherein the average particle size of the tiotropium bromide crystals of the invention is determined within the scope of the invention using determination methods known in the art (see, e.g., WO 03/078429A 1, paragraph D.2).
Excipient:
lactose monohydrate was used as excipient in the following examples. It can be selected from, for example: borculo Domo Ingredients, Borculo/NL, available under the product name Lactochem Extra Fine Powder. This grade of lactose meets the particle size and specific surface area specifications according to the invention. For example, in the following examples, the lactose batches used had the following specifications:
preparation of powder formulation:
device for measuring the position of a moving object
For example, the following machines and equipment may be used to prepare inhalable powders:
mixing vessel or powder mixer: turbulamischer type 2L, 2C; CH-4500 Basel, manufactured by Willy A. Bachofen AG
Hand held sieves: 0.135mm mesh
The inhalable powder containing tiotropium may be filled manually or mechanically into empty inhalation capsules. The following equipment may be used.
Capsule filling machine:
MG2, form G100, manufacturer: MG2 S.r.1, I-40065 Pian di Macina dipianato (BO), Italy.
Preparation example:
formulation example 1-powder mixture:
a powder mixture was prepared using 299.39g of excipient and 0.61g of micronized anhydrous crystalline tiotropium bromide.
About 40-45g of the excipient was added to a suitable mixing container through a 0.315mm mesh handsaw sieve. And alternately layering about 90-110mg of anhydrous crystalline tiotropium bromide per batch and about 40-45g of excipient per batch. 7 and 6 layers of excipients and active substance were added, respectively.
After sieving, the ingredients were mixed again (mixing speed 900 rpm). The final mixture was sieved through a hand held sieve two more times and mixed again at 900 rpm.
Using the method described in formulation example 1, an inhalable powder was obtained which, when filled into suitable plastic capsules, was used to produce the following capsules for inhalation.
Preparation example 2:
anhydrous tiotropium bromide: 0.0113mg
Lactose monohydrate: 5.4887mg
And (3) capsule preparation: 100.0mg
Totaling: 105.5mg
Preparation example 3:
anhydrous tiotropium bromide: 0.0225mg
Lactose monohydrate: 5.4775mg
Polyethylene capsule: 100.0mg
Totaling: 105.5mg
Preparation example 4:
anhydrous tiotropium bromide: 0.0056mg
Lactose monohydrate: 5.4944mg
Polyethylene capsule: 100.0mg
Totaling: 105.5mg
Preparation example 5:
anhydrous tiotropium bromide: 0.0113mg
Lactose monohydrate:* 5.4887mg
and (3) capsule preparation: 100.0mg
Totaling: 105.5mg
*) The lactose contains a particulate content of 5% of specifically added micronized lactose monohydrate with an average particle size of about 4 μm.
Preparation example 6:
anhydrous tiotropium bromide: 0.0225mg
Lactose monohydrate:* 5.4775mg
polyethylene capsule: 100.0mg
Totaling: 105.5mg
*) The lactose contains a particulate content of 5% of specifically added micronized lactose monohydrate with an average particle size of about 4 μm.
Formulation example 7:
anhydrous tiotropium bromide: 0.0056mg
Lactose monohydrate:* 5.4944mg
polyethylene capsule: 100.0mg
Totaling: 105.5mg
*) The lactose contains a particulate content of 5% of specifically added micronized lactose monohydrate with an average particle size of about 4 μm.
It will be apparent to those of ordinary skill in the art that the foregoing examples may be similarly applied to one of the other crystalline forms of tiotropium bromide specifically identified above. To obtain a product comprising one other solvate according to the invention, the powder mixtures as formulation example 1 and formulation examples 2 to 7 can be obtained simply by using one other solvate according to the invention in crystalline form instead of anhydrous tiotropium bromide.
Aerosol suspension containing propellant
The crystalline forms of tiotropium bromide according to the invention may also optionally be administered in the form of an inhalable aerosol containing a propellant. Aerosol suspensions are particularly suitable for this purpose.
