WO2009053733A2

WO2009053733A2 - Novel crystalline forms

Info

Publication number: WO2009053733A2
Application number: PCT/GB2008/050967
Authority: WO
Inventors: Abhay Gaitonde; Bindu Manojkumar; Sandeep Sonawane; Dattatrey Kokane; Sinderpal Tank; Vikas Padalkar
Original assignee: Generics UK Ltd; Mylan Development Centre Pvt Ltd
Current assignee: Generics UK Ltd; Mylan Pharmaceuticals Pvt Ltd
Priority date: 2007-10-24
Filing date: 2008-10-18
Publication date: 2009-04-30
Anticipated expiration: 2010-04-24
Also published as: WO2009053733A3

Abstract

The present invention relates to novel crystalline forms of the succinate salt of tegaserod, and to processes for the preparation of these novel crystalline forms. The invention also relates to pharmaceutical compositions containing these novel polymorphs, and to uses of said compositions to provide methods of treating patients suffering from gastrointestinal disorders.

Description

Novel Crystalline Forms

Field of the invention

Background of the invention

Tegaserod, chemically named 2-[(5-methoxy-liϊ-indol-3-yl)methylene]-IV-pentylhydrazine- carboximidamide, 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 pseudoobstruction, 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 novel crystalline forms of the succinate salt of tegaserod.

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 crystalline 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 novel crystalline forms of tegaserod succinate 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 novel crystalline forms of tegaserod succinate which have advantageous properties, for example, better solubility, bioavailability, stability including chemical and polymorphic stability, flowability, tractability, compressibility, compactability, toxicity, efficacy, or safety.

According to a first aspect of the present invention there is provided a novel crystalline form of tegaserod succinate, designated form 3, with a characteristic XRD spectrum having two or more peaks (preferably three or more, four or more, five or more, or all six peaks) with 2Θ values at 5.05, 5.87, 14.45, 17.35, 19.94, 25.16 ± 0.2 °2Θ.

In a second aspect according to the invention there is provided a novel crystalline form of tegaserod succinate, designated form 3, having an XRPD trace substantially as shown in figure 1. - A -

In a third aspect there is provided a novel crystalline form of tegaserod succinate, designated form 3, characterized by a DSC with endothermic peaks at about 104⁰C and about 159°C, preferably at about 103.68⁰C and about 158.71⁰C, all ± 2°C.

In a fourth aspect according to the invention there is provided a novel crystalline form of tegaserod succinate, designated form 3, having a DSC trace substantially as shown in figure

2.

According to a fifth aspect of the present invention there is provided a process for the preparation of tegaserod succinate crystalline form 3 according to the invention comprising the steps of:

(a) dissolving or suspending tegaserod succinate, or tegaserod and succinic acid, in one or more solvent(s);

(b) causing tegaserod succinate form 3 to precipitate from the solution or suspension obtained in step (a); and

(c) isolating the tegaserod succinate form 3.

Preferably tegaserod succinate is dissolved in step (a). In one preferred embodiment the solvent used in step (a) is dimethyl sulphoxide (DMSO). Preferably about 5 volumes of DMSO are used. In another embodiment the DMSO is heated to between about 30-40⁰C, preferably about 36°C. In a further preferred embodiment the tegaserod succinate form 3 is caused to precipitate by cooling the solution or suspension obtained in step (a) to between about 0-30⁰C, preferably about 0-5⁰C. In yet another embodiment the tegaserod succinate form 3 is isolated by filtration. In a particularly preferred embodiment the tegaserod succinate form 3 is washed, preferably with DMSO, preferably about 1 volume. In another embodiment tegaserod succinate form 3 is dried under reduced pressure, preferably under vacuum, preferably until a constant weight is achieved. Preferably the drying occurs at between about 20-40⁰C, most preferably about 30⁰C.

According to a sixth aspect of the present invention there is provided a novel crystalline form of tegaserod succinate, designated form 4, with a characteristic XRD spectrum having two or more peaks (preferably three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, or all fourteen peaks) with 2Θ values at 5.00, 5.77, 6.40, 6.74, 7.49, 7.94, 12.75, 14.47, 14.96, 18.02, 18.55, 20.25, 24.76, 25.13 ± 0.2 °2Θ.

In a seventh aspect according to the invention there is provided a novel crystalline form of tegaserod succinate, designated form 4, having an XRPD trace substantially as shown in figure 3.

In an eighth aspect there is provided a novel crystalline form of tegaserod succinate, designated form 4, characterized by a DSC with endothermic peaks at about 117°C and about 158°C, preferably at about 117.26°C and about 157.90⁰C, all ± 2°C.

In a ninth aspect according to the invention there is provided a novel crystalline form of tegaserod succinate, designated form 4, having a DSC trace substantially as shown in figure 4.

According to a tenth aspect of the present invention there is provided a process for the preparation of tegaserod succinate crystalline form 4 according to the invention comprising the steps of:

(b) causing tegaserod succinate form 4 to precipitate from the solution or suspension obtained in step (a); and

(c) isolating the tegaserod succinate form 4.

