Sertraline is a well-known antidepressant drug that has been on the market for some years. Its systematic name is (lS, 4S)-4- (3, 4-dichlorophenyl)-1, 2,3, 4-tetrahydro-N-methyl-l- naphthaleneamine. Its structure is : It is the cis isomer in the 1S, 4S form. Sertraline is marketed in the 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.

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, (1S, 4S)-4- (3, 4- dichlorophenyl)-1, 2,3, 4-tetrahydro-N-methyl-l-naphthaleneamine, 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.

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 mixture"refer to the fact 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 mixture 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 hydroxide or ammonia. The sertraline base may be separated from the organic phase, such as by evaporation of the solvent in order to obtain the base most probably as an oil. The oil can then be dissolved in a suitable solvent, such as an alkane, including n-heptane, hexane and isooctan, or a C-1 to C-4 alcohol such as methanol, ethanol and isopropanol, and the base crystallised therefrom.

Pharmaceutically acceptable salts of sertraline, such as the hydrochloride, may be prepared from the crystalline base of the invention, by methods known in the art. Thus, for example, the base may be reacted with either the calculated amount of acid in a water- miscible solvent, such as acetone or ethanol, with subsequent isolation of the salt by concentration and cooling, or with an excess of the acid in a water immiscible solvent, such as ethylether, ethylacetate or dichloromethane, with the salt separating spontaneously. The hydrochloride of sertraline obtained by the method of the invention can have a very high purity, eg more than 99.8% or even more than 99.9%. Other salts of sertraline, eg the oxalate, may also be obtained in a very pure form from the crystalline base of the invention.

The pharmaceutical compositions of the invention may be administered in any suitable way and in any suitable form, for example orally in the form of tablets, capsules, powders or syrups, or parenterally in the form of usual sterile solutions for injection.

The pharmaceutical formulations of the invention may be prepared by conventional methods in the art. For example, tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine. Examples of adjuvants or diluents comprise: corn starch, potato starch, talcum, magnesium, stearate, gelatine, lactose, gums and the like. Any other adjuvant or additive such as colourings, aroma, preservatives etc may be used provided it is compatible with the active ingredients.

Solutions for injections may be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilisation of the solution and filling in suitable ampoules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc.

According to the present invention, the crystalline base of sertraline has been found to be stable and form excellent white crystals. It has been found that the base may easily be crystallised in a very pure form. Accordingly, the process of the invention for preparing salts of sertraline has been found to give the salts as very pure products of pharmaceutically acceptable quality. Thus, the yield of sertraline may be improved substantially during the manufacture of sertraline by avoiding one or more conventional recrystallisation steps.

Finally, it has been found that the base may be formulated into very good and stable solid formulations with good release properties.

The invention is further illustrated by the following Examples.

Example 1 Crystallisation of sertraline as the free base.

(lS, 4S)-4- (3, 4-dichlorophenyl)-1, 2,3, 4-tetrahydro-N-methyl-l-naphthaleneamine hydrochloride (101 g, 0.25 mole) is suspended in water (500 ml) and toluene (500 ml).

NaOH (60 ml, 5 N (aq)) is added and the mixture (pH>10) is stirred for 15 minutes before the phases are separated. The organic phase is washed with water (2 times, 100 ml) and filtered through a pad of filter aid. The volatiles are removed in vacuo and the title compound is obtained as an oil. N-Heptane (400 ml) is added and the mixture is heated to 70°C. On cooling, crystals form. The white crystals of the title compound are filtered off and dried at ambient temperature overnight in vacuo. Yield: 75.4 grams (93%). DSC (onset, open capsule) : 64-67°C. Purity: >99.8% (peak area).

Example 2 (1S, 4S)-4- (3, 4-dichlorophenyl)-1, 2,3, 4-tetrahydro-N-methyl-l-naphthaleneamine D (-) mandelate salt (101 g, 0.25 mole) is suspended in water (500 ml) and ethylacetate (500 <BR> <BR> ml). NaOH (60 ml, 5 N (aq) ) is added and the mixture (ph>10) is stirred for 15 minutes before the phases are separated. The organic phase is washed with water (2 times, 100 ml) and filtered through a pad of filter aid. The volatiles are removed in vacuo and the title compound is obtained as an oil. N-hexane (150 ml) is added and the mixture is heated to 50°C. On cooling, crystals form. The white crystals of the title compound are filtered off and dried at ambient temperature overnight in vacuo. Yield: 68 grams (93%). DSC (onset, open capsule): 64-67°C Purity: >99.8% (peak area), Example 3 (1 S, 4S)-4- (3, 4-dichlorophenyl)-1, 2,3, 4-tetrahydro-N-methyl-1-naphthaleneamine D (-) mandelate salt (101 g, 0.25 mole) is suspended in water (500 ml) and ethylacetate (500 <BR> <BR> ml). NaOH (60 ml, 5 N (aq) ) is added and the mixture (pH>10 is stirred for 15 minutes before the phases are separated. The organic phase is washed with water (2 times, 100 ml) 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 off and dried at ambient temperature overnight in vacuo. Yield: 68 grams (93%). DSC (onset, open capsule): 64-67°C. Purity: >99.8% (peak area).

The tablets can be made by any suitable technique such as by granulation eg wet granulation, non-aqueous granulation, direct compression etc.

Example 4 Wet granulation and preparation of tablets Using a batch size of 200 g, granulation was performed in a small-scale laboratory high shear mixer (Micromixer).

Crystalline sertraline base of the invention was sieved through a sieve aperture of 0.3 mm. The ingredients of the intragranular phase were mixed at 600 rmp. Then, 25 ml of purified water was added in 30 sec and the granulation terminated after a total processing time of 3 min. The granulate was wet sieved through a 0.7 mm sieve aperture and dried at 40°C in 30 minutes to equilibrium relative humidity of 32%. The dried granulate was finally sieved through a 0.7 mm sieve aperture.

The dried granulate was mixed for 3 minutes with the extragranular phase in a Turbula mixer and finally mixed with the lubricant for 30 sec.

The formulation consisted of Parts by wt Sertraline base 16.00 Kollidan VA64 2.32 Lactose 350 mesh 38.98 Cornstarch 20. 00 Purified water 25.00 Avicel PH 200 (microcrystalline cellulose) 20. 00 Ac-Di-Sol (croscarmellase sodium) 2. 00 Magnesium stearate 0.7 The tablets were produced on a single punch tabletting machine.