WO2009053754A2

WO2009053754A2 - Novel crystalline forms

Info

Publication number: WO2009053754A2
Application number: PCT/GB2008/050992
Authority: WO
Inventors: Abhay Gaitonde; Bindu Manojkumar; Rahul Bhalerao; 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: 2008-10-24
Publication date: 2009-04-30
Anticipated expiration: 2010-04-24
Also published as: WO2009053754A3

Abstract

The present invention relates to novel crystalline forms of the citrate 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 citrate 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 citrate 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 citrate 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 citrate, 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, eleven or more, twelve or more, thirteen or more, or all fourteen peaks) with 2Θ values at 4.6, 5.6, 9.4, 11.3, 14.1, 17.1, 17.6, 18.3, 19.2, 21.2, 22.2, 23.0, 25.0, 26.0 ± 0.2 °2Θ. Preferably the novel crystalline form 1 of tegaserod citrate 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, eleven or more, twelve or more, thirteen or more, or all fourteen peaks) with 2Θ values at 4.6, 5.57, 9.42, 11.3, 14.10, 17.10, 17.60, 18.33, 19.17, 21.21, 22.24, 22.96, 24.97, 25.97 ± 0.2 °2Θ. - A -

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

In a third aspect there is provided a novel crystalline form of tegaserod citrate, designated form 1, characterized by a DSC with endothermic peaks at about 82°C and about 127°C, preferably at about 82.15°C and about 127.38°C, all ± 2°C.

In a fourth aspect according to the invention there is provided a novel crystalline form of tegaserod citrate, designated form 1, 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 citrate crystalline form 1 according to the invention comprising the steps of:

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

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

Preferably tegaserod citrate is dissolved in step (a). In one preferred embodiment the solvent used in step (a) is a C₁-C₆ alcohol, preferably a C₁-C₃ alcohol, preferably a primary alcohol, preferably ethanol. Preferably about 40 volumes of ethanol are used. In another embodiment the ethanol is heated to between about 70-90⁰C, preferably about 78°C. In a further preferred embodiment the tegaserod citrate form 1 is caused to precipitate by cooling the solution or suspension obtained in step (a) to between about 0-5⁰C. In yet another embodiment the tegaserod citrate form 1 is isolated by filtration and most preferably is dried, particularly preferred is drying 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 citrate, 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, eleven or more, twelve or more, fifteen or more, twenty or more, twenty-five or more, thirty or more, thirty-five or more or all fourty-two peaks) with 2Θ values at 4.94, 5.27, 5.64, 9.29, 10.03, 10.75, 11.51, 11.83, 13.11, 13.57, 13.90, 14.56, 15.42, 16.02, 16.84, 17.36, 17.95, 18.82, 19.33, 20.30, 20.94, 21.47, 21.90, 22.58, 23.27, 24.09, 24.62, 25.82, 26.48, 27.07, 27.91, 28.50, 29.36, 30.18, 30.86, 31.32, 33.87, 34.21, 34.90, 35.91, 36.91 and 39.04 ± 0.2 °2Θ. Preferably the novel crystalline form 2 of tegaserod citrate 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, eleven or more, twelve or more, fifteen or more, twenty or more, or all twenty-five peaks) with 2Θ values at 4.94, 5.27, 5.64, 9.29, 10.03, 10.75, 13.11, 13.57, 14.56, 15.42, 16.02, 17.36, 17.95, 18.82, 19.33, 20.30, 20.94, 21.47, 21.90, 22.58, 24.62, 25.82, 26.48, 27.91 and 31.32 ± 0.2 °2Θ. More preferably the novel crystalline form 2 of tegaserod citrate 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, eleven or more, twelve or more, fifteen or more, or all seventeen peaks) with 2Θ values at 4.94, 5.27, 5.64, 10.03, 13.11, 13.57, 15.42, 16.02, 17.36, 18.82, 20.30, 21.90, 22.58, 24.62, 25.82, 26.48 and 27.91 ± 0.2 °2Θ. Most preferably the novel crystalline form 2 of tegaserod citrate 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, or all nine peaks) with 2Θ values at 4.94, 5.27, 5.64, 10.03, 15.42, 18.82, 20.30, 25.82 and 26.48 ± 0.2 °2Θ.

