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SITAGLIPTIN SALTS, PROCESSES FOR THEIR PREPARATION AND THEIR USE FOR THE PREPARATION OF PHARMACEUTICAL DOSAGE FORMS

IP.com Disclosure Number: IPCOM000200626D
Publication Date: 2010-Oct-21

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SITAGLIPTIN SALTS, PROCESSES FOR THEIR PREPARATION AND THEIR USE FOR THE PREPARATION OF PHARMACEUTICAL DOSAGE FORMS

Novel cinnamic, (phenylthio)acetic, caffeic, crotonic, nitric, hydroiodic, malonic, hippuric, 4-hydroxybenzoic acid salts of the dipeptidyl peptidase-IV (DPP-IV) inhibitor (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1, 2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine were prepared. Such salts, and hydrates thereof, have advantages in the preparation of pharmaceutical compositions of (2R)-4-oxo-4-[3-(trifluoromethyl)-5, 6-dihydro [1,2,4] triazolo[4,3-a] pyrazin-7(8H)-yl]-1-(2,4,5- trifluorophenyl)butan-2-amine (sitagliptin), such as ease of processing, handling, and dosing. In particular, they exhibit improved physicochemical properties, such as solubility, stability to stress, and rate of solution, rendering them particularly suitable for the manufacture of various pharmaceutical dosage forms. Pharmaceutical compositions containing the novel salts, or hydrates thereof, as well as methods for using them as DPP-IV inhibitors, in particular for the prevention or treatment of Type 2 diabetes, obesity, and high blood pressure, optionally in combination with metformin were also investigated.

FIG. 1 is a characteristic X-ray diffraction pattern of the cinnamic acid salt (Form I) of Compound I of the present invention.

FIG. 2 is a typical differential scanning calorimetry (DSC) curve of the cinnamic acid salt (Form I) of Compound I of the present invention.

Fig. 3 is a typical FT-IR spectrum of the cinnamic acid salt (Form I) of Compound I of the present invention.

FIG. 4 is a characteristic X-ray diffraction pattern of the cinnamic acid salt (Form I + II) of Compound I of the present invention.

FIG. 5 is a typical differential scanning calorimetry (DSC) curve of the cinnamic acid salt (Form I + II) of Compound I of the present invention.

Fig. 6 is a typical FT-IR spectrum of the cinnamic acid salt (Form I + II) of Compound I of the present invention.

FIG. 7 is a characteristic X-ray diffraction pattern of the cinnamic acid salt (Form II+III) of Compound I of the present invention.

FIG. 8 is a typical differential scanning calorimetry (DSC) curve of the cinnamic acid salt (Form II+III) of Compound I of the present invention.

Fig. 9 is a typical FT-IR spectrum of the cinnamic acid salt (Form II+III) of Compound I of the present invention.

FIG. 10 is a characteristic X-ray diffraction pattern of the cinnamic acid salt (Form II+IV) of Compound I of the present invention.

FIG. 11 is a characteristic X-ray diffraction pattern of the caffeic acid salt (Form I) of Compound I of the present invention.

Fig. 12 is a typical differential scanning calorimetry (DSC) curve of the caffeic acid salt (Form I) of Compound I of the present invention.

FIG. 13 is a typical FT-IR spectrum of the caffeic acid salt (Form I) of Compound I of the present invention.

FIG. 14 is a characteristic X-ray diffraction pattern of the nitric a...