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WO2011015883A1 - Solvate de dichlorométhane du bromure de tiotropium et son utilisation - Google Patents

Solvate de dichlorométhane du bromure de tiotropium et son utilisation Download PDF

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Publication number
WO2011015883A1
WO2011015883A1 PCT/GB2010/051311 GB2010051311W WO2011015883A1 WO 2011015883 A1 WO2011015883 A1 WO 2011015883A1 GB 2010051311 W GB2010051311 W GB 2010051311W WO 2011015883 A1 WO2011015883 A1 WO 2011015883A1
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WO
WIPO (PCT)
Prior art keywords
tiotropium bromide
solvate
anhydrous
less
thienyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB2010/051311
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English (en)
Inventor
Vinayak Govind Gore
Bindu Manojkumar
Dattatraya Shinde
Dattatrey Kokane
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Generics UK Ltd
Mylan Pharmaceuticals Pvt Ltd
Original Assignee
Generics UK Ltd
Mylan India Pvt Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Generics UK Ltd, Mylan India Pvt Ltd filed Critical Generics UK Ltd
Publication of WO2011015883A1 publication Critical patent/WO2011015883A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics

Definitions

  • the present invention relates to a novel solvate of tiottopium bromide, a process to prepare this solvate and the use of this and other solvates in processes for the preparation of anhydrous tiotropium bromide.
  • the present invention also relates to pharmaceutical compositions comprising anhydrous tiotropium bromide and uses of the compositions.
  • Tiotropium bromide (1) is a highly effective anticholinergic agent with specificity for muscarinic receptors and it is presently approved for the treatment of respiratory disorders, such as asthma or chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.
  • COPD chronic obstructive pulmonary disease
  • Tiotropium bromide is used in low (microgram) therapeutic doses and it is therefore particularly necessary to develop an industrial process for the commercial preparation of tiotropium bromide which ensures that the product is prepared not only in a high, economical yield but also with exceptional chemical and polymorphic purity.
  • the manufacturing process for many pharmaceuticals is hindered by the fact that the organic compound, which is the active ingredient, has handling difficulties during the manufacturing process and may impart undesirable properties to the final drug or dosage form. In addition it can be difficult to control the polymorphic form of the active pharmaceutical ingredient throughout the manufacturing process.
  • the active ingredient can exist in more than one polymorphic or crystalline form, it is particularly important to ensure that the manufacturing process for the active ingredient affords a single, pure polymorph with a consistent level of polymorphic purity. If the manufacturing process leads to a polymorph with varying degrees of polymorphic purity and/or or where the process does not control polymorphic interconversion, serious problems in dissolution and/ or bioavailability can result in the finished pharmaceutical composition comprising the active ingredient.
  • a further method, disclosed in US2007/0092453 involves converting tiotropium bromide monohydrate to anhydrous tiotropium bromide by heating at 50 0 C in a 1:1 N 5 N- dimethylacetamide/water mixture. Also reported are 14 different solvates of tiotropium bromide.
  • this method in US2007/0092453 involves evaporation of high volumes of high boiling solvents at room temperature under a vacuum of 1 Kpa until crystals appear in the solution.
  • the method is not particularly reproducible and as both N 5 N- dimethylacetamide and water are high boiling solvents (164°C and 100 0 C respectively), the removal of these solvents at room temperature requires high vacuum. Therefore removal of such volumes of N,N-dimethylacetamide and water at room temperature is practically very difficult for production on a commercial scale.
  • the process is limited to tiotropium bromide monohydrate as starting material.
  • anhydrous tiotropium bromide typically contains 0.1-0.5% of impurity scopine di-(2-thienyl)glycolate.
  • the anhydrous tiotropium bromide formed in the prior art processes is not polymorphically pure.
  • a first aspect of the present invention provides a dichloromethane solvate of tiotropium bromide.