Preferably tegaserod succinate is dissolved in step (a). In one preferred embodiment the solvent, one of the solvents or each solvent(s) used in step (a) is a C₁-C₆ alcohol, preferably a C₄-C₆ alcohol, preferably a secondary or tertiary alcohol, preferably the solvent is t- butanol. Preferably about 25 volumes of t-butanol are used. In another embodiment the t- butanol is heated to between about 80-90⁰C, preferably about 83°C. In a further preferred embodiment the tegaserod succinate form 4 is caused to precipitate by cooling the solution or suspension obtained in step (a), preferably to about 20-30⁰C. In yet another embodiment the tegaserod succinate form 4 is isolated by filtration. In a particularly preferred embodiment the tegaserod succinate form 4 is washed, preferably with t-butanol, preferably about 5 volumes. In another embodiment the tegaserod succinate form 4 is dried under reduced pressure, preferably under vacuum, preferably until a constant weight is achieved. Preferably the drying occurs at between about 20-40⁰C, preferably at about 35°C.

According to an eleventh aspect of the present invention there is provided a novel crystalline form of tegaserod succinate, designated form 5, with a characteristic XRD spectrum having two or more peaks (preferably three or more, four or more, five or more, six or more, seven or more, or all eight peaks) with 2Θ values at 6.45, 6.88, 9.27, 12.96, 15.20, 18.12, 24.36, 25.33 ± 0.2 °2Θ.

In a twelfth aspect according to the invention there is provided a novel crystalline form of tegaserod succinate, designated form 5, having an XRPD trace substantially as shown in figure 5.

In a thirteenth aspect there is provided a novel crystalline form of tegaserod succinate, designated form 5, characterized by a DSC with an endothermic peak at about 115°C i 2°C, preferably at about 115.00⁰C ± 2°C.

In a fourteenth aspect according to the invention there is provided a novel crystalline form of tegaserod succinate, designated form 5, having a DSC trace substantially as shown in figure 6.

According to a fifteenth aspect of the present invention there is provided a process for the preparation of tegaserod succinate crystalline form 5 according to the invention comprising the steps of:

(b) causing tegaserod succinate form 5 to precipitate from the solution or suspension obtained in step (a); and

(c) isolating the tegaserod succinate form 5. Preferably tegaserod succinate is dissolved in step (a). In one preferred embodiment the solvent used in step (a) is acetonitrile. Preferably about 25 volumes of acetonitrile are used. In another embodiment the acetonitrile is heated to between about 70-90⁰C, preferably about 82°C. In a further preferred embodiment the tegaserod succinate form 5 is caused to precipitate by cooling the solution or suspension obtained in step (a), preferably to about 20-30⁰C. In yet another embodiment the tegaserod succinate form 5 is isolated by filtration. In a further embodiment the tegaserod succinate form 5 is washed, preferably with acetonitrile, preferably about 5 volumes. In another embodiment the tegaserod succinate form 5 is dried under reduced pressure, preferably until a constant weight is achieved, preferably under vacuum. Preferably the drying occurs at a temperature of between about 20-40⁰C, preferably about 35°C.

According to a sixteenth aspect of the present invention there is provided a novel crystalline form of tegaserod succinate, designated form 6, with a characteristic XRD spectrum having two or more peaks (preferably three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or all ten peaks) with 2Θ values at 3.90, 5.20, 7.82, 8.96, 11.75, 13.22, 16.07, 17.60, 18.68, 22.96 ± 0.2 °2Θ.

In a seventeenth aspect according to the invention there is provided a novel crystalline form of tegaserod succinate, designated form 6, having an XRPD trace substantially as shown in figure 7.

In an eighteenth aspect there is provided a novel crystalline form of tegaserod succinate, designated form 6, characterized by a DSC with endothermic peaks at about 75°C and about 149°C, preferably at about 75.20⁰C and about 148.63°C, all ± 2°C.

In a nineteenth aspect according to the invention there is provided a novel crystalline form of tegaserod succinate, designated form 6, having a DSC trace substantially as shown in figure 8.

According to a twentieth aspect of the present invention there is provided a process for the preparation of tegaserod succinate crystalline form 6 according to the invention comprising the steps of: (a) dissolving or suspending tegaserod succinate, or tegaserod and succinic acid, in one or more solvent(s);

(b) causing tegaserod succinate form 6 to precipitate from the solution or suspension obtained in step (a); and (c) isolating the tegaserod succinate form 6.

Preferably tegaserod succinate is dissolved in step (a). In one preferred embodiment the solvent used in step (a) is tetrahydrofuran (THF). Preferably about 5 volumes of THF are used. In another embodiment the THF is heated to between about 60-70⁰C, preferably about 66°C. In a further preferred embodiment the tegaserod succinate form 6 is caused to precipitate by cooling the solution or suspension obtained in step (a), preferably to about 20-30⁰C. In yet another embodiment the tegaserod succinate form 6 is isolated by filtration. In a further embodiment the tegaserod succinate form 6 is washed, preferably with THF, preferably about 5 volumes. In another embodiment the tegaserod succinate form 6 is dried under reduced pressure, preferably until a constant weight is achieved, preferably under vacuum. Preferably the drying occurs at a temperature of between about 20-40⁰C, preferably about 35°C.

