WO2009063247A1

WO2009063247A1 - Novel crystalline forms

Info

Publication number: WO2009063247A1
Application number: PCT/GB2008/051067
Authority: WO
Inventors: Abhay Gaitonde; Bindu Manojkumar; Sandeep Sonawane; Dattatrey Kokane; Vikas Padalkar
Original assignee: Generics [Uk] Limited; Mylan Development Centre Private Limited
Priority date: 2007-11-15
Filing date: 2008-11-14
Publication date: 2009-05-22

Abstract

The present invention relates to novel crystalline forms of the salicylate salt of tegaserod, and to processes for the preparation of these novel 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

The present invention relates to novel crystalline forms of the salicylate salt of tegaserod, and to processes for the preparation of these novel 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.

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 the formula (I), was first described in US 5 510 353 as well as processes for its preparation. The maleate salt of tegaserod is also disclosed, 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, dihydrogen phosphate and oxalate salts of tegaserod. Also claimed is a process for preparing the hydrochloride, hydrobromide, dihydrogen phosphate, tartrate, citrate, lactate, mesylate, oxalate, succinate, glutarate, adipate, salicylate, sulfate, mandelate, camphor sulfonate and hydrogen sulfate salts of tegaserod from a specific crystalline form of tegaserod base. Another process described is a method of preparing the dihydrogen phosphate, maleate, tartrate, citrate, mesylate, lactate, succinate, oxalate, hydrochloride, salicylate, glutarate, adipate, hydrobromide, sulfate and hydrogen sulfate 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, solvates and amorphous forms 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 salicylate 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 form to another. It is important that stable forms, whether they be crystalline, amorphous or pseudo-amorphous, 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 salicylate which 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 salicylate which may 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 salicylate, designated form 2, with a characteristic XRD spectrum comprising two or more peaks (preferably three or more, four or more, five or more, six or more, or seven peaks) with 2Θ values at 5.33, 10.10, 11.06, 15.45, 16.35, 17.33, 25.37 ± 0.2 °2Θ.

In a second aspect according to the invention there is provided tegaserod salicylate form 2 having an XRPD trace substantially as shown in figure 1. - A -

In a third aspect there is provided tegaserod salicylate form 2 characterized by a DSC comprising endothermic peaks at about 90⁰C, about 116⁰C and about 149°C all + 2°C (preferably at about 90.20⁰C, 116.21°C and 149.04⁰C ± 2°C).

In a fourth aspect according to the invention there is provided tegaserod salicylate form 2 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 salicylate form 2 according to the invention, comprising the steps of:

(a) dissolving tegaserod salicylate, or tegaserod and salicylic acid, in one or more solvent(s);

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

Preferably tegaserod and salicylic acid are dissolved in step (a). In a preferred embodiment the solvent used in step (a) is methanol or water or both. In a further preferred embodiment in step (a) a solution of salicylic acid in water and a solution of tegaserod in methanol are added together. In a further preferred embodiment the tegaserod salicylate form 2 is caused to precipitate by stirring the solution obtained in step (a). In yet another embodiment the tegaserod salicylate form 2 is isolated by filtration, preferably under reduced pressure, preferably under vacuum. In a particularly preferred embodiment the tegaserod salicylate form 2 is washed with methanol. In another embodiment tegaserod salicylate form 2 is dried under reduced pressure, preferably under vacuum, preferably until a constant weight is achieved. Preferably the drying occurs at between about 30-50⁰C, preferably at about 35°C.

In a particularly preferred embodiment, the process comprises the steps of: (a) dissolving tegaserod in one or more solvent(s);

(b) adding salicylic acid to the solution obtained in step (a);

(c) causing tegaserod salicylate form 2 to precipitate from the solution obtained in step (b); and (d) isolating the tegaserod salicylate form 2.

In one preferred embodiment the solvent from step (a) is methanol. In another preferred embodiment, in step (b) the salicylic acid is added as a solution with water. In a further preferred embodiment the tegaserod salicylate form 2 is caused to precipitate by stirring the solution from step (b). In yet another embodiment the tegaserod salicylate form 2 is isolated by filtration, preferably under reduced pressure, preferably under vacuum. In a particularly preferred embodiment the tegaserod salicylate form 2 is washed with methanol.

In another embodiment tegaserod salicylate form 2 is dried under reduced pressure, preferably under vacuum, preferably until a constant weight is achieved. Preferably the drying occurs at between about 30-50⁰C, preferably at about 35°C.

