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
  • C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
• • 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
  • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• • 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

Definitions

• the present invention is directed to pure and stable
• MW J 472 .4 is an anticholinergic drug with specificity for muscarinic receptors .
• COPD chronic obstructive pulmonary disease
• This pharmaceutical ingredient is administered by inhalation, and is available commercially as SPIRIVA® HandiHaler®.
• Tiotropium bromide can contain extraneous compounds or impurities that can come from many sources. Some of these extraneous compounds or impurities may be unreacted starting materials, by-products of the reaction including the products of side reactions, or degradation products; wherein the degradation products are related to the stability of the API during storage.
• Impurities in Tiotropium bromide or any active pharmaceutical ingredient (API) are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API . [0009] Therefore, there is a need in the art for stable Tiotropium bromide, and also for pure Tiotropium bromide solvates .
• the present invention provides a Tiotropium bromide solvate of the following formulas:
• the present invention provides a Tiotropium bromide solvate, with less than about 0.15% area by HPLC of 2,2-dithienyl glycolic acid of the following formula.
• the present invention provides Tiotropium bromide solvate with a purity of at least 99% area as measured by HPLC, and with less than about 0.15% area as measured by HPLC of 2 , 2-dithienyl glycolic acid
• the present invention provides stable Tiotropium bromide solvate.
• the present invention provides stable Tiotropium bromide solvate with a purity of at least 99% area as measured by HPLC, and with less than about 0.15% area by HPLC of 2 , 2-dithienyl glycolic acid.
• the present invention provides an HPLC method for determining the purity of Tiotropium bromide solvate, and the amount of 2 , 2-dithienyl glycolic acid in Tiotropium bromide.
• the method comprises:
• the present invention provides a process for preparing stable Tiotropium bromide solvate having a purity of at least 99% area by HPLC and with less than about 0.15% area of 2, 2-dithienyl glycolic acid as measured by HPLC, comprises crystallizing Tiotropium bromide from a solvent system comprising an organic acid wherein the ratio of Tiotropium bromide to the solvent system is of at least about 1 to about 5, respectively.
• Organic acids which may be utilized as part of the present invention include, but are not limited to, acetic acid, propanoic acid, oxalic acid, maleic acid, fumaric acid, and tartaric acid.
• the organic acid is acetic acid.
• the present invention provides process for preparing stable Tiotropium bromide solvate having a purity of at least 99% area by HPLC and with less than about 0.05% area of 2 , 2-dithienyl glycolic acid as measured by HPLC, comprises crystallizing Tiotropium bromide from a solvent system comprising an organic acid wherein the ratio of Tiotropium bromide to the solvent system is of at least about 1 to about 10, respectively.
• Organic acids which may be utilized as part of the present invention include, but are not limited to, acetic acid, propanoic acid, oxalic acid, maleic acid, fumaric acid, and tartaric acid. In a preferred embodiment, the organic acid is acetic acid.
• the present invention provides a process for preparing stable Tiotropium bromide solvate having a purity of at least 99% area by HPLC and with less than about 0.02% area of 2, 2-dithienyl glycolic acid as measured by HPLC, comprises crystallizing Tiotropium bromide from a solvent system comprising an organic acid wherein the ratio of Tiotropium bromide to the solvent system is of at least about 1 to about 20, respectively.
• Organic acids which may be utilized as part of the present invention include, but are not limited to, acetic acid, propanoic acid, oxalic acid, maleic acid, fumaric acid, and tartaric acid.
• the organic acid is acetic acid.
• the present invention provides a process for preparing stable Tiotropium bromide solvate having a purity of at least 99% area by HPLC and with less than about 0.01% area of 2, 2-dithienyl glycolic acid as measured by HPLC, comprises crystallizing Tiotropium bromide from a solvent system comprising an organic acid wherein the ratio of Tiotropium bromide to the solvent system is of at least about 1 to about 30, respectively.
• Organic acids which may be utilized as part of the present invention include, but are not limited to, acetic acid, propanoic acid, oxalic acid, maleic acid, fumaric acid, and tartaric acid.
