WO2012026906A1 - New tiotropium bromide crystal and its production method - Google Patents
New tiotropium bromide crystal and its production method Download PDFInfo
- Publication number
- WO2012026906A1 WO2012026906A1 PCT/TR2011/000196 TR2011000196W WO2012026906A1 WO 2012026906 A1 WO2012026906 A1 WO 2012026906A1 TR 2011000196 W TR2011000196 W TR 2011000196W WO 2012026906 A1 WO2012026906 A1 WO 2012026906A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tiotropium bromide
- crystalline form
- acetone
- formulation
- range
- Prior art date
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Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
-
- 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
-
- 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
-
- 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
Definitions
- the present invention relates to a new crystalline form of (la, 2 ⁇ , 4 ⁇ , 5a, 7P)-7-[(Hydroxidi- 2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0 2 ' 4 ]nonan-bromide and a new method for production of said crystalline form.
- Tiotropium bromide is a highly effective anticholinergic agent and for this reason, it is widely used in the treatment of asthma and/or COPD (chronic obstructive pulmonary disease).
- the active agent to be administered by the inhalation route has to meet essential requirements such as appropriate aerodynamic particle size, appropriate particle shape, uniformity of particle size distribution, low aerodynamic dispersion forces, low density, high physical and chemical stability optimally.
- Appropriate particle size and uniformity of particle size distribution are closely related to structural properties of the active ingredient. While coarse particles accumulate in areas other than the target area, fine particles reach the target area as required and they are absorbed there. In order to ensure homogenization of the particle size distribution to attain to required activity, particle size needs to be reduced to the required size. To this end, the powder mixture comprising the active agent is applied difficult operations such as micronization. At the same time, the active agent has to have a stable structure that allows micronization and it has to maintain its crystalline form under said mechanical effect.
- the present invention relates to a new crystalline form of anhydrous tiotropium bromide.
- a stable tiotropium bromide crystal has been obtained which can remain stable under physical effects such as mechanical effect, heat effect by crystallizing the crude tiotropium obtained as a result of the reaction by using methanol which is an alcohol derivative solvent and acetone which is a ketone derivative solvent.
- the present invention comprises a method for obtainment of the crystalline form A.
- the inventors have found that the appropriate solvent system to be used in order to obtain the crystalline form A is composed of methanol and acetone.
- tiotropium bromide When methanol is used, tiotropium bromide can be hydrolyzed and transform into different byproducts due to the ester bond in its structure. So as to prevent this and obtain a stable crystalline form, it is required to determine the amount of the solvent to be used in crystallization stage and the procedure to be used carefully.
- the present invention comprises use of methanol: acetone in the range of 1 :8 to 1 :18, preferably in the range of 1 :9 to 1 :16, more preferably in the range of 1:10 to 1 :15 by volume in a method so as to be used to obtain anhydrous crystalline form A of tiotropium bromide.
- crystalline form A is obtained without formation of any impurity in the case that the ratio of methanohacetone used in the crystallization is in the range of 1:8 to 1 :18, preferably in the range of 1 :9 to 1:16, more preferably in the range of l rlO to 1:15.
- the present invention relates to anhydrous tiotropium bromide which is named crystalline from A and characterized by the peaks it gives in the range of 15,06, 18,03, 21,84, 23,10 ⁇ 0,2 2 ⁇ in X-ray powder diffraction diagram.
- the crystalline form A of the present invention can further comprise the peaks in the range of 9,85, 18,34, 20,90, 25,88, 33,94 ⁇ 0,2 2 ⁇ in addition to the peaks specified above. 2 ⁇ values given about the present invention were obtained by an X-ray diffractometer equipped with Cu-al radiation source.
- the subject of the present invention is realized by using the methanol :acetone system mentioned above; reducing the temperature or adding anti-solvent or a method that is a combination thereof.