The invention therefore also relates to a suspension of tiotropium bromide crystals according to the invention in a propellant gas HFA227 and/or HFA134a, optionally mixed with one or more propellant gases, preferably selected from: propane, butane, pentane, dimethyl ether, CHClF2、CH2F2、CF3CH3Isobutane, isopentane and neopentane.
Preference is given according to the invention to suspensions which contain only HFA227, a mixture of HFA227 and HFA134a or only HFA134a as propellant gas. If a mixture of the propellant gases HFA227 and HFA134a is used in the suspension formulation according to the invention, the weight ratio of the two propellant gas components used therein can be varied freely.
If one or more of the propellant gases HFA227 and/or HFA134a selected from the group consisting of propane, butane, pentane, dimethyl ether, CHClF are used in addition to the propellant gases HFA227 and/or HFA134a in the suspension formulations according to the invention2、CH2F2、CF3CH3Isobutane, isopentane and neopentane, the amount of these other propellant gas components is preferably less than 50%, preferably less than 40%, particularly preferably less than 30%.
The suspension according to the invention preferably contains tiotropium bromide in such an amount that the amount of tiotropium cation according to the invention is between 0.001 and 0.8%, preferably between 0.08 and 0.5%, and particularly preferably between 0.2 and 0.4%.
The percentages given within the scope of the present invention are percentages by weight, unless otherwise indicated.
In some cases, the term "suspension formulation" is used within the scope of the present invention instead of the term "suspension". These two terms are considered equivalents within the scope of the present invention.
The propellant-containing inhalable aerosol or suspension formulations according to the invention may also contain other ingredients, such as: surface-active agents, adjuvants, antioxidants or flavoring agents.
The surfactants optionally present in the suspension according to the invention are preferably selected from: polysorbate 20, polysorbate 80, Myvacet 9-45, Myvacet 9-08, isopropyl myristate, oleic acid, propylene glycol, polyethylene glycol, Brij, ethyl oleate, glyceryl trioleate, glyceryl monolaurate, glyceryl monooleate, glyceryl monostearate, glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol, cetylpyridinium chloride, block polymers, natural oils, ethanol, and isopropanol. Among the above suspension adjuvants, polysorbate 20, polysorbate 80, Myvacet 9-45, Myvacet 9-08 or isopropyl myristate are preferably used. Most preferably, Myvacet 9-45 or isopropyl myristate is used.
If the suspension according to the invention contains a surfactant, the amount thereof is preferably from 0.0005 to 1%, particularly preferably from 0.005 to 0.5%.
The adjuvant optionally contained in the suspension according to the invention is preferably selected from: alanine, albumin, ascorbic acid, aspartame, betaine, cysteine, phosphoric acid, nitric acid, hydrochloric acid, sulfuric acid, and citric acid. Preferably, ascorbic acid, phosphoric acid, hydrochloric acid or citric acid is used, and most preferably hydrochloric acid or citric acid is used.
The adjuvants are preferably present in the suspensions according to the invention in amounts of from 0.0001 to 1.0%, preferably from 0.0005 to 0.1%, particularly preferably from 0.001 to 0.01%, and particularly important according to the invention in amounts of from 0.001 to 0.005%.
The antioxidant optionally contained in the suspension according to the invention is preferably chosen from: ascorbic acid, citric acid, sodium edetate, ethylenediaminetetraacetic acid, tocopherol, butylhydroxytoluene, butylhydroxyanisole, and ascorbyl palmitate, and tocopherol, butylhydroxytoluene, butylhydroxyanisole, or ascorbyl palmitate are preferably used.