• the organic acid is acetic acid.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising stable Tiotropium bromide solvate with a purity of at least 99% area as measured by HPLC, and with less than about 0.15% area as measured by HPLC of 2,2- dithienyl glycolic acid, and pharmaceutically acceptable excipients .
• the present invention provides a process for preparing pharmaceutical composition
• a process for preparing pharmaceutical composition comprising stable Tiotropium bromide solvate with a purity of at least 99% area as measured by HPLC, and with less than about 0.15% area as measured by HPLC of 2, 2-dithienyl glycolic acid, and pharmaceutically acceptable excipients .
• the present invention provides the use of the stable Tiotropium bromide solvate with a purity of at least 99% area as measured by HPLC, and with less than about 0.15% area by HPLC of 2 , 2-dithienyl glycolic acid, of the present invention for the manufacture of a pharmaceutical composition.
• the present invention encompasses a process for preparing Tiotropium bromide with less than about 0.15% area by HPLC of 2, 2-dithienyl glycolic acid comprising the steps of
• step (c) selecting the Tiotropium bromide batch that comprises a level of 2, 2-dithienyl glycolic acid of less than about 0.15% area by HPLC, based on the measurement or measurements conducted in step (b) ; and (d) using the batch selected in step (c) to prepare said any Tiotropium bromide comprising less than about 0.15% area by HPLC of 2 ,2-dithienyl glycolic acid.
• acceptable purities of drug products for human treatment are generally greater than 99.0% area by HPLC, and preferably greater than 99.55% area as measured by HPLC, where the content of each single impurity is preferably less than about 0.15% area as measured by HPLC.
• providing such pure Tiotropium bromide solvate, which is also less prone to decomposition upon storage, is preferable considering that prolonged shelf life is an advantage for industrial manufacturing and safety of patients .
• the present invention provides Tiotropium bromide solvate of the following formula:
• the above Tiotropium bromide has purity ranging from about 99% area to about 100% area as measured, by HPLC, more preferably ranging from about 99.5% area to about 100% area as measured by HPLC, and most preferably ranging from about 99.7% area to about 100% area as measured by HPLC.
• the solvate may contain any number of solvent molecules.
• the term "solvate” as used herein refers to a substance that includes any solvent other than water at levels of more than 1%.
• the solvate form of Tiotropium bromide is selected from a group consisting of an alcoholate and an acetic acid solvate.
• the alcoholate is a Ci-s alcoholate, more preferably a Ci-e alcoholate, even more preferably a C ⁇ -5 alcoholate, and most preferably a C1-4 alcoholate.
• the C 1 - 4 alcoholate is selected from the group consisting of methanolate, ethanolate, isopropanolate, n- propanolate and n-butanolate .
• the C1-4 alcoholate is methanolate, ethanolate or n-propanolate .
• the present invention also provides Tiotropium bromide solvate containing less than about 0.15% area of 2, 2-dithienyl glycolic acid as measured by HPLC.
• the said Tiotropium bromide is with about 0.15% area by HPLC to the detection limit of an HPLC method of 2 , 2-dithienyl glycolic acid.
• the terms "detection limit” or “detection limit of an HPLC method” refer to any HPLC method used to determine the purity of Tiotropium bromide, and in particular, to determine the amount of 2, 2-dithienyl glycolic acid in any Tiotropium bromide sample.
• the detection limit is the detection limit of the HPLC method used in the present invention, or of any other equivalent method.
• Tiotropium bromide solvate is containing less than about 0.05% area as measured by HPLC of 2 , 2-dithienyl glycolic acid, more preferably, the said Tiotropium bromide is with, about 0.05% area by HPLC to the detection limit of an HPLC method of 2 , 2-dithienyl glycolic acid.
• Tiotropiu ⁇ i bromide solvate is containing less than about 0.02% area as measured by HPLC of 2, 2-dithienyl glycolic acid, more preferably, the said Tiotropium bromide is with about 0.02% area by HPLC to the detection limit of an HPLC method of 2, 2-dithienyl glycolic acid.