  • a second aspect of the present invention provides a dichloromethane solvate of tiotropium bromide having an XRPD pattern comprising at least three peaks (preferably at least four- peaks, preferably at least five peaks, preferably at least six peaks, preferably at least seven peaks, preferably at least eight peaks, preferably at least nine peaks, preferably at least ten peaks, preferably at least twelve peaks, preferably at least fourteen peaks, preferably at least sixteen peaks, preferably all eighteen peaks) selected from peaks with 2 ⁇ angles of about 10.00, 11.13, 13.46, 15.38, 16.38, 18.17, 19.98, 20.33, 20.98, 21.48, 23.70, 24.03, 24.73, 25.15, 26.06, 27.12, 27.89 and 32.05 ⁇ 0.2 degrees.
  • the second aspect of the present invention provides a dichloromethane solvate of tiotropium bromide with an XRPD spectrum substantially as shown in Figure 1.
  • the dichloromethane solvate of tiotropium bromide according to the second aspect of the present invention has a DSC spectrum with an endothermic peak at about 225 0 C + 2°C, preferably with endothermic peaks at about 164°C ⁇ 2°C and about 225°C ⁇ 2 0 C.
  • the dichloromethane solvate of tiotropium bromide according to the second aspect of the present invention has a DSC spectrum substantially as shown in Figure 2.
  • the dichloromethane solvate of tiotropium bromide according to the second aspect of the present invention has a TGA spectrum substantially as shown in Figure 3.
  • the dichloromethane solvate of tiotropium bromide according to the second aspect of the present invention comprise less than 5% of other polymorphic forms of tiotropium bromide, preferably less than 3%, preferably less than 2%, preferably less than 1%, preferably less than 0.5%, preferably less than 0.2%, and most preferably less than 0.1% (as measured by XRPD).
  • a third aspect of the present invention provides a process for the preparation of a dichloromethane solvate of tiotropium bromide, comprising (i) reacting tiotropium base with methyl bromide in a solvent system comprising DCM and isolating the product, or (ii) dissolving tiotropium bromide in a solvent system comprising DCM and isolating the product.
  • the solvent system comprises one or more solvents in addition to DCM.
  • the one or more solvents in addition to DCM is an organic solvent, preferably an organic polar aprotic solvent, preferably acetonitrile.
  • DCM tiotropium base or tiotropium bromide starting material
  • tiotropium base or tiotropium bromide starting material preferably about 7-20 volumes, preferably about 10 volumes.
  • DCM and the additional solvent are used in a ratio of from 2:1 to 8:1.
  • tiotropium base is reacted with methyl bromide, preferably the methyl bromide is added to the reaction mixture as methyl bromide gas.
  • the process according to the third aspect of the present invention provides a dichloromethane solvate of tiotfopium bromide according to the first or second aspect of the present invention.
  • a fourth aspect of the present invention provides a dichloromethane solvate of tiotropium bromide prepared by a process according to the third aspect of the present invention.
  • the dichloromethane solvate of tiotropium bromide is prepared in a yield of at least 80% from the starting material (tiotropium base or tiotropium bromide), preferably at least 90%, preferably at least 95%, preferably at least 96%, preferably at least 97%, preferably at least 98%.
  • a fifth aspect of the present invention provides a dichloromethane solvate of tiotropium bromide comprising less than 0.5% of impurity scopine di-(2-thienyl)glycolate, preferably less than 0.3%, preferably less than 0.2%, preferably less than 0.1%, preferably less than 0.05%, and most preferably less than 0.03% (as measured by HPLC).
  • the dichloromethane solvate of tiotropium bromide according to the fifth aspect of the present invention is prepared by a process according to the third aspect of the present invention.
  • a sixth aspect of the present invention provides a dichloromethane solvate of tiotropium bromide with an HPLC purity of at least 98%, preferably at least 99%, preferably at least 99.5%, preferably at least 99.6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9%.
  • the dichloromethane solvate of tiotropium bromide according to the sixth aspect of the present invention is prepared by a process according to the third aspect of the present invention.
  • the dichloromethane solvate of tiotropium bromide according to the fourth, fifth and sixth aspects of the present invention has the same polymorphic form as the dichloromethane solvate of tiotropium bromide according to the second aspect of the present invention, preferably comprising less than 5% of other polymorphic forms of tiotropium bromide, preferably less than 3%, preferably less than 2%, preferably less than 1%, preferably less than 0.5%, preferably less than 0.2%, and most preferably less than 0.1% (as measured by XRPD).
