WO2008149137A2

WO2008149137A2 - Tegazerod benzoate and polymorphic forms

Info

Publication number: WO2008149137A2
Application number: PCT/GB2008/050393
Authority: WO
Inventors: Abhay Gaitonde; Bindu Manojkumar; Dattatrey Kokane
Original assignee: Generics [Uk] Limited; Mylan Development Centre Private Limited
Priority date: 2007-06-04
Filing date: 2008-05-30
Publication date: 2008-12-11
Also published as: WO2008149137A3

Abstract

The present invention relates to a novel salt of tegaserod, tegaserod benzoate, and also to polymorphic forms of this salt. The invention further relates to processes for the preparation of the salt and polymorphic forms. The invention also relates to pharmaceutical compositions comprising the salt, optionally in a polymorphic form, and to uses of said compositions for treating patients suffering from gastrointestinal disorders.

Description

Novel Salt Field of the invention

Background of the invention

Tegaserod, chemically named 2-[(5-methoxy-l_FJ-indol-3-yl)methylene]-iV- pentylhydrazinecarboximidamide, is a selective serotonin 4 (5-HT₄) receptor agonist, which can be used to treat gastrointestinal disorders such as heartburn, bloating, postoperative ileus, abdominal pain and discomfort, epigastric pain, nausea, vomiting, regurgitation, intestinal pseudo-obstruction, irritable bowel syndrome and gastro-oesophageal reflux. Tegaserod as the maleate salt is marketed for the short-term treatment of irritable bowel syndrome in women whose primary bowel symptom is constipation.

Tegaserod, represented by formula (I), was first described in US 5 510 353 as well as processes for its preparation. Also described is the maleate salt of tegaserod, but interestingly a method of manufacturing tegaserod maleate is not disclosed. The only characterizing data is the melting point which is disclosed as 190⁰C for the maleate salt and 124°C for the tegaserod base.

WO 2006/116953 describes crystalline forms of the hydrobromide, fumarate and oxalate salts of tegaserod. Also claimed is a process for preparing the hydrochloride, hydrobromide, fumarate, tartrate, citrate, lactate, mesylate, oxalate, succinate, glutarate, adipate, salicylate, sulphate, mandelate, camphor sulphonate and hydrogen sulphate salts of tegaserod from a specific crystalline form of tegaserod base. Another process described is a method of preparing the fumarate, maleate, tartrate, citrate, mesylate, lactate, succinate, oxalate, hydrochloride, salicylate, glutarate, adipate, hydrobromide, sulphate and hydrogen sulphate from a hydrogen halide salt of tegaserod.

There are often major hurdles to overcome before an active pharmaceutical ingredient (API) can be formulated into a composition that can be marketed. For example, the rate of dissolution of an API that has poor aqueous solubility is often problematic. The aqueous solubility is a major influence on the bioavailability of the API such that a poorly soluble API can mean the API is not available to have a pharmaceutical effect on the body. The API can also cause problems during manufacture of a pharmaceutical composition. For example, flowability, compactability and stickiness are all factors affected by the solid state properties of an API.

It has thus always been an aim of the pharmaceutical industry to provide many forms of an API in order to mitigate the problems described above. Different salts, crystalline forms also known as polymorphs, amorphous forms, solvates and hydrates are all forms of an

API that can have different physiochemical and biological characteristics. Indeed, it has been discovered that the tegaserod maleate product on the market, Zelnorm , has been linked to an increase in heart problems in a proportion of individuals. One possible reason is that the maleate moiety reacts with the tegaserod, resulting over time in the production of a toxic impurity. This impurity could be a contributor to the heart problems seen in some patients.

It would therefore be advantageous for the medicinal chemist to have a wide repertoire of alternative salts and crystalline forms of these and other known salts to aid in the preparation of products that are both efficacious and safe. Summary of the invention

Accordingly, the present invention provides a novel salt of tegaserod, namely tegaserod benzoate, as well as a crystalline form of said salt.

As alluded to above, polymorphism influences every aspect of the solid state properties of an API and one of the important aspects of polymorphism in pharmaceuticals is the possibility of interconversion from one polymorphic form to another. It is important that stable crystalline forms are used in pharmaceutical dosage forms as, for example, conversion from a form showing greater aqueous dissolution and potentially better bioavailability to a less soluble form can potentially have disastrous consequences.

Thus it is an object of the present invention to provide a novel tegaserod salt and crystalline forms thereof which may have an advantageous dissolution rate in vivo, leading to improved bioavailability, and further provide advantageous characteristics during dosage form manufacture, for example, good conversion stability and formulation characteristics.

