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NOVEL CRYSTALLINE FORMS OF EDOXABAN TOSYLATE

IP.com Disclosure Number: IPCOM000250032D
Publication Date: 2017-May-19
Document File: 3 page(s) / 477K

Publishing Venue

The IP.com Prior Art Database

Abstract

This disclosure relates to novel crystalline forms of Edoxaban tosylate and process for their preparation thereof.

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This is the abbreviated version, containing approximately 53% of the total text.

NOVEL CRYSTALLINE FORMS OF EDOXABAN TOSYLATE

Edoxaban Tosylate is chemically known as (N1-(5-chloropyridin-2-yl)-N2-((1S, 2R, 4S)-4- [(dimethylamino) carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2- yl)carbonyl]amino} cyclohexyl)ethane diamide p-toluene sulfonate monohydrate and represented by the following formula (1).

Formula-1

This disclosure relates to novel crystalline forms of Edoxaban tosylate and process for their preparation thereof.

Preparation of Form III of Edoxaban tosylate

Example 1

Edoxaban tosylate (0.5 g) was dissolved in acetic acid (3.5mL) at 25-30°C. To the clear solution, methyl tert-butyl ether (7.5 mL) was added slowly and stirred at 25-30°C for 15h. Filtered the reaction mass, washed with methyl tert-butyl ether and dried at 40°C under vacuum for 3h to yield crystalline Edoxaban tosylate Form III.

Form-III characterized by powder X-ray diffraction pattern having peaks at 13.0, 17.4, 18.6, 20.9, and

24.6 ±0.2 degrees 2θ.

Example 2

Charged Edoxaban tosylate (0.5g) and 15% water in Isopropyl alcohol (15ml) into a round bottomed flask at 25-30°C. Heated to 70-75°C for complete dissolution. The clear solution was slowly cooled to 40-45°C, add seeds of Form III further cooled to 25-30°C and maintained under stirring at 25-30°C for 30-60min. The product obtained was filtered, washed with isopropyl alcohol and dried at 40°C under vacuum for 3h to yield crystalline Edoxaban tosylate Form III.

Example 3

Edoxaban tosylate (0.5 g) was dissolved in acetic acid (2.5 mL) at 25-30°C. The clear solution was heated to 100°C and maintained under stirring for 1h at 100°C. The solution was slowly cooled to 50°C and added methyl tert-butyl ether (10 mL) to reaction mixture at same temperature. Cool the reaction mass to 25-30°C and stirred for 1h. The product obtained was filtered, washed with methyl tert-butyl ether (5 mL) and dried at 40°C under vacuum for 3h to yield crystalline Edoxaban tosylate Form III.

Example 4

Edoxaban tosylate (0.5 g) was dissolved in acetic acid (2.5 mL) and anisole (5 mL) at 25-30°C. The clear solution was heated to 100°C and maintained under stirring for 1h at 100°C. The solution was slowly cooled to 50°C. Methyl tert butyl ether (2 mL) was added drop wised to reaction mixture at

50°C followed by addition of seeds of form III (5mg), coo...