Novel Polymorphic Forms

Field of the invention

The present invention relates to novel polymorphic forms of the oxalate salt of tegaserod, and to processes for the preparation of these novel polymorphic forms. The invention also relates to pharmaceutical compositions comprising these novel polymorphs, and to uses of said compositions for treating patients suffering from gastrointestinal disorders.

Background of the invention

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

Tegaserod, represented by formula (I), was first described in US 5 510 353 as well as processes for its preparation. Also described is the maleate salt of tegaserod, but interestingly a method of manufacturing tegaserod maleate is not disclosed. The only characterizing data is the melting point which is disclosed as 190 ⁰ C 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 polymorphic forms of the oxalate 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 polymorphic form to another. It is important that stable crystalline forms are used in pharmaceutical dosage forms as, for example, conversion from a form showing greater aqueous dissolution and potentially better bioavailability to a less soluble form can potentially have disastrous consequences.

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

A first aspect according to the invention provides a novel crystalline form of tegaserod oxalate, designated as form 2, characterized by an X-ray diffraction pattern having at least four peaks (preferably at least five or six) selected from peaks at 2θ values 4.3, 6.0, 13.6, 18.0, 20.6 and 25.3 ± 0.2 degree. Preferably the novel crystalline form of tegaserod oxalate, designated as form 2, is characterized by an X-ray diffraction pattern having peaks at 2θ values 4.3, 6.0, 13.6, 18.0, 20.6 and 25.3, preferably ± 0.2 degree.

A second aspect according to the invention provides a crystalline form of tegaserod oxalate, designated as form 2, characterized by a DSC with endothermic peaks at about 109 ⁰ C and about 206 ⁰ C, preferably at about 109.19 ⁰ C and about 205.84 ⁰ C.

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A third aspect according to the invention provides a novel crystalline form of tegaserod oxalate, designated as form 3, characterized by an X-ray diffraction pattern having at least five peaks (preferably at least six, seven, eight, or nine) selected from peaks at 2θ values 5.5, 6.2, 10.9, 19.1, 20.1, 23.0, 23.8, 24.5 and 25.9 ± 0.2 degree. Preferably the novel crystalline form of tegaserod oxalate, designated as form 3, is characterized by an X-ray diffraction pattern having peaks at 2θ values 5.45, 6.20, 10.90, 19.11, 20.13, 23.0, 23.8, 24.5 and 25.9, preferably ± 0.2 degree.

A fourth aspect according to the invention provides a crystalline form of tegaserod oxalate, designated as form 3, characterized by a DSC with endothermic peaks at about 97°C, about 111°C and about 162°C, preferably at about 96.9°C, about 110.9 ⁰ C and about 161.65°C.

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

According to a fifth aspect of the present invention there is provided a process for the preparation of the above novel crystalline forms according to the invention, comprising the steps of: (a) dissolving or suspending tegaserod oxalate or tegaserod and oxalic acid in a solvent;

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

(c) isolating the resultant solid precipitate.

Preferably tegaserod oxalate is dissolved in step (a).

Preferably the solvent is an organic solvent. Preferably the organic solvent is an alcohol or a polar aprotic solvent. Preferred alcohols include C _{1 5} alcohols, preferably methanol, ethanol, 1-propanol, isopropanol, 1-butanol, isobutanol or tert-butanol, more preferably ethanol. Preferred polar aprotic solvents include acetonitrile and ethyl acetate.

Preferred solvents include ethanol and acetonitrile. Preferably tegaserod oxalate form 2 is obtained from ethanol; and preferably tegaserod oxalate form 3 is obtained from acetonitrile.

In a preferred embodiment the tegaserod oxalate used in step (a) is dissolved at the reflux temperature of the particular solvent employed.

In another embodiment the tegaserod oxalate is caused to precipitate by cooling the solution obtained in step (a) until a precipitate forms. Preferably the solution or suspension is cooled to about 20-25 ⁰ C for about 0.5-2 hours. Alternatively, an anti-solvent can be added to cause the tegaserod oxalate to precipitate from the solution or suspension.

In a further preferred embodiment the precipitate is isolated by filtration, preferably by vacuum filtration. Most preferably the filtered solid is dried to constant weight.

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

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

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

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

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

Brief description of the accompanying figures

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

Figure 4 describes the XRPD of tegaserod oxalate form 3. Figure 5 describes the DSC of tegaserod oxalate form 3. Figure 6 describes the TGA of tegaserod oxalate form 3.

Detailed description of the invention

The present invention provides novel polymorphs of tegaserod oxalate 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 polymorphic purity of greater than 95%, preferably greater than 96%, more preferably greater than 97%, particularly preferred is a purity of greater than 98% and most preferred is a purity of greater than 99% irrespective of the scale of preparation.

A preferred process according to the invention for preparing any of the crystalline or polymorphic forms of tegaserod oxalate disclosed herein and as claimed below comprises adding tegaserod oxalate to an organic solvent, the solvent type being dependent on the crystalline or polymorphic form desired. Preferably form 2 is obtained from ethanol; and preferably form 3 is obtained from acetonitrile. Of course it will be understood that the tegaserod oxalate can be completely or only partially dissolved and the process still falls within the scope of the invention. Preferably to aid in dissolution of the tegaserod oxalate, the solvent is heated. In preferred embodiments the solution is heated to the reflux temperature of the solvent being employed.