• Tiotropium bromide solvate is containing less than about 0.01% area as measured by HPLC of 2, 2-dithienyl glycolic acid, more preferably, the said Tiotropium bromide is with about 0.01% area by HPLC to the detection limit of an HPLC method, of 2, 2-dithienyl glycolic acid.
• the present invention further provides Tiotropium bromide solvate with a purity of at least 99% area as measured by HPLC, and containing less than about 0.15% area as measured by HPLC of 2, 2-dithienyl glycolic acid.
• the present invention also provides stable Tiotropium bromide solvate.
• stable in reference to Tiotropium bromide, means Tiotropium bromide wherein the level of a specific impurity does not increase to more than a specific limit, when maintained at a specific relative humidity and temperature for a specific period of time. More specifically, the term “stable” means Tiotropium bromide wherein the level of the 2 , 2-dithienyl glycolic acid, shown below, does not increase to more than 0.15% of the total amount of tiotropium bromide area as measured by HPLC, when maintained at a temperature ranging from about 4 2 C to about 30 2 C, for at least about two months.
• the present invention provides stable Tiotropium bromide solvate with a purity of at least 99% area as measured by HPLC, and containing less than about 0.15% area as measured by HPLC of 2,2-dithienyl glycolic acid.
• the eluent used may be a mixture of eluent A and eluent B, wherein the ratio of them varies over the time, i.e. a gradient eluent.
• the eluent contains 70% of eluent A and 300% of eluent B.
• the eluent contains 55% of eluent A and 45% of eluent B.
• the eluent contains 50% of eluent A and 50% of eluent B.
• the eluent contains 50% of eluent A and 50% of eluent B.
• the eluent contains 35% of eluent A and 65% of eluent B, and at 41 minutes, the eluent contains 70%> of eluent A and 30% of eluent B. .
• the 2 , 2-dithienyl glycolic acid content is measured at a wave length of 240 run.
• Such pure and stable Tiotropium bromide solvates can be prepared by a process comprises crystallizing Tiotropium bromide from a suitable solvent system; wherein the solvent system comprises acetic acid.
• the process for preparing stable Tiotropium bromide solvate having a purity of at least 99% area by HPLC and with less than about 0.15% area of 2 , 2-dithienyl glycolic acid as measured by HPLC comprises crystallizing Tiotropium bromide from a solvent system comprising acetic acid; wherein the ratio of Tiotropium bromide to the solvent system is of at least about 1 to about 5, respectively.
• the process for preparing stable Tiotropium bromide solvate having a purity of at least 99% area by HPLC and with less than about 0.05% area of 2, 2-dithienyl glycolic acid as measured by HPLC comprises crystallizing Tiotropium bromide from a solvent system comprising an organic acid wherein the ratio of Tiotropium bromide to the solvent system is of at least about 1 to about 10, respectively.
• Organic acids which may be utilized as part of the present invention include, but are not limited to, acetic acid, propanoic acid, oxalic acid, maleic acid, fumaric acid, and tartaric acid.
• the organic acid is acetic acid.
• the process for preparing stable Tiotropium bromide solvate having a purity of at least 99% area by HPLC and with less than about 0.02% area of 2 , 2-dithienyl glycolic acid as measured by HPLC comprises crystallizing Tiotropium bromide from a solvent system comprising an organic acid wherein the ratio of Tiotropium bromide to the solvent system is of at least about 1 to about 20, respectively.
• Organic acids which may be utilized as part of the present invention include, but are not limited to, acetic acid, propanoic acid, oxalic acid, maleic acid, fuitiaric acid, and tartaric acid.
• the organic acid is acetic acid.
• the process for preparing stable Tiotropium bromide solvate having a purity of at least 99% area by HPLC and with less than about 0.01% area of 2 , 2-dithienyl glycolic acid as measured by HPLC comprises crystallizing Tiotropium bromide from a solvent system comprising an organic acid wherein the ratio of Tiotropium bromide to the solvent system is of at least about 1 to about 30, respectively.
• Organic acids which may be utilized as part of the present invention include, but are not limited to, acetic acid, propanoic acid, oxalic acid, maleic acid, fumaric acid, and tartaric acid.
