US 2003/0114479 A1 · Novel crystal forms III, IV, V, and novel amorphous form of clopidogrel hydrogensulfate, processes for their preparation, processes for the preparation of form I, compositions containing the new forms and methods of administering the new forms

Abstract

The present invention provides new crystalline Forms III, IV and V of clopidogrel hydrogensulfate and the amorphous form of clopidogrel hydrogensulfate, as well as their pharmaceutical compositions, and method of treatments with such compositions. The present invention also provides novel processes for preparation of clopidogrel hydrogensulfate Form I, Form III, Form IV, Form V and the amorphous form. The present invention further provides a novel process where the amorphous form is converted to Form I by contacting Form I with an ether.

Claims93

Dependent claims

Clopidogrel hydrogensulfate Form III.

Clopidogrel hydrogensulfate having a powder X-ray diffraction pattern with peaks at about 8.1, 8.7, 14.3, 15.4, 20.1, 22.3, 22.5, 23.5, and 24.1±0.2 degrees two-theta.

Clopidogrel hydrogensulfate characterized by a differential scanning calorimetric thermogram having an endothermic peak at about 105° C.

Clopidogrel hydrogensulfate having a FTIR spectrum with peaks at about 581, 707, 755, 971, 1057, 1196, 1252, 1436, 1476, 1748, 2590, 2670 and 2963 cm−1.

A process for preparing clopidogrel hydrogensulfate Form III comprising the steps of:

a) preparing a solution of clopidogrel hydrogensulfate in 1-butanol;
b) removing the 1-butanol from the solution to obtain a residue;
c) adding an antisolvent to the residue to cause formation of a precipitate;
d) separating the precipitate;
and
e) drying the precipitate.

3 more elements

Amorphous form of clopidogrel hydrogensulfate.

Clopidogrel hydrogensulfate having a PXRD pattern as substantially depicted in FIG. 4.

Clopidogrel hydrogensulfate having a FTIR spectrum with peaks at about 583, 723, 762, 846, 1040, 1167, 1223, 1438, 1478, 1638, 1752, 2585 and 2960 cm−1.

A process for preparing amorphous form of clopidogrel hydrogensulfate comprising the steps of:

a) preparing a solution of clopidogrel hydrogensulfate in an alcohol selected from the group consisting of methanol and ethanol;
b) adding the solution to an antisolvent to cause formation of a precipitate;
and
c) separating the precipitate.

1 more element

A process for preparing amorphous form of clopidogrel hydrogensulfate comprising the steps of:

a) preparing a solution of clopidogrel hydrogensulfate in an alcohol selected from the group consisting of methanol and ethanol;
b) removing the alcohol from the solution to obtain a residue;
c) adding an antisolvent to the residue to cause formation of a precipitate;
and
d) separating the precipitate.

2 more elements

A process for preparing amorphous form of clopidogrel hydrogensulfate comprising the steps of:

a) preparing a solution of clopidogrel hydrogensulfate in an alcohol selected from the group consisting of methanol and ethanol;
b) adding the solution to an antisolvent;
and
c) removing the alcohol and the antisolvent.

1 more element

A process for preparing amorphous form of clopidogrel hydrogensulfate comprising preparing a solution of clopidogrel hydrogensulfate in acetone, and removing the acetone.

A process for preparing clopidogrel hydrogensulfate Form I comprising contacting amorphous clopidogrel hydrogensulfate with an ether, and separating clopidogrel Form I.

Clopidogrel hydrogensulfate Form IV.

Clopidogrel hydrogensulfate characterized by a PXRD pattern with peaks at about 22.0, 25.9, 26.9, 27.4, 28.1, 28.6 and 28.9±0.2 degrees two theta.

Clopidogrel hydrogensulfate characterized by a DTG thermogram with an endothermic peak at about 160-170° C.

Clopidogrel hydrogensulfate characterized by a FTIR spectrum with peaks at about 618, 769, 842, 893, 935, 974, 1038, 1116, 1370, 1384 cm−1.

A process for preparing clopidogrel hydrogensulfate Form IV comprising forming a precipitate from a solution of clopidogrel hydrogensulfate and isopropanol, and separating the precipitate.

Clopidogrel hydrogensulfate Form V.

Clopidogrel hydrogensulfate characterized by a PXRD diffraction pattern with peaks at about 25.5, 26.6, 27.8 and 28.5±0.2 degrees two theta.

Clopidogrel hydrogensulfate characterized by a DSC profile with an endothermic peak at about 126-132° C.

Clopidogrel hydrogensulfate characterized by a FTIR spectrum with peaks at about 623, 743, 802, 817, 843, 963, 972, 1028 and 1374 cm−1.

A process for preparing clopidogrel Form V comprising the steps of:

a) preparing a solution of clopidogrel hydrogensulfate in 2-butanol;
b) adding an antisolvent to the solution to cause formation of a precipitate;
and
c) separating the precipitate.

1 more element

A process for preparing clopidogrel Form V comprising the steps of:

a) preparing a solution of clopidogrel hydrogensulfate in 2-butanol;
b) removing the 2-butanol from the solution to obtain a residue;
c) adding an antisolvent to the residue to cause formation of a precipitate;
and
d) separating the precipitate.

2 more elements

A pharmaceutical composition comprising clopidogrel hydrogensulfate selected from the group consisting of clopidogrel hydrogensulfate Form III, Form IV, Form V and amorphous form, and a pharmaceutically acceptable excipient.

Dependencies are inferred from the claim text.

Novel crystal forms III, IV, V, and novel amorphous form of clopidogrel hydrogensulfate, processes for their preparation, processes for the preparation of form I, compositions containing the new forms and methods of administering the new forms

Life of this patent

Novel crystal forms III, IV, V, and novel amorphous form of clopidogrel hydrogensulfate, processes for their preparation, processes for the preparation of form I, compositions containing the new forms and methods of administering the new forms

Life of this patent

Abstract

Claims93