Polymorphs of fexofenadine hydrochloride
OwnerBen-Zion Dolitzky, Shlomit Wizel +3inventors
InventorsBen-Zion Dolitzky, Shlomit Wizel, Barnaba Krochmal, Dov Diller, Irwin Gross
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Abstract
The present invention provides novel crystal forms of fexofenadine hydrochloride Forms V, VI and VIII through XV and processes for their preparation and preparation of amorphous form and other crystalline forms of fexofenadine hydrochloride. Forms XIV and XV are solvates of ethyl acetate, while Form IX is anhydrous, but can be crystallized as a solvate of MTBE or cyclohexane. The forms are useful for administration to humans and animals to alleviate symptoms caused by histamine. The present invention further provides pharmaceutical compositions of the new crystalline forms.
Claims120
A process for preparing amorphous fexofenadine hydrochloride comprising the steps of:
- a) preparing a solution of fexofenadine hydrochloride in THF;
- b) removing a portion of THF from the solution;
- c) adding a C5 to a C12 saturated hydrocarbon to the remaining THF to form an upper and a lower layer, wherein the lower layer is oily;
- d) separating the upper layer from the lower layer;
- and
- e. drying the lower layer to obtain amorphous fexofenadine hydrochloride.
A process for preparing amorphous fexofenadine hydrochloride comprising:
- a) preparing a solution of fexofenadine hydrochloride in an organic solvent;
- and
- b) reomoving the solvent to obtain amorphous fexofenadine hydrochloride.
Fexofenadine hydrochloride Form V.
Fexofenadine hydrochloride of claim II chracterized by a water content of from about 30 to about 56%.
Fexofenadine hydrochloride having a PXRD pattern with peaks at about 15.9, 16.8, 17.2, 20.9, 21.5, 21.8±0.2 degrees two theta.
A process for preparing fexofenadine hydrochloride Form V comprising the steps of:
- a) preparing a solution of fexofenadine hydrochloride in a mixture of water and an alcohol selected from the group consisting of methanol, isopropanol, ethanol and 1-butanol;
- b) precipitating fexofenadine hydrochloride from the solution;
- and
- c) separating the precipitate.
Fexofenadine hydrochloride Form VI.
Fexofenadine hydrochloride having a PXRD pattern with peaks at about 15.7, 16.1, 17.0, 17.3, 18.6, 18.8±0.2 degrees two theta.
A process for preparing fexofenadine hydrochloride Form VI comprising the steps of:
- a) preparing a solution of fexofenadine hydrochloride in a mixture of water and 1-propanol;
- b) precipitating fexofenadine hydrochloride from the solution;
- and
- c) separating the precipitate.
A process for preparing fexofenadine hydrochloride Form VI comprising the steps of:
- a) preparing a solution of fexofenadine hydrochloride in THF;
- b) adding water to the solution to form a precipitate;
- and
- c) separating the precipitate.
A process for preparing fexofenadine hydrochloride Form II comprising heating fexofenadine hydrochloride selected from the group consisting of Form V and Form VI to a temperature of from about 40° C. to about 80° C.
Fexofenadine hydrochloride Form VIII.
Fexofenadine hydrochloride having a PXRD pattern with peaks at 8.5, 11.0, 11.4, 13.4, 13.8, 17.1, 20.0, 21.5±0.2 degrees two theta.
Fexofenadine hydrochloride having a DSC thermogram with endothermic peaks at about 84° C. and about 142° C.
Fexofenadine hydrochloride having a DTG profile as depicted in FIG. 5.
A process for preparing fexofenadine hydrochloride Form VIII comprising the steps of:
- a) preparing a solution of fexofenadine free base in a basic aqueous solvent;
- b) adding hydrochloric acid to the solution to form a precipitate;
- and
- c) separating the precipitate.
Fexofendine hydrochloride Form IX.
Fexofenadine hydrochloride characterized by a PXRD pattern with peaks at about 4.7, 9.3, 17.4, 18.2, 19.4, 19.6, 21.6 and 24.0±0.2 degrees two theta.
Fexofenadine hydrochloride characterized by a differential scanning calorimetry endothermic peak at about 139° C.
A process for preparing fexofenadine hydrochloride Form IX comprising the steps of:
- a) preparing a solution of fexofenadine hydrochloride in acetone;
- b) adding the solution to an anti-solvent to form a precipitate;
- and
- c) separating the precipitate.
Fexofenadine hydrochloride MTBE solvate.
A process for preparing fexofenadine hydrochloride MTBE solvate comprising the steps of:
- a) adding fexofenadine hydrochloride Form IX to MTBE to form the solvate;
- and
- b) separating the solvate.
Fexofenadine hydrochloride cyclohexane solvate.
A process for preparing fexofenadine hydrochloride cyclohexane solvate comprising the steps of:
- a) adding fexofenadine hydrochloride Form IX to cyclohexane to form the solvate;
- and
- b) separating the solvate.
Fexofenadine hydrochloride Form X.
Fexofenadine hydrochloride having a PXRD pattern with peaks at about 4.2, 8.0, 9.3, 14.2, 16.0, 16.8, 17.6, 18.8, 20.0, 20.6, 21.7, 22.9, 23.8, 24.2 and 25.4±0.2 degrees two theta.
