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PROCESSES FOR THE PREPARATION OF DESVENLAFAXINE SUCCINATE POLYMORPHIC FORMS

IP.com Disclosure Number: IPCOM000219486D
Publication Date: 2012-Jul-03

Publishing Venue

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Abstract

The present disclosure provides processes for the preparation of polymorphic Form II, Form III, Form IV and the amorphous form of desvenlafaxine succinate.

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PROCESSES FOR THE PREPARATION OF DESVENLAFAXINE SUCCINATE POLYMORPHIC FORMS

Abstract

The present disclosure provides processes for the preparation of polymorphic Form II, Form III, Form IV and the amorphous form of desvenlafaxine succinate.

O-desmethyl venlafaxine is a major metabolite of venlafaxine and has been shown to inhibit norepinephrine and serotonin uptake (Klamerus, K. J. et al., “Introduction of the Composite Parameter to the Pharmokinetics of Venlafaxine and is Active O-Desmethyl Metabolite”, J. Clin. Pharmacol., 32, p. 716-724 (1992)).

Desvenlafaxine succinate represented by structural Formula I and chemical name succinate salt of the base RS-4-[2-dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol and has been used for the treatment of Major Depressive Disorder (MDD).

Formula I

U.S. Patent No. 6,673,838 (herein after referred to as

U.S.

‘838), is the compound patent for desvenlafaxine succinate which describes the process for the preparation of desvenlafaxine succinate along with its pharmaceutically acceptable composition and method of use.  It also describes polymorphic Form I, Form II, Form III, Form IV and the amorphous form of desvenlafaxine succinate and the processes for preparation thereof.

U.S.

‘838 describes preparation of Form I of desvenlafaxine succinate involving reaction of desvenlavaxine free base with succinic acid in a mixture of organic solvent and water, particularly acetone followed by slow cooling over several hours.

As per U.S. ‘838, Form I can also be prepared by slurrying Form I, Form II, Form III or mixture thereof in an organic solvent or a mixture of solvents and water in different proportions.

U.S.

‘838 also provides a process for the preparation of Form II of desvenlafaxine succinate involving slow/fast evaporation or rotary evaporation or slow/fast cooling of a mixture containing Form I in water or a suitable organic solvent or a mixture of organic solvents and water.  It also relates to preparation of Form II involving solvent-antisolvent technique comprising adding mixture of Form I in a suitable solvent to cold antisolvent.  Form II can also be prepared by subjecting the amorphous form of desvenlafaxine succinate to relative humidity greater than or equal to 75%.

The preparation of Form III of desvenlafaxine succinate as illustrated in U.S. ‘838 comprises milling of Form I of the desvenlafaxine succinate, wherein milling has been carried out by either ball milling or cryo-grinding at low temperature (<90°C).

The preparation of Form IV of desvenlafaxine succinate as described in U.S. ‘838 comprises slurring of a mixture containing equal amounts of Form I and Form II in organic solvent at 54°C for several days followed by heating at 120°C for several hours.

The preparation of amorphous form of desvenlafaxine succinate as per U.S. ‘838 comprises melt cooling of Form I, Form II, Form III or Form IV, or a mixture thereof. 

The processes described in U.S. ‘838 for the preparat...