WO2010015794A1 - Nouvelles formes polymorphes - Google Patents

Nouvelles formes polymorphes Download PDF

Info

Publication number
WO2010015794A1
WO2010015794A1 PCT/GB2008/050677 GB2008050677W WO2010015794A1 WO 2010015794 A1 WO2010015794 A1 WO 2010015794A1 GB 2008050677 W GB2008050677 W GB 2008050677W WO 2010015794 A1 WO2010015794 A1 WO 2010015794A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystalline form
tegaserod
mixture
base
volumes
Prior art date
Application number
PCT/GB2008/050677
Other languages
English (en)
Inventor
Abhay Gaitonde
Bindu Manojkumar
Sandeep Sonawane
Dattatrey Kokane
Original Assignee
Generics [Uk] Limited
Mylan Development Centre Private Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Generics [Uk] Limited, Mylan Development Centre Private Limited filed Critical Generics [Uk] Limited
Priority to PCT/GB2008/050677 priority Critical patent/WO2010015794A1/fr
Publication of WO2010015794A1 publication Critical patent/WO2010015794A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system

Definitions

  • the present invention relates to novel crystalline forms of tegaserod base and to processes for the preparation of these novel crystalline forms.
  • the invention also relates to pharmaceutical compositions comprising these novel crystalline forms and to uses of said compositions in the treatment of patients suffering from gastrointestinal disorders.
  • Tegaserod chemically named l-[(5-methoxy-l_FJ-indol-3-yl)methyleneamino]-3-pentyl- guanidine, is a selective serotonin 4 (5-HT 4 ) receptor agonist.
  • 5-HT 4 serotonin 4
  • it 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, and in particular is marketed for the short-term treatment of irritable bowel syndrome in women whose primary bowel symptom is constipation.
  • Tegaserod represented by formula (T) was first described in US 5 510 353 as well as processes for its preparation. Also described is the maleate salt of tegaserod, but 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.
  • API active pharmaceutical ingredient
  • 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.
  • US 2005/0119328 discloses four polymorphic forms, forms I to IV, of tegaserod maleate.
  • WO 2005/014544 describes crystal modifications, designated forms A and B, of tegaserod maleate; form A is disclosed as the more stable and suitable for pharmaceutical application.
  • WO 2007/002314 discloses polymorphic forms A, B, Bl, B2, B3, C, M and Z of tegaserod maleate.
  • CN 1176077 discloses polymorphic forms S and W of tegaserod maleate.
  • WO 2006/116953 describes crystalline forms of various salts of tegaserod; also claimed is a process for preparing various salts of tegaserod from a specific crystalline form of tegaserod base.
  • WO 2005/058819 and US 2005/0165085 disclose polymorphic forms A, B, Bl, B2, B3, C, D, E and M of tegaserod maleate, amorphous tegaserod maleate, polymorphic forms F and H of tegaserod base, polymorphic form J of tegaserod acetate, and a polymorphic form of tegaserod hemi-maleate; tegaserod free base form F shows one DSC endotherm at 154°C and form H shows two DSC endotherms at 134°C and 156°C respectively.
  • 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 consequently better bioavailability to a less soluble form can potentially have disastrous consequences.
  • a crystalline form 1 of tegaserod base characterized by an X-ray diffraction pattern having at least four peaks (preferably at least five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen or nineteen peaks) selected from peaks at 2 ⁇ values 7.72, 9.06, 10.23, 11.36, 12.54, 15.35, 16.90, 18.16, 18.44, 19.30, 20.46, 21.00, 22.02, 22.36, 22.78, 24.12, 24.48, 27.72, 30.48 ⁇ 0.2.
  • a second aspect provides a crystalline form 1 of tegaserod base having an X-ray diffractogram as shown in Figure 1. - A -
  • a third aspect provides a crystalline form 1 of tegaserod base characterized by a DSC with an endothermic peak as shown in Figure 2.
  • the crystalline form 1 of tegaserod base is characterized by a DSC with endothermic peaks at about 88°C and about 155°C.
  • the crystalline form 1 of tegaserod base comprises less than 10% of other crystalline or amorphous forms of tegaserod base, preferably less than 5%, more preferably less than 1%, and most preferably less than 0.1%, and in a particularly preferred embodiment there is provided crystalline form 1 substantially free from any other crystalline or amorphous forms of tegaserod base.
  • a crystalline form 2 of tegaserod base characterized by an X-ray diffraction pattern having at least four peaks (preferably at least five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen or seventeen peaks) selected from peaks at 2 ⁇ values 7.56, 8.87, 12.35, 15.12, 16.24, 16.98, 17.97, 18.27, 19.12, 20.19, 20.78, 21.84, 22.14, 22.41, 23.18, 23.86, 30.22 ⁇ 0.2.