• the organic acid is acetic acid.
• the crystallization process comprises providing a solution of tiotropium bromide in the solvent system comprising organic acid, and cooling to obtain a suspension.
• the organic acid is acetic acid.
• the present invention encompasses a process for preparing Tiotropium bromide with less than about 0.15% area by HPLC of 2 , 2-dithienyl glycolic acid comprising the steps of
• step (c) selecting the Tiotropium bromide batch that comprises a level of 2, 2-dithienyl glycolic acid of less than about 0.15% area by HPLC, based on the measurement or measurements conducted in step (b) ;
• the Tiotrpium bromide of step (a) comprises a sufficiently low level of 2 , 2-dithienyl glycolic acid. More preferably, the Tiotrpium bromide of step (a) comprises less than about 0.15% area by HPLC of 2 , 2-dithienyl glycolic acid.
• the sample of Tiotrpium bromide of formula II of step (a) comprises more than about 0.15% area by HPLC of 2,2- dithienyl glycolic acid
• the sample may be purified, prior to performing step (C) .
• the purifed Tiotropium bromide comprises a lower level of 2, 2-dithienyl glycolic acid than the level present before purification.
• the tiotrpium bromide sample of step (a) obtained after purification comprises less than about 0.15% area by HPLC of 2 , 2-dithienyl glycolic acid.
• the tiotropium bromide of step (d) of the above process may be any form tiotropium bromide, including, for example, crystalline forms and amorphous form of tiotropium bromide .
• the Tiotropium bromide used as a starting material for the crystallization processes may be prepared, for example, according to the process disclosed in Co-pending application No. 60/835,201 entitled PROCESS FOR THE PREPARATION OF TRIOTROPIUM BROMIDE filed in the U.S. Patent and Trademark Office on August 3, 2006, according to the process disclosed in Co- pending application No. 60/830,231 entitled PROCESS FOR THE PREPARATION OF TIOTROPIUM BROMIDE filed in the U.S. Patent and Trademark Office on July 10, 2006, or by any other process known to one skilled in the art .
• the process may be performed according to the following scheme :
• glycolate of formula I may be prepared by combining 2-bromo-thiophene of the following formula,
• Methyl di- (2-thienyl) glycolate of formula I may be purified by crystallization from a mixture of ethanol and heptane, absolute ethanol and heptane, isopropanol and heptane, or from toluene and heptane.
• the scopine salt of formula II-s is suspended in a polar organic solvent.
• the polar organic solvent is selected from a group consisting of dimethylformamide, N-methyl-2-pyrrolidone, dimethy1acetamide, dimethylsulfoxide, acetonitrile, sulfolane, and mixtures thereof. More preferably, the polar organic solvent is dimethylformamide.
• the salt is an HBr salt.
• the inorganic base and methyl-di- (2- thienyl) -glycolate of formula I are added to the suspension. More preferably, the inorganic base is anhydrous. Even more preferably, the inorganic base has a pKa of about 6 to about 12, more preferably of about 9 to about 10. Yet even more preferably, the inorganic base is selected from a group consisting of: K 2 CO 3 , NaHCO 3 , Wa 2 CO 3 , Li 2 CO 3 , Cs 2 CO 3 , KX ⁇ Bu, and LiO 1 ⁇ Bu. Most preferably, the inorganic base is K 2 CO 3 . The inorganic base is added in an amount of 0.45 to 2.5 mole equivalent per mole equivalent, more preferably, 2 to 2.5 mole equivalent per mole equivalent of scopine salt.
• methyl-di- (2-thienyl) -glycolate of formula I is added in the form of a solution in the polar organic solvent.
• the inorganic base and methyl-di- (2- thienyl) -glycolate of formula I are added at a temperature of about 25°C to about 65°C, more preferably at about 60 2 C to about 65 a C.
• the suspension containing all the above substances is heated to a temperature of below 70 2 C, more preferably to a temperature ranging from about 25 a C to about 65 e C, even more preferably at a temperature ranging from about 60 2 C to about 65 2 C, ⁇ and most preferably at a temperature ranging from about 63 2 C to about 65 a C.
