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SITAGLIPTIN HYDROBROMIDE POLYMORPHIC FORM

IP.com Disclosure Number: IPCOM000246063D
Publication Date: 2016-May-02
Document File: 6 page(s) / 663K

Publishing Venue

The IP.com Prior Art Database

Abstract

This publication relates to a novel crystalline polymorphic form of sitagliptin hydrobromide.

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SITAGLIPTIN HYDROBROMIDE POLYMORPHIC FORM

Sitagliptin dihydrogen phosphate, chemically named as (2R)-4-oxo-4-[3-(trifluoro- methyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2-amine dihydrogen phosphate, is an oral antihyperglycemic of the dipeptidyl peptidase-IV (DPP-IV) inhibitor class. Inhibition of DPP-IV, an enzyme that inactivates both glucose- dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-I), represents a recent approach to the treatment and prevention of type-2 diabetes, also known as non- insulin dependent diabetes mellitus (NIDDM). Sitagliptin also has an effect on appetite as it slows down gastric motility and induces a feeling of satiety. This reduction of appetite can help patients to lose weight which is also a useful effect in patients with diabetes.


Formula-I

Sitagliptin exists in different salts and the present disclosure relates to sitagliptin hydrobromide crystalline form.

Example 1: Preparation of crystalline sitagliptin hydrobromide form-M.

Sitagliptin free base (125gm) was dissolved in isopropyl alcohol (1000 mL) below 70 °C, cooled the reaction mass to 30±5 °C. To the clear solution hydrobromide (60 gm) was added at same temperature and maintaining the pH 2.0 to 3.5. The reaction temperature was raised to below 70 °C and maintained for one hour, then slowly cooled to room temperature and seeded with sitagliptin hydrobromide form-M (0.1gm). Reaction mass was cooled to 0-5°C and maintained stirring for 1-2 hours. The obtained crystalline sitagliptin hydrobromide form-M was filtered and washed with isopropyl alcohol (50mL), dried the material under vacuum below 70 °C (90 gm).

The above form-M was dissolved in ethanol (350 mL) at reflux temperature and slowly cooled to room temperature, filtered the pure crystalline sitagliptin hydrobromide form-M (60 gm).

Example 2: Preparation of crystalline sitagliptin hydrobromide form-M.

Sitagliptin free base (125 gm) was dissolved in ethanol (800 mL) below 70 °C, cooled the reaction mass to 30±5 °C. To the clear solution hydrobromide (60 gm) was added at same temperature and maintaining the pH 2.0 to 3.5. The reaction mass temperature was raised to below 70 °C and maintained for one hour, then slowly cooled to room temperature and seeded with sitagliptin hydrobromide form-M (0.1gm). Reaction mass was cooled to 0-5°C and maintained stirring for 1-2 hours. The obtained crystalline sitagliptin hydrobromide form-M was filtered and washed with pre-cooled isopropyl alcohol (50mL), dried the material under vacuum below 70 °C (90 gm).

The above form-M was dissolved in ethanol (350 mL) at reflux temperature and slowly cooled to room temperature, filed the pure crystalline sitagliptin hydrobromide form-M (60 gm).

Stability data

The sitagliptin hydrobromide Form-M prepared according to the present disclosure may have purity of more than...