It is a further object of the present invention to provide a novel tegaserod salt and crystalline forms thereof which have advantageous properties, for example, better solubility, bioavailability, stability including chemical and polymorphic stability, flowability, tractability, compressibility, compactability, toxicity, efficacy, or safety.

Accordingly, a first aspect according to the invention provides the compound tegaserod benzoate or a tautomeric form thereof and/or a pharmaceutically acceptable solvate or hydrate thereof.

The tegaserod benzoate may exist in one or more polymorphic, tautomeric, hydrate and/or solvate forms. The present invention embraces all polymorphic forms and their mixtures, all tautomeric forms and their mixtures, all hydrate forms and their mixtures, and all solvate forms and their mixtures. Although tegaserod is defined for convenience by reference to one guanidino form only, the invention is not to be understood as being in any way limited by the particular nomenclature or graphic representation employed. - A -

In a second aspect according to the invention a novel polymorphic form of tegaserod benzoate is provided with a characteristic XRD spectrum having at least five peaks (preferably at least six, seven, eight, nine, ten, or eleven peaks) selected from peaks with 2Θ values at 5.5, 6.0, 7.1, 8.2, 10.7, 11.0, 17.7, 19.3, 21.0, 22.1 and 25.1 ± 0.2 degree. Preferably the novel polymorphic form of tegaserod benzoate has a characteristic XRD spectrum having major peaks with 2Θ values at 5.54, 6.00, 7.1, 8.2, 10.7, 11.0, 17.7, 19.3, 21.0, 22.1 and 25.1 ± 0.2 degree.

According to a third aspect of the present invention there is provided a polymorphic form of tegaserod benzoate characterized by a DSC with two endothermic peaks at about 70⁰C and about 215°C respectively.

Preferably the tegaserod benzoate according to the above described aspects and embodiments has a chemical purity of greater than 95%, 96%, 97%, 98%, or 99% (as measured by HPLC). Preferably the tegaserod benzoate according to the above described aspects and embodiments has a polymorphic purity of greater than 95%, 96%, 97%, 98%, or 99% (as measured by XRPD or DSC).

A fourth aspect provides a process for the preparation of tegaserod benzoate according to the above described aspects and embodiments, comprising the steps of:

(a) dissolving or suspending tegaserod benzoate or tegaserod and benzoic acid in a solvent; and

(b) isolating the resultant salt.

Preferably tegaserod and benzoic acid are used in step (a).

Preferably the solvent used in step (a) is water or an organic solvent or a mixture thereof. Preferably the organic solvent is an alcohol or ethyl acetate, preferably an alcohol, preferably a C_{1 5} alcohol. Preferably the alcohol is methanol, ethanol, 1-propanol, isopropanol, 1-butanol, isobutanol or tert-butanol, preferably methanol.

In a preferred embodiment of the process, step (a) is carried out by (al) dissolving or suspending tegaserod in a solvent, and (a2) adding a solution or suspension of benzoic acid. Preferably the solvent used in step (al) is an organic solvent, preferably an alcohol or ethyl acetate, preferably an alcohol, preferably a C_{1 5} alcohol. Preferably the alcohol is methanol, ethanol, 1-propanol, isopropanol, 1-butanol, isobutanol or tert-butanol, preferably methanol. Preferably tegaserod is suspended in the solvent in step (al).

Preferably the solvent used in step (a2) is water or an organic solvent or a mixture thereof. If an organic solvent is used, then it is preferably an alcohol, preferably a C_{1 5} alcohol. Preferably the alcohol is methanol, ethanol, 1-propanol, isopropanol, 1-butanol, isobutanol or tert-butanol, preferably methanol. Preferably the benzoic acid is added as a solution of the acid, preferably in water or alternatively in methanol.

Preferably the reaction mixture obtained in step (a) is stirred to increase the precipitation of the tegaserod benzoate salt. It is preferred that the stirring occurs at about 20-30⁰C for about 0.5-2 hours. Alternatively, an anti-solvent can be added to increase the precipitation of the tegaserod besylate salt.

In a further embodiment, the salt in step (b) is isolated by filtration, preferably by vacuum filtration.

In a further embodiment, the tegaserod benzoate is obtained on an industrial scale, preferably in batches of 0.5kg, lkg, 5kg, 10kg, 50kg, 100kg, 500kg or more.

A fifth aspect according to the invention provides a pharmaceutical composition comprising tegaserod benzoate according to any of the aspects or embodiments described above and one or more pharmaceutically acceptable excipients. Preferably the composition is a solid composition, most preferably a tablet or capsule composition.