The optional flavouring agent comprised in the suspension according to the invention is preferably selected from: mint, saccharin, dantemin (Dentomint)Aspartame and essential oils (e.g. cinnamon, anise, menthol, camphor), of which mint or Dentomint is particularly preferred。
In view of administration by inhalation, the active substances must be provided in a well-separated form. For this purpose, the tiotropium bromide crystals according to the invention are obtained in well separated form using methods known in the art. Methods of micronizing active substances are known in the art. The active substance after micronization preferably has an average particle diameter of 0.5 to 10 μm, preferably 1 to 6 μm, and particularly preferably 1.5 to 5 μm. Preferably at least 50%, preferably at least 60%, particularly preferably at least 70%, of the active substance particles have a particle size range within the above-mentioned particle size range. It is particularly preferred that at least 80%, most preferably at least 90%, of the active material particles have a particle size range within the above particle size range.
Another aspect of the invention relates to a suspension containing only one of the two active substances according to the invention without any further additives.
The suspension according to the invention can be prepared using methods known in the art. For this purpose, the components of the formulation can be mixed with one or more propellant gases (optionally at low temperature) and filled into suitable containers.
The suspension according to the invention containing the propellant gas described above can be administered using inhalers known in the art (pMDIs ═ pressurized metered dose inhalers). Thus, in a further aspect, the invention relates to pharmaceutical compositions in the form of suspensions as described above in combination with one or more inhalers suitable for the administration of such suspensions. Furthermore, the invention relates to an inhaler, characterized in that it contains the propellant-containing suspension of the invention described above.
The invention also relates to a container (cartridge) which, when fitted with a suitable valve, can be used in a suitable inhaler and which contains a propellant-containing suspension of the invention as described above. Suitable containers (cartridges) and methods of filling such cartridges with a propellant-containing suspension according to the invention are known in the art.
From the standpoint of the pharmaceutical activity of tiotropium, the invention also relates to the use of the suspension according to the invention for the preparation of a pharmaceutical composition for inhalation or nasal administration, preferably for the inhalation or nasal treatment of diseases, in which an anticholinergic agent can improve the therapeutic efficacy.
Particularly preferred the present invention also relates to the use of a suspension according to the present invention for the preparation of a pharmaceutical composition for the inhaled treatment of a respiratory disease, preferably asthma or COPD.
The following examples serve to illustrate the invention in more detail by way of example and without restricting the invention thereto.
Examples of aerosol suspension formulations
The suspension contains, in addition to the active substance and the propellant gas, further constituents:
preparation example 8:
| composition (I) | Concentration [% w/w] |
| Anhydrous tiotropium bromide | 0.04 |
| Oleic acid | 0.005 |
| HFA-227 | 99.955 |
Preparation example 9:
| composition (I) | Concentration [% w/w] |
| Anhydrous tiotropium bromide | 0.02 |
| Oleic acid | 0.01 |
| HFA-227 | 60.00 |
| HFA-134a | 39.97 |
Preparation example 10:
| composition (I) | Concentration [% w/w] |
| Anhydrous tiotropium bromide | 0.02 |
| Myristic acid isopropyl ester | 1.00 |
| HFA-227 | 98.98 |
Formulation example 11:
| composition (I) | Concentration [% w/w] |
| Anhydrous tiotropium bromide | 0.02 |
| Myvacet 9-45 | 0.3 |
| HFA-227 | 99.68 |
