WO2009053732A1

WO2009053732A1 - Novel salt

Info

Publication number: WO2009053732A1
Application number: PCT/GB2008/050965
Authority: WO
Inventors: Abhay Gaitonde; Bindu Manojkumar; Sandeep Sonawane; Dattatrey Kokane; Sinderpal Tank
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

Abstract

The present invention relates to a novel salt of tegaserod, namely the dihydrogen phosphate salt. The present invention also relates to novel amorphous and crystalline forms of the dihydrogen phosphate salt of tegaserod. The invention further relates to processes for the preparation of the novel salt and the novel amorphous and crystalline forms. The invention also relates to pharmaceutical compositions containing the novel salt or the novel amorphous or crystalline forms, and to uses of said compositions to provide methods of treating patients suffering from gastrointestinal disorders.

Description

Novel Salt Field of the invention

Background of the invention

Tegaserod, chemically named 2-[(5-methoxy-lH-indol-3-yl)methylene]-N-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 and amorphous 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 dihydrogen phosphate, as well as novel crystalline forms and a novel amorphous form of the dihydrogen phosphate 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 or amorphous form to another. It is important that stable crystalline or amorphous 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 dihydrogen phosphate salt and novel crystalline or amorphous 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 dihydrogen phosphate salt and novel crystalline or amorphous 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 dihydrogen phosphate or a tautomeric form thereof and/or a pharmaceutically acceptable solvate or hydrate thereof.

The tegaserod dihydrogen phosphate 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 - A -

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.

According to a second aspect of the present invention there is provided a novel crystalline form of tegaserod dihydrogen phosphate, designated form 1, 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, twelve or more, fifteen or more, twenty or more, twenty-one or more, or all twenty-two peaks) with 2Θ values at 7.6, 10.8, 11.3, 12.9, 15.1, 16.3, 16.7, 17.5, 19.1, 20.0, 20.8, 21.1, 21.8, 22.8, 23.5, 24.0, 24.4, 24.6, 25.7, 26.5, 27.1, 29.2 ± 0.2 °2Θ. Preferably the novel crystalline form 1 of tegaserod dihydrogen phosphate has 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, twelve or more, fifteen or more, twenty or more, twenty-one or more, or all twenty-two peaks) with 2Θ values at 7.63, 10.78, 11.30, 12.91, 15.07, 16.32, 16.69, 17.46, 19.10, 19.97, 20.83, 21.09, 21.80, 22.78, 23.46, 24.03, 24.38, 24.56, 25.73, 26.47, 27.07, 29.21 ± 0.2 °2Θ.

In a third aspect according to the invention there is provided a novel crystalline form of tegaserod dihydrogen phosphate, designated form 1, having an XRPD trace substantially as shown in figure 1.

In a fourth aspect there is provided a novel crystalline form of tegaserod dihydrogen phosphate, designated form 1, characterized by a DSC with an endothermic peak at about 204⁰C ± 2°C, preferably at about 204.06⁰C ± 2°C.

In a fifth aspect according to the invention there is provided a novel crystalline form of tegaserod dihydrogen phosphate, designated form 1, having a DSC trace substantially as shown in figure 2. According to a sixth aspect of the present invention there is provided a process for the preparation of tegaserod dihydrogen phosphate crystalline form 1 according to the invention comprising the steps of:

(a) dissolving or suspending tegaserod dihydrogen phosphate, or tegaserod and phosphoric acid, in one or more solvent(s);

(b) causing tegaserod dihydrogen phosphate form 1 to precipitate from the solution or suspension obtained in step (a); and

(c) isolating the tegaserod dihydrogen phosphate form 1.

Preferably tegaserod dihydrogen phosphate 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 dihydrogen phosphate form 1 is caused to precipitate by cooling the solution or suspension obtained in step (a) to between about 20-30⁰C. In yet another embodiment the tegaserod dihydrogen phosphate form 1 is isolated by filtration. In a particularly preferred embodiment the filtered tegaserod dihydrogen phosphate form 1 is washed, preferably with acetonitrile, preferably about 5 volumes. Preferably the tegaserod dihydrogen phosphate form 1 is dried, particularly preferred is drying under vacuum, preferably until a constant weight is achieved. Preferably the drying occurs at about 20-40⁰C, preferably about 35°C.