In a sixth aspect according to the invention there is further provided a method of treating or preventing a gastrointestinal disorder selected from the group comprising: heartburn, bloating, postoperative ileus, abdominal pain and discomfort, epigastric pain, nausea, vomiting, regurgitation, intestinal pseudo-obstruction, irritable bowel syndrome and gastro- oesophageal reflux (preferably irritable bowel syndrome), comprising administering a composition comprising a pharmaceutically or prophylactically effective amount of tegaserod benzoate according to any of the aspects or embodiments described above.

In a seventh aspect there is provided tegaserod benzoate according to any of the aspects or embodiments described above for use as a medicament, for example, for use in the treatment or prevention of gastrointestinal disorders. Preferably the disorder is irritable bowel syndrome.

An eighth aspect provides the use of tegaserod benzoate according to any of the aspects or embodiments described above in the manufacture of a medicament for use in the treatment or prevention of a gastrointestinal disorder. In a preferred embodiment the gastrointestinal disorder is selected from the group comprising heartburn, bloating, postoperative ileus, abdominal pain and discomfort, epigastric pain, nausea, vomiting, regurgitation, intestinal pseudo-obstruction, irritable bowel syndrome and gastro-oesophageal reflux, preferably irritable bowel syndrome.

Brief description of the accompanying figures

Figure 1 describes the XRPD of tegaserod benzoate. Figure 2 describes the DSC of tegaserod benzoate. Figure 3 describes the TGA of tegaserod benzoate.

Detailed description of the invention

The present invention provides the novel benzoate salt of tegaserod and a process for its preparation. The process disclosed is simple and amenable to scale up and is capable of providing the salt in consistent polymorphic and chemical purity of greater than 95% respectively, preferably greater than 96%, more preferably greater than 97%, particularly preferred is a purity of greater than 98% and most preferred is a purity of greater than 99% irrespective of the scale of preparation.

A preferred process according to the invention for preparing tegaserod benzoate according to the invention comprises adding tegaserod to methanol. Preferably the tegaserod is in the form of the free base. Of course it will be understood that the tegaserod can be completely or only partially dissolved and the process still falls within the scope of the invention. To this solution is added benzoic acid preferably in solution, either in methanol or in alternative embodiments in water.

The resulting reaction mixture comprising methanol, tegaserod and the benzoic acid solution in certain embodiments can be stirred to increase the precipitation of the solid salt. It is preferred that the stirring occurs at about 25°C or approximately room temperature, but it is envisaged that the stirring conditions may be varied and still remain within the scope of the invention.

The solid product obtained can then be isolated by any means common in the field or known to the skilled artisan. In one embodiment the solid is obtained by evaporation of the solvent. However, in a particularly preferred embodiment the solid product is filtered and dried. Preferably the product is dried at a temperature that does not induce conversion of the polymorphic form or cause the resultant form to degrade. The inventors have found that drying the product at about 40⁰C is advantageous. Preferably, in certain embodiments, the solid product is dried under vacuum until a constant weight is obtained.

A further embodiment of the invention comprises pharmaceutical compositions of the tegaserod benzoate or a tautomeric form thereof and/or a pharmaceutically acceptable solvate or hydrate thereof with one or more pharmaceutically acceptable excipient(s).

Another aspect of the present invention is the pharmaceutical compositions containing the tegaserod benzoate in any form according to the invention and uses of the pharmaceutical compositions to provide methods of treating patients suffering from gastrointestinal disorders, comprising providing to a patient a pharmaceutically effective amount of the tegaserod salt.

Illustrative of the invention is a pharmaceutical composition made by mixing a tegaserod salt, namely tegaserod benzoate according to the invention, and a pharmaceutically acceptable carrier. A further embodiment of the invention is a process for making a pharmaceutical composition comprising mixing the benzoate salt according to the invention and a pharmaceutically acceptable carrier. In one embodiment of the invention there is provided a method for the treatment of a 5-HT₄ receptor mediated disorder in a subject in need thereof comprising administering to the subject a composition comprising a therapeutically effective amount of a tegaserod salt according to the invention. In a further embodiment according to the invention there is provided the use of a tegaserod salt according to the invention substantially free of other polymorphic forms, for the preparation of a medicament for treating a 5-HT₄ receptor mediated disorder in a subject in need thereof. Of course, it will be realised that the tegaserod benzoate may be in amorphous form, or indeed any of a number of crystalline forms.

5-HT₄ receptor mediated disorders comprise gastrointestinal disorders such as heartburn, bloating, postoperative ileus, abdominal pain and discomfort, epigastric pain, nausea, vomiting, regurgitation, intestinal pseudo-obstruction, irritable bowel syndrome and gastro- oesophageal reflux, preferably irritable bowel syndrome.