Preparation example 12:
| composition (I) | Concentration [% w/w] |
| Anhydrous tiotropium bromide | 0.02 |
| Myvacet 9-45 | 0.1 |
| HFA-227 | 60.00 |
| HFA-134a | 39.88 |
Formulation example 13:
| composition (I) | Concentration [% w/w] |
| Anhydrous tiotropium bromide | 0.04 |
| Polysorbate 80 | 0.04 |
| HFA-227 | 99.92 |
Preparation example 14:
| composition (I) | Concentration [% w/w] |
| Anhydrous tiotropium bromide | 0.01 |
| Polysorbate 20 | 0.20 |
| HFA-227 | 99.78 |
Formulation example 15:
| composition (I) | Concentration [% w/w] |
| Anhydrous tiotropium bromide | 0.04 |
| Myvacet 9-08 | 1.00 |
| HFA-227 | 98.96 |
Preparation example 16:
| composition (I) | Concentration [% w/w] |
| Anhydrous tiotropium bromide | 0.02 |
| Myristic acid isopropyl ester | 0.30 |
| HFA-227 | 20.00 |
| HFA-134a | 79.68 |
Preparation example 17:
| composition (I) | Concentration [% w/w] |
| Anhydrous tiotropium bromide | 0.02 |
| HFA-227 | 60.00 |
| HFA-134a | 39.98 |
Preparation example 18:
| composition (I) | Concentration [% w/w] |
| Anhydrous tiotropium bromide | 0.02 |
| HFA-227 | 99.98 |
Preparation example 19:
| composition (I) | Concentration [% w/w] |
| Anhydrous tiotropium bromide | 0.02 |
| HFA-134a | 99.98 |
Preparation example 20:
| composition (I) | Concentration [% w/w] |
| Anhydrous tiotropium bromide | 0.02 |
| HFA-227 | 99.98 |
Preparation example 21:
| composition (I) | Concentration [% w/w] |
| Anhydrous tiotropium bromide | 0.02 |
| HFA-134a | 99.98 |
Formulation example 22:
| composition (I) | Concentration [% w/w] |
| Anhydrous tiotropium bromide | 0.02 |
| HFA-227 | 20.00 |
| HFA-134a | 79.98 |
Preparation example 23:
| composition (I) | Concentration [% w/w] |
| Anhydrous tiotropium bromide | 0.04 |
| HFA-227 | 40.00 |
| HFA-134a | 59.96 |
Preparation example 24:
| composition (I) | Concentration [% w/w] |
| Anhydrous tiotropium bromide | 0.04 |
| HFA-227 | 80.00 |
| HFA-134a | 19.96 |
It will be apparent to those of ordinary skill in the art that the foregoing examples may be similarly applied to one of the other crystalline forms of tiotropium bromide specifically described hereinabove. To obtain a product comprising one other solvate according to the invention, the formulations of examples 8 to 24 can be readily obtained using one other solvate crystal according to the invention instead of anhydrous tiotropium bromide.
Claims (6)
1. Tiotropium bromide anhydrous crystals characterized by an X-ray structural analysis: orthorhombic with space group P bca and unit cell parameter a 11.7420(4)b＝17.7960(7)c＝19.6280(11)And the unit cell volume is 4101.5(3)
2. Pharmaceutical composition characterized in that it contains anhydrous crystalline tiotropium bromide according to claim 1.
3. Use of an anhydrous crystalline tiotropium bromide according to claim 1 for the preparation of a pharmaceutical composition for the treatment of respiratory diseases.
4. The use according to claim 3, wherein the respiratory disease is asthma or chronic obstructive pulmonary disease.
5. A process for the preparation of anhydrous crystalline tiotropium bromide according to claim 1, characterized in that crystalline tiotropium bromide monohydrate is dissolved in a solvent mixture comprising N, N-dimethylacetamide, heated to a temperature in the range of 30-70 ℃, and upon cooling to a temperature below 15 ℃ anhydrous crystals are produced, the crystals thus obtained are isolated and dried.
6. Use of crystalline tiotropium bromide monohydrate as starting material for the preparation of the crystalline form of tiotropium bromide according to claim 1.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US67680705P | 2005-05-02 | 2005-05-02 | |
| US60/676,807 | 2005-05-02 | ||
| PCT/EP2006/061763 WO2006117299A2 (en) | 2005-05-02 | 2006-04-21 | Novel crystalline forms of tiotropium bromide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1114856A1 HK1114856A1 (en) | 2008-11-14 |
| HK1114856B true HK1114856B (en) | 2012-03-02 |
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