  • a seventh aspect of the present invention provides a process for the preparation of anhydrous tiotropium bromide, comprising the steps of:
  • step (b) isolating and drying the anhydrous tiotropium bromide obtained in step (a).
  • the mixture of a tiotropium bromide solvate or hydrate and organic solvent is heated at 40-80 0 C, more preferably at about 55-60°C.
  • the mixture of a tiotropium bromide solvate or hydrate and organic solvent is heated at the reflux temperature of the organic solvent.
  • the organic solvent is a ketone, preferably selected from acetone, methyl isobutyl ketone, methyl ethyl ketone, methyl vinyl ketone, diethyl ketone, methyl n-propyl ketone, methyl isopropyl ketone, methyl n-butyl ketone and methyl tert-butyl ketone.
  • the organic solvent is acetone.
  • the drying temperature in step (b) is between 25 to 8O 0 C, more preferably between 40 to 80 0 C, more preferably about 6O 0 C.
  • a solvate is used in the process according to the seventh aspect of the present invention.
  • the solvate is the DCM solvate according to the first, second, fourth, fifth or sixth aspect of the present invention.
  • the solvate is preferably an ethanol solvate. Solvates, including ethanol solvates, are disclosed in US2007/0092453 and WO2006/117300, which are hereby incorporated herein by reference in their entirety.
  • the process according to the seventh aspect of the present invention is carried out without seeding.
  • the process according to the seventh aspect of the present invention excluding drying of the anhydrous tiotropium bromide product, is carried out in less than 10 hours, preferably in less than 8 hours, preferably in less than 6 hours.
  • An eighth aspect of the present invention provides anhydrous tiotropium bromide prepared by a process according to the seventh aspect of the present invention.
  • the anhydrous tiotropium bromide is prepared in a yield of at least 80% from the starting material (tiotropium bromide solvate or hydrate), preferably at least 90%, preferably at least 95%, preferably at least 96%, preferably at least 97%, preferably at least 98%.
  • a ninth aspect of the present invention provides anhydrous tiotropium bromide comprising less than 0.5% of impurity scopine di-(2-thienyl)glycolate, preferably less than 0.3%, preferably less than 0.2%, preferably less than 0.1%, preferably less than 0.05%, and most preferably less than 0.03% (as measured by HPLC).
  • the anhydrous tiotropium bromide according to the ninth aspect of the present invention is prepared by a process according to the seventh aspect of the present invention.
  • a tenth aspect of the present invention provides anhydrous tiotropium bromide with an HPLC purity of at least 98%, preferably at least 99%, preferably at least 99.5%, preferably at least 99.6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9%.
  • the anhydrous tiotropium bromide according to the tenth aspect of the present invention is prepared by a process according to the seventh aspect of the present invention.
  • the anhydrous tiotropium bromide according to the eighth, ninth and tenth aspects of the present invention has an XRPD pattern comprising at least three peaks (preferably at least four peaks, preferably at least five peaks, preferably at least six peaks, preferably at least seven peaks, preferably at least eight peaks, preferably at least nine peaks, preferably at least ten peaks, preferably at least twelve peaks, preferably at least fifteen peaks, preferably at least twenty peaks, preferably all twenty-two peaks) selected from peaks with 2 ⁇ angles of about 8.49, 11.38, 13.58, 14.24, 14.74, 16.01, 17.03, 17.93, 18.60, 19.15, 21.80, 22.62, 22.92, 23.29, 25.29, 25.57, 26.23, 27.29, 28.07, 28.61, 30.24 and 31.83 ⁇ 0.2 degrees.
  • the anhydrous tiotropium bromide according to the eighth, ninth and tenth aspects of the present invention has an XRPD spectrum substantially as shown in Figure 4.
  • the anhydrous tiotropium bromide according to the eighth, ninth and tenth aspects of the present invention has a DSC spectrum with endotliermic peaks at about 208°C ⁇ 2°C and about 221 °C ⁇ 2°C.
  • the anhydrous tiottopium bromide according to the eighth, ninth and tenth aspects of the present invention has a DSC spectrum substantially as shown in Figure 5.