In addition to the active ingredient(s), the pharmaceutical compositions of the present invention may contain one or more excipients. Excipients are added to the composition for a variety of purposes. Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. Avicel ), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulphate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit^®), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.

Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. Carbopol ), carboxymethyl cellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel^®), hydroxypropyl methyl cellulose (e.g. Methocel ), liquid glucose, magnesium aluminium silicate, maltodextrin, methyl cellulose, polymethacrylates, povidone (e.g. Kollidon^®, Plasdone^®), pregelatinized starch, sodium alginate and starch. The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium (e.g. Ac-Di-SoI , Primellose ), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon^®, Polyplasdone^*1), guar gum, magnesium aluminium silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab ) and starch.

Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.

When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulphate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.

Flavouring agents and flavour enhancers make the dosage form more palatable to the patient. Common flavouring agents and flavour enhancers for pharmaceutical products that may be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol and tartaric acid.

Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level. In liquid pharmaceutical compositions of the present invention, the tegaserod salt and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerine.

Liquid pharmaceutical compositions may further contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that may be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl alcohol.

Liquid pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouth-feel or organoleptic qualities of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid, bentonite, carbomer, carboxymethyl cellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethyl cellulose, gelatine, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.

Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar may be added to improve the taste.

Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxytoluene, butylated hydroxyanisole and ethylenediaminetetraacetic acid may be added at levels safe for ingestion to improve storage stability.

According to the present invention, a liquid composition may also contain a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate. Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.

The solid compositions of the present invention include powders, granulates, aggregates and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral. The dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts. Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and lozenges, as well as liquid syrups, suspensions and elixirs.

The dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or a soft shell. The shell may be made from gelatin and optionally contain a plasticizer such as glycerine and sorbitol, and an opacifying agent or colourant. The active ingredient and excipients may be formulated into compositions and dosage forms according to methods known in the art.

A composition for tableting or capsule filling may be prepared by wet granulation. In wet granulation, some or all of the active ingredient and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules. The granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size. The granulate may then be tableted, or other excipients may be added prior to tableting, such as a glidant and/or a lubricant.

A tableting composition may be prepared conventionally by dry granulation. For example, the blended composition of the active and excipients may be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet. As an alternative to dry granulation, a blended composition may be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.

A capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting, however, they are not subjected to a final tableting step.

In further embodiments the composition of the invention may further comprise one or more additional active ingredients. Further active ingredients may include other 5-HT₄ receptor agonists such as prucalopride, RS 67333 (l-(4-amino-5-chloro-2-methoxyphenyl)- 3-(l-butyl-4-piperidinyl)-l-propanone), RS 67506 (l-(4-amino-5-chloro-2-methoxyphenyl)- 3- [1 - [2- [(methylsulphonyl) amino] ethyl] -4-piperidinyl] - 1 -propanone) , cisapride, renzapride, norcisapride, mosapride, zacopride, SB 205149, SC 53116, BIMU 1, and BIMU 8; proton pump inhibitors such as omeprazole, rabeprazole, pantoprazole, and lansoprazole; 5-HT₃ receptor agonists such as cilansetron which is described in EP 297 651, alosetron which is described in WO 99/17755, ramosetron, azasetron, ondansetron, dolasetron, ramosetron, granisetron, and tropisetron; selective serotonin reuptake inhibitors such as citalopram, escitalopram, fluoxetine, fluvoxamine, sertraline, paroxetine, zimeldine, norzimeldine, clomipramine, alaproclate, venlafaxine, cericlamine, duloxetine, milnacipran, nefazodone, OPC 14503, and cyanodothiepin; and dipeptidyl peptidase IV (DPP-IV) inhibitors. Of course it will be obvious that the above is not an exhaustive list.

The details of the invention, its objects and advantages are explained hereunder in greater detail in relation to non-limiting exemplary illustrations. Examples

Example 1

Tegaserod free base was added to 3.3 vol of methanol to provide a clear solution, to which was added a solution of benzoic acid (2eq) in 3.3 vol of methanol. The reaction mixture was stirred at 25°C for 1 hour and then filtered. The resultant solid product was dried at

40⁰C under vacuum until a constant weight was obtained.

The ¹H-NMR indicated formation of tegaserod benzoate. XRPD data (see Figure 1) confirmed that the tegaserod benzoate product obtained had a crystalline structure. The DSC and TGA are shown in Figures 2 and 3 respectively.