In one embodiment of the sixth aspect of the present invention, the novel crystalline form 2 of tegaserod citrate 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, or all nine peaks) with 2Θ values at 5.27, 10.75, 16.02, 18.82, 21.47, 21.90, 24.62, 26.48 and 27.91 ± 0.2 °2Θ.

In an alternative embodiment according to a sixth aspect of the present invention there is provided a novel crystalline form of tegaserod citrate, designated form 2, with a characteristic XRD spectrum having peaks with 2Θ values at 4.9 and 5.2 + 0.2 °2Θ. Preferably the novel crystalline form 2 of tegaserod citrate has a characteristic XRD spectrum having peaks with 2Θ values at 4.94 and 5.20 ± 0.2 °2Θ.

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

In an eighth aspect there is provided a novel crystalline form of tegaserod citrate, designated form 2, characterized by a DSC with endothermic peaks at about 58°C, about 100⁰C and about 135°C, preferably at about 57.80⁰C, about 99.96°C and about 135.34°C, all ± 2°C.

In a ninth aspect according to the invention there is provided a novel crystalline form of tegaserod citrate, designated form 2, 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 citrate crystalline form 2 according to the invention comprising the steps of: (a) dissolving or suspending tegaserod citrate, or tegaserod and citric acid, in one or more solvent(s);

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

(c) isolating the tegaserod citrate form 2.

Preferably tegaserod citrate is dissolved in step (a). In one preferred embodiment the solvent used in step (a) is acetone. Preferably about 40 volumes of acetone are used. In another embodiment the acetone is heated to between about 50-60⁰C, preferably about 56°C. In a further preferred embodiment the tegaserod citrate form 2 is caused to precipitate by cooling the solution or suspension obtained in step (a), preferably to about 0- 5°C. In yet another embodiment the tegaserod citrate form 2 is isolated by filtration, most preferably the tegaserod citrate form 2 is dried under vacuum, preferably until a constant weight is achieved. Preferably the drying occurs at between about 20-40⁰C, preferably at about 30⁰C.

According to an eleventh aspect of the present invention there is provided a novel crystalline form of tegaserod citrate, designated form 3, 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, fifteen or more, twenty or more, or all twenty-five peaks) with 2Θ values at 5.0, 7.2, 7.7, 9.2, 11.0, 11.8, 13.1, 14.6, 16.5, 17.2, 17.6, 18.3, 19.4, 19.7, 20.5, 22.1, 22.6, 22.9, 23.1, 23.7, 24.0, 24.7, 25.2, 25.9, 29.2 ± 0.2 °2Θ. Preferably the novel crystalline form 3 of tegaserod citrate 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, eleven or more, twelve or more, fifteen or more, twenty or more, or all twenty-five peaks) with 2Θ values at 5.01, 7.2, 7.65, 9.23, 11.04, 11.78, 13.08, 14.60, 16.48, 17.17, 17.62, 18.32, 19.35, 19.70, 20.46, 22.12, 22.60, 22.85, 23.13, 23.70, 24.03, 24.72, 25.17, 25.89, 29.23 ± 0.2 °2Θ.

In a twelfth aspect according to the invention there is provided a novel crystalline form of tegaserod citrate, designated form 3, having an XRPD trace substantially as shown in figure 5.

In a thirteenth aspect there is provided a novel crystalline form of tegaserod citrate, designated form 3, characterized by a DSC with endothermic peaks at about 70⁰C and about 111°C, preferably at about 69.98°C and about 111.21°C, all ± 2°C.