• heating is done under reduced pressure.
• the pressure is of about 70 to about 100 milibar.
• nitrogen is bubbled during the reaction, through a second inlet.
• nitrogen is bubbled in a rate of about 1.8 to about 2.6 L/min, even more preferably of about 2.0 to about 2.4 L/min, and yet even more preferably of about 2.2 to about 2.4 L/min.
• Heating under pressure, while bubbling nitrogen from a second inlet, assists in evaporating methanol, which is formed during the reaction. As such, the reaction shifts towards the formation of the product.
• heating is done for a time ranging from about 17 to about 24 hours, more preferably for about 18 to about 20 hours.
• N-demethyl-tiotropium of formula III may be recovered by a) cooling the suspension; b) adding an acid; c) extracting the aqueous phase; d) adding a base to the aqueous phase; e) filtering; and f) washing and drying.
• the acid is HBr.
• the suspension is cooled to a temperature of about 10 a C to about -10 a C, more preferably to about 5 3 C to about O 3 C.
• the addition of the acid provides a pH of about 3.
• the aqueous phase is extracted with toluene.
• the base is added at a temperature of about 0 a C to about 5 a C. More preferably, the base is K 2 CCh.
• the addition of the base causes precipitation of N-demethyl- tiotropium of formula III.
• the precipitate is washed with water to obtain a pH of about 7.
• scopine base may be used.
• scopine base preferably a smaller amount of the inorganic base is used.
• the organic solvent is selected from a group consisting of: C2-4 nitrile, C 4 -s linear or cyclic ether, mixtures of C 2 -4 nitrile and C4-8 linear or cyclic ether, mixtures of C7-8 aromatic hydrocarbon and C 2 - 4 nitrile, and mixtures of C2-4 nitrile and C 3 -I 0 ketone.
• the C 2 -4 nitrile is acetonitrile.
• a preferred C4_s linear or cyclic ether is tetrahydrofuran.
• C 4 _ 8 linear or cyclic ether is that of acetonitrile and tetrahydrofuran.
• a preferred mixture of C7-8 aromatic hydrocarbon and C2-4 nitrile is that of toluene and acetonitrile.
• a mixture of C2- 4 nitrile and C3- 1 0 ketone is that of acetone and acetonitrile, and heating is conducted to a temperature of about 20 2 C to about 40 a C.
• the solvent is acetonitrile.
• heating is done to a temperature of about 20 2 C to about 25 a C. More, preferably, heating is done for about 12 to about 64 hours, even more preferably, for about 18 to about 22 hours .
• crude Tiotropium bromide is dissolved in the solvent system which is comprised of an organic acid.
• organic acids include, but are not limited to, trifluoroacetic acid, tartaric acid, maleic acid, propionic acid, oxalic acid, p-toluen sulphonic acid, methan sulphonic acid, HCl, HBr, H2SO 4 and acetic acid.
• the organic acid is acetic acid.
• the solvent system comprises acetic acid, Ci- S alcohol and acetic acid, Ci_g alcohol, acetic acid and acetone or Ci-S alcohol, acetic acid and water.
• the alcoholate is a Ci_ ⁇ alcohol, more preferably a C ⁇ _ 6 alcohol, even more preferably a Ci_ 5 alcohol, and most preferably a Ci- 4 alcohol.
• the C1-4 alcohol is selected from the group consisting of methanolate, ethanolate, isopropanolate, n-propanolate and n- butanolate.
• the C3.-.4 alcoholate is methanolate, ethanolate or n-propanolate .
• the dissolution is achieved by heating the combination of Tiotropium bromide and the solvent system.
• the heating is to a temperature ranging from about 60 2 C to about 78 a C, more preferably from to about 65 S C to about 78 2 C, most preferably from about 65 a C to about 75 S C.
• the solution is then cooled to a temperature ranging from about 25 2 C to about 0 a C, more preferably from about 25 a C to about 5 a C, and most preferably from about 5 52 C to about 0 a C, to induce precipitation of the crystallized product.