  • a fifth aspect provides a crystalline form 2 of tegaserod base having an X-ray diffractogram as shown in Figure 4.
  • a crystalline form 2 of tegaserod base characterized by a DSC with an endothermic peak as shown in Figure 5 is provided.
  • the crystalline form 2 of tegaserod base is characterized by a DSC with endothermic peaks at about 92°C and about 132°C.
  • the crystalline form 2 of tegaserod base comprises less than 10% of other crystalline or amorphous forms of tegaserod base, preferably less than 5%, more preferably less than 1%, and most preferably less than 0.1%, and in a particularly preferred embodiment there is provided crystalline form 2 substantially free from any other crystalline or amorphous forms of tegaserod base.
  • a crystalline form 3 of tegaserod base characterized by an X-ray diffraction pattern having at least four peaks (preferably at least five, six, seven, eight, nine or ten peaks) selected from peaks at 2 ⁇ values 5.35, 10.75, 15.73, 26.23, 18.27, 21.35, 23.01, 24.07, 25.24, 27.45 ⁇ 0.2.
  • An eighth aspect provides a crystalline form 3 of tegaserod base having an X-ray diffractogram as shown in Figure 7.
  • a crystalline form 3 of tegaserod base characterized by a DSC with an endothermic peak as shown in Figure 8.
  • the crystalline form 3 of tegaserod base is characterized by a DSC with endothermic peaks at about 74°C and about 196°C.
  • the crystalline form 3 of tegaserod base comprises less than 10% of other crystalline or amorphous forms of tegaserod base, preferably less than 5%, more preferably less than 1%, and most preferably less than 0.1%, and in a particularly preferred embodiment there is provided crystalline form 2 substantially free from any other crystalline or amorphous forms of tegaserod base.
  • tegaserod For the purposes of the present invention, the terms “tegaserod”, “tegaserod base” and “tegaserod free base” are used interchangeably herein.
  • tegaserod base 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.
  • 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.
  • the crystalline or polymorphic forms of tegaserod base of the present invention have a chemical purity of greater than 90%, 95%, 96%, 97%, 98%, 99% or 99.9% (as measured by HPLC).
  • the crystalline or polymorphic forms of tegaserod base of the present invention have a polymorphic purity of greater than 90%, 95%, 96%, 97%, 98%, 99%, or 99.9% (as measured by XRPD or DSC).
  • the crystalline forms of tegaserod base hereinbefore described can be used in medicine, preferably for treating or preventing a gastrointestinal disorder.
  • 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. More preferably the gastrointestinal disorder is irritable bowel syndrome.
  • the invention also relates to methods for preparing the crystalline forms of tegaserod base hereinbefore described.
  • a process for the preparation of crystalline form 1 of tegaserod base comprising the steps of: (a) dissolving or suspending tegaserod in an organic solvent;
  • step (c) isolating the crystalline form 1 from the mixture from step (b).
  • the tegaserod is dissolved in the organic solvent to form a solution.
  • the organic solvent is selected from the group comprising: methanol, isobutanol and amyl alcohol.
  • the mixture of tegaserod and organic solvent is heated to aid dissolution of the tegaserod, preferably to a temperature of between about 30 and 90 0 C.
  • the anti-solvent used in step (b) is water.
  • the organic solvent used is methanol or isobutanol, preferably about 3-8 volumes, more preferably about 5 volumes, of water are used as anti-solvent; when the organic solvent used is amyl alcohol, preferably about 8-13 volumes, more preferably about 10 volumes, of water are used as anti-solvent.
  • the water temperature is chilled, preferably to between about 5 and 20 0 C; more preferably the range is between about 5 and 10 0 C.
  • Another embodiment provides that the crystalline form 1 is isolated by filtration, and preferably the filtered crystalline form 1 is further washed and dried.
  • An eleventh aspect provides a process for the preparation of crystalline form 1 of tegaserod base, comprising the steps of:
  • step (b) adding water at a temperature of between about 5 and 20 0 C to the solution obtained in step (a), wherein when the solution comprises methanol or isobutanol, about 5 volumes of water are added, and when the solution comprises amyl alcohol, about 10 volumes of water are added; and (c) isolating the resultant crystalline form 1 from the mixture from step (b).
  • the mixture of tegaserod and organic solvent(s) is heated to aid dissolution of the tegaserod, preferably to a temperature of between about 30 and 90 0 C.
  • the crystalline form 1 is isolated by filtration. Most preferably the filtered crystalline form 1 is further washed and dried.
  • a process for the preparation of crystalline form 2 of tegaserod base comprising the steps of: (a) dissolving or suspending tegaserod in an organic solvent; (b) adding an anti-solvent to the mixture from step (a); and
  • step (c) isolating the crystalline form 2 from the mixture from step (b).