  • the anhydrous tiottopium bromide according to the eighth, ninth and tenth aspects of the present invention has a TGA spectrum substantially as shown in Figure 6.
  • the anhydrous tiottopium bromide according to the eighth, ninth and tenth aspects of the present invention comprises less than 5% of other polymorphic forms of tiottopium bromide, preferably less than 3%, preferably less than 2%, preferably less than 1%, preferably less than 0.5%, preferably less than 0.2%, and most preferably less than 0.1% (as measured by XRPD).
  • the dichlofomethane solvate of tiottopium bromide according to the first, second, fourth and fifth aspects of the present invention and the anhydrous tiottopium bromide according to the eighth and ninth aspects of the present invention have an HPLC purity of at least 98%, preferably at least 99%, preferably at least 99.5%, preferably at least 99.6%, preferably at least 99.7%, preferably at least 99.8%, preferably at least 99.9%.
  • the dichloromethane solvate of tiottopium bromide according to the first, second, fourth and sixth aspects of the present invention and the anhydrous tiottopium bromide according to the eighth and tenth aspects of the present invention comprise less than 0.5% of impurity scopine di-(2-thienyl)glycolate, preferably less than 0.3%, preferably less than 0.2%, preferably less than 0.1%, preferably less than 0.05%, and most preferably less than 0.03% (as measured by HPLC).
  • the dichloromethane solvate of tiottopium bromide according to the first, second, fourth, fifth and sixth aspects of the present invention and the anhydrous tiottopium bromide according to the eighth, ninth and tenth aspects of the present invention are suitable for use in medicine, preferably for the treatment of a respiratory disordef.
  • the respiratory disorder comprises asthma and COPD.
  • the COPD includes chronic bronchitis and emphysema.
  • An eleventh aspect of the present invention provides a pharmaceutical composition comprising a dichloromethane solvate of tiotropium bromide according to the first, second, fourth, fifth or sixth aspect of the present invention, or anhydrous tiotropium bromide according to the eighth, ninth or tenth aspect of the present invention.
  • the pharmaceutical composition is suitable for use in a dry powder inhaler (DPI), an aqueous nebulizer or a pressurized metered dosage inhaler (pMDI).
  • DPI dry powder inhaler
  • pMDI pressurized metered dosage inhaler
  • the pharmaceutical composition is suitable for the treatment of a respiratory disorder.
  • the respiratory disorder comprises asthma and COPD.
  • COPD includes chronic bronchitis and emphysema.
  • a twelfth aspect of the present invention provides the use of a dichloromethane solvate of tiotropium bromide according to the first, second, fourth, fifth or sixth aspect of the present invention, or use of anhydrous tiotropium bromide according to the eighth, ninth or tenth aspect of the present invention, or use of the pharmaceutical composition according to the eleventh aspect of the present invention, in the manufacture of a medicament for the treatment of a respiratory disorder.
  • the respiratory disorder comprises asthma and COPD, wherein the COPD preferably includes chronic bronchitis and emphysema.
  • a thirteenth aspect of the present invention provides a method of treating a respiratory disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a dichloromethane solvate of tiotropium bromide according to the first, second, fourth, fifth or sixth aspect of the present invention, or a therapeutically effective amount of anhydrous tiotropium bromide according to the eighth, ninth or tenth aspect of the present invention, or a therapeutically effective amount of the pharmaceutical composition according to the eleventh aspect of the present invention.
  • the respiratory disorder comprises asthma and COPD.
  • the COPD includes chronic bronchitis and emphysema.
  • the patient is a mammal, preferably a human.
  • Figure 1 shows an XRPD spectrum of tiotropium bromide dichloromethane solvate according to the present invention.
  • Figure 2 shows a DSC spectrum of tiotropium bromide dichloromethane solvate according to the present invention.
  • Figure 3 shows a TGA spectrum of tiotropium bromide dichloromethane solvate according to the present invention.
  • Figure 4 shows an XRPD spectrum of anhydrous tiotropium bromide according to the present invention.
  • Figure 5 shows a DSC spectrum of anhydrous tiotropium bromide according to the present invention.
  • Figure 6 shows a TGA spectrum of anhydrous tiotropium bromide according to the present invention.