According to a twenty-first aspect of the present invention there is provided a novel crystalline form of tegaserod succinate, designated form 7, with a characteristic XRD spectrum having two or more peaks (preferably three or more, or all four peaks) with 2Θ values at 5.10, 6.74, 13.47, 20.42 ± 0.2 °2Θ.

In a twenty-second aspect according to the invention there is provided a novel crystalline form of tegaserod succinate, designated form 7, having an XRPD trace substantially as shown in figure 9.

In a twenty-third aspect there is provided a novel crystalline form of tegaserod succinate, designated form 7, characterized by a DSC with endothermic peaks at about 125°C and about 159°C, preferably at about 125.49°C and about 158.89°C, all ± 2°C. In a twenty-fourth aspect according to the invention there is provided a novel crystalline form of tegaserod succinate, designated form 7, having a DSC trace substantially as shown in figure 10.

According to a twenty-fifth aspect of the present invention there is provided a process for the preparation of tegaserod succinate crystalline form 7 according to the invention comprising the steps of:

(a) dissolving or suspending tegaserod succinate, or tegaserod and succinic acid, in one or more solvent(s); (b) causing tegaserod succinate form 7 to precipitate from the solution or suspension obtained in step (a); and (c) isolating the tegaserod succinate form 7.

Preferably tegaserod succinate is dissolved in step (a). In one preferred embodiment the solvent used in step (a) is ethyl acetate. Preferably about 5 volumes of ethyl acetate are used. In another embodiment the ethyl acetate is heated to between about 70-80⁰C, preferably about 77°C. In a further preferred embodiment the tegaserod succinate form 7 is caused to precipitate by cooling the solution or suspension obtained in step (a), preferably to about 20-30⁰C. In yet another embodiment the tegaserod succinate form 7 is isolated by filtration. In a further embodiment the tegaserod succinate form 7 is washed, preferably with ethyl acetate, preferably about 5 volumes. In another embodiment the tegaserod succinate form 7 is dried under reduced pressure, preferably until a constant weight is achieved, preferably under vacuum. Preferably the drying occurs at a temperature of between about 20-40⁰C, preferably about 35°C.

According to a twenty-sixth aspect of the present invention there is provided a novel crystalline form of tegaserod succinate, designated form 8, with a characteristic XRD spectrum having two or more peaks (preferably three or more, or all four peaks) with 2Θ values at 4.77, 5.57, 14.10, 19.65 ± 0.2 °2Θ.

In a twenty-seventh aspect according to the invention there is provided a novel crystalline form of tegaserod succinate, designated form 8, having an XRPD trace substantially as shown in figure 11. In a twenty-eighth aspect there is provided a novel crystalline form of tegaserod succinate, designated form 8, characterized by a DSC with endothermic peaks at about 106⁰C, about 119°C and about 158°C, preferably at about 105.70⁰C, about 118.90⁰C and about 157.75°C, all ± 2°C.

In a twenty-ninth aspect according to the invention there is provided a novel crystalline form of tegaserod succinate, designated form 8, having a DSC trace substantially as shown in figure 12.

According to a thirtieth aspect of the present invention there is provided a process for the preparation of tegaserod succinate crystalline form 8 according to the invention comprising the steps of:

(b) causing tegaserod succinate form 8 to precipitate from the solution or suspension obtained in step (a); and

(c) isolating the tegaserod succinate form 8.

Preferably tegaserod succinate is dissolved in step (a). In one preferred embodiment the solvent, one of the solvents or each solvent(s) used in step (a) is a C₁-C₆ alcohol, preferably a C₁-C₃ alcohol, preferably a primary alcohol, preferably the solvent is 2-methoxy-ethanol. Preferably about 5 volumes of 2-methoxy-ethanol are used. In another embodiment the 2- methoxy-ethanol is heated to between about 30-40⁰C, preferably about 36°C. In a further preferred embodiment the tegaserod succinate form 8 is caused to precipitate by cooling the solution or suspension obtained in step (a), preferably to about 5-10⁰C, and by adding water to the solution or suspension in step (b), preferably at a temperature of about 5-10⁰C, preferably about 10 volumes of water. In yet another embodiment the tegaserod succinate form 8 is isolated by filtration. In a further embodiment the tegaserod succinate form 8 is washed, preferably with water, preferably about 5 volumes. In another embodiment the tegaserod succinate form 8 is dried under reduced pressure, preferably until a constant weight is achieved, preferably under vacuum. Preferably the drying occurs at a temperature of between about 20-40⁰C, preferably about 35°C. The crystalline forms of tegaserod succinate of the present invention may exist in one or more tautomeric, hydrate and/or solvate forms. The present invention embraces 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.

Preferably the crystalline forms of tegaserod succinate according to the above described aspects and embodiments have a chemical purity of greater than 90%, 95%, 96%, 97%, 98%, 99% or 99.9% (as measured by HPLC). Preferably the crystalline forms of tegaserod succinate according to the above described aspects and embodiments have a polymorphic purity of greater than 90%, 95%, 96%, 97%, 98%, 99% or 99.9% (as measured by XRPD or DSC).

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

A thirty-first aspect according to the invention provides a pharmaceutical composition comprising any of the crystalline forms of the present invention or prepared by any of the processes of the present invention and one or more pharmaceutically acceptable excipients. Preferably the composition is a solid composition, most preferably a tablet or capsule composition.

