EP2609096A1 - New tiotropium bromide crystal and its production method - Google Patents

New tiotropium bromide crystal and its production method

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Publication number
EP2609096A1
EP2609096A1 EP11773329.5A EP11773329A EP2609096A1 EP 2609096 A1 EP2609096 A1 EP 2609096A1 EP 11773329 A EP11773329 A EP 11773329A EP 2609096 A1 EP2609096 A1 EP 2609096A1
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EP
European Patent Office
Prior art keywords
tiotropium bromide
crystalline form
acetone
formulation
range
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.)
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Application number
EP11773329.5A
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German (de)
French (fr)
Inventor
Mahmut Bilgic
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Individual
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Individual
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Publication date
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Publication of EP2609096A1 publication Critical patent/EP2609096A1/en
Withdrawn legal-status Critical Current

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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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Abstract

The present invention relates to a new crystalline form of (1α, 2β, 4β, 5α, 7β)-7-[(hydroxidi-2- thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonan-bromide and a new method for production of said crystalline form.

Description

NEW TIOTROPIUM BROMIDE CRYSTAL AND ITS PRODUCTION METHOD
The present invention relates to a new crystalline form of (la, 2β, 4β, 5a, 7P)-7-[(Hydroxidi- 2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02'4]nonan-bromide and a new method for production of said crystalline form.
Background of the Invention
The compound whose chemical name is (la, 2β, 4β, 5a, 7β)-7-[(Hydroxidi-2- thienylacetyl)oxy] -9,9-dimethyl-3 -oxa-9-azoniatricyclo [3.3.1.02'4] nonan-bromide is generally known as tiotropium bromide. The compound illustrated in formula 1 below was firstly disclosed the in the patent numbered EP418716.
Formula 1
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).
There are various difficulties that should be considered during converting the active ingredient to a form suitable for use by the inhalation route. 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.
In conclusion, new forms of the active ingredient having better structural features which can meet said requirements need to be produced.
Detailed Description of the Invention:
The present invention relates to a new crystalline form of anhydrous tiotropium bromide. Surprisingly, 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.
In another aspect, 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.
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.
The inventors have found that 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 2Θ 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 2Θ in addition to the peaks specified above. 2Θ values given about the present invention were obtained by an X-ray diffractometer equipped with Cu-al radiation source.
X-ray powder diffraction patterns were obtained by the instrument Bruker D8 Advance which utilizes copper a source. X-ray tube was operated with a current of 40 n A and a potential difference of 40 kV. Obtained X-ray powder diffraction patterns were restricted by 20 angles in the range of 3 to 40°. Step range is determined as 20=0.02°, and step duration is determined as 37 seconds. Samples were spun by 30 cycles per minute.
The subject of the present invention, crystallization, 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;
• Tiotropium bromide is heated and dissolved in methanol,
• Acetone is added afterwards and the mixture is cooled to 0°C,
• The precipitate produced is filtered and taken away, and washed with acetone,
• It is dried at 110°C for 16 hours.
Example 1 : Crystallization method for the present invention:
600 mg of tiotropium bromide 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.
Brief description of the figures:
Figure 1 : XRD diagram of crystalline form A of tiotropium bromide Results of X-ray powder diffraction analysis:
X-ray diffraction diagram belonging to crystalline form A of tiotropium bromide is given in Figure 1.
Peak values regarding tiotropium bromide form A is given in table 1. Table 1:
31,731 2,81772 17,7
33,45 2,67672 13,4
33,942 2,63902 33,7
34,81 2,57515 21,8
35,791 2,50682 16,1
36,729 2,44495 15,8
37,31 2,40817 13
37,792 2,37854 16,4
38,725 2,32338 12,4
39,604 2,2738 14,8
40,56 2,22241 15,5
41,192 2,18972 14,4
42,112 2,144 10,9
42,693 2,11617 13
43,481 2,07964 13,1
43,767 2,06667 12,5
44,59 2,03045 14,8
45,222 2,00351 12,6
46,2 1,96335 12,1
46,946 1,93387 13,7
47,411 1,91601 11,8
48,534 1,87427 12
49,562 1,83778 11,1
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.
Pharmaceutical 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 2Θ 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.
During the preparation process of dry powder inhalation compositions, two methods are frequently used to transmit the medicament to the target area in sufficient amounts. One of these depends on controlled aggregation of undiluted medicament whilst the other one relies on adhesion of micronized drug particles on the surface of a coarse inert carrier. The pharmaceutical compositions of the present invention are preferably prepared by the second method. In the event that the second method is applied, 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.
The expression "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 μιη, preferably in the range of 1-5 μηι. 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 μηι, preferably in the range of 10-150 μιη, more preferably of 150 μπι. Fine carrier, on the other hand, is characterized by having an average particle size (d50) in the range of 1-10 μιη, preferably of 10 μπι. 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.
During the preparation process of pressures metered-dose inhalation compositions, two formulation strategies are applied according to the physicochemical characteristics of the active agent and the propellant gas system. One of these is solution whilst the other one is suspension formulation. 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.
The term "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 μη , preferably in the range of 1-5 μιη. 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 sweeteners.
Pharmaceutical 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.
Methods for preparation of pharmaceutical compositions comprising the crystalline form of the present invention
The process for preparation of dry powder compositions of the present invention is characterized by comprising the following steps:
- The coarse inert carrier and the fine inert carrier are sieved separately;
- The first mixture is obtained by adding the sieved fine inert carrier into crystalline form A of tiotropium bromide;
- The first mixture obtained is sieved;
- 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 process for preparation of pressurized metered-dose inhalation compositions of the present invention is characterized by comprising the following steps:
- The production vessel is cooled to -25°C;
- The propellant gas is pumped into the vessel;
- Crystalline form A of tiotropium bromide is added into the vessel and the mixture obtained is mixed;
- The final mixture is filled into suitable containers.
Examples of pharmaceutical compositions comprising the suitable crystal for the invention
Examples of the pharmaceutical compositions of the present invention are given below. These examples are provided so as to explain the invention, yet the invention is not limited to these. Example 1 : Dry powder inhalation formulation
Example 3 : Pressurized metered-dose inhalation formulation Example 4: Pressurized metered-dose inhalation formulation