  • the desolvation process for the preparation of anhydrous tiotropium bromide comprises the steps of: (a) refluxing a mixture of tiotropium bromide DCM solvate and an organic solvent, preferably acetone, and (b) isolating and drying the anhydrous tiotropium bromide obtained in step (a).
  • the drying temperature in step (b) is between 25 to 8O 0 C, more preferably about 6O 0 C.
  • anhydrous tiotropium bromide can be prepared under similar mild conditions from tiotropium bromide ethanol solvate instead of the DCM solvate.
  • Tiotropium bromide ethanol solvate can be prepared as disclosed in WO2006/117300 or US2007/0092453, which are hereby incorporated herein by reference in their entirety.
  • Isolation of the resulting anhydrous tiotiOpium bromide in step (b) is preferably achieved by filtration.
  • the isolated anhydrous tiotropium bromide is preferably dried in conditions that do not cause anhydrous tiotropium bromide to degrade, preferably until a constant weight is achieved.
  • the anhydrous tiotropium bromide is dried under conditions of reduced pressure, at a preferred temperature of 45-75°C, more preferably at about 6O 0 C.
  • the desolvation method of the present invention preferably involves refluxing tiotropium bromide solvate in acetone, cooling and filtering. This is a simple and scaleable process which is a good general method where all solvates and hydrates can be converted to anhydrous tiotropium bromide consistently with good yields of pure product.
  • highly pure anhydrous tiotropium bromide comprising less than 0.2%, preferably less than 0.1%, more preferably less than 0.05%, and most preferably less than 0.03% of scopine di-(2- thienyl)glycolate (as measured by HPLC).
  • highly polymorphically pure anhydrous tiotropium bromide comprising less than 5% of other polymorphic forms of tiotropium bromide, preferably less than 3%, preferably less than 2%, preferably less than 1%, preferably less than 0.5%, preferably less than 0.2%, and most preferably less than 0.1% of other polymorphic forms of tiotropium bromide (as measured by XRPD).
  • the crystalline anhydrous tiotropium bromide form in accordance with the invention can be used to advantage in the preparation of pharmaceutical dosage or drug forms.
  • the crystalline form in accordance with the present invention is stable and free flowing and does not present any of the stability (e.g. polymorphic conversion or chemical conversion) or handling difficulties associated with the prior art forms.
  • the crystalline form according to the invention therefore, can be employed in the manufacture of pharmaceutical compositions that do not suffer from the problems, such as inconsistent drug substance dissolution rates and the like, that can be manifest in dosage forms manufactured using previously available forms of tiotropium bromide.
  • the DPI compositions of the present invention preferably contain, in addition to the active substance, the following physiologically acceptable excipients: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, sucrose, maltose), oligo- and polysaccharides (e.g. dextrane), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients with one another.
  • monosaccharides e.g. glucose or arabinose
  • disaccharides e.g. lactose, sucrose, maltose
  • oligo- and polysaccharides e.g. dextrane
  • polyalcohols e.g. sorbitol, mannitol, xylitol
  • salts e.g. sodium chloride, calcium carbonate
  • lactose is the particularly preferred excipient, while lactose monohydrate is most particularly preferred.
  • the pMDI of the present invention uses HFA 134a, HFA 227 or mixtures thereof as propellant gas.
  • compositions of the present invention preferably contain about 0.001 to 20% tiotropium bromide in admixture with one or more physiologically acceptable excipients.
  • Preferred compositions contain 0.01 to 10% of tiotropium bromide, more preferred are compositions which contain 0.01 to 2% of tiotropium bromide, and most preferred are compositions which contain 0.04 to 0.8% of tiotropium bromide.
  • Scopine di-(2-thienyl)grycolate (1 eq) was dissolved in dichloromethane (DCM) (10 vol) and acetonitrile (3 vol) and purged with methyl bromide gas for 20 minutes. The solution was kept at 25-3O 0 C for 30 hours. The precipitated solid was filtered and washed with DCM (20 vol). Drying of the solid at 25-3O 0 C under vacuum gave the product as a white solid.
  • DCM dichloromethane
  • Tiotropium bromide ethanol solvate (leq) was mixed with acetone (15 vol) and refluxed for 4 hours at 55-6O 0 C. The mixture was cooled to 0-5 0 C and stirred at 0-5 0 C for 1 hour.