- the method preferred in the present invention is composed of the following steps;
- Example 1 Crystallization method for the present invention:
- tiotropium bromide 600 mg is added into 2 ml of methanol; the suspension obtained is heated with a heat gun and tiotropium bromide is ensured to be dissolved. 25 ml of acetone is added into the solution obtained and the mixture is cooled to 0°C by placing it in an ice bath. The crystals produced are filtered and taken away and they are dried at a temperature of 110°C in a vacuum furnace for 16 hours.
- Figure 1 XRD diagram of crystalline form A of tiotropium bromide Results of X-ray powder diffraction analysis:
- Crystalline form A prepared according to the present invention is characterized by the peaks valuing at 15,06, 18,03, 21,84, 23,10 ⁇ 0,2 20 in the X-ray powder diffraction diagram.
- compositions of the present invention comprising crystalline form A of tiotropium bromide
- Crystal of tiotropium bromide suitable for the invention has better structural characteristics so as to meet the needs for administration by the oral route.
- Crystal of tiotropium bromide suitable for the invention refers to crystalline form A of tiotropium bromide wherein said crystal is characterized by peaks at the values of 15,06, 18,03, 21,84, 23,10 ⁇ 0,2 2 ⁇ in X-ray diffraction diagram. Said form has to be formulated in order to be used in inhalation treatment.
- the pharmaceutical compositions comprising pharmaceutically acceptable, nontoxic and therapeutically effective amounts of the new crystal of tiotropium bromide suitable for the invention and preparation methods thereof are characteristic features of the invention.
- the pharmaceutical compositions comprising the crystal of tiotropium bromide suitable for the invention are in the form of dry powder or pressurized metere " d ⁇ dose ⁇ inhalation composition, preferably in dry powder inhalation composition form.
- compositions of the present invention are preferably prepared by the second method.
- the pharmaceutical composition comprises at least one pharmaceutically acceptable inert carrier and optionally at least one pharmaceutically acceptable excipient different from the carrier(s) along with the active agent.
- micronized drug particles refers to crystalline form A of tiotropium bromide.
- the crystal of tiotropium bromide suitable for the invention is characterized by having an average particle size in the range of 1-10 ⁇ , preferably in the range of 1-5 ⁇ .
- the pharmaceutical compositions of the present invention are characterized by comprising crystalline form A of tiotropium bromide in a percentage in the range of 0.001-50%, preferably in the range of 0.01-10%.
- the carrier referred with the term "inert carrier” is preferably lactose, more preferably lactose monohydrate for dry powder inhalation compositions suitable for the invention.
- Pharmaceutical compositions of the present invention can comprise at least one coarse and fine inert carrier and optionally at least one excipient together.
- Coarse inert carrier of the invention is characterized by having an average particle size in the range of 10-250 ⁇ , preferably in the range of 10-150 ⁇ , more preferably of 150 ⁇ .
- Fine carrier is characterized by having an average particle size (d 50 ) in the range of 1-10 ⁇ , preferably of 10 ⁇ .
- Coarse and fine inert carriers may be of the same substance having different particle sizes or of different substances.
- At least one pharmaceutically acceptable excipient can be selected from a group comprising carbohydrates such as lactose, glucose, fructose, galactose, sucrose, maltose, trehalose, maltodextrines, dextranes, cyclodextrines, starch and cellulose; polyalcohols such as sorbitol, mannitol and xylitol; amino acids such as glycine, arginine, lysine, aspartic acid and glutamic acid; peptides such as human serum albumin; gelatin, various salts and taste masking agents. Said at least one pharmaceutically acceptable excipient is not limited to these substances.
- the pharmaceutical composition preferred comprises at least one essential excipient selected from a group comprising propellant gases, surfactants and cosolvents; and optionally at least one other pharmaceutically acceptable excipient in addition to the active agent.
- active agent refers to crystalline form A of tiotropium bromide.
- the crystal of tiotropium bromide suitable for the invention is characterized by having an average particle size in the range of 1-10 ⁇ , preferably in the range of 1-5 ⁇ .
- the pharmaceutical compositions of the present invention are characterized by comprising the crystalline form A of tiotropium bromide in a percentage in the range of 0.001-50 %, preferably in the range of 0.01-10 %.
