FIELD OF THE INVENTION
 The present invention relates to novel crystalline, water-soluble salts of the 2S,3S enantiomer of reboxetine, which are the fumarate and succinate salts thereof, to a process for their preparation, to their utility in therapy and to pharmaceutical compositions containing them.
BACKGROUND OF THE INVENTION
 Reboxetine, 2-[.alpha.-(2-ethoxy-phenoxy)-benzyl]-morpholine, was first taught by GB 2014981B, which describes its utility for the treatment of depression. Reboxetine is a selective norepinephrine reuptake inhibitor, it is a safe drug and a superior treatment for those disorders in mammals, comprising humans, that need a selective norepinephrine reuptake inhibition. In fact it has few if any physiological effects besides those on norepinephrine processing, and therefore is free of side effects and unwanted activities. GB 2176407B provides single 2R,3R and 2S,3S enantiomers of reboxetine. The 2S,3S enantiomer of reboxetine, hereafter named as SS-reboxetine, was found to be endowed with a selective norepinephrine reuptake inhibition activity significantly higher that racemate reboxetine.
 There are several patent documents describing new uses of reboxetine, for instance U.S. Pat. No. 6,391,876; U.S. Pat. No. 6,046,193; U.S. Pat. No. 6,184,222 U.S. Pat. No. 6,028,070 and WO 02/36125. However the single fumarate and succinate salts of SS-reboxetine have never been described before. Reboxetine mesylate salt is on the market as racemate and is preferably administered in solid pharmaceutical forms. Similarly, SS-reboxetine mesylate is under development for administration to mammals in solid pharmaceutical forms, which are the most appropriate for administration to patients in need of selective norepinephrine reuptake inhibition. However, compound SS-reboxetine mesylate has shown poor physicochemical characteristics and instability due to its hygroscopicity.
 Moisture uptake is a significant concern for pharmaceutical powders. Moisture have been shown to have a significant impact, for example, on the physical, chemical and manufacturing properties of drugs, excipients and formulations. It is also a key factor in taking decisions related to packaging, storage, handling and shelf life and successful development requires a sound understanding of hygroscopic properties.
 For instance, conversion from an anhydrous to a hydrate form may be observed when the relative humidity exceeds a critical level and moisture content rapidly increases in the solid. This has not only an impact on the physico-pharmaceutical properties of the drug per se, but also on its biopharmaceutical perspective. Moreover, it is well known, that hydrate forms usually tends to be less soluble with respect to a homologous anhydrous form, with potential detrimental effect also on the dissolution rate properties of the active compound per se and on its absorption profile through the gastrointestinal tract. At the same manner, conversion from a crystalline to an amorphous form may be observed in presence of relative humidity, with potential disadvantages in terms of physical stability (the active drug substance can for instance behave in a deliquescent way) or chemical stability, in fact the amorphous structure being thermodynamically activated is more prone to chemical degradation and to chemical interaction with other chemical species. Thus the performance and the efficacy of both formulation and active ingredient may be significantly changed.
 In particular, as far as SS-reboxetine is concerned, it has been ascertained that the anhydrous mesylate salt is per se thermodynamically unstable and tends to transform itself with ageing into a hydrate form. Even more, the anhydrous form tends to lose its crystalline structure while exposed to high relative humidity environment, thus transforming it into a less chemically stable amorphous form.
 Accordingly, there is a need in therapy of a water-soluble SS-reboxetine salt endowed with lower hygroscopicity and good and reproducible biopharmaceutical properties for allowing a safer and efficacious oral administration.
 The above technical problem has been solved by the inventors of the present invention by providing two novel salts of SS-reboxetine having improved physico-chemical properties. In fact, the novel salts are crystalline, poorly hygroscopic, rapidly-dissolving solids with high water solubility and in addition are substantially more stable than the mesylate salt. They thus possess important advantages in handling, storage and formulations, etc., in addition to possessing all the other advantages, in particular therapeutic advantages, exhibited by the mesylate salt
DESCRIPTION OF THE INVENTION
 A first object the invention is to provide a novel crystalline, water-soluble salt of 2S,3S enantiomer of 2-[.alpha.-(2-ethoxy-phenoxy)-benzyl]-morpholine, which is the fumarate salt and the succinate salt thereof.
 2S,3S enantiomer of 2-[.alpha.-(2-ethoxy-phenoxy)-benzyl]-morpholine is hereafter named as SS-reboxetine.
 Fumarate and succinate salts of SS-reboxetine can be obtained by known analogy methods by means of stoichiometric adding of aqueous solutions of the counterion to the free base dissolved in a suitable solvent. Such solvent is preferably an organic, in particular anhydrous, solvent chosen preferably from methanol, ethanol, dioxane and dimethylformamide. If necessary, the precipitation of the obtained salt may be favoured by adding an anhydrous apolar solvent, for instance diethylether, n-hexane or cyclohexane.
 The free SS-reboxetine base can be obtained by the corresponding mesylate salt by known methods The mesylate salt of SS-reboxetine can be obtained as described in GB 2167407B.
 According to a preferred feature of the invention, fumarate and succinate salts of SS-reboxetine can be obtained by reacting SS-reboxetine freebase with fumaric acid or succinic acid, respectively, in a suitable lower alkanol preferably ethanol, followed by controlled crystallization process. A lower alkanol is for instance a C1-C4 alkanol, preferably ethanol.
 SS-reboxetine freebase in its turn can be obtained by reacting SS-reboxetine mandelate with a suitable basic agent, for instance sodium hydroxide. SS-reboxetine mandelate in its turn can be obtained by reacting reboxetine freebase with (S)-(+)-mandelic acid in a suitable lower alkanol followed by controlled crystallization process. Reboxetine freebase can be obtained by reacting reboxetine mesylate with a suitable basic agent, for instance sodium hydroxide.
 Such preferred feature, which is a further object of this invention can be exemplified as follows:
 The fumarate and succinate SS-reboxetine salts thus obtained have a crystalline structure.
 Intermediate compound SS-reboxetine mandelate is a novel compound and a further object of the invention.
 Object of the invention are also metabolites, metabolic precursors (also known as pro-drugs) and hydrate forms of SS-reboxetine fumarate and succinate salts.
 A further object of the invention is to provide a pharmaceutical composition comprising a salt of SS-reboxetine, which is the fumarate salt or the succinate salt thereof, as active ingredient and a pharmaceutically acceptable excipient and/or carrier.
 A pharmaceutical composition can be formulated according to known method in the art in any of the pharmaceutical forms known in the art for administration to a mammal, including humans. For instance, a pharmaceutical composition containing a compound of the invention, as an active ingredient, and a suitable carrier and/or excipient can be prepared as known from GB 2014981B.
 A further object of the invention is to provide a salt of SS-reboxetine, which is the fumarate salt or the succinate salt thereof, for the use as a medicament, in particular as a selective norepinephrine reuptake inhibitor.