  • the samples of anhydrous tiotropium bromide prepared in examples 2 and 3 were found to be substantially pure polymorphically with no levels of other forms detected (>99.7% polymorphically pure, as measured by XRPD).
  • the samples of anhydrous tiotropium bromide prepared were also found to be very stable chemically and polytnorphically with no conversion over time to other polymorphs.
  • the stability of the samples was tested by subjecting the samples to accelerated stability conditions (4O 0 C ⁇ 2 0 C temperature and 75% ⁇ 5% relative humidity) for 6 months.
  • the XRPDs were recorded on a Bruker D 8 Advance Diffractometer, using Cu Ka 1 radiation as the X-ray source and LynxEye as the detector, with a 2 ⁇ range of from 3° to 50°, a step-size of 0.05° and a time/step of 1 sec.
  • the DSCs were recorded on a Perkin Elmer Pyris 6 Instrument over a temperature range of from 25 0 C to 250 0 C at a rate of heating of 10°C/min.
  • the TGAs were recorded on a Perkin Elmer Pyris 1 Instrument over a temperature range of from 25°C to 25O 0 C at a rate of heating of 10°C/min.

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Abstract

La présente invention porte sur un nouveau solvate du bromure de tiotropium, sur un procédé pour préparer ce solvate et sur l'utilisation de celui-ci et d'autres solvates dans des procédés pour la préparation de bromure de tiotropium anhydre. La présente invention porte également sur des compositions pharmaceutiques comprenant du bromure de tiotropium anhydre et sur des utilisations des compositions.
PCT/GB2010/051311 2009-08-07 2010-08-06 Solvate de dichlorométhane du bromure de tiotropium et son utilisation Ceased WO2011015883A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8163913B2 (en) 2005-12-19 2012-04-24 Sicor Inc. Forms of tiotropium bromide and processes for preparation thereof
WO2012118461A1 (fr) * 2011-03-03 2012-09-07 Mahmut Bilgic Composé cristallin comprenant du bromure de tiotropium
CZ304368B6 (cs) * 2011-11-28 2014-04-02 Zentiva, K.S. Směsný solvát tiotropium bromidu a způsob jeho přípravy
US8697719B2 (en) 2009-08-07 2014-04-15 Generics [Uk] Limited Anhydrate of tiotropium bromide
WO2014067499A1 (fr) 2012-11-05 2014-05-08 Zentiva, K.S. Stabilisation de solvates de tiotropium
US9108962B2 (en) 2005-12-19 2015-08-18 Sicor, Inc. Forms of tiotropium bromide and processes for preparation thereof

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0418716A1 (fr) 1989-09-16 1991-03-27 Boehringer Ingelheim Kg Esters aminoalcohol d'acide thienylcarboxyliques leurs produits quaternaires, leur préparation et l'utilisation de ces composés
WO2002030928A1 (fr) 2000-10-12 2002-04-18 Boehringer Ingelheim Pharma Gmbh & Co. Kg Monohydrate cristallin, procede permettant sa preparation et son utilisation pour la preparation d'un produit pharmaceutique
US6608055B2 (en) 2001-06-22 2003-08-19 Boehringer Ingelheim Pharma Kg Crystalline anticholinergic, processes for preparing it and its use for preparing a pharmaceutical composition
US20050143410A1 (en) 2003-11-03 2005-06-30 Boehringer Ingelheim International Gmbh Novel crystalline anhydrate with anticholinergic efficacy
WO2006117300A2 (fr) 2005-05-02 2006-11-09 Boehringer Ingelheim International Gmbh Formes cristallines de bromure de tiotropium
US20070092453A1 (en) 2005-05-02 2007-04-26 Boehringer Ingelheim International Gmbh Novel Crystalline Forms of Tiotropium Bromide
WO2007075858A2 (fr) 2005-12-19 2007-07-05 Sicor Inc. Nouvelles formes de bromure de tiotropium et processus de preparation de celles-ci