- At least one pharmaceutically acceptable excipient can be selected based on the formulation strategy from a group comprising propellant gases such as chlorofluorocarbons, hydrofluoroalkanes and hydrocarbons; surfactants such as oleic acid, polysorbates, propyleneglycol, polyethyleneglycol, cetyl alcohol, stearyl alcohol, sorbitan fatty acid esters, sugar esters of fatty acids, glycerides of fatty acids, isopropyl myristate and lecithin; cosolvents such as ethanol, water and diethyl ether; antioxidants such as butylhydroxyanisole (BHA), sodium ascorbate, butylhydroxytoluene (BHT), sodium sulphite, gallates (such as propyl gallates), tocopherol, citric acid, malic acid, ascorbic acid, acetylcystein, fumaric acid, lecithin, ascorbyl palmitate, ethylenediamine triacetate and
- compositions comprising the crystal of tiotropium bromide suitable for the invention can additionally comprise at least one active agent selected from drugs such as other anticholinergic agents, adrenergic agonists, anti-inflammatory agents, antihistaminics, steroids, leukotriene receptor antagonists, antimuscarinic agents, PDE inhibitors and EGFR inhibitors.
- the crystal of tiotropium bromide suitable for the invention and at least one active agent selected from said group can be used separately, sequentially or simultaneously.
- Another characteristic feature of the invention is use of the pharmaceutical compositions comprising the crystal of tiotropium bromide suitable for the invention in the treatment of respiratory diseases, particularly in asthma and COPD.
- the first mixture is obtained by adding the sieved fine inert carrier into crystalline form A of tiotropium bromide;
- the second mixture is obtained by adding the sieved coarse inert carrier into the first mixture
- the second mixture obtained is sieved and mixed
- the final product is prepared ready for capsule/blister filling.
- the propellant gas is pumped into the vessel
- Example 1 Dry powder inhalation formulation
- Example 3 Pressurized metered-dose inhalation formulation
- Example 4 Pressurized metered-dose inhalation formulation
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Otolaryngology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11773329.5A EP2609096A1 (en) | 2010-08-25 | 2011-08-23 | New tiotropium bromide crystal and its production method |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
TR2010/07108 | 2010-08-25 | ||
TR2010/07108A TR201007108A2 (tr) | 2010-08-25 | 2010-08-25 | Yeni tiotropyum bromür kristali ve üretim yöntemi.@ |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2012026906A1 true WO2012026906A1 (en) | 2012-03-01 |
Family
ID=44903330
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/TR2011/000196 WO2012026906A1 (en) | 2010-08-25 | 2011-08-23 | New tiotropium bromide crystal and its production method |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP2609096A1 (tr) |
TR (1) | TR201007108A2 (tr) |
WO (1) | WO2012026906A1 (tr) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012118462A1 (en) * | 2011-03-03 | 2012-09-07 | Mahmut Bilgic | Anhydrous crystalline form of tiotropium bromide |
WO2014042605A1 (en) * | 2012-09-11 | 2014-03-20 | Mahmut Bilgic | New tiotropium bromide crystalline form |
CN104341412A (zh) * | 2013-07-29 | 2015-02-11 | 天津金耀集团有限公司 | 一种无水噻托溴铵结晶的制备方法 |
CN104341413A (zh) * | 2013-07-29 | 2015-02-11 | 天津金耀集团有限公司 | 一种无水噻托溴铵的新晶型 |
US9108962B2 (en) | 2005-12-19 | 2015-08-18 | Sicor, Inc. | Forms of tiotropium bromide and processes for preparation thereof |