In a thirty-second aspect according to the invention there is further provided a method of treating or preventing a gastrointestinal disorder selected from the list 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 to a patient in need thereof a therapeutically or prophylactically effective amount of any of the crystalline forms of the present invention or prepared by any of the processes of the present invention, or a therapeutically or prophylactically effective amount of a pharmaceutical composition of the present invention. Preferably the patient is a mammal, preferably a human.

In a thirty-third aspect there are provided any of the crystalline forms of the present invention or prepared by any of the processes of the present invention for use as a medicament, for example, for use in the treatment or prevention of a gastrointestinal disorder. Preferably the disorder is irritable bowel syndrome.

A thirty-fourth aspect provides the use of any of the crystalline forms of the present invention or prepared by any of the processes of the present invention 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 succinate form 3. Figure 2 describes the DSC of tegaserod succinate form 3.

Figure 3 describes the XRPD of tegaserod succinate form 4. Figure 4 describes the DSC of tegaserod succinate form 4.

Figure 5 describes the XRPD of tegaserod succinate form 5. Figure 6 describes the DSC of tegaserod succinate form 5.

Figure 7 describes the XRPD of tegaserod succinate form 6. Figure 8 describes the DSC of tegaserod succinate form 6.

Figure 9 describes the XRPD of tegaserod succinate form 7. Figure 10 describes the DSC of tegaserod succinate form 7. Figure 11 describes the XRPD of tegaserod succinate form 8. Figure 12 describes the DSC of tegaserod succinate form 8.

Detailed description of the invention

As used herein the terms 'polymorph', 'polymorphic form', 'crystalline' and 'crystalline form' are used interchangeably.

Further, as used herein the term 'reduced pressure' refers to an atmospheric pressure of below about 100 mbar, preferably below about 15 mbar, and the term 'vacuum' as used herein refers to an atmospheric pressure of below about 10 mbar.

The terms 'XRD spectrum' and 'X-ray diffraction pattern' are used interchangeably herein and preferably refer to an X-ray powder diffraction (XRPD) trace, spectrum or pattern.

The present invention provides novel polymorphs of tegaserod succinate, processes for their preparation, and compositions comprising said crystalline forms. The processes disclosed are simple and amenable to scale up and are capable of providing these novel forms in consistent purity. Particularly preferred embodiments comprise tegaserod succinate form 3, form 4, form 5, form 6, form 7 and form 8 respectively, wherein each of the novel crystalline forms according to the invention comprises less than 10%, preferably less than 5%, more preferably less 1%, most preferably less than 0.1% of other forms of tegaserod irrespective of the scale of preparation. The other forms include but are not limited to amorphous forms, hydrates, crystalline forms which are not the subject of this invention and, for example, an embodiment relating to tegaserod succinate form 4 according to the present embodiment will comprise less than 10%, preferably less than 5%, more preferably less 1%, most preferably less than 0.1% of other forms of tegaserod including tegaserod succinate forms 3, 5, 6, 7 and 8.

A preferred process according to the invention for preparing any of the crystalline forms of tegaserod succinate disclosed herein and as claimed below comprises adding tegaserod succinate, or tegaserod and succinic acid, preferably tegaserod succinate, to an organic solvent. The solvent type is dependent on the crystalline form desired. Preferably form 3 is obtained from DMSO, form 4 is obtained from t-butanol, form 5 is obtained from acetonitrile, form 6 is obtained from THF, form 7 is obtained from ethyl acetate, and form 8 is obtained from 2-methoxy-ethanol. Of course it will be understood that the tegaserod succinate can be completely or only partially dissolved and the process still falls within the scope of the invention. Preferably to aid in rapid or increased dissolution of the tegaserod succinate, the solvent is heated. In preferred embodiments the solution is heated until the solution is clear. In alternative embodiments one or more further solvents may be added to facilitate dissolution of the tegaserod succinate. The or each additional solvent may the same or different as the initial solvent.

In a preferred embodiment of a process according to the invention the novel crystalline tegaserod succinate according to the invention is caused to precipitate from the tegaserod succinate solution. In some preferred embodiments, the precipitation is caused by cooling the solution until the precipitate is no longer soluble and is forced out of solution and a slurry is formed. In preferred embodiments the solution is cooled to between about 0- 10⁰C, preferably about 0-5⁰C. Alternatively one or more anti-solvents may be added to the solution to cause the novel crystalline form according to the invention to precipitate out of solution. For example in one preferred embodiment water is added to the reaction mixture of tegaserod succinate and 2-methoxy-ethanol in the preparation of tegaserod succinate form 8.

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. Preferably, the product is dried at a temperature that does not induce conversion of the crystalline forms respectively or causes the resultant form to degrade. The inventors have found that drying the product at between about 20-40⁰C is advantageous. In certain preferable embodiments the solid product is dried under reduced atmospheric pressure, preferably until a constant weight is obtained, preferably the solid product is dried under vacuum.

A further embodiment of the invention comprises pharmaceutical compositions of the novel polymorph(s) according to the invention with one or more pharmaceutically acceptable excipient(s). Another aspect of the present invention is the pharmaceutical compositions containing these novel polymorph(s) 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 these novel polymorph (s).