WO2007075838A2 (fr) * 2005-12-19 2007-07-05 Sicor Inc. Bromure de tiotropium pur et stable
WO2008008376A2 (fr) * 2006-07-10 2008-01-17 Sicor Inc. Procédé pour la préparation de bromure de tiotropium
WO2008089852A1 (fr) * 2007-01-26 2008-07-31 Boehringer Ingelheim Pharma Gmbh & Co.Kg Nouveau procédé de préparation de sels de tiotropium

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0418716A1 (fr) 1989-09-16 1991-03-27 Boehringer Ingelheim Kg Esters aminoalcohol d'acide thienylcarboxyliques leurs produits quaternaires, leur préparation et l'utilisation de ces composés
WO2002030928A1 (fr) 2000-10-12 2002-04-18 Boehringer Ingelheim Pharma Gmbh & Co. Kg Monohydrate cristallin, procede permettant sa preparation et son utilisation pour la preparation d'un produit pharmaceutique
US6608055B2 (en) 2001-06-22 2003-08-19 Boehringer Ingelheim Pharma Kg Crystalline anticholinergic, processes for preparing it and its use for preparing a pharmaceutical composition
US20050143410A1 (en) 2003-11-03 2005-06-30 Boehringer Ingelheim International Gmbh Novel crystalline anhydrate with anticholinergic efficacy
WO2006117300A2 (fr) 2005-05-02 2006-11-09 Boehringer Ingelheim International Gmbh Formes cristallines de bromure de tiotropium
US20070092453A1 (en) 2005-05-02 2007-04-26 Boehringer Ingelheim International Gmbh Novel Crystalline Forms of Tiotropium Bromide
WO2007075858A2 (fr) 2005-12-19 2007-07-05 Sicor Inc. Nouvelles formes de bromure de tiotropium et processus de preparation de celles-ci
WO2007075838A2 (fr) * 2005-12-19 2007-07-05 Sicor Inc. Bromure de tiotropium pur et stable
WO2008008376A2 (fr) * 2006-07-10 2008-01-17 Sicor Inc. Procédé pour la préparation de bromure de tiotropium
WO2008089852A1 (fr) * 2007-01-26 2008-07-31 Boehringer Ingelheim Pharma Gmbh & Co.Kg Nouveau procédé de préparation de sels de tiotropium

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Crystalline (1[alpha],2[beta],4[beta],5[alpha],7[beta])-7-[(hydroxydi 2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0]no nane bromide and process for preparation thereof", IP.COM JOURNAL, IP.COM INC., WEST HENRIETTA, NY, US, 30 November 2006 (2006-11-30), XP013116939, ISSN: 1533-0001 *
"Crystalline forms of 1Î+-,2Î,4Î,5Î+-,7Î)-7-[(hydroxydi-2-thienylacety l)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0]nonane bromide", IP.COM JOURNAL, IP.COM INC., WEST HENRIETTA, NY, US, 17 June 2009 (2009-06-17), XP013132381, ISSN: 1533-0001 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8163913B2 (en) 2005-12-19 2012-04-24 Sicor Inc. Forms of tiotropium bromide and processes for preparation thereof
US20120165364A1 (en) * 2005-12-19 2012-06-28 Sicor Inc. Novel forms of tiotropium bromide and processes for preparation thereof
US8846926B2 (en) 2005-12-19 2014-09-30 Sicor Inc. Forms of tiotropium bromide and processes for preparation thereof
US9108962B2 (en) 2005-12-19 2015-08-18 Sicor, Inc. Forms of tiotropium bromide and processes for preparation thereof
US8697719B2 (en) 2009-08-07 2014-04-15 Generics [Uk] Limited Anhydrate of tiotropium bromide
US9181268B2 (en) 2009-08-07 2015-11-10 Generics [Uk] Limited Anhydrate of tiotropium bromide
WO2012118461A1 (fr) * 2011-03-03 2012-09-07 Mahmut Bilgic Composé cristallin comprenant du bromure de tiotropium
CZ304368B6 (cs) * 2011-11-28 2014-04-02 Zentiva, K.S. Směsný solvát tiotropium bromidu a způsob jeho přípravy
WO2014067499A1 (fr) 2012-11-05 2014-05-08 Zentiva, K.S. Stabilisation de solvates de tiotropium

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