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

The solid product obtained can then be isolated by any means common in the field or known to the skilled artisan. In one embodiment the solid is obtained by evaporation of the solvent. However, in a particularly preferred embodiment the solid product is filtered and dried. Preferably the product is dried at a temperature that does not induce conversion of the crystalline or polymorphic form or cause the resultant form to degrade. The inventors have found that drying the product at between about 30-40 ⁰ C is advantageous. In certain preferable embodiments the solid product is dried under vacuum until a constant weight is obtained.

A further embodiment of the invention comprises 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 polymorphs 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 polymorph(s).

Illustrative of the invention is a pharmaceutical composition made by mixing a novel polymorph of tegaserod oxalate according to the invention and a pharmaceutically acceptable carrier. A further embodiment of the invention is a process for making a pharmaceutical composition comprising mixing a novel polymorph of tegaserod oxalate according to the invention and a pharmaceutically acceptable carrier. In one embodiment of the invention there is provided a method for the treatment of a 5-HT ₄ 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 oxalate according to the invention. In a further embodiment according to the invention there is provided the use of a novel polymorph of tegaserod oxalate according to the invention substantially free of other polymorphic forms, for the preparation of a medicament for treating a 5-HT ₄ receptor mediated disorder in a subject in need thereof, preferably the polymorphic purity is greater than 95%, more preferably greater than 96%, more preferably still greater than 97%, particularly preferred is a purity of greater than 98% and most preferred is a purity of greater than 99%.

5-HT ₄ receptor mediated disorders comprise gastrointestinal disorders such as heartburn, bloating, postoperative ileus, abdominal pain and discomfort, epigastric pain, nausea, vomiting, regurgitation, intestinal pseudo-obstruction, irritable bowel syndrome and gastro- oesophageal reflux, preferably irritable bowel syndrome.

In addition to the active ingredient(s), the pharmaceutical compositions of the present invention may contain one or more excipients. Excipients are added to the composition for a variety of purposes. Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle. Diluents for solid compositions include, for

example, microcrystalline cellulose (e.g. Avicel ), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulphate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit ), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.

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

The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium (e.g. Ac-Di-SoI , Primellose ), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon ^® , Polyplasdone ^® ), guar gum, magnesium aluminium silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab ) and starch.

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

When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A

lubiicant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulphate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.

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

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

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

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

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

propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.

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

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

According to the present invention, a liquid composition may also contain a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate.

Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.

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

Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and lozenges, as well as liquid syrups, suspensions and elixirs.

The dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or a soft shell. The shell may be made from gelatin and optionally contain a plasticizer such as glycerine and sorbitol, and an opacifying agent or colourant. The active

ingredient and excipients may be formulated into compositions and dosage forms according to methods known in the art.

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

A tableting composition may be prepared conventionally by dry granulation. For example, the blended composition of the active and excipients may be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet.

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

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

In further embodiments the composition of the invention may further comprise one or more additional active ingredients. Further active ingredients may include other 5-HT ₄ receptor agonists such as prucalopride, RS 67333 (l-(4-amino-5-chloro-2-methoxyphenyl)- 3-(l-butyl-4-piperidinyl)-l-propanone), RS 67506 (l-(4-amino-5-chloro-2-methoxyphenyl)- 3- [1 - [2- [(methylsulphonyl) amino] ethyl] -4-piperidinyl] - 1 -propanone) , cisapride, renzapride, norcisapride, mosapride, zacopride, SB 205149, SC 53116, BIMU 1, and BIMU 8; proton

pump inhibitors such as omeprazole, rabeprazole, pantoprazole, and lansoprazole; 5-HT ₃ receptor agonists such as cilansetron which is described in EP 297 651, alosetron which is described in WO 99/17755, ramosetron, azasetron, ondansetron, dolasetron, ramosetron, granisetron, and tropisetron; selective serotonin reuptake inhibitors such as citalopram, escitalopram, fluoxetine, fluvoxamine, sertraline, paroxetine, zimeldine, norzimeldine, clomipramine, alaproclate, venlafaxine, cericlamine, duloxetine, milnacipran, nefazodone, OPC 14503, and cyanodothiepin; and dipeptidyl peptidase IV (DPP-IV) inhibitors. Of course it will be obvious that the above is not an exhaustive list.

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

Examples

Example 1

Tegaserod oxalate was added to 15 vol of ethanol and heated to reflux (78°C). The suspension was cooled to 25°C within 45 minutes and the resultant solid was isolated by filtration. The solid product was dried at 45°C under vacuum until a constant weight was obtained. The ¹ H-NMR indicated formation of tegaserod oxalate. XRPD (see Figure 1) and DSC (see Figure 2) analysis data confirmed that the product obtained was a novel polymorph of tegaserod oxalate, designated as form 2. The TGA is shown in Figure 3. Chemical purity > 99% (as measured by HPLC) Polymorphic purity = high (as measured by DSC)

Example 2

Tegaserod oxalate was added to 15 vol of acetonitrile and heated to reflux temperature (80 ⁰ C). The suspension was cooled to 25°C within 60 minutes and the resultant solid was isolated by filtration. The solid product was dried at 45°C under vacuum until a constant weight was obtained.

The ¹ H-NMR indicated formation of tegaserod oxalate. XRPD (see Figure 4) and DSC (see Figure 5) analysis data confirmed that the product obtained was a novel polymorph of tegaserod oxalate, designated as form 3. The TGA is shown in Figure 6.

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