In a fourteenth aspect according to the invention there is provided a novel crystalline form of tegaserod citrate, designated form 3, 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 citrate crystalline form 3 according to the invention comprising the steps of: (a) dissolving or suspending tegaserod citrate, or tegaserod and citric acid, in one or more solvent(s);

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

Preferably tegaserod citrate is dissolved in step (a). In one preferred embodiment the solvent used in step (a) is ethylene glycol. Preferably about 5 volumes of ethylene glycol are used. In another embodiment the ethylene glycol is heated to between about 70-90⁰C, preferably about 80⁰C. In a particularly preferred embodiment a further solvent is added to the mixture before step (b) to complete the dissolution and form a solution of the tegaserod citrate, most preferably the further solvent is ethylene glycol, preferably about 5 volumes are added. Preferably this solution is heated to between about 100-120⁰C, most preferably about 107⁰C. In a further preferred embodiment the tegaserod citrate form 3 is caused to precipitate by cooling the solution or suspension, preferably to about 0-5⁰C. In yet another embodiment the tegaserod citrate form 3 is isolated by filtration, most preferably the tegaserod citrate form 3 is dried under vacuum, preferably until a constant weight is achieved. Preferably the drying occurs at a temperature of between about 20- 40⁰C, preferably about 30⁰C.

According to a sixteenth aspect of the present invention there is provided a novel crystalline form of tegaserod citrate, designated form 4, 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 5.3, 5.8, 6.1, 15.9, 19.3, 26.9 ± 0.2 °2Θ. Preferably the novel crystalline form 4 of tegaserod citrate has 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 5.34, 5.75, 6.05, 15.85, 19.26, 26.88 ± 0.2 °2Θ.

In a seventeenth aspect according to the invention there is provided a novel crystalline form of tegaserod citrate, designated form 4, having an XRPD trace substantially as shown in figure 7. In an eighteenth aspect there is provided a novel crystalline form of tegaserod citrate, designated form 4, characterized by a DSC with endothermic peaks at about 75°C, about 102⁰C, about 134°C and about 146°C, preferably at about 74.65°C, about 101.92⁰C, about 134.22°C and about 145.97°C, all ± 2°C.

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

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

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

(c) isolating the tegaserod citrate form 4.

Preferably tegaserod citrate is dissolved in step (a). In one preferred embodiment the solvent used in step (a) is a C₁-C₆ alcohol, preferably a C₄-C₆ alcohol, preferably a primary alcohol, preferably 2-ethoxy-ethanol. Preferably about 5 volumes of 2-ethoxy-ethanol are used. In another embodiment the 2-ethoxy- ethanol is heated to between about 75-95°C, preferably about 85°C. In a further preferred embodiment the tegaserod citrate 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 citrate form 4 is isolated by filtration. Preferably the tegaserod citrate form 4 is dried under vacuum, preferably until a constant weight is achieved. Preferably the drying occurs at between about 20-40⁰C, most preferably at about 30⁰C.

The crystalline forms of tegaserod citrate 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 citrate 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 citrate 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 citrate is obtained on an industrial scale, preferably in batches of 0.5kg, lkg, 5kg, 10kg, 50kg, 100kg, 500kg or more.

A twenty-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 twenty-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 twenty-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 twenty-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 citrate form 1. Figure 2 describes the DSC of tegaserod citrate form 1.

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

Figure 5 describes the XRPD of tegaserod citrate form 3. Figure 6 describes the DSC of tegaserod citrate form 3.

Figure 7 describes the XRPD of tegaserod citrate form 4. Figure 8 describes the DSC of tegaserod citrate form 4.

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 citrate, 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 citrate form 1, form 2, form 3 or form 4 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 citrate 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 citrate forms 1-3.

A preferred process according to the invention for preparing any of the crystalline forms of tegaserod citrate disclosed herein and as claimed below comprises adding tegaserod citrate, or tegaserod and citric acid, preferably tegaserod citrate, to an organic solvent. The solvent type is dependent on the crystalline form desired. Preferably form 1 is obtained from ethanol, form 2 is obtained from acetone, form 3 is obtained from ethylene glycol, and form 4 is obtained from 2-ethoxy-ethanol. Of course it will be understood that the tegaserod citrate 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 citrate, 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 citrate. The or each additional solvent may be the same or different as the initial solvent.

In a preferred embodiment of a process according to the invention the novel crystalline tegaserod citrate according to the invention is caused to precipitate from the tegaserod citrate 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. 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.