• cooling is done over a period of about 4 to about 10 hours, more preferably from about 6 to about 9 hours, most preferably of about 8 to about 9 hours.
• the suspension is maintained to increase the yield of the precipitated crystallized product.
• the suspension is maintained for a time period ranging from at least about 3 hours to about 21 hours, more preferably from about 6 hours to about 12 hours, and most preferably from about 13 hours to about 18 hours .
• the crystallization process may further comprise a recovery step.
• the precipitate may be recovered by any method known to a skilled artisan.
• the recover comprises filtering the suspension, washing the filtered product, and drying.
• the present invention also provides a pharmaceutical composition comprising a stable Tiotropium bromide solvate having a purity of at least 99% area as measured by HPLC, and with less than about 0.15% area by HPLC of 2, 2-dithienyl glycolic acid, and pharmaceutically acceptable excipients .
• the present invention also provides a pharmaceutical composition comprising a stable Tiotropium bromide solvate having a purity of at least 99.3% area as measured by HPLC, and with less than about 0.15% area by HPLC of 2, 2-dithienyl glycolic acid, and pharmaceutically acceptable excipients .
• the present invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising a stable Tiotropium bromide solvate having a purity of at least 99.5% area as measured by HPLC, and with less than about 0.15% area by HPLC of 2, 2-dithienyl glycolic acid, and pharmaceutically acceptable excipients.
• the present invention further provides a process for preparing pharmaceutical composition
• a process for preparing pharmaceutical composition comprising stable Tiotropium bromide solvate with a purity of at least 99% area by HPLC, and containing less than about 0.15% area as measured by HPLC of 2,2- dithienyl glycolic acid, and pharmaceutically acceptable excipients .
• the pure and stable Tiotropium bromide can be micronized to prepare material suitable for formulation.
• the term "suitable for formulation" in reference to micronized Tiotropium bromide corresponds to Tiotropium bromide having at least 90% of the particles below 20 microns.
• the micronization process can, optionally, be followed by a process comprising exposing the micronized form to a suitable solvent to restore the initial content of solvent in the solvate.
• suitable solvent corresponds to the kind of solvent in the original solvated form.
• the present invention further provides a method of treating asthma or chromic pulmonary disease by administration of an effective amount of a pharmaceutical composition comprising stable Tiotropium bromide solvate having a purity of at least 99% area as measured by HPLC, and containing less than about 0.15% area as measured by HPLC of 2 , 2-dithienyl glycolic acid, and pharmaceutical excipients .
• the present invention provides the use of the stable Tiotropium bromide solvate with a purity of at least 99% area as measured by HPLC, and containing less than about 0.15% area as measured by HPLC of 2 , 2-dithienyl glycolic acid, of the present invention for the manufacture of a pharmaceutical composition.
• Methods of administration of a pharmaceutical composition of the present invention can be administered in various preparations depending on the age, sex, and symptoms of the patient.
• the pharmaceutical compositions can -be administered, for example, as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injection preparations (solutions and suspensions), and the like.
• compositions of the present invention can optionally be mixed with other forms of Tiotropium bromide solvate and/or other active ingredients such as HMG-CoA reductase inhibitors .
• pharmaceutical compositions of the present invention can contain inactive ingredients such as diluents, carriers, fillers, bulking agents, binders, disintegrants, disintegration inhibitors, absorption accelerators, wetting agents, lubricants, glidants, surface active agents, flavoring agents, and the like.
• Diluents increase the bulk of a solid pharmaceutical composition and can make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle.
• Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., Avicel ® ) , microfine cellulose, lactose, starch, pregelitinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., Eudragit ® ) , potassium chloride, powdered cellulose, sodium chloride, sorbitol, or talc.
• microcrystalline cellulose e.g., Avicel ®
• microfine cellulose e.g., lactose, starch, pregelitinized starch
• Carriers for use in the pharmaceutical compositions may include, but are not limited to, lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, or silicic acid.
• Binders help bind the active ingredient and other excipients together after compression.
• Binders for solid pharmaceutical compositions include for example acacia, alginic acid, carbomer (e.g. carbopol) , carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel ® ) , hydroxypropyl methyl cellulose (e.g. Methocel ® ) , liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g.