According to a seventh aspect of the present invention there is provided a novel crystalline form of tegaserod dihydrogen phosphate, designated form 2, 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, twelve or more, fifteen or more, twenty or more, twenty-five or more, or all twenty-seven peaks) with 2Θ values at 7.1, 10.3, 10.8, 11.3, 12.4, 13.0, 14.6, 15.8, 16.2, 16.9, 18.7, 19.4, 19.9, 20.3, 20.5, 21.0, 21.3, 22.9, 23.5, 23.8, 24.0, 24.5, 25.3, 25.9, 26.5, 28.7, 29.3 ± 0.2 °2Θ. Preferably the novel crystalline form 2 of tegaserod dihydrogen phosphate has 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, twelve or more, fifteen or more, twenty or more, twenty-five or more, or all twenty-seven peaks) with 2Θ values at 7.06, 10.33, 10.80, 11.32, 12.43, 13.0, 14.55, 15.8, 16.20, 16.93, 18.65, 19.44, 19.85, 20.28, 20.54, 21.01, 21.26, 22.93, 23.50, 23.83, 24.01, 24.48, 25.30, 25.90, 26.51, 28.66, 29.31 ± 0.2 °2Θ.

In an eighth aspect according to the invention there is provided a novel crystalline form of tegaserod dihydrogen phosphate, designated form 2, having an XRPD trace substantially as shown in figure 3.

In a ninth aspect there is provided a novel crystalline form of tegaserod dihydrogen phosphate, designated form 2, characterized by a DSC with an endothermic peak at about 204⁰C ± 2°C, preferably at about 203.76⁰C ± 2°C.

In a tenth aspect according to the invention there is provided a novel crystalline form of tegaserod dihydrogen phosphate, designated form 2, having a DSC trace substantially as shown in figure 4.

According to an eleventh aspect of the present invention there is provided a process for the preparation of tegaserod dihydrogen phosphate crystalline form 2 according to the invention comprising the steps of:

(b) causing tegaserod dihydrogen phosphate form 2 to precipitate from the solution or suspension obtained in step (a); and

(c) isolating the tegaserod dihydrogen phosphate form 2.

Preferably tegaserod dihydrogen phosphate is dissolved in step (a). In one preferred embodiment the solvent used in step (a) is a C₁-C₆ alcohol, preferably a C₃-C₆ alcohol, preferably a secondary or tertiary alcohol, preferably isobutanol. Preferably about 25 volumes of isobutanol are used. In another embodiment the isobutanol is heated to between about 80-85⁰C, preferably about 82°C. In a further preferred embodiment the tegaserod dihydrogen phosphate form 2 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 dihydrogen phosphate form 2 is isolated by filtration. In a particularly preferred embodiment the filtered tegaserod dihydrogen phosphate form 2 is washed, preferably with isobutanol, preferably about 5 volumes. Preferably the tegaserod dihydrogen phosphate form 2 is dried, particularly preferred is drying under vacuum, preferably until a constant weight is achieved. Preferably the drying occurs at about 20- 40⁰C, preferably about 35°C.

According to a twelfth aspect of the present invention there is provided a novel amorphous form of tegaserod dihydrogen phosphate.

In a thirteenth aspect according to the invention there is provided a novel amorphous form of tegaserod dihydrogen phosphate having an XRPD trace substantially as shown in figure

5.

In a fourteenth aspect there is provided a novel amorphous form of tegaserod dihydrogen phosphate characterized by a DSC with endothermic peaks at about 73°C, about 147°C and about 157°C, preferably at about 73.21°C, about 146.87°C and about 157.27°C, all ± 2°C.

In a fifteenth aspect according to the invention there is provided a novel amorphous form of tegaserod dihydrogen phosphate having a DSC trace substantially as shown in figure 6.

According to a sixteenth aspect of the present invention there is provided a process for the preparation of amorphous tegaserod dihydrogen phosphate according to the invention comprising the steps of:

(b) causing amorphous tegaserod dihydrogen phosphate to precipitate from the solution or suspension obtained in step (a); and

(c) isolating the amorphous form of tegaserod dihydrogen phosphate.