Chemical purity > 99% (as measured by HPLC)

Polymorphic purity = high (as measured by DSC)

Claims

1. Tegaserod benzoate or a tautomeric form thereof and/or a pharmaceutically acceptable solvate or hydrate thereof.

2. A polymorphic form of tegaserod benzoate with a characteristic XRD spectrum having at least five peaks selected from peaks with 2Θ values at 5.5, 6.0, 7.1, 8.2, 10.7, 11.0, 17.7, 19.3, 21.0, 22.1 and 25.1 ± 0.2 degree.

3. A polymorphic form of tegaserod benzoate characterised by a DSC with two endothermic peaks at about 70⁰C and about 215°C respectively.

4. Tegaserod benzoate according to any one of claims 1 to 3, having a chemical purity of greater than 95% (as measured by HPLC).

5. Tegaserod benzoate according to any one of claims 1 to 4, having a polymorphic purity of greater than 95% (as measured by XRPD or DSC).

6. A process for the preparation of tegaserod benzoate according to any one of claims 1 to 5, comprising the steps of:

(b) isolating the resultant salt.

7. A process according to claim 6, wherein the solvent used in step (a) is water or an organic solvent or a mixture thereof.

8. A process according to claim 7, wherein the organic solvent is an alcohol or ethyl acetate.

9. A process according to claim 8, wherein the alcohol is methanol.

10. A process according to any one of claims 6 to 9, wherein step (a) is carried out by (al) dissolving or suspending tegaserod in a solvent, and (a2) adding a solution or suspension of benzoic acid.

11. A process according to claim 10, wherein the solvent used in step (al) is an organic solvent.

12. A process according to claim 11, wherein the organic solvent is an alcohol or ethyl acetate.

13. A process according to claim 12, wherein the alcohol is methanol.

14. A process according to any one of claims 10 to 13, wherein the solvent used in step (a2) is water or an organic solvent or a mixture thereof.

15. A process according to claim 14, wherein the solvent used in step (a2) is water or an alcohol or a mixture thereof.

16. A process according to claim 15, wherein the solvent used in step (a2) is water or methanol or a mixture thereof.

17. A process according to any one of claims 10 to 16, wherein the benzoic acid is added as a solution of the acid in water or methanol.

18. A process according to any one of claims 6 to 17, wherein the salt in step (b) is isolated by filtration.

19. A process according to claim 18, wherein the salt is isolated by vacuum filtration.

20. A process according to any one of claims 6 to 19, wherein the tegaserod benzoate is obtained on an industrial scale.

21. A pharmaceutical composition comprising tegaserod benzoate according to any one of claims 1 to 5, or prepared by a process according to any one of claims 6 to 20, and one or more pharmaceutically acceptable excipients.

22. A composition according to claim 21, wherein the composition is a solid composition.

23. A composition according to claim 21 or 22, wherein the composition is a tablet or capsule composition.

24. A method of treating or preventing a gastrointestinal disorder selected from the group comprising: heartburn, bloating, postoperative ileus, abdominal pain and discomfort, epigastric pain, nausea, vomiting, regurgitation, intestinal pseudo-obstruction, irritable bowel syndrome and gastro-oesophageal reflux, comprising administering a composition comprising a pharmaceutically or prophylactically effective amount of tegaserod benzoate according to any one of claims 1 to 5, or prepared by a process according to any one of claims 6 to 20.

25. A method according to claim 24, wherein the gastrointestinal disorder is irritable bowel syndrome.

26. Tegaserod benzoate according to any one of claims 1 to 5, or prepared by a process according to any one of claims 6 to 20, for use as a medicament.

27. Tegaserod benzoate according to claim 26, for use in the treatment or prevention of a gastrointestinal disorder.

28. Tegaserod benzoate according to claim 27, wherein the gastrointestinal disorder is heartburn, bloating, postoperative ileus, abdominal pain or discomfort, epigastric pain, nausea, vomiting, regurgitation, intestinal pseudo-obstruction, irritable bowel syndrome or gastro-oesophageal reflux.

29. Tegaserod benzoate according to claim 28, wherein the gastrointestinal disorder is irritable bowel syndrome.

30. Use of tegaserod benzoate according to any one of claims 1 to 5, or prepared by a process according to any one of claims 6 to 20, in the manufacture of a medicament for use in the treatment or prevention of a gastrointestinal disorder.

31. Use according to claim 30, wherein the gastrointestinal disorder is heartburn, bloating, postoperative ileus, abdominal pain or discomfort, epigastric pain, nausea, vomiting, regurgitation, intestinal pseudo-obstruction, irritable bowel syndrome or gastro- oesophageal reflux.

32. Use according to claim 31, wherein the gastrointestinal disorder is irritable bowel syndrome.