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 citrate 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 citrate 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 citrate according to the invention. In a further embodiment according to the invention there is provided the use of a novel polymorph of tegaserod citrate 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 citrate form 1, form 2, form 3 or form 4 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^®), micro fine 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. SoMd 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 citrate according to the invention. In all the examples below the starting material comprises Ig of tegaserod citrate.

Example 1 — Preparation of tegaserod citrate form 1

Tegaserod citrate was dissolved in 40 volumes of ethanol and heated to 78°C. The solution was cooled to between 0-5⁰C for about 15 minutes. The resultant slurry was filtered, and dried under vacuum at about 30⁰C.

XRPD and DSC analysis data (see figures 1 and 2) confirmed that the product obtained was the novel polymorph tegaserod citrate form 1.

Yield = 90% Chemical purity > 99% (measured by HPLC)

Polymorphic purity = high (measured by DSC)

Example 2 — Preparation of tegaserod citrate form 2

Tegaserod citrate was dissolved in 40 volumes of acetone and heated to 56°C. The solution was cooled to between 0-5⁰C. The resultant slurry was stirred for about 10 minutes, filtered, and dried under vacuum at 30⁰C.

XRPD and DSC analysis data (see figures 3 and 4) confirmed that the product obtained was the novel polymorph tegaserod citrate form 2.

Yield = 65% Chemical purity > 99% (measured by HPLC)

Polymorphic purity = high (measured by DSC) Example 3 - Preparation of tegaserod citrate form 3

Tegaserod citrate was mixed in 5 volumes of ethylene glycol and heated to 80°C. A further 5 volumes of ethylene glycol were added to the resultant slurry and heated further to 107⁰C until a clear solution was obtained. The solution was cooled to between 0-5⁰C for about 15 minutes. The resultant slurry was filtered, and then dried under vacuum at 30⁰C.

XRPD and DSC analysis data (see figures 5 and 6) confirmed that the product obtained was the novel polymorph tegaserod citrate form 3. Yield = 81%

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

Example 4 — Preparation of tegaserod citrate form 4

Tegaserod citrate was dissolved in 5 volumes of 2-ethoxy-ethanol and heated to 85°C until the solution was clear. The solution was cooled to between 20-30⁰C. The resultant slurry was stirred for about 10 minutes, filtered, and dried under vacuum at about 30⁰C.

XRPD and DSC analysis data (see figures 7 and 8) confirmed that the product obtained was the novel polymorph tegaserod citrate form 4.

Yield = 77%

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 citrate, designated form 1, characterized by an X-ray diffraction pattern having two or more peaks at 2Θ values 4.6, 5.6, 9.4, 11.3, 14.1, 17.1, 17.6, 18.3, 19.2, 21.2, 22.2, 23.0, 25.0, 26.0 ± 0.2 °2Θ.

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

3. A crystalline form of tegaserod citrate, designated form 1, characterized by a DSC with endothermic peaks at about 82°C ± 2°C and about 127°C ± 2°C.

4. A crystalline form of tegaserod citrate, designated form 1, having a DSC trace substantially as shown in figure 2.

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

(a) dissolving or suspending tegaserod citrate, or tegaserod and citric acid, in one or more solvent(s); (b) causing tegaserod citrate form 1 to precipitate from the solution or suspension obtained in step (a); and (c) isolating the tegaserod citrate form 1.

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

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

8. A process according to claim 7, wherein about 40 volumes of ethanol are used.

9. A process according to claim 7 or 8, wherein the ethanol is heated to between about 70-90⁰C.

10. A process according to claim 9, wherein the ethanol is heated to about 78°C.

11. A process according to any one of claims 5-10, wherein the tegaserod citrate form 1 is caused to precipitate by cooling the solution or suspension obtained in step (a) to between about 0-5⁰C.

12. A process according to any one of claims 5-11, wherein the tegaserod citrate form 1 is isolated by filtration.

13. A process according to any one of claims 5-12, wherein the isolated tegaserod citrate form 1 is dried under vacuum until a constant weight is achieved.