WO2017138896A1 (en) * | 2016-02-11 | 2017-08-17 | Sima Patent Ve Lisanslama Hizmetleri Ltd. Şti | Crystalline form of tiotropium bromide anhydrate |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0418716A1 (de) | 1989-09-16 | 1991-03-27 | Boehringer Ingelheim Kg | Neue Thienylcarbonsäureester von Aminoalkoholen, ihre Quaternierungsprodukte sowie die Herstellung und Verwendung dieser Verbindungen |
US20020133010A1 (en) * | 2000-12-22 | 2002-09-19 | Rolf Banholzer | Process for preparing an anticholinergic |
WO2003000265A1 (de) * | 2001-06-22 | 2003-01-03 | Boehringer Ingelheim Pharma Gmbh & Co.Kg | Kristallines anticholinergikum, verfahren zu dessen herstellung und dessen verwendung zur herstellung eines arzneimittels |
CN1634921A (zh) * | 2004-10-26 | 2005-07-06 | 江苏正大天晴药业股份有限公司 | 结晶性抗胆碱能药噻托溴铵晶体 |
WO2006021559A2 (de) * | 2004-08-26 | 2006-03-02 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verfahren zur herstellung von tiotropiumsalzen und silicium-derivate als zwischenprodukte |
WO2006117299A2 (en) * | 2005-05-02 | 2006-11-09 | Boehringer Ingelheim International Gmbh | Novel crystalline forms of tiotropium bromide |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1879888A2 (en) * | 2005-05-02 | 2008-01-23 | Boehringer Ingelheim International GmbH | Crystalline forms of tiotropium bromide |
-
2010
- 2010-08-25 TR TR2010/07108A patent/TR201007108A2/tr unknown
-
2011
- 2011-08-23 WO PCT/TR2011/000196 patent/WO2012026906A1/en active Application Filing
- 2011-08-23 EP EP11773329.5A patent/EP2609096A1/en not_active Withdrawn
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0418716A1 (de) | 1989-09-16 | 1991-03-27 | Boehringer Ingelheim Kg | Neue Thienylcarbonsäureester von Aminoalkoholen, ihre Quaternierungsprodukte sowie die Herstellung und Verwendung dieser Verbindungen |
US20020133010A1 (en) * | 2000-12-22 | 2002-09-19 | Rolf Banholzer | Process for preparing an anticholinergic |
WO2003000265A1 (de) * | 2001-06-22 | 2003-01-03 | Boehringer Ingelheim Pharma Gmbh & Co.Kg | Kristallines anticholinergikum, verfahren zu dessen herstellung und dessen verwendung zur herstellung eines arzneimittels |
WO2006021559A2 (de) * | 2004-08-26 | 2006-03-02 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verfahren zur herstellung von tiotropiumsalzen und silicium-derivate als zwischenprodukte |
CN1634921A (zh) * | 2004-10-26 | 2005-07-06 | 江苏正大天晴药业股份有限公司 | 结晶性抗胆碱能药噻托溴铵晶体 |
WO2006117299A2 (en) * | 2005-05-02 | 2006-11-09 | Boehringer Ingelheim International Gmbh | Novel crystalline forms of tiotropium bromide |
Non-Patent Citations (1)
Title |
---|
See also references of EP2609096A1 |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9108962B2 (en) | 2005-12-19 | 2015-08-18 | Sicor, Inc. | Forms of tiotropium bromide and processes for preparation thereof |
WO2012118462A1 (en) * | 2011-03-03 | 2012-09-07 | Mahmut Bilgic | Anhydrous crystalline form of tiotropium bromide |
WO2014042605A1 (en) * | 2012-09-11 | 2014-03-20 | Mahmut Bilgic | New tiotropium bromide crystalline form |
CN104341412A (zh) * | 2013-07-29 | 2015-02-11 | 天津金耀集团有限公司 | 一种无水噻托溴铵结晶的制备方法 |
CN104341413A (zh) * | 2013-07-29 | 2015-02-11 | 天津金耀集团有限公司 | 一种无水噻托溴铵的新晶型 |
WO2017138896A1 (en) * | 2016-02-11 | 2017-08-17 | Sima Patent Ve Lisanslama Hizmetleri Ltd. Şti | Crystalline form of tiotropium bromide anhydrate |
Also Published As
Publication number | Publication date |
---|---|
TR201007108A2 (tr) | 2012-03-21 |
EP2609096A1 (en) | 2013-07-03 |
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