Claims

CLAIMS:
1. A method for obtainment of crystalline form A of anhydrous tiotropium bromide characterized by peaks at 15,06, 18,03, 21,84, 23,10 ± 0,2 20 in X-ray powder diffraction diagram characterized in that crystallization is carried out by using methanol :acetone in the range of 1 :8 to 1 : 18 by volume.
2. The method according to claim 1 , wherein the ratio of methanol :acetone is in the range of 1:9 to 1 :16.
3. The method according to claim 2, wherein the ratio of methanol: acetone is in the range of 1 :10 to 1:15.
4. The method according to claim 1, wherein crystallization can be realized by reducing the temperature or adding anti-solvent or by a combination thereof.
5. The method according to claim 1, wherein said method comprises the steps of;
• Dissolving tiotropium bromide by heating in methanol
• Adding acetone and cooling the mixture to 0°C afterwards
• Separating the formed precipitate by filtering, and washing it with acetone
• Drying at 110°C for 16 hours.
6. Crystalline form A of anhydrous tiotropium bromide characterized by peaks at 15,06, 18,03, 21,84, 23,10 ± 0,2 2Θ in X-ray powder diffraction diagram.
7. The crystalline form A of tiotropium bromide according to claim 6, wherein said crystalline form A of tiotropium bromide further comprises peaks at 9,85, 18,34, 20,90, 25,88, 33,94 ± 0,2 2Θ in X-ray powder diffraction diagram.
8. The crystalline form of tiotropium bromide according to claim 6, wherein said crystalline form of tiotropium bromide has the x-ray powder diffraction diagram shown in figure 1.
9. The crystalline form of tiotropium bromide according to claim 6, wherein said crystalline form of tiotropium bromide is prepared by the method described in claim 1.
10. The crystal of tiotropium bromide as claimed in any of the preceding claims, wherein said crystal is formulated with at least one excipient.
11. The formulation according to claim 10, wherein said formulation comprises at least one diluent and/or propellant gas as excipient.
12. The formulation according to claim 10, wherein said formulation is prepared in the form of dry powder or pressurized metered-dose inhalation composition.
13. The formulation according to claim 10, wherein said formulation comprises at least one active agent selected from a group of drugs comprising other anticholinergic agents, adrenergic agonists, anti-allergic agents, anti-inflammatory agents, antihistaminics, steroids, leukotriene receptor antagonists, antimuscarinic agents, PDE inhibitors and EGFR inhibitors.
14. The crystalline form of tiotropium bromide according to claim 6, wherein said crystalline form of tiotropium bromide is used in the production of a drug for use in the treatment of respiratory diseases, particularly asthma and COPD.
EP11773329.5A 2010-08-25 2011-08-23 New tiotropium bromide crystal and its production method Withdrawn EP2609096A1 (en)

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US9108962B2 (en) 2005-12-19 2015-08-18 Sicor, Inc. Forms of tiotropium bromide and processes for preparation thereof
TR201111589A2 (en) * 2011-03-03 2012-09-21 Bi̇lgi̇ç Mahmut Tiotropium bromide anhydrous crystal form.
WO2014042605A1 (en) * 2012-09-11 2014-03-20 Mahmut Bilgic New tiotropium bromide crystalline form
CN104341413A (en) * 2013-07-29 2015-02-11 天津金耀集团有限公司 Anhydrous tiotropium bromide new crystal form
CN104341412A (en) * 2013-07-29 2015-02-11 天津金耀集团有限公司 Anhydrous tiotropium bromide crystal preparation method
WO2017138896A1 (en) * 2016-02-11 2017-08-17 Sima Patent Ve Lisanslama Hizmetleri Ltd. Şti Crystalline form of tiotropium bromide anhydrate

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060246009A1 (en) * 2005-05-02 2006-11-02 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel Crystalline Forms of Tiotropium Bromide

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PL208137B1 (en) * 2001-06-22 2011-03-31 Boehringer Ingelheim Pharma Crystalline anticholinergic, method for its production, and use thereof in the production of a drug
DE102004041253A1 (en) * 2004-08-26 2006-03-02 Boehringer Ingelheim Pharma Gmbh & Co. Kg New process for the preparation of tiotropium salts
CN1271073C (en) * 2004-10-26 2006-08-23 江苏正大天晴药业股份有限公司 Crystalline anti-cholinergic tiotropium crystal
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Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060246009A1 (en) * 2005-05-02 2006-11-02 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel Crystalline Forms of Tiotropium Bromide

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