Pure and stable tiotropium bromide
AssigneeSicor Inc.
InventorsRoberta Volonte, Nicola Diulgheroff, Francesca Scarpitta, Alessandro Pontiroli, Roberto Casalone
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Abstract
This invention relates to solvates of tiotropium bromide having a purity of at least 99%, process for preparing such pure solvates, and their use in pharmaceutical formulations. This invention also provides tiotropium bromide solvates containing less than about 0.15% area by HPLC of 2,2-dithienyl glycolic acid.
Claims59
Tiotropium bromide solvate of the following formula:
- having a purity of at least 99%.
A Tiotropium bromide solvate with less than about 0.15% of 2,2-dithienyl glycolic acid.
A stable Tiotropium bromide solvate.
An HPLC method comprising:
- (a) combining a Tiotropium bromide sample with a mixture of acetonitrile:acetic acid in water in a ratio of about 0.1%:99.9%, to obtain a solution;
- (b) injecting the solution into a column;
- (c) eluting the sample from the column at about 3.63 min using an eluent mixture comprised of a first eluent and a second eluent, the first eluent comprising perchloric acid:water in a ratio of 7:3 and the second eluent comprising acetonitrile;
- and
- (d) measuring the 2,2-dithienyl glycolic acid content in the relevant sample with a UV detector.
A process for preparing stable Tiotropium bromide solvate having a purity of at least 99% and containing less than about 0.15% of 2,2-dithienyl glycolic acid, comprising crystallizing Tiotropium bromide from a solvent system comprising an organic acid, wherein the ratio of Tiotropium bromide to the solvent system is at least about 1 to about 5.
A process for preparing stable Tiotropium bromide solvate having a purity of at least 99% and with less than about 0.05% of 2,2-dithienyl glycolic acid as measured by HPLC, comprising crystallizing Tiotropium bromide from a solvent system comprising an organic acid, wherein the ratio of Tiotropium bromide to the solvent system is at least about 1 to about 10.
A process for preparing stable Tiotropium bromide solvate having a purity of at least 99% and with less than about 0.02% of 2,2-dithienyl glycolic acid, comprising 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.
A process for preparing stable Tiotropium bromide solvate having a purity of at least 99% and with less than about 0.01% of 2,2-dithienyl glycolic acid, comprising comprising an organic acid, wherein the ratio of Tiotropium bromide to the solvent system is of at least about 1 to about 30.
A pharmaceutical composition comprising a stable. Tiotropium bromide solvate having a purity of at least 99%, and with less than about 0.15% of 2,2-dithienyl glycolic acid, and pharmaceutically acceptable excipients.
A process for preparing pharmaceutical composition comprising stable Tiotropium bromide solvate with a purity of at least 99%, and with less than about 0.15% of 2,2-dithienyl glycolic acid, and pharmaceutically acceptable excipients.
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%, and with less than about 0.15% of 2,2-dithienyl glycolic acid, and pharmaceutical excipients.
The use of the stable Tiotropium bromide solvate with a purity of at least 99%, and with less than about 0.15% of 2,2-dithienyl glycolic acid, of the present invention for the manufacture of a pharmaceutical composition.
A process for preparing Tiotropium bromide including less than about 0.15% area by HPLC of 2,2-dithienyl glycolic acid comprising the steps of:
- (a) obtaining one or more samples of one or more Tiotrpium bromide batches;
- (b) measuring a level of 2,2-dithienyl glycolic acid in each of the samples by HPLC;
- (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;
- and
- (d) using the selected batch to prepare a Tiotropium bromide comprising less than about:
- 0.15% area by HPLC of 2,2-dithienyl glycolic acid.
Dependencies are inferred from the claim text.