A Process For Purifying Sertraline Salt

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION (See section 10, rule 13) 'A PROCESS FOR PURIFYING SERTRALINE SALT" CIPLA LIMITED, an Indian company, of 289 Bellasis Road, Mumbai Central, Mumbai 400 008, India GRANTED 14-2-2007 The following specification particularly describes the invention and the manner in which it is to be performed.

Field of the invention The present invention relates to a process for purifying sertraline salt. The present invention relates to sertraline and, in particular, to a novel form thereof, and to pharmaceutically acceptable salts made therefrom. Background of the Invention Sertraline is a well-known antidepressant drug that has been on the market for some years. Its systematic name is (lS,4S)^(3,4-diebloropheayl)-l,2,3,4-tetrahydrch-N-memyl-l-naphthaleneamine. Its structure is:

It is the cis isomer in the 1S.4S form Sertraline is marketed in Hie form of its hydrochloride. The preparation of sertraline and of sertraline hydrochloride are described in EP-A-0030081. However, there is no specific description in this specification of sertraline (ie the 1S,4S) free base. It is known that sertraline hydrochloride can exist in several crystalline polymorphic forms, which differ from each other in their stability, physical properties, spectral data and methods of preparation. US-A-5248699 describes the production of sertraline hydrochloride in various polymorphic forms, designated as Form I to IV. It does not, however, refer to different forms of sertraline base. Summary of the Invention We have now found that sertraline can be obtained as a pure crystalline product, which may easily be handled and conveniently be formulated into tablets and other pharmaceutical forms. Furthermore, it has surprisingly been found that a very good and efficient purification of sertraline can be effected, such as during its manufacture, by releasing and crystallising the base. In one aspect, the present invention provides sertraline free base, (lS,4S)-4-(3,4-dichlrophenyl)-l,2,3,4-tetrahydro-N-methyl-l-naphthaleneamme, in crystalline form. In another aspect, the invention provides a method of making crystalline sertraline base, which comprises treating a salt of sertraline with a base, and recovering the sertraline

free base in crystalline form. In a further aspect, the invention provides a method of making a salt of sertraline, which comprises converting crystalline sertraline base to a salt. In a further aspect, the invention relates to a salt so made, especially a pure crystalline salt, most preferably the hydrochloride. The invention also provides a pharmaceutical formulation made from the crystalline free base or from a salt of the invention. Preferably, the formulation is for oral administration, such as a tablet or capsule. Detailed Description of the Invention The crystalline base of sertraline is preferably at least 99.5% w/w pure, most preferably at least 99.8% w/w pure (peak area). The melting point is preferably in the range 64-67°C (DSC; open capsule). The crystalline free base has an X-ray diffraction pattern as given in Fig. 2 of the accompanying drawings. The base may be set free from a crude salt of sertraline. The nature of the salt is not critical and may, for example, be the hydrochloride, sulphate, oxalate, phosphate, or mandelate, preferably the mandelate (salts of other inorganic or organic acids can also be used). The terms "crude salt" and "crude mixture11 refer to the feet that the salt and the mixture, respectively, comprise impurities which must be removed or which it is desired to remove. The crude salt may be a salt separated directly from a reaction mixture, or it may have been subjected to some initial purification, eg recrystallisation and/or treatment with activated carbon or silica gel. The salt may have been prepared by any suitable process, eg it may have been obtained directly by reaction, or it may have been formed subsequently by treatment with an acid. The salt may be isolated by precipitation or it may be in a solvent, eg in the nuxture resulting directly from the synthesis of the compound. Similarly, the crude mixture comprising sertraline base may have been obtained directly from synthesis of the compound, or it may have been subjected to some initial purification, eg recrystallisation or treatment with activated carbon or silica gel. Sertraline base may be set free from a crude "salt by, for example, dissolving or suspending the crude salt in a mixture of water and an organic solvent, and then adding a base. Alternatively, sertraline base may be isolated from a crude mixture of the base by purification and extraction The organic solvent may be, for example, toluene, ethyl acetate or any other suitable solvent, and the base may be any convenient base, preferably sodium

and filtered through a pad of filter aid. The volatiles are removed in vacuo and the title compound is obtained as an oil. Methanol (100 ml) is added and the mixture is heated to 50°C. On cooling, crystals form. The white crystals of the title compound are filtered affand dried at ambient temperature overnight in vavno ld: 68 grams (93%).; BSC (onset, open capsule): 64-67°C. Purity: >99.8% (peak area) The tablets can be made byany suitable technique such as by granulation eg wet grawiation, non-aqueow granulation direct compression etc