In one preferred embodiment the solvent used in step (a) is a mixture of a C₁-C₆ alcohol and water, preferably the C₁-C₆ alcohol is a C₁-C₂ alcohol, preferably a primary alcohol, preferably methanol. Preferably about 3.3 volumes of methanol are used. Preferably about 3.3 volumes of water are used. Preferably tegaserod and phosphoric acid are used in step (a), preferably about 2 molar equivalents (eq) of phosphoric acid. In a further preferred embodiment the amorphous form is caused to precipitate by cooling the solution obtained in step (a), preferably to about 0-5⁰C. In yet another embodiment the amorphous form is isolated by filtration. In a particularly preferred embodiment the filtered amorphous form is washed, preferably with water preferably chilled and preferably about 5 volumes. In a further embodiment the water is chilled to a temperature of between about 0-15⁰C, more preferably about 0-10⁰C, and most preferably about 0-5⁰C. In another embodiment the filtered amorphous form is dried, particularly preferred is drying under reduced pressure, most preferred is drying under vacuum, preferably until a constant weight is achieved.

In a preferred embodiment of the sixteenth aspect of the present invention the process comprises the steps of:

(a) dissolving tegaserod in one or more solvent(s);

(b) adding a solution of phosphoric acid in water; (c) causing amorphous tegaserod dihydrogen phosphate to precipitate from the solution obtained in step (b); and (d) isolating the amorphous form of tegaserod dihydrogen phosphate.

In one preferred embodiment the solvent used in step (a) is a C₁-C₆ alcohol, preferably a C₁-C₂ alcohol, preferably a primary alcohol, preferably methanol. Preferably about 3.3 volumes of methanol are used. In a particularly preferred embodiment about 2 molar equivalents (eq) of phosphoric acid in about 3.3 volumes of water are added in step (b). In a further preferred embodiment the amorphous form is caused to precipitate by cooling the solution obtained in step (b), preferably to about 0-5⁰C. In yet another embodiment the amorphous form is isolated by filtration. In a particularly preferred embodiment the filtered amorphous form is washed, preferably with water preferably chilled and preferably about 5 volumes. In a further embodiment the water is chilled to a temperature of between about

0-15⁰C, more preferably about 0-10⁰C, and most preferably about 0-5⁰C. In another embodiment the filtered amorphous form is dried, particularly preferred is drying under reduced pressure, most preferred is drying under vacuum, preferably until a constant weight is achieved. Preferably the tegaserod dihydrogen phosphate salt and the crystalline and amorphous forms thereof 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 and amorphous forms of tegaserod dihydrogen phosphate 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 dihydrogen phosphate salt and the crystalline and amorphous forms thereof are obtained on an industrial scale, preferably in batches of 0.5kg, lkg, 5kg, 10kg, 50kg, 100kg, 500kg or more.

A seventeenth aspect according to the invention provides a pharmaceutical composition comprising tegaserod dihydrogen phosphate or any of the crystalline or amorphous 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 an eighteenth 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 tegaserod dihydrogen phosphate or any of the crystalline or amorphous 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 nineteenth aspect there are provided tegaserod dihydrogen phosphate or any of the crystalline or amorphous 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 twentieth aspect provides the use of tegaserod dihydrogen phosphate or any of the crystalline or amorphous 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 dihydrogen phosphate form 1. Figure 2 describes the DSC of tegaserod dihydrogen phosphate form 1.

Figure 3 describes the XRPD of tegaserod dihydrogen phosphate form 2. Figure 4 describes the DSC of tegaserod dihydrogen phosphate form 2.

Figure 5 describes the XRPD of amorphous tegaserod dihydrogen phosphate. Figure 6 describes the DSC of amorphous tegaserod dihydrogen phosphate.

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 the novel dihydrogen phosphate salt of tegaserod and a process for its preparation. The present invention also provides novel polymorphs of tegaserod dihydrogen phosphate, a novel amorphous form of tegaserod dihydrogen phosphate, and processes for their preparation. The present invention further provides compositions comprising said salt or crystalline or amorphous forms. The processes disclosed are simple and amenable to scale up and are capable of providing the salt and novel forms in consistent purity. Particularly preferred embodiments comprise tegaserod dihydrogen phosphate form 1, form 2 or the amorphous form respectively, wherein each of these novel 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 the amorphous form of tegaserod dihydrogen phosphate 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 dihydrogen phosphate form 1 or form 2.