14. A process according to claim 13, wherein the drying occurs at between about 20- 40⁰C.

15. A crystalline form of tegaserod citrate, designated form 2, with a characteristic XRD spectrum having two or more peaks with 2Θ values at 4.94, 5.27, 5.64, 9.29, 10.03, 10.75, 11.51, 11.83, 13.11, 13.57, 13.90, 14.56, 15.42, 16.02, 16.84, 17.36, 17.95, 18.82, 19.33, 20.30, 20.94, 21.47, 21.90, 22.58, 23.27, 24.09, 24.62, 25.82, 26.48, 27.07, 27.91, 28.50, 29.36, 30.18, 30.86, 31.32, 33.87, 34.21, 34.90, 35.91, 36.91 and 39.04 ± 0.2 °2Θ.

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

17. A crystalline form of tegaserod citrate, designated form 2, characterized by a DSC with endothermic peaks at about 58°C ± 2°C, about 100⁰C ± 2°C and about 135°C ± 2°C.

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

19. A process for the preparation of tegaserod citrate crystalline form 2 according to any one of claims 15-18, comprising the steps of:

(a) dissolving or suspending tegaserod citrate, or tegaserod and citric acid, in one or more solvent(s); (b) causing tegaserod citrate form 2 to precipitate from the solution or suspension obtained in step (a); and

(c) isolating the tegaserod citrate form 2.

20. A process according to claim 19, wherein tegaserod citrate is dissolved in step (a).

21. A process according to claim 19 or 20, wherein the solvent used in step (a) is acetone.

22. A process according to claim 21, wherein about 40 volumes of acetone are used.

23. A process according to claim 21 or 22, wherein the acetone is heated to between about 50-60⁰C.

24. A process according to claim 23, wherein the acetone is heated to about 56°C.

25. A process according to any one of claims 19-24, wherein the tegaserod citrate form 2 is caused to precipitate by cooling the solution or suspension obtained in step (a) to between about 0-5⁰C.

26. A process according to any one of claims 19-25, wherein the tegaserod citrate form 2 is isolated by filtration.

27. A process according to any one of claims 19-26, wherein the isolated tegaserod citrate form 2 is dried under vacuum until a constant weight is achieved.

28. A process according to claim 27, wherein the drying occurs at about 20-40⁰C.

29. A crystalline form of tegaserod citrate, designated form 3, with a characteristic XRD spectrum having two or more peaks with 2Θ values at 5.0, 7.2, 7.7, 9.2, 11.0, 11.8,

13.1, 14.6, 16.5, 17.2, 17.6, 18.3, 19.4, 19.7, 20.5, 22.1, 22.6, 22.9, 23.1, 23.7, 24.0, 24.7, 25.2, 25.9, 29.2 ± 0.2 °2Θ.

30. A crystalline form of tegaserod citrate, designated form 3, having an XRPD trace substantially as shown in figure 5.

31. A crystalline form of tegaserod citrate, designated form 3, characterized by a DSC with endothermic peaks at about 70⁰C ± 2°C and about 111°C ± 2°C.

32. A crystalline form of tegaserod citrate, designated form 3, having a DSC trace substantially as shown in figure 6.

33. A process for the preparation of tegaserod citrate crystalline form 3 according to any one of claims 29-32, comprising the steps of:

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

(c) isolating the tegaserod citrate form 3.

34. A process according to claim 33, wherein tegaserod citrate is dissolved in step (a).

35. A process according to claim 33 or 34, wherein the solvent used in step (a) is ethylene glycol.

36. A process according to claim 35, wherein about 5 volumes of ethylene glycol are used.

37. A process according to claim 35 or 36, wherein the ethylene glycol is heated to between about 70-90⁰C.

38. A process according to claim 37, wherein the ethylene glycol is heated to about 80⁰C.

39. A process according to any one of claims 33-38, wherein a further solvent is added to the mixture before step (b) to complete the dissolution and form a solution of tegaserod citrate.

40. A process according to claim 39, wherein the further solvent is ethylene glycol.

41. A process according to claim 40, wherein the solution of tegaserod citrate is heated to between about 100-120⁰C.

42. A process according to claim 41, wherein the solution is heated to about 107⁰C.

43. A process according to any one of claims 33-42, wherein the tegaserod citrate form 3 is caused to precipitate by cooling the tegaserod citrate solution or suspension to between about 0-5⁰C.