• Disintegrants can increase dissolution.
• Disintegrants include, for example, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol ® , Primellose ® ) , colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon ® , Polyplasdone ® ) , guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab ® ) and starch.
• alginic acid carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol ® , Primellose ® ) , colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon ® , Polyplasdone ® ) , guar
• Disintegration inhibitors may include, but are not limited to, white sugar, stearin, coconut butter, hydrogenated oils, and the like.
• Absorption accelerators may include, but are not limited to, quaternary ammonium base, sodium laurylsulfate, and the like.
• Wetting agents may include, but are not limited to, glycerin, starch, and the like.
• Adsorbing agents used include, but are not limited to, starch, lactose, kaolin, bentonite, colloidal silicic acid, and the like.
• a lubricant can be added to the composition to reduce adhesion and ease release of the product from a punch or dye during tableting.
• Lubricants include for example magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
• Glidants can be added to improve the flowability of non-compacted solid composition and improve the accuracy of dosing.
• Excipients that can function as glidants include for example colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
• Flavoring agents and flavor enhancers make the dosage form more palatable to the patient.
• Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present invention include for example maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
• Tablets can be further coated with commonly known coating materials such as sugar coated tablets, gelatin film coated tablets, tablets coated with enteric coatings, tablets coated with films, double layered tablets, and multi-layered tablets.
• Capsules can be coated with shell made, for example, from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
• Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
• liquid pharmaceutical compositions of the present invention the Tiotropium bromide solvate forms described herein and any other solid ingredients are dissolved or suspended in a liquid carrier, such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
• a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
• Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier.
• Emulsifying agents that can be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl alcohol .
• Liquid pharmaceutical compositions of the present invention can also contain viscosity enhancing agents to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract.
• agents include for example acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.
• Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar can be added to improve the taste.
• Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid can be added at safe levels to improve storage stability.
• a liquid composition according to the present invention can also contain a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate.
• a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate.
• a composition for tableting or capsule filing can be prepared by wet granulation. In wet granulation some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, which causes the powders to clump up into granules. The granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size. The granulate can then be tableted or other excipients can be added prior to tableting, such as a glidant and/or a lubricant.
• a tableting composition can be prepared conventionally by dry blending.
• the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules .
• the compacted granules can be compressed subsequently into a tablet.
• a blended composition can be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules.
• Excipients that are particularly well-suited to direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
• a capsule filling of the present invention can comprise any of the aforementioned blends and granulates that were described with reference to tableting, only they are not subjected to a final tableting step.
• any commonly known excipient used in the art can be used.
• carriers include, but are not limited to, lactose, starch, coconut butter, hardened vegetable oils, kaolin, talc, and the like.
• Binders used include, but are not limited to, gum arabic powder, tragacanth gum powder, gelatin, ethanol, and the like.
• Disintegrating agents used include, but are not limited to, agar, laminalia, and the like.
• excipients include, but are not limited to, polyethylene glycols, coconut butter, higher alcohols, esters of higher alcohols, gelatin, semisynthesized glycerides, and the like.
• injectable pharmaceutical compositions When preparing injectable pharmaceutical compositions, solutions and suspensions are sterilized and are preferably made isotonic to blood.
• injection preparations may use carriers commonly known in the art.
• carriers for injectable preparations include, but are not limited to, water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyoxyethylene sorbitan.
• carriers for injectable preparations include, but are not limited to, water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyoxyethylene sorbitan.
• dissolving agents such as dissolving agents, buffer agents, and analgesic agents may be added.
• coloring agents, preservatives, perfumes, seasoning agents, sweetening agents, and other medicines may also be added to the desired preparations during the treatment of schizophrenia.
• Tiotr ⁇ pium bromide solvate or pharmaceutically acceptable salt thereof contained in a pharmaceutical composition for reducing cholesterol according to the present invention is not specifically restricted; however, the dose should be sufficient to treat, ameliorate, or reduce the condition.
• Tiotropium bromide solvate may be present in an amount of about 1% to about 70%.
