Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-11
2002-10-15
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S294000, C546S293000, C546S291000, C514S346000
Reexamination Certificate
active
06465496
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel polymorphic forms of torsemide and amorphous torsemide. The present invention also relates to methods of making polymorphic forms of torsemide. The present invention also relates to methods of making solvent adducts of torsemide.
BACKGROUND OF THE INVENTION
1-Isopropyl-3-[(4-m-toluidino-3-pyridyl) sulfonyl]urea, which has the chemical structure
is approved, under the trademark DEMADEX®, by the U.S. Food and Drug Administration for the treatment of hypertension and edema associated with congestive heart failure, renal disease, or hepatic disease. The USAN approved generic name for this compound is torsemide, although this compound is also referred to as “torasemide” in the art. Torsemide is a loop diuretic that has been found to be particularly effective for the treatment of edema associated with chronic renal failure.
U.S. Pat. No. Re. 30,633 describes a synthesis of torsemide. It is known that torsemide can occur in at least two different crystalline forms, Acta Cryst. 1978, pp. 2659-2662 and Acta Cryst., 1978, pp. 1304-1310, in which the crystal identified by space group P21/c is designated Dupont Form 1 herein and the crystal identified by space group P2
is designated Dupont Form 2 herein. U.S. Pat. No. 4,822,807, which reissued as U.S. Pat. No. Re. 34,672, describes two crystalline forms of torsemide, designated modification I and modification II. Torsemide modification I is defined herein as the torsemide characterized by the x-ray powder diffraction pattern of
FIG. 1
, in the 37 C.F.R. § 1.132 declaration by Dr. Fritz Topfmeier filed on Dec. 30, 1987, which is located in the file wrapper of U.S. Pat. No. 4,822,807 (the “Topfmeier Declaration”). Torsemide modification II is defined herein as the torsemide characterized by the x-ray powder diffraction pattern of
FIG. 2
, in the Topfmeier Declaration. U.S. Pat. No. 5,914,336 describes a crystalline form of torsemide designated modification III, herein designated as “the '336 modification III.” PCT Publication WO 00/20395 describes a crystalline form of torsemide also designated modification III, which herein is designated as “Pliva modification III.”
Dupont reports in Acta Crystallographica (1978) B34, 2659-2662, a torsemide polymorph with unit cell dimensions (in angstroms) a=20.446, b=11.615, c=16.877, a space group of P2
and tabulated x-ray data crystal data therein, which herein is designated “Dupont Form 2”. The reference Acta Crystallographica (1978) B34, 2659-2662 is incorporated herein by reference.
SUMMARY OF THE INVENTION
The existence of new forms of torsemide has now been discovered. They are designated torsemide Form V and amorphous torsemide. New solvent adducts of Dupont Form 2 have been discovered including an ethanol solvent adduct and an isopropanol solvent adduct, both of which have x-ray powder diffraction patterns which correspond to torsemide Dupont Form 2.
New processes for the preparation of torsemide modification I have also been discovered. New processes of the present invention include the preparation of torsemide modification I from torsemide modification II or from mixtures of torsemide modification II and modification I. The processes of the present invention provides more efficient and quicker methods for making pure torsemide modification I.
The present invention relates to a process for making torsemide Dupont Form 2 comprising the steps of: (a) suspending torsemide in water; (b) basifying the torsemide suspension of step (a) with sufficient base to substantially dissolve the torsemide; (c) adding an organic solvent to the resulting torsemide solution in an amount sufficient to induce the formation of torsemide Dupont Form 2; (d) adding an acid to the torsemide solution of step (c) until torsemide Dupont Form 2 begins to precipitate; and (e) isolating torsemide Dupont Form 2
The present invention also relates to a pharmaceutical composition comprising torsemide Dupont Form 2 and a pharmaceutically acceptable carrier.
The present invention also relates to a method for treating edema comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of the torsemide Dupont Form 2.
The present invention also relates to processes for making torsemide Dupont Form 2 solvent adduct comprising the steps of: (a) suspending torsemide in water; (b) basifying the torsemide suspension of step (a) with sufficient base to substantially dissolve the torsemide; (c) adding an organic solvent to the resulting torsemide solution in an amount sufficient to induce the formation of torsemide Dupont Form 2 solvent adduct; (d) adding an acid to the torsemide solution of step (c) until torsemide Dupont Form 2 solvent adduct begins to precipitate; and (e) isolating torsemide Dupont Form 2 solvent adduct.
The present invention also relates to torsemide Dupont Form 2 solvent adducts.
The present invention also relates to torsemide Dupont Form 2 isopropanol adduct.
The present invention also relates to torsemide Dupont Form 2 ethanol adduct.
The present invention also relates to a torsemide solvent adduct wherein the solvent content is up to about 2.5% by weight.
The present invention also relates to torsemide Dupont Form 2 isopropanol adduct which is characterized by a powder x-ray diffraction pattern comprising peaks at about 6.0±0.2, 9.2±0.2, 9.7±0.2, 11.3±0.2, 12.0±0.2, 15.8±0.2, 18.4±0.2, 19.7±0.2, 20.4±0.2, 22.6±0.2, 23.5±0.2, 25.5±0.2, and 27.5±0.2 degrees two-theta.
The present invention also relates to a pharmaceutical composition comprising the torsemide Dupont Form 2 ethanol adduct and a pharmaceutically acceptable carrier.
The present invention also relates to a pharmaceutical composition comprising the torsemide Dupont Form 2 isopropanol adduct and a pharmaceutically acceptable carrier.
The present invention also relates to a pharmaceutical composition comprising the torsemide Dupont Form 2 solvent adduct and a pharmaceutically acceptable carrier.
The present invention also relates to a method for treating edema comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of the torsemide Dupont Form 2 isopropanol adduct.
The present invention also relates to a method for treating edema comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of the torsemide Dupont Form 2 ethanol adduct.
The present invention also relates to a method for treating edema comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of the torsemide Dupont Form 2 solvent adduct.
The present invention also relates to processes for making torsemide Dupont Form 2 ethanol adduct from amorphous torsemide comprising the steps of: (a) suspending amorphous torsemide in ethanol; (b) heating the suspension to 80° C. ; and (c) isolating torsemide Dupont Form 2 ethanol adduct.
The present invention also relates to processes for making torsemide modification I from torsemide Dupont Form 2 comprising the steps of: suspending torsemide Dupont Form 2 in water at pH 5; and isolating torsemide modification I.
The present invention also relates to processes for making torsemide Form V comprising the steps of: (a) suspending torsemide in a solvent; (b) increasing the pH of the torsemide suspension with base sufficient to substantially dissolve the torsemide; (c) precipitating torsemide Form V from the resulting solution; and (d) isolating torsemide Form V.
The present invention also relates to the new form of torsemide: torsemide Form V.
The present invention also relates to torsemide which is characterized by a powder x-ray diffraction pattern comprising peaks at about: 5.9±0.2, 8.4±0.2, 12.0±0.2, 12.5±0.2, 13.30±0.2, 16.0±0.2, 17.7±0.2, 19.9±0.2, 21.5±0.2, 22.7±0.2, 24.0±0.2, 24.7&p
Aronhime Judith
Dolitzky Ben-Zion
Kordova Marko
Leonov David
Schwartz Anchel
Aulakh Charanjit S.
Kenyon & Kenyon
Teva Pharmaceutical Industries Ltd.
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