A preferred process according to the invention for preparing tegaserod dihydrogen phosphate salt or any of the crystalline or amorphous forms of tegaserod dihydrogen phosphate disclosed herein and as claimed below comprises adding tegaserod dihydrogen phosphate, or tegaserod and phosphoric acid, preferably tegaserod dihydrogen phosphate, to an organic solvent. The solvent type is dependent on the crystalline or amorphous form desired. Preferably form 1 is obtained from acetonitrile, form 2 is obtained from isobutanol, and the amorphous form according to the invention is obtained from methanol. Of course it will be understood that the tegaserod dihydrogen phosphate 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 dihydrogen phosphate, the solvent is heated. In preferred embodiments the solution is heated until the solution is clear.

In a preferred embodiment of a process according to the invention the novel salt or the novel crystalline or amorphous form according to the invention is caused to precipitate from the tegaserod dihydrogen phosphate 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 0-5⁰C.

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 most preferably is washed, preferably with acetonitrile when form 1 is prepared, preferably with isobutanol when form 2 is prepared, and preferably with chilled water of about 0- 10⁰C, preferably about 0-5⁰C, when the amorphous form is prepared, and dried. Preferably, the product is dried at a temperature that does not induce conversion of the crystalline or amorphous forms respectively or causes the resultant salt or 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 salt or the novel polymorphic or amorphous form(s) according to the invention with one or more pharmaceutically acceptable excipient(s). Another aspect of the present invention is the pharmaceutical compositions containing the novel salt or the novel polymorphic or amorphous form(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 the novel salt or the novel polymorphic or amorphous form(s).

Illustrative of the invention is a pharmaceutical composition comprising tegaserod dihydrogen phosphate or a novel polymorph or amorphous form of tegaserod dihydrogen phosphate according to the invention and one or more pharmaceutically acceptable excipient(s) . A further embodiment of the invention is a process for preparing a pharmaceutical composition comprising mixing tegaserod dihydrogen phosphate or a novel polymorph or amorphous form of tegaserod dihydrogen phosphate 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 tegaserod dihydrogen phosphate or the crystalline or amorphous 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 tegaserod dihydrogen phosphate or a novel polymorph of tegaserod dihydrogen phosphate or amorphous form according to the invention. In a further embodiment according to the invention there is provided the use of tegaserod dihydrogen phosphate or a novel polymorph or amorphous form of tegaserod dihydrogen phosphate according to the invention substantially free of other crystalline or amorphous forms, for the preparation of a medicament for treating a 5-HT₄ receptor mediated disorder in a subject in need thereof. Preferably the polymorphic purity is in the order of tegaserod dihydrogen phosphate form 1, form 2 or the amorphous form 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-SoI , 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 lubiicant 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 or amorphous 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 and amorphous forms of tegaserod dihydrogen phosphate according to the invention. In all the examples below the starting material comprises Ig of tegaserod dihydrogen phosphate.

Example 1 - Preparation of amorphous tegaserod dihydrogen phosphate

Tegaserod was dissolved in methanol (3.3 volumes) and a solution of phosphoric acid (2 eq.) in water (3.3 volumes) was added at 25-30⁰C. The clear solution was stirred for 10 minutes and cooled to 0-5⁰C. The slurry was stirred at 0-5⁰C for 30 minutes. The solid obtained was filtered under vacuum, washed with chilled water (5 volumes), and dried at 25-30⁰C under vacuum for 1.5 hours.

XRPD and DSC analysis data (see figures 5 and 6) confirmed that the product obtained was the novel amorphous form of tegaserod dihydrogen phosphate.

Yield = 98.55%

Chemical purity > 99% (measured by HPLC) Polymorphic purity = high (measured by DSC) Example 2 — Preparation of tegaserod dihydrogen phosphate form 1

Tegaserod dihydrogen phosphate 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, washed with 5 volumes of acetonitrile, and dried on a rotavapor under vacuum at 35°C for 30 minutes.

XRPD and DSC analysis data (see figures 1 and 2) confirmed that the product obtained was the novel polymorph form 1 of tegaserod dihydrogen phosphate. Yield = 63%

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

Example 3 - Preparation of tegaserod dihydrogen phosphate form 2

Tegaserod dihydrogen phosphate was dissolved in 25 volumes of isobutanol and heated to

82°C. The solution was cooled to between 25-30⁰C for about 15 minutes. The resultant slurry was filtered, washed with 5 volumes of isobutanol, and then dried under a lOmbar vacuum at 35°C.

XRPD and DSC analysis data (see figures 3 and 4) confirmed that the product obtained was the novel polymorph form 2 of tegaserod dihydrogen phosphate. Yield = 51% Chemical purity > 99% (measured by HPLC) Polymorphic purity = high (measured by DSC)

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. Tegaserod dihydrogen phosphate or a tautomeric form thereof and/or a pharmaceutically acceptable solvate or hydrate thereof.