Illustrative of the invention is a pharmaceutical composition comprising a novel polymorph of tegaserod succinate according to the invention and one or more pharmaceutically acceptable excipients. A further embodiment of the invention is a process for preparing a pharmaceutical composition comprising mixing a novel polymorph of tegaserod succinate according to the invention and one or more pharmaceutically acceptable excipient(s). Said composition may comprise solid pharmaceutical compositions which in certain embodiments may comprise tablets including for example dispersible tablets, capsules containing pellets, mini-tablets, powders or mixtures thereof, caplets, or any of the solid dosage forms that are within the repertoire of the skilled formulation scientist. These may further include immediate release forms of the above solid dosage forms or controlled release forms of the above including sustained release, delayed release and prolonged release compositions. It is also envisaged that the invention comprises liquid formulations which may be prepared by mixing the crystalline forms according to the invention with a pharmaceutically suitable liquid carrier or solvent.

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 novel polymorph of tegaserod succinate according to the invention. In a further embodiment according to the invention there is provided the use of a novel polymorph of tegaserod succinate according to the invention substantially free of other crystalline forms, for the preparation of a medicament for treating a 5-HT₄ receptor mediated disorder in a subject in need thereof, preferably the purity is in the order of tegaserod succinate form 3, form 4, form 5, form 6, form 7 or form 8 comprising less than 10%, preferably less than 5%, more preferably less 1%, most preferably less than 0.1% of other forms of tegaserod.

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.

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-Sol^®, Primellose^®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon , Polyplasdone ), 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 crystalline 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, gelatin, 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 actives 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 but are not limited to other 5-HT₄ receptor agonists such as prucalopride, RS 67333 (l-(4-amino-5- chloro-2-methoxyphenyl)-3-(l-n-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, tegaserod, 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

The following examples describe specific methods for preparing crystalline forms of tegaserod succinate according to the invention. In all the examples below the starting material comprises Ig of tegaserod succinate.

Example 1 — Preparation of tegaserod succinate form 3

Tegaserod succinate was dissolved in 5 volumes of DMSO and heated to 36°C. The solution was cooled to between 0-5⁰C for about 15 minutes. The resultant slurry was filtered, and the solid obtained was washed with DMSO (1 volume) and dried under vacuum at about 30⁰C for about 30 minutes.

XRPD and DSC analysis data (see figures 1 and 2) confirmed that the product obtained was the novel polymorph form 3 of tegaserod succinate. Yield = 35%

Chemical purity > 99% (measured by HPLC) Polymorphic purity = high (measured by DSC)

Example 2 - Preparation of tegaserod succinate form 4 Tegaserod succinate was dissolved in 25 volumes of t-butanol and heated to 83°C. The solution was cooled to between 25-30⁰C for about 15 minutes. The resultant slurry was filtered, and the solid obtained was washed with t-butanol (5 volumes) and dried under vacuum at 35°C until a constant weight was achieved.

XRPD and DSC analysis data (see figures 3 and 4) confirmed that the product obtained was the novel polymorph form 4 of tegaserod succinate.

Yield = 78%

Chemical purity > 99% (measured by HPLC)

Polymorphic purity = high (measured by DSC)

Example 3 - Preparation of tegaserod succinate form 5

Tegaserod succinate was dissolved in 25 volumes of acetonitrile and heated to 82°C. The solution was cooled to between 25-30⁰C for about 15 minutes. The resultant slurry was filtered, and the solid obtained was washed with acetonitrile (5 volumes) and dried under vacuum at 35°C. XRPD and DSC analysis data (see figures 5 and 6) confirmed that the product obtained was the novel polymorph form 5 of tegaserod succinate.

Yield = 87%

Chemical purity > 99% (measured by HPLC)

Polymorphic purity = high (measured by DSC)

Example 4 - Preparation of tegaserod succinate form 6

Tegaserod succinate was dissolved in 5 volumes of THF and heated to 66°C. The solution was cooled to between 20-30⁰C for about 15 minutes. The resultant slurry was filtered, and the solid obtained was washed with THF (5 volumes) and dried under vacuum at about 35°C.

XRPD and DSC analysis data (see figures 7 and 8) confirmed that the product obtained was the novel polymorph form 6 of tegaserod succinate. Yield = 65%

Example 5 - Preparation of tegaserod succinate form 7 Tegaserod succinate was dissolved in 5 volumes of ethyl acetate and heated to 77°C. The solution was cooled to between 20-30⁰C for about 15 minutes. The resultant slurry was filtered, and the solid obtained was washed with ethyl acetate (5 volumes) and dried under vacuum at about 35°C.

XRPD and DSC analysis data (see figures 9 and 10) confirmed that the product obtained was the novel polymorph form 7 of tegaserod succinate.

Yield = 67%

Chemical purity > 99% (measured by HPLC)

Polymorphic purity = high (measured by DSC)

Example 6 - Preparation of tegaserod succinate form 8

Tegaserod succinate was dissolved in 5 volumes of 2-methoxy-ethanol and heated to 36°C.

The solution was cooled to between 5-10⁰C. 10 ml of water, chilled to 5-10⁰C, was added to the reaction mixture. After about 30 minutes, the resultant slurry was filtered, and the solid obtained was washed with water (5 volumes) and dried under vacuum (lOmbar pressure) at about 35°C.