44. A process according to any one of claims 33-43, wherein the tegaserod citrate form 3 is isolated by filtration.

45. A process according to any one of claims 33-44, wherein the isolated tegaserod citrate form 3 is dried under vacuum until a constant weight is achieved.

46. A process according to claim 45, wherein the drying occurs at about 30⁰C.

47. A crystalline form of tegaserod citrate, designated form 4, characterized by an X-ray diffraction pattern having two or more peaks at 2Θ values 5.3, 5.8, 6.1, 15.9, 19.3, 26.9 ± 0.2

°2Θ.

48. A crystalline form of tegaserod citrate, designated form 4, having an XRPD trace substantially as shown in figure 7.

49. A crystalline form of tegaserod citrate, designated form 4, characterized by a DSC with endothermic peaks at about 75°C ± 2°C, about 102⁰C ± 2°C, about 134°C ± 2°C and about 146°C ± 2°C.

50. A crystalline form of tegaserod citrate, designated form 4, having a DSC trace substantially as shown in figure 8.

51. A process for the preparation of tegaserod citrate crystalline form 4 according to any one of claims 47-50, comprising the steps of:

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

(c) isolating the tegaserod citrate form 4.

52. A process according to claim 51, wherein tegaserod citrate is dissolved in step (a).

53. A process according to claim 51 or 52, wherein the solvent used in step (a) is 2- ethoxy-ethanol.

54. A process according to claim 53, wherein about 5 volumes of 2-ethoxy-ethanol are used.

55. A process according to claim 53 or 54, wherein the 2-ethoxy-ethanol is heated to between about 75-95°C.

56. A process according to claim 55, wherein the 2-ethoxy-ethanol is heated to about 85°C.

57. A process according to any one of claims 51-56, wherein the tegaserod citrate form 4 is caused to precipitate by cooling the solution or suspension obtained in step (a) to between about 20-30⁰C.

58. A process according to any one of claims 51-57, wherein the tegaserod citrate form 4 is isolated by filtration.

59. A process according to any one of claims 51-58, wherein the isolated tegaserod citrate form 4 is dried under vacuum until a constant weight is achieved.

60. A process according to claim 59, wherein the drying occurs at between about 20- 40⁰C.

61. Tegaserod citrate according to any one of claims 1-4, 15-18, 29-32 or 47-50, or tegaserod citrate prepared by a process according to any one of claims 5-14, 19-28, 33-46 or 51-60, comprising less than 10% of other forms of tegaserod.

62. Tegaserod citrate according to claim 61, comprising less than 5% of other forms of tegaserod.

63. Tegaserod citrate according to claim 62, comprising less than 1% of other forms of tegaserod.

64. Tegaserod citrate according to claim 63, comprising less than 0.1% of other forms of tegaserod.

65. Tegaserod citrate according to any one of claims 1-4, 15-18, 29-32, 47-50 or 61-64, or tegaserod citrate prepared by a process according to any one of claims 5-14, 19-28, 33- 46 or 51-60, for use in medicine.

66. Tegaserod citrate according to claim 65, for treating or preventing a gastrointestinal disorder.

67. Tegaserod citrate according to claim 66, 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.

68. A pharmaceutical composition comprising tegaserod citrate according to any one of claims 1-4, 15-18, 29-32, 47-50 or 61-67, or tegaserod citrate prepared by a process according to any one of claims 5-14, 19-28, 33-46 or 51-60, and one or more pharmaceutically acceptable excipients.

69. A composition according to claim 68, wherein the composition is a solid composition.

70. A composition according to claim 69, wherein the composition is a tablet or capsule.

71. 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 citrate according to any one of claims 1-4, 15-18, 29-32, 47-50 or 61-67, or of tegaserod citrate prepared by a process according to any one of claims 5-14, 19-28, 33-46 or 51-60, or of a pharmaceutical composition according to any one of claims 68-70.

72. A method according to claim 71, wherein the patient is a mammal.

73. A method according to claim 72, wherein the mammal is a human.