According to a sixth aspect of the present invention there is provided a novel crystalline form of tegaserod salicylate, designated form 3, with a characteristic XRPD trace comprising two or more peaks (preferably three or more, four or more, five or more, six or more, seven or more, or eight peaks) with 2Θ values at 6.40, 10.79, 15.74, 16.61, 19.52, 24.10, 26.03, 27.50 ± 0.2 °2Θ; or with 2Θ values at 6.4, 10.79, 15.74, 16.61, 19.52, 24.10, 26.03, 27.50 ± 0.2 °2Θ.

In a seventh aspect according to the invention there is provided tegaserod salicylate form 3 having an XRPD trace substantially as shown in figure 3.

In an eighth aspect there is provided tegaserod salicylate form 3 characterized by a DSC comprising endothermic peaks at about 112°C and about 174°C both + 2°C (preferably at about 112.20⁰C and 173.81°C ± 2°C).

In a ninth aspect according to the invention there is provided tegaserod salicylate form 3 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 salicylate form 3 according to the invention, comprising the steps of: (a) dissolving tegaserod salicylate, or tegaserod and salicylic acid, in one or more solvent(s);

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

Preferably tegaserod salicylate is dissolved in step (a). In one preferred embodiment the solvent used in step (a) is acetonitrile. In another embodiment the acetonitrile is heated to between about 70-90⁰C, preferably about 82°C. In a further preferred embodiment the tegaserod salicylate form 3 is caused to precipitate by cooling the solution from step (a), preferably to about 20-30⁰C. In yet another embodiment the tegaserod salicylate form 3 is isolated by filtration. In a particularly preferred embodiment the tegaserod salicylate form 3 is washed with acetonitrile. In another embodiment the tegaserod salicylate form 3 is dried under reduced pressure, preferably under vacuum, preferably until a constant weight is achieved. Preferably the drying occurs at between about 30-50⁰C, preferably at about 35°C.

The crystalline forms of tegaserod salicylate 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 salicylate 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 salicylate 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 of the processes of the present invention, the tegaserod salicylate is obtained on an industrial scale, preferably in batches of 0.5kg, lkg, 5kg, 10kg, 50kg, 100kg, 500kg or more. An eleventh aspect according to the invention provides a pharmaceutical composition comprising any of the tegaserod salicylate forms according to the invention or prepared according to the invention and one or more pharmaceutically acceptable excipients. Preferably the composition is a solid composition, most preferably a tablet or capsule composition.

In a twelfth 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 thirteen 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, such as heartburn, bloating, postoperative ileus, abdominal pain and discomfort, epigastric pain, nausea, vomiting, regurgitation, intestinal pseudo-obstruction, irritable bowel syndrome and gastro-oesophageal reflux. Preferably the disorder is irritable bowel syndrome.

A fourteenth 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 salicylate form 2. Figure 2 describes the DSC of tegaserod salicylate form 2.

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

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', 'X-ray diffraction pattern' and 'XRPD trace' 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 salicylate and processes for their preparation. 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 salicylate form 2 and form 3 respectively, wherein each of the 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 and crystalline forms which are not the subject of this invention and, for example, an embodiment relating to tegaserod salicylate form 3 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 including tegaserod salicylate form 2 or any other form. A preferred process according to the invention for preparing any of the forms of tegaserod salicylate disclosed herein and as claimed below comprises adding tegaserod salicylate, or tegaserod and salicylic acid, to an organic solvent and/or water. The solvent type is dependent on the form desired. Preferably, form 2 is obtained from methanol, or methanol and water, and form 3 is obtained from acetonitrile. Of course it will be understood that the tegaserod salicylate, or tegaserod and salicylic acid, 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 salicylate, or tegaserod and salicylic acid, 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 salicylate, or tegaserod and salicylic acid. The or each additional solvent may the same or different as the initial solvent.

In a preferred embodiment of a process according to the invention the novel tegaserod salicylate is caused to precipitate from the tegaserod salicylate solution. In some preferred embodiments, the precipitation is caused by cooling the solution until the precipitate is no longer soluble, is forced out of solution and a slurry is formed. In preferred embodiments the solution is cooled to between about 5-35°C. Alternatively one or more anti-solvent(s) may be added to the solution to cause the novel 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. In another embodiment the solid is obtained by filtration. Preferably, the product is dried at a temperature that does not induce conversion of the forms or causes the resultant form to degrade. The inventors have found that drying the product at between about 20-50⁰C is advantageous. In certain preferable embodiments the solid product is dried under reduced atmospheric pressure 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 their 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 salicylate according to the invention and one or more pharmaceutically acceptable excipients. Said composition may comprise solid pharmaceutical compositions which in certain embodiments may comprise tablets including for example orodispersible 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 novel forms according to the invention with a pharmaceutically suitable liquid carrier or solvent.