XRPD and DSC analysis data (see figures 11 and 12) confirmed that the product obtained was the novel polymorph form 8 of tegaserod succinate.

Yield = 60%

The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Since modifications of the described embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, the invention should be construed broadly to include all variations within the scope of the appended claims and equivalents thereof.

Claims

1. A crystalline form of tegaserod succinate, designated form 3, characterized by an X- ray diffraction pattern having two or more peaks at 2Θ values 5.05, 5.87, 14.45, 17.35, 19.94, 25.16 ± 0.2 °2Θ.

2. A crystalline form of tegaserod succinate, designated form 3, having an XRPD trace substantially as shown in figure 1.

3. A crystalline form of tegaserod succinate, designated form 3, characterized by a

DSC with endothermic peaks at about 104⁰C ± 2°C and about 159°C ± 2°C.

4. A crystalline form of tegaserod succinate, designated form 3, having a DSC trace substantially as shown in figure 2.

5. A process for the preparation of tegaserod succinate crystalline form 3 according to any one of claims 1-4, comprising the steps of:

(a) dissolving or suspending tegaserod succinate, or tegaserod and succinic acid, in one or more solvent(s); (b) causing tegaserod succinate form 3 to precipitate from the solution or suspension obtained in step (a); and (c) isolating the tegaserod succinate form 3.

6. A process according to claim 5, wherein tegaserod succinate is dissolved in step (a).

7. A process according to claim 5 or 6, wherein the solvent used in step (a) is DMSO.

8. A process according to claim 7, wherein about 5 volumes of DMSO are used.

9. A process according to claim 7 or 8, wherein the DMSO is heated to between about 30-40⁰C.

10. A process according to claim 9, wherein the DMSO is heated to about 36°C.

11. A process according to any one of claims 5-10, wherein the tegaserod succinate form 3 is caused to precipitate by cooling the solution or suspension obtained in step (a) to between about 0-30⁰C.

12. A process according to any one of claims 5-11, wherein the tegaserod succinate form 3 is isolated by filtration.

13. A process according to claims 12, wherein the filtered tegaserod succinate form 3 is washed with DMSO.

14. A process according to any one of claims 5-13, wherein the isolated tegaserod succinate form 3 is dried under reduced pressure until a constant weight is achieved.

15. A process according to claim 14, wherein the tegaserod succinate form 3 is dried under vacuum.

16. A process according to claim 14 or 15, wherein the drying occurs at between about 20-40⁰C.

17. A crystalline form of tegaserod succinate, designated form 4, with a characteristic XRD spectrum having two or more peaks with 2Θ values at 5.00, 5.77, 6.40, 6.74, 7.49, 7.94, 12.75, 14.47, 14.96, 18.02, 18.55, 20.25, 24.76, 25.13 ± 0.2 °2Θ.

18. A crystalline form of tegaserod succinate, designated form 4, having an XRPD trace substantially as shown in figure 3.

19. A crystalline form of tegaserod succinate, designated form 4, characterized by a DSC with endothermic peaks at about 117°C ± 2°C and about 158°C ± 2°C.

20. A crystalline form of tegaserod succinate, designated form 4, having a DSC trace substantially as shown in figure 4.

21. A process for the preparation of tegaserod succinate crystalline form 4 according to any one of claims 17-20, comprising the steps of:

(a) dissolving or suspending tegaserod succinate, or tegaserod and succinic acid, in one or more solvent(s); (b) causing tegaserod succinate form 4 to precipitate from the solution or suspension obtained in step (a); and (c) isolating the tegaserod succinate form 4.

22. A process according to claim 21, wherein tegaserod succinate is dissolved in step (a).

23. A process according to claim 21 or 22, wherein the solvent, one of the solvents or each solvent(s) used in step (a) is a C₁-C₆ alcohol.

24. A process according to claim 23, wherein the solvent used in step (a) is t-butanol.

25. A process according to claim 24, wherein about 25 volumes of t-butanol are used.

26. A process according to claims 24 or 25, wherein the t-butanol is heated to between about 80-90⁰C.

27. A process according to claim 26, wherein the t-butanol is heated to about 83°C.

28. A process according to any one of claims 21-27, wherein the tegaserod succinate form 4 is caused to precipitate by cooling the solution or suspension obtained in step (a) to between about 20-30⁰C.

29. A process according to any one of claims 21-28, wherein the tegaserod succinate form 4 is isolated by filtration.

30. A process according to any one of claims 21-29, wherein the isolated tegaserod succinate form 4 is washed with t-butanol.

31. A process according to any one of claims 21-30, wherein the isolated tegaserod succinate form 4 is dried under reduced pressure until a constant weight is achieved.

32. A process according to claim 31, wherein the tegaserod succinate form 4 is dried under vacuum.

33. A process according to claim 31 or 32, wherein the drying occurs at about 20-40⁰C.

34. A crystalline form of tegaserod succinate, designated form 5, with a characteristic XRD spectrum having two or more peaks with 2Θ values at 6.45, 6.88, 9.27, 12.96, 15.20,

18.12, 24.36, 25.33 ± 0.2 °2Θ.

35. A crystalline form of tegaserod succinate, designated form 5, having an XRPD trace substantially as shown in figure 5.