  • the tegaserod is dissolved in the organic solvent to form a solution.
  • the organic solvent is selected from the group comprising: acetone, 1-butanol and 2-ethoxyethanol.
  • Preferably about 3-8 volumes, more preferably about 5 volumes, of the organic solvent are used.
  • the mixture of tegaserod and organic solvent is heated to aid dissolution of the tegaserod, preferably to a temperature of between about 30 and 90 0 C.
  • the anti-solvent used in step (b) is water.
  • about 3-8 volumes, more preferably about 5 volumes, of water are used as anti-solvent.
  • the water temperature is chilled, preferably to between about 5 and 20 0 C; more preferably the range is between about 5 and 10 0 C.
  • a further embodiment provides that the crystalline form 2 is isolated by filtration, and preferably the filtered crystalline form 2 is further washed and dried.
  • a process for the preparation of crystalline form 2 of tegaserod base comprising the steps of:
  • step (b) adding about 5 volumes of water at a temperature of between about 5 and 20 0 C to the solution obtained in step (a);
  • the mixture of tegaserod and organic solvent(s) is heated to aid dissolution of the tegaserod, preferably to a temperature of between about 30 and 90 0 C.
  • the crystalline form 2 is isolated by filtration. Preferably the filtered crystalline form 2 is further washed and dried.
  • a fourteenth aspect according to the invention provides a process for the preparation of crystalline form 2 of tegaserod base, comprising the steps of:
  • step (b) isolating the crystalline form 2 from the mixture from step (a).
  • the tegaserod is dissolved in the ethyl acetate to form a solution.
  • ethyl acetate Preferably about 6-10 volumes, more preferably about 8 volumes, of ethyl acetate are used.
  • the mixture of tegaserod and ethyl acetate is heated to aid dissolution of the tegaserod, preferably to a temperature of between about 30 and 90 0 C.
  • the crystalline form 2 is isolated by filtration. More preferably the filtered crystalline form 2 is further washed in ethyl acetate and dried.
  • step (b) adding an anti-solvent to the mixture from step (a); and (c) isolating the crystalline form 3 from the mixture from step (b).
  • the tegaserod is dissolved in the organic solvent to form a solution.
  • the organic solvent is allyl alcohol.
  • about 3-8 volumes, more preferably about 5 volumes, of allyl alcohol are used.
  • the mixture of tegaserod and allyl alcohol is heated to aid dissolution of the tegaserod, preferably to a temperature of between about 30 and 90 0 C.
  • the anti-solvent used in step (b) is water.
  • the water temperature is chilled, preferably to between about 5 and 20 0 C; more preferably the range is between about 5 and 10 0 C.
  • the crystalline form 3 is isolated by filtration.
  • the filtered crystalline form 3 is further washed and dried.
  • a process for the preparation of crystalline form 3 of tegaserod base comprising the steps of: (a) dissolving tegaserod free base in about 5 volumes of allyl alcohol;
  • step (b) adding about 5 volumes of water at a temperature of between about 5 and 20 0 C to the solution obtained in step (a);
  • the mixture of tegaserod and allyl alcohol is heated to aid dissolution of the tegaserod, preferably to a temperature of between about 30 and 90 0 C.
  • the crystalline form 3 is isolated by filtration. In another embodiment, the filtered crystalline form 3 is further washed and dried.
  • the tegaserod base is preferably obtained on an industrial scale, preferably in batches of 0.5kg, lkg, 5kg, 10kg, 50kg, 100kg, 500kg or more.
  • a pharmaceutical composition according to a seventeenth aspect of the invention comprising a pharmaceutically effective amount of any of the crystalline forms hereinbefore described and one or more pharmaceutically acceptable excipients.
  • the composition is a solid composition, preferably a tablet or capsule composition.
  • An eighteenth aspect provides a method of treating or preventing a gastrointestinal disorder in a human being, the method comprising administering a composition according to the seventeenth aspect.
  • the gastrointestinal disorder is 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. More preferably the gastrointestinal disorder is irritable bowel syndrome.
  • a nineteenth aspect provides a use of a crystalline form of tegaserod base as hereinbefore described in the manufacture of a medicament for the treatment or prevention of a gastrointestinal disorder.
  • a 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. More preferably the gastrointestinal disorder is irritable bowel syndrome.
  • Figure 1 shows the XRPD of form 1 of tegaserod base according to the invention.
  • Figure 2 shows the DSC of form 1 of tegaserod base according to the invention.
  • Figure 3 shows the TGA of form 1 of tegaserod base according to the invention.
  • Figure 4 shows the XRPD of form 2 of tegaserod base according to the invention.
  • Figure 5 shows the DSC of form 2 of tegaserod base according to the invention.
  • Figure 6 shows the TGA of form 2 of tegaserod base according to the invention.