2. Tegaserod dihydrogen phosphate, designated form 1, characterized by an X-ray diffraction pattern having peaks at 2Θ values 7.6, 10.8, 11.3, 12.9, 15.1, 16.3, 16.7, 17.5, 19.1, 20.0, 20.8, 21.1, 21.8, 22.8, 23.5, 24.0, 24.4, 24.6, 25.7, 26.5, 27.1, 29.2 ± 0.2 °2Θ.

3. Tegaserod dihydrogen phosphate, designated form 1, having an XRPD trace substantially as shown in figure 1.

4. Tegaserod dihydrogen phosphate, designated form 1, characterized by a DSC with an endothermic peak at about 204⁰C + 2°C.

5. Tegaserod dihydrogen phosphate, designated form 1, having a DSC trace substantially as shown in figure 2.

6. A process for the preparation of tegaserod dihydrogen phosphate crystalline form 1 according to any one of claims 2-5, comprising the steps of:

(b) causing tegaserod dihydrogen phosphate form 1 to precipitate from the solution or suspension obtained in step (a); and (c) isolating the tegaserod dihydrogen phosphate form 1.

7. A process according to claim 6, wherein tegaserod dihydrogen phosphate is dissolved in step (a).

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

9. A process according to claim 8, wherein about 25 volumes of acetonitrile are used.

10. A process according to claim 8 or 9, wherein the acetonitrile is heated to between about 70-90⁰C.

11. A process according to claim 10, wherein the acetonitrile is heated to about 82°C.

12. A process according to any one of claims 6-11, wherein the tegaserod dihydrogen phosphate form 1 is caused to precipitate by cooling the solution or suspension obtained in step (a) to between about 20-30⁰C.

13. A process according to any one of claims 6-12, wherein the tegaserod dihydrogen phosphate form 1 is isolated by filtration.

14. A process according to claim 13, wherein the filtered tegaserod dihydrogen phosphate form 1 is washed with about 5 volumes of acetonitrile.

15. A process according to any one of claims 6-14, wherein the isolated tegaserod dihydrogen phosphate form 1 is dried under vacuum until a constant weight is achieved.

16. A process according to claim 15, wherein the drying occurs at about 35°C.

17. Tegaserod dihydrogen phosphate, designated form 2, with a characteristic XRD spectrum having two or more peaks with 2Θ values at 7.1, 10.3, 10.8, 11.3, 12.4, 13.0, 14.6, 15.8, 16.2, 16.9, 18.7, 19.4, 19.9, 20.3, 20.5, 21.0, 21.3, 22.9, 23.5, 23.8, 24.0, 24.5, 25.3, 25.9, 26.5, 28.7, 29.3 ± 0.2 °2Θ.

18. Tegaserod dihydrogen phosphate, designated form 2, having an XRPD trace substantially as shown in figure 3.

19. Tegaserod dihydrogen phosphate, designated form 2, characterized by a DSC with an endothermic peak at about 204⁰C ± 2°C.

20. Tegaserod dihydrogen phosphate, designated form 2, having a DSC trace substantially as shown in figure 4.

21. A process for the preparation of tegaserod dihydrogen phosphate crystalline form 2 according to any one of claims 17-20, comprising the steps of:

(b) causing tegaserod dihydrogen phosphate form 2 to precipitate from the solution or suspension obtained in step (a); and (c) isolating the tegaserod dihydrogen phosphate form 2.

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

23. A process according to claim 21 or 22, wherein the solvent used in step (a) is isobutanol.

24. A process according to claim 23, wherein about 25 volumes of isobutanol are used.

25. A process according to claim 23 or 24, wherein the isobutanol is heated to between about 80-85⁰C.

26. A process according to claim 25, wherein the isobutanol is heated to about 82°C.

27. A process according to any one of claims 21-26, wherein the tegaserod dihydrogen phosphate form 2 is caused to precipitate by cooling the solution or suspension obtained in step (a) to between about 20-30⁰C.

28. A process according to any one of claims 21-27, wherein the tegaserod dihydrogen phosphate form 2 is isolated by filtration.

29. A process according to claim 28, wherein the filtered tegaserod dihydrogen phosphate form 2 is washed with about 5 volumes of isobutanol.