36. A crystalline form of tegaserod succinate, designated form 5, characterized by a DSC with an endothermic peak at about 115°C ± 2°C.

37. A crystalline form of tegaserod succinate, designated form 5, having a DSC trace substantially as shown in figure 6.

38. A process for the preparation of tegaserod succinate crystalline form 5 according to any one of claims 34-37, comprising the steps of:

(c) isolating the tegaserod succinate form 5.

39. A process according to claim 38, wherein tegaserod succinate is dissolved in step

(a).

40. A process according to claim 38 or 39, wherein the solvent used in step (a) is acetonitrile.

41. A process according to claim 40, wherein about 25 volumes of acetonitrile are used.

42. A process according to claim 40 or 41, wherein the acetonitrile is heated to between about 70-90⁰C.

43. A process according to claim 42, wherein the acetonitrile is heated to about 82°C.

44. A process according to any one of claims 38-43, wherein the tegaserod succinate form 5 is caused to precipitate by cooling the solution or suspension obtained in step (a) to between about 20-30⁰C.

45. A process according to any one of claims 38-44, wherein the tegaserod succinate form 5 is isolated by filtration.

46. A process according to any one of claims 38-45, wherein the isolated tegaserod succinate form 5 is washed with acetonitrile.

47. A process according to any one of claims 38-46, wherein the isolated tegaserod succinate form 5 is dried under reduced pressure until a constant weight is achieved.

48. A process according to claim 47, wherein the isolated tegaserod succinate form 5 is dried under vacuum.

49. A process according to claim 47 or 48, wherein the drying occurs at a temperature of between about 20-40⁰C.

50. A crystalline form of tegaserod succinate, designated form 6, characterized by an X- ray diffraction pattern having two or more peaks at 2Θ values 3.90, 5.20, 7.82, 8.96, 11.75, 13.22, 16.07, 17.60, 18.68, 22.96 ± 0.2 °2Θ.

51. A crystalline form of tegaserod succinate, designated form 6, having an XRPD trace substantially as shown in figure 7.

52. A crystalline form of tegaserod succinate, designated form 6, characterized by a DSC with endothermic peaks at about 75°C ± 2°C and about 149°C ± 2°C.

53. A crystalline form of tegaserod succinate, designated form 6, having a DSC trace substantially as shown in figure 8.

54. A process for the preparation of tegaserod succinate crystalline form 6 according to any one of claims 50-53, comprising the steps of:

(b) causing tegaserod succinate form 6 to precipitate from the solution or suspension obtained in step (a); and

(c) isolating the tegaserod succinate form 6.

55. A process according to claim 54, wherein tegaserod succinate is dissolved in step (a).

56. A process according to claim 54 or 55, wherein the solvent used in step (a) is THF.

57. A process according to claim 56, wherein about 5 volumes of THF are used.

58. A process according to claim 56 or 57, wherein the THF is heated to between about 60-70⁰C.

59. A process according to claim 58, wherein the THF is heated to about 66°C.

60. A process according to any one of claims 54-59, wherein the tegaserod succinate form 6 is caused to precipitate by cooling the solution or suspension obtained in step (a) to between about 20-30⁰C.

61. A process according to any one of claims 54-60, wherein the tegaserod succinate form 6 is isolated by filtration.

62. A process according to any one of claims 54-61, wherein the isolated tegaserod succinate form 6 is washed with THF.

63. A process according to any one of claims 54-62, wherein the isolated tegaserod succinate form 6 is dried under reduced pressure until a constant weight is achieved.

64. A process according to claim 63, wherein the tegaserod succinate form 6 is dried under vacuum.

65. A process according to claim 63 or 64, wherein the drying occurs at between about 20-40⁰C.

66. A crystalline form of tegaserod succinate, designated form 7, characterized by an X- ray diffraction pattern having two or more peaks at 2Θ values 5.10, 6.74, 13.47, 20.42 + 0.2 °2Θ.

67. A crystalline form of tegaserod succinate, designated form 7, having an XRPD trace substantially as shown in figure 9.

68. A crystalline form of tegaserod succinate, designated form 7, characterized by a DSC with endothermic peaks at about 125°C ± 2°C and about 159°C ± 2°C.

69. A crystalline form of tegaserod succinate, designated form 7, having a DSC trace substantially as shown in figure 10.

70. A process for the preparation of tegaserod succinate crystalline form 7 according to any one of claims 66-69, comprising the steps of:

(a) dissolving or suspending tegaserod succinate, or tegaserod and succinic acid, in one or more solvent(s); (b) causing tegaserod succinate form 7 to precipitate from the solution or suspension obtained in step (a); and

(c) isolating the tegaserod succinate form 7.

71. A process according to claim 70, wherein tegaserod succinate is dissolved in step

(a).

72. A process according to claim 70 or 71, wherein the solvent used in step (a) is ethyl acetate.

73. A process according to claim 72, wherein about 5 volumes of ethyl acetate are used.

74. A process according to claim 72 or 73, wherein the ethyl acetate is heated to between about 70-80⁰C.

75. A process according to claim 74, wherein the ethyl acetate is heated to about 77°C.

76. A process according to any one of claims 70-75, wherein the tegaserod succinate form 7 is caused to precipitate by cooling the solution or suspension obtained in step (a) to between about 20-30⁰C.