A further embodiment of the invention is a process for preparing a pharmaceutical composition comprising mixing a novel polymorph of tegaserod salicylate according to the invention and one or more pharmaceutically acceptable excipients. 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 salicylate according to the invention. In a further embodiment according to the invention there is provided the use of a novel polymorph of tegaserod salicylate 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 salicylate form 2 or form 3, comprising less than 10%, preferably less than 5%, more preferably less 1%, most preferably less than 0.1% of other forms of tegaserod or tegaserod salicylate. 5-HT₄ receptor mediated disorders comprise gastrointestinal disorders such as heartburn, bloating, postoperative ileus, abdominal pain and discomfort, epigastric pain, nausea, vomiting, regurgitation, intestinal pseudo-obstruction, irritable bowel syndrome and gastro- oesophageal reflux, preferably irritable bowel syndrome.

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

Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. Carbopol ), carboxymethyl cellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel ), hydroxypropyl methyl cellulose (e.g. Methocel ), liquid glucose, magnesium aluminium silicate, maltodextrin, methyl cellulose, polymethacrylates, povidone (e.g. Kollidon^®, Plasdone^®), pregelatinized starch, sodium alginate and starch.

The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium (e.g. Ac-Di-Sol^®, Primellose^®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon^®, Polyplasdone^®), guar gum, magnesium aluminium silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab ) and starch. Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.

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

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

Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.

In liquid pharmaceutical compositions of the present invention, the tegaserod salt and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerine.

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

Liquid pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouth-feel or organoleptic qualities of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid, bentonite, carbomer, carboxymethyl cellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethyl cellulose, 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- [(methylsulfonyl) 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 novel crystalline forms of tegaserod salicylate according to the invention.

Example 1 — preparation of tegaserod salicylate form 2 Tegaserod (Ig) was dissolved in 3.3 volumes of methanol. A solution of salicylic acid (2 equivalents) in water (3.3 volumes) was added at about 25-30⁰C. The solution was stirred for about 30 minutes and the resultant slurry was filtered. The solid obtained was washed with methanol (0.5 volumes) and dried under vacuum until a constant weight was achieved, for about 2 hours at 35°C.

XRPD and DSC analysis data confirmed that the product obtained was the novel polymorph of tegaserod salicylate designated form 2. Yield = 96%.

Example 2 — preparation of tegaserod salicylate form 3

Tegaserod salicylate (Ig) was dissolved in 10 volumes of acetonitrile and heated to about

82°C. The solution was cooled to between about 25-30⁰C for about 1 hour. The resultant slurry was filtered. The solid obtained was washed with acetonitrile (2 volumes) and dried under vacuum at 35°C until a constant weight was achieved.

XRPD and DSC analysis data confirmed that the product obtained was the novel polymorph of tegaserod salicylate designated form 3. Yield = 31%.

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 salicylate form 2 characterized by an X-ray diffraction pattern comprising two or more peaks at 2Θ values 5.33, 10.10, 11.06, 15.45, 16.35, 17.33, 25.37 ± 0.2 °2Θ.

2. Tegaserod salicylate form 2 having an XRPD trace substantially as shown in figure 1.

3. Tegaserod salicylate form 2 characterized by a DSC comprising endothermic peaks at about 90.20⁰C, about 116.21°C and about 149.04⁰C, all ± 2°C.

4. Tegaserod salicylate form 2 having a DSC trace substantially as shown in figure 2.

5. A process for the preparation of tegaserod salicylate form 2 according to any one of claims 1-4, comprising the steps of:

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

(c) isolating the tegaserod salicylate form 2.

6. A process according to claim 5, wherein in step (a) tegaserod and salicylic acid are dissolved.

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

8. A process according to any one of claims 5-7, wherein in step (a) a solution of salicylic acid in water and a solution of tegaserod in methanol are added together.

9. A process according to any one of claims 5-8, wherein the tegaserod salicylate form 2 is caused to precipitate by stirring the solution obtained in step (a).

10. A process for the preparation of tegaserod salicylate form 2 according to any one of claims 1-4, comprising the steps of: (a) dissolving tegaserod in one or more solvent(s); (b) adding salicylic acid to the solution obtained in step (a);

(c) causing tegaserod salicylate form 2 to precipitate from the solution obtained in step (b); and

(d) isolating the tegaserod salicylate form 2.

