Crystals Including a Malic Acid Salt of a 3-Pyrrole Substituted 2-Indolinone, and Compositions Thereof
AssigneePharmacia & Upjohn Company
InventorsMichael Hawley, Thomas Fleck, Stephen Prescott, Mark Maloney
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Abstract
The present invention provides crystals, and compositions thereof, wherein the crystals include a malic acid salt of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide. Methods of preparing such crystals are also disclosed.
Claims54
An anhydrous crystal comprising a malic acid salt of a compound having the structure:
An anhydrous crystal comprising a malic acid salt of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide.
A crystal comprising a malic acid salt of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, wherein the crystal has characteristic diffraction peaks at about 13.2 and 24.2 degrees two-theta in a powder X-ray diffraction pattern.
A crystal comprising a malic acid salt of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, wherein the crystal has a melting point of at least about 190° C.
A crystal comprising a malic acid salt of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, wherein the crystal has characteristic diffraction peaks at about 3.0 and 27.7 degrees two-theta in a powder X-ray diffraction pattern.
A crystal comprising a malic acid salt of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, wherein the crystal has a melting point of at most about 185° C.
A method of preparing an anhydrous crystal comprising a malic acid salt of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, the method comprising:
- combining malic acid;
- N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide;
- and a solvent;
- and
- inducing the salt to crystallize under crystallization conditions comprising one or more factors comprising:
- a difference between the initial and final temperatures of the crystallization solution of at most about 100° C.;
- a rate of cooling of at most about 50° C. per hour;
- no seeding;
- a supersaturation ratio of at most about 10;
- no precipitant;
- and/or combinations thereof.
A method of preparing an anhydrous crystal comprising a malic acid salt of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, the method comprising contacting a crystal comprising a malic acid salt of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide with a solvent in which the contacting crystal has substantial solubility, wherein the contacting crystal has characteristic diffraction peaks at about 3.0 and 27.7 degrees two-theta in a powder X-ray diffraction pattern.
A method of preparing a crystal comprising a malic acid salt of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, the method comprising:
- combining malic acid;
- N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide;
- and a solvent;
- and
- inducing the salt to crystallize under crystallization conditions comprising one or more factors comprising:
- a difference between the initial and final temperatures of the crystallization solution of at least about 25° C.;
- a rate of cooling of at least about 25° C. per hour;
- seeding;
- a supersaturation ratio of at least about 2;
- presence of a precipitant;
- and/or combinations thereof.
A composition comprising anhydrous crystals comprising a malic acid salt of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide.
A composition comprising crystals comprising a malic acid salt of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, wherein the crystals have characteristic diffraction peaks at about 13.2 and 24.2 degrees two-theta in a powder X-ray diffraction pattern.
A composition comprising crystals comprising a malic acid salt of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, wherein the crystals have a melting point of at least about 190° C.
A composition comprising crystals comprising a malic acid salt of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, wherein the crystals have characteristic diffraction peaks at about 3.0 and 27.7 degrees two-theta in a powder X-ray diffraction pattern.
A composition comprising crystals comprising a malic acid salt of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, wherein the crystals have a melting point of at most about 185° C.
Dependencies are inferred from the claim text.