77. A process according to any one of claims 70-76, wherein the tegaserod succinate form 7 is isolated by filtration.

78. A process according to any one of claims 70-77, wherein the isolated tegaserod succinate form 7 is washed with ethyl acetate.

79. A process according to any one of claims 70-78, wherein the isolated tegaserod succinate form 7 is dried under reduced pressure until a constant weight is achieved.

80. A process according to claim 79, wherein the tegaserod succinate form 7 is dried under vacuum.

81. A process according to claim 79 or 80, wherein the drying occurs at between about 20-40⁰C.

82. A crystalline form of tegaserod succinate, designated form 8, characterized by an X- ray diffraction pattern having two or more peaks at 2Θ values 4.77, 5.57, 14.10, 19.65 ± 0.2

°2Θ.

83. A crystalline form of tegaserod succinate, designated form 8, having an XRPD trace substantially as shown in figure 11.

84. A crystalline form of tegaserod succinate, designated form 8, characterized by a DSC with endothermic peaks at about 106⁰C ± 2°C, about 119°C ± 2°C and about 158°C ± 2°C.

85. A crystalline form of tegaserod succinate, designated form 8, having a DSC trace substantially as shown in figure 12.

86. A process for the preparation of tegaserod succinate crystalline form 8 according to any one of claims 82-85, comprising the steps of: (a) dissolving or suspending tegaserod succinate, or tegaserod and succinic acid, in one or more solvent(s);

(c) isolating the tegaserod succinate form 8.

87. A process according to claim 86, wherein tegaserod succinate is dissolved in step (a).

88. A process according to claim 86 or 87, wherein the solvent used in step (a) is 2- methoxy-ethanol.

89. A process according to claim 88, wherein about 5 volumes of 2-methoxy-ethanol are used.

90. A process according to claim 88 or 89, wherein the 2-methoxy-ethanol is heated to between about 30-40⁰C.

91. A process according to claim 90, wherein the 2-methoxy-ethanol is heated to about 36°C.

92. A process according to any one of claims 86-91, wherein the tegaserod succinate form 8 is caused to precipitate by cooling the solution or suspension obtained in step (a) to between about 5-10⁰C and by adding water.

93. A process according to claim 92, wherein the water has a temperature of about 5- 10⁰C.

94. A process according to any one of claims 86-93, wherein the tegaserod succinate form 8 is isolated by filtration.

95. A process according to any one of claims 86-94, wherein the isolated tegaserod succinate form 8 is washed with water.

96. A process according to any one of claims 86-95, wherein the isolated tegaserod succinate form 8 is dried under reduced pressure until a constant weight is achieved.

97. A process according to claim 96, wherein the tegaserod succinate form 8 is dried under vacuum.

98. A process according to claim 96 or 97, wherein the drying occurs at between about 20-40⁰C.

99. Tegaserod succinate according to any one of claims 1-4, 17-20, 34-37, 50-53, 66-69 or 82-85, or tegaserod succinate prepared by a process according to any one of claims 5-16, 21-33, 38-49, 54-65, 70-81 or 86-98, comprising less than 10% of other forms of tegaserod.

100. Tegaserod succinate according to claim 99, comprising less than 5% of other forms of tegaserod.

101. Tegaserod succinate according to claim 100, comprising less than 1% of other forms of tegaserod.

102. Tegaserod succinate according to claim 101, comprising less than 0.1% of other forms of tegaserod.

103. Tegaserod succinate according to any one of claims 1-4, 17-20, 34-37, 50-53, 66-69, 82-85 or 99-102, or tegaserod succinate prepared by a process according to any one of claims 5-16, 21-33, 38-49, 54-65, 70-81 or 86-98, for use in medicine.

104. Tegaserod succinate according to claim 103, for treating or preventing a gastrointestinal disorder.

105. Tegaserod succinate according to claim 104, wherein the gastrointestinal disorder is heartburn, bloating, postoperative ileus, abdominal pain and discomfort, epigastric pain, nausea, vomiting, regurgitation, intestinal pseudo-obstruction, irritable bowel syndrome or gastro-oesophageal reflux.

106. A pharmaceutical composition comprising tegaserod succinate according to any one of claims 1-4, 17-20, 34-37, 50-53, 66-69, 82-85 or 99-105, or tegaserod succinate prepared by a process according to any one of claims 5-16, 21-33, 38-49, 54-65, 70-81 or 86-98, and one or more pharmaceutically acceptable excipients.

107. A composition according to claim 106, wherein the composition is a solid composition.

108. A composition according to claim 107, wherein the composition is a tablet or capsule.

109. A method of treating or preventing a gastrointestinal disorder selected from the list 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 to a patient in need thereof a therapeutically or prophylactically effective amount of tegaserod succinate according to any one of claims 1-4, 17-20, 34-37, 50-53, 66-69, 82-85 or 99-105, or of tegaserod succinate prepared by a process according to any one of claims 5-16, 21-33, 38- 49, 54-65, 70-81 or 86-98, or of a pharmaceutical composition according to any one of claims 103-108.

110. A method according to claim 109, wherein the patient is a mammal.

111. A method according to claim 110, wherein the mammal is a human.