30. A process according to any one of claims 21-29, wherein the isolated tegaserod dihydrogen phosphate form 2 is dried under reduced pressure until a constant weight is achieved.

31. A process according to claim 30, wherein the isolated tegaserod dihydrogen phosphate form 2 is dried under vacuum.

32. A process according to claim 30 or 31, wherein the drying occurs at about 35°C.

33. An amorphous form of tegaserod dihydrogen phosphate.

34. An amorphous form of tegaserod dihydrogen phosphate having an XRPD trace substantially as shown in figure 5.

35. An amorphous form of tegaserod dihydrogen phosphate characterized by a DSC with endothermic peaks at about 73°C ± 2°C, about 147°C ± 2°C and about 157°C ± 2°C.

36. An amorphous form of tegaserod dihydrogen phosphate having a DSC trace substantially as shown in figure 6.

37. A process for the preparation of amorphous tegaserod dihydrogen phosphate according to any one of claims 33-36, comprising the steps of:

(c) isolating the amorphous tegaserod dihydrogen phosphate.

38. A process for the preparation of amorphous tegaserod dihydrogen phosphate according to any one of claims 33-36, comprising the steps of:

(a) dissolving tegaserod in one or more solvent(s);

(b) adding a solution of phosphoric acid in water; (c) causing amorphous tegaserod dihydrogen phosphate to precipitate from the solution obtained in step (b); and

(d) isolating the amorphous tegaserod dihydrogen phosphate.

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

40. A process according to claim 39, wherein about 3.3 volumes of methanol are used.

41. A process according to any one of claims 38-40, wherein about 2 molar equivalents of phosphoric acid in about 3.3 volumes of water are added in step (b).

42. A process according to any one of claims 38-41, wherein the amorphous form is caused to precipitate by cooling the solution obtained in step (b).

43. A process according to claim 42, wherein the solution is cooled to about 0-5⁰C.

44. A process according to any one of claims 38-43, wherein the amorphous form is isolated by filtration.

45. A process according to any one of claims 38-44, wherein the isolated amorphous form is washed with water.

46. A process according to claim 45, wherein the water is chilled.

47. A process according to any one of claims 38-46, wherein the isolated amorphous tegaserod dihydrogen phosphate is dried.

48. A process according to claim 47, wherein the amorphous tegaserod dihydrogen phosphate is dried under reduced pressure until a constant weight is achieved.

49. A process according to claim 48, wherein the amorphous tegaserod dihydrogen phosphate is dried under vacuum.

50. Tegaserod dihydrogen phosphate according to any one of claims 1-5, 17-20 or 33- 36, or tegaserod dihydrogen phosphate prepared by a process according to any one of claims 6-16, 21-32 or 37-49, comprising less than 10% of other forms of tegaserod.

51. Tegaserod dihydrogen phosphate according to claim 50, comprising less than 5% of other forms of tegaserod.

52. Tegaserod dihydrogen phosphate according to claim 51, comprising less than 1% of other forms of tegaserod.

53. Tegaserod dihydrogen phosphate according to claim 52, comprising less than 0.1% of other forms of tegaserod.

54. Tegaserod dihydrogen phosphate according to any one of claims 1-5, 17-20, 33-36 or 50-53, or tegaserod dihydrogen phosphate prepared by a process according to any one of claims 6-16, 21-32 or 37-49, for use in medicine.

55. Tegaserod dihydrogen phosphate according to claim 54, for treating or preventing a gastrointestinal disorder.

56. Tegaserod dihydrogen phosphate according to claim 55, 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.

57. A pharmaceutical composition comprising tegaserod dihydrogen phosphate according to any one of claims 1-5, 17-20, 33-36 or 50-56, or tegaserod dihydrogen phosphate prepared by a process according to any one of claims 6-16, 21-32 or 37-49, and one or more pharmaceutically acceptable excipients.

58. A composition according to claim 57, wherein the composition is a solid composition.

59. A composition according to claim 58, wherein the composition is a tablet or capsule.

60. 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 dihydrogen phosphate according to any one of claims 1-5, 17-20, 33-36 or 50-56, or of tegaserod dihydrogen phosphate prepared by a process according to any one of claims 6-16, 21-32 or 37-49, or of a pharmaceutical composition according to any one of claims 57-59.

61. A method according to claim 60, wherein the patient is a mammal.

62. A method according to claim 61, wherein the mammal is a human.