11. A process according to claim 10, wherein the solvent used in step (a) is methanol.

12. A process according to claim 10 or 11, wherein in step (b) the salicylic acid is added as a solution with water.

13. A process according to any one of claims 10-12, wherein the tegaserod salicylate form 2 is caused to precipitate by stirring the solution obtained in step (b).

14. A process according to any one of claims 5-13, wherein the tegaserod salicylate form 2 is isolated by filtration.

15. A process according to claim 14, wherein the tegaserod salicylate form 2 is filtered under reduced pressure.

16. A process according to claim 15, wherein the tegaserod salicylate form 2 is filtered under vacuum.

17. A process according to any one of claims 5-16, wherein the isolated tegaserod salicylate form 2 is washed with methanol.

18. A process according to any one of claims 5-17, wherein the isolated tegaserod salicylate form 2 is dried under reduced pressure until a constant weight is achieved.

19. A process according to claim 18, wherein the tegaserod salicylate form 2 is dried under vacuum.

20. Tegaserod salicylate form 3 with a characteristic XRD spectrum comprising two or more peaks with 2Θ values at 6.40, 10.79, 15.74, 16.61, 19.52, 24.10, 26.03, 27.50 ± 0.2 °2Θ.

21. Tegaserod salicylate form 3 having an XRPD trace substantially as shown in figure 3.

22. Tegaserod salicylate form 3 characterized by a DSC comprising endothermic peaks at about 112.20⁰C and about 173.81°C, both ± 2°C.

23. Tegaserod salicylate form 3 having a DSC trace substantially as shown in figure 4.

24. A process for the preparation of tegaserod salicylate form 3 according to any one of claims 20-23, comprising the steps of:

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

(c) isolating the tegaserod salicylate form 3.

25. A process according to claim 24, wherein in step (a) tegaserod salicylate is dissolved.

26. A process according to claim 24 or 25, wherein the solvent used in step (a) is acetonitrile.

27. A process according to claim 26, wherein the acetonitrile is heated to between about 70-90⁰C.

28. A process according to claim 27, wherein the acetonitrile is heated to about 82°C.

29. A process according to any one of claims 24-28, wherein the tegaserod salicylate form 3 is caused to precipitate by cooling the solution obtained in step (a).

30. A process according to claim 29, wherein the solution is cooled to between about 20-30⁰C.

31. A process according to any one of claims 24-30, wherein tegaserod salicylate form 3 is isolated by filtration.

32. A process according to any one of claims 24-31, wherein the isolated tegaserod salicylate form 3 is washed with acetonitrile.

33. A process according to any one of claims 24-32, wherein the isolated tegaserod salicylate form 3 is dried under reduced pressure until a constant weight is achieved.

34. A process according to claim 33, wherein the tegaserod salicylate form 3 is dried under vacuum.

35. A process according to claim 33 or 34, wherein the drying occurs at about 30-50⁰C.

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

37. Tegaserod salicylate according to any one of claims 1-4 or 20-23, or tegaserod salicylate prepared by a process according to any one of claims 5-19 or 24-36, comprising less than 10% of other forms of tegaserod.

38. Tegaserod salicylate according to claim 37, comprising less than 5% of other forms of tegaserod.

39. Tegaserod salicylate according to claim 38, comprising less than 1% of other forms of tegaserod.

40. Tegaserod salicylate according to claim 39, comprising less than 0.1% of other forms of tegaserod.

41. Tegaserod salicylate according to any one of claims 1-4, 20-23 or 37-40, or tegaserod salicylate prepared by a process according to any one of claims 5-19 or 24-36, for use as a medicament.

42. Tegaserod salicylate according to claim 41, for 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.

43. Tegaserod salicylate according to claim 42, for treating or preventing irritable bowel syndrome.

44. A pharmaceutical composition comprising tegaserod salicylate according to any one of claims 1-4, 20-23 or 37-43, or tegaserod salicylate prepared by a process according to any one of claims 5-19 or 24-36, and one or more pharmaceutically acceptable excipients.

45. A composition according to claim 44, wherein the composition is a solid composition.

46. A composition according to claim 45, wherein the composition is a tablet or capsule.

47. 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 salicylate according to any one of claims 1-4, 20-23 or 37-43, or tegaserod salicylate prepared by a process according to any one of claims 5-19 or 24-36, or a composition according to any one of claims 44-46.

48. A method according to claim 47, wherein the gastrointestinal disorder is irritable bowel syndrome.

49. A method according to claim 47 or 48, wherein the patient is a mammal.

50. A method according to claim 49, wherein the mammal is a human.