Fexofenadine hydrochloride characterized by a DTG profile with a maximum endotherm at about 100° C. and a minor endotherm at about 138° C.
A process for preparing fexofenadine hydrochloride Form X comprising the steps of:
- a) preparing a solution of fexofenadine hydrochloride in methanol, and optionally adding dichloromethane to said solution;
- b) adding a C5 to a C12 saturated hydrocarbon to the solution to form a precipitate;
- and
- c) separating the precipitate.
A process for preparing fexofenadine hydrochloride Form X comprising the steps of.
- a) preparing a solution of fexofenadine hydrochloride in methanol;
- b) removing methanol to obtain a residue;
- c) adding a mixture of methanol and an anti-solvent to the residue to form a precipitate;
- and
- d) separating the precipitate.
Fexofenadine hydrochloride Form XI.
Fexofenadine hydrochloride having a PXRD pattern with peaks at about 8.7, 14.5, 14.9, 16.6, 17.2, 18.3, 19.5, 21.2, 22.1 and 23.3±0.2 degrees two theta.
A process for preparing fexofenadine hydrochloride Form XI comprising the steps of:
- a) preparing a solution of fexofenadine hydrochloride in methanol;
- b) adding the solution to toluene to form a precipitate;
- and
- c) separating the precipitate.
Fexofenadine hydrochloride Form XII.
Fexofenadine hydrochloride that produces a PXRD pattern with peaks at about 5.2, 7.9, 8.1, 12.1, 18.5, 19.0±0.2 degrees two theta.
Fexofenadine hydrochloride characterized by a FTIR spectrum with peaks at about 731, 845, 963, 986, 999, 1072, 1301, 1412 and 3313 cm−1.
A process for preparing fexofenadine hydrochloride Form XII comprising the steps of:
- a) preparing a solution of fexofenadine hydrochloride in ethanol;
- b) removing ethanol to obtain a residue;
- c) adding a mixture of ethanol and toluene to the residue to form a precipitate;
- and
- d) separating the precipitate.
Fexofenadine hydrochloride Form XIII.
Fexofenadine hydrochloride characterized by a PXRD pattern with peaks at about 5.5, 6.8, 16.0, 16.3±0.2 degrees two theta.
Fexofenadine hydrochloride characterized by a DSC thermogram with an endothermic peak at about 185-195° C.
Fexofenadine hydrochloride characterized by a FTIR spectrum with peaks at about 1249, 1365, 1719 and 3366 cm−1.
A process for preparing fexofenadine hydrochloride Form XIII by heating fexofenadine hydrochloride Form XII for a sufficient amount of time to obtain Form XIII.
A fexofenadine hydrochloride ethyl acetate solvate.
Fexofenadine hydrochloride ethyl acetate solvate Form XIV.
Fexofenadine hydrochloride ethyl acetate solvate characterized by a PXRD diffraction pattern with peaks at about 5.4, 5.7, 10.9, 11.4, 11.6±0.2 degrees two theta.
Fexofenadine hydrochloride ethyl acetate solvate characterized by a DSC thermogram with an endothermic peak at about 100° C.
Fexofenadine hydrochloride ethyl acetate solvate characterized by a FTIR spectrum with peaks at about 634.3, 699.5, 1335, 1359 and 1725 cm−1, wherein the peaks at 1335, 1359 and 1725 are split.
A process for preparing fexofenadine hydrochloride ethyl acetate solvate Form XIV comprising:
- a) dissolving fexofenadine hydrochloride in methanol;
- b) removing methanol to obtain a residue;
- c) adding a mixture of methanol and toluene to the residue to form a precipitate;
- d) separating the precipitate;
- e) adding the precipitate to ethyl acetate to form the solvate;
- and
- f) separating the solvate.
A process for preparing fexofenadine hydrochloride ethyl acetate solvate Form XIV comprising triturating fexofenadine hydrochloride From X in ethyl acetate.
Fexofenadine hydrochloride ethyl acetate solvate Form XV.
Fexofenadine hydrochloride characterized by a PXRD pattern with peaks at about 5.5, 5.8, 16.4, 16.9, 18.4±0.2 degrees two theta.
Fexofenadine hydrochloride characterized by a DSC thermogram with an endotherm at about 140° C.
Fexofenadine hydrochloride ethyl acetate solvate characterized by a FTIR spectrum as substantially depicted in FIG. 21.
A process for preparing fexofenadine hydrochloride ethyl acetate solvate Form XV comprising the steps of:
- a) dissolving fexofenadine hydrochloride in ethanol;
- b) removing ethanol to obtain a residue;
- c) adding a mixture of toluene and ethanol to the residue to form a precipitate;
- d) separating the precipitate;
- e) adding the precipitate to ethyl acetate to form the solvate;
- and
- f) separating the solvate.
A process for preparing fexofenadine hydrochloride Form XV comprising triturating fexofenadine hydrochloride Form XII in ethyl acetate.
A pharmaceutical composition comprising:
- a) fexofenadine hydrochloride selected from the group consisting of Form V, Form VI, Form VIII, Form IX, Form IX-MTBE solvate, Form IX-cyclohexane solvate, Form X, Form XI, Form XII, Form XIII, Form XIV and Form XV;
- and
- b) a pharmaceutically acceptable excipient.
Dependencies are inferred from the claim text.