• the dosage of a pharmaceutical composition for reducing cholesterol according to the present invention will depend on the method of use, the age, sex, weight and condition of the patient. Typically, about 1 mg to 200 mg of Tiotropium bromide solvate may be contained in an administration unit form, preferably a 10 mg tablet.
• Example 2 Preparation of crude Tiotropium bromide [0109] 0.52 g of N-demethyl tiotropium (1.39 mmol) was suspended in 5.23 iriL of CH3CN under nitrogen.
• Tiotropium bromide (1.00 g) was dissolved in absolute ethanol ⁇ 65 ml) at 78 0 C. The solution was heated to 78 0 C for about 30 rain, and then was cooled to 22°C in at least 6 hours. The obtained suspension was maintained at 22 0 C for at least 3 hours, and then was filtered on a sintered glass funnel, and the solid was washed two times with absolute ethanol (2 x 1.0 ml). The solid was dried for 30 min. at 22°C under N 2 flow, and then for 9 hours at 6O 0 C under reduced pressure (17 mbar). 0.66 g of Tiotropium bromide (purity 99.68%, dithienylglycolic acid-0.01%) were obtained.
• Example 5 Crystallization of Tiotropium bromide from a mixture of ethanol and acetic acid
• Crude Tiotropium bromide (18.6 g) was suspended in ethanol 96%/CH 3 COOH 98/2 (558 ml) .
• the suspension was heated to 65/70 0 C until a solution was obtained, and then was cooled to 55°C in at least 3 hours and at 0+5 0 C in at least 3 hours.
• the obtained suspension was maintained at 0 ⁇ 5°C for at least 6 hours, and then was filtered on a sintered glass funnel, and the solid was washed two times with ethanol 96%/CH 3 COOH 98/2 (3 x 10.0 ml).
• the solid was dried for 20 min. at 45 0 C under reduced pressure (4 mbar) .
• 16.04 g of Tiotropium bromide was obtained (purity 99.9%, dithienylglycolic acid -not detected) .
• Example 6 Crystallization of Tiotropium bromide from a mixture of ethanol and acetic acid
• Example 7 Crystallization of Tiotropium bromide from a mixture of ethanol and acetic acid
• Example 9 Crystallization of Tiotropium bromide from a mixture of methanol and acetic acid
• Example 10 Crystallization of Tiotropium bromide from a mixture of methanol, acetone and acetic acid
• Tiotropium bromide 8.2 g is obtained (purity 99.9%, dithienylglycolic acid 0.05%).
• Example 12 Crystallization of Tiotropium bromide from a mixture of methanol , acetone and acetic acid
• Tiotropium bromide 7.7 g of Tiotropium bromide is obtained (purity 99.9%, dithienylglycolic acid 0.03%).
• Example 13 Crystallization of Tiotropium bromide from a mixture of methanol, acetone and acetic acid
• Example 14 Crystallization of Tiotropium bromide from a mixture of n-propanol, water and acetic acid
• Example 16 Crystallization of Tiotropium bromide from a mixture of n-propanol and acetic acid
• Example 17 Crystallization of Tiotropium bromide from a mixture of n-propanol and acetic acid
• Tiotropium bromide (1.00 g) was dissolved at 45°C with a mixture 7/2 (V/V) of acetic acid/methanol (11 ml) , the solution was heated to 45°C for 1.5 hours and n-heptane (2.75 ml) was then added drop-wise in at least 20 min.. The obtained solution was heated to 45°C for one hour (no solid formation observed), was cooled to 23.5°C in at least 3 hours and the suspension was maintained at 23.5°C for at least 3 hours. After filtration on a sintered glass funnel, the solid was washed three times with 3.0 itiL of n-heptane.
• the micronizer in use was a Jet-mill MC 50 (made by Micro- Mac:inazionne) . 32°05' angle nozzles were installed.
• Nitrogen was used as the micronization gas.
• Micronization air Pressure was 10 bars.
• Feed rate was 0.2 kg/hr.
• the micronized Tiotropium bromide obtained by the above process has a PSD value:

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