  • Figure 7 shows the XRPD of form 3 of tegaserod base according to the invention.
  • Figure 8 shows the DSC of form 3 of tegaserod base according to the invention.
  • Figure 9 shows the TGA of form 3 of tegaserod base according to the invention.
  • the present invention provides novel polymorphs of tegaserod base 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.
  • the processes according to the invention for preparing any of the crystalline forms as claimed below comprise adding tegaserod free base to an organic solvent.
  • the tegaserod can be completely or only partially dissolved and the processes still fall within the scope in the invention; although it is preferred that the tegaserod base is completely dissolved.
  • the organic solvent may be heated.
  • water is added as an anti-solvent and serves to precipitate the desired crystalline forms from the solution.
  • anti-solvents the skilled person can contemplate a number of anti-solvents and it is well within the skillset of the skilled person to determine further anti-solvents that may be useful in preparing crystalline forms according to the invention.
  • the solvent is ethyl acetate in the preparation of crystalline form 2
  • water is not needed as an anti-solvent, rather the solution only needs to be cooled in order to effect precipitation of the desired crystalline form.
  • water is used as anti- solvent, it is preferred that the water is chilled.
  • the resulting mixture comprising the crystalline tegaserod base can be stirred to increase the precipitation of the desired crystalline form. It is preferred that the stirring occurs at between about 20 and 30 0 C, most preferably at about 25°C or approximately room temperature, but it is envisaged that the stirring conditions may be varied and still remain within the scope of the invention.
  • the solid crystalline product obtained can then be isolated by any means common in the field or known to the skilled artisan.
  • the solid is washed with water, preferably about 5 volumes of water.
  • the organic solvent used is ethyl acetate in the preparation of form 2, it is preferred that the solid is washed with ethyl acetate.
  • the solid is obtained by evaporation of the solvent.
  • the solid product is filtered and dried.
  • the product is dried at a temperature that does not induce conversion of the polymorphic form or causes the resultant crystalline form to degrade.
  • drying the product at between about 30 and 50 0 C, preferably at about 45°C is advantageous.
  • the solid product is dried under vacuum, most preferably at about 45°C until a constant weight is obtained.
  • a further aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically effective amount of a novel polymorph according to the invention and one or more pharmaceutically acceptable excipient(s).
  • Illustrative of the invention is a pharmaceutical composition made by mixing a crystalline form of tegaserod base according to the invention and a pharmaceutically acceptable carrier.
  • a method for the treatment or prevention of a 5-HT 4 receptor mediated disorder in a subject in need thereof comprising administering to the subject a composition comprising a therapeutically or prophylactically effective amount of crystalline tegaserod base according to the invention.
  • 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.
  • 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.
  • povidone e.g. Kollidon ® , Plasdone ®
  • 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.
  • alginic acid include alginic acid, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium (e.g. Ac-Di-Sol ® , Primellose ® ), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.
  • 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.
  • a dosage form such as a tablet
  • 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 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.
  • liquid pharmaceutical compositions of the present invention the crystalline tegaserod and any other solid excipients are dissolved, partially dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerine.
  • a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerine.
  • the crystalline forms of tegaserod base of the present invention are preferably in a form suitable for preparing liquid pharmaceutical compositions such as solutions, suspensions, syrups and elixirs.
  • 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.
  • a viscosity enhancing agent 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.
  • 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.
  • a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate.
  • 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.
  • 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 blending.
  • 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.
  • 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.
  • 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
  • Tegaserod free base was dissolved in methanol (5 volumes) and a clear solution was obtained. Chilled water (5 volumes) at a temperature of between about 5-10 0 C was then added to precipitate out a solid and the resultant slurry was stirred at 26°C for 30 minutes. The mixture was filtered and the residue was washed with water (5 volumes). The washed solid was then dried under vacuum at 45°C for 2 hours (molar yield: 85%). The XRPD data confirmed that the solid obtained was crystalline form 1 according to the invention. The DSC data confirmed that the crystalline form was polymorphically pure.
  • Example 2 Tegaserod free base was heated in isobutanol (5 volumes) to 55°C until a clear solution was obtained. The solution was then cooled to about 30 0 C within about 45 minutes. Chilled water (5 volumes) at a temperature of between about 5-10 0 C was added to precipitate a solid and the resultant slurry was stirred at that temperature for 35 minutes. The mixture was filtered and the residue was washed with water (5 volumes). The washed solid was then dried under vacuum at 45°C for 2 hours (molar yield: 17%).
  • the XRPD data confirmed that the solid obtained was crystalline form 1 according to the invention.
  • the DSC data confirmed that the crystalline form was polymorphically pure.
  • Example 3 Tegaserod free base was heated in amyl alcohol (5 volumes) to 50 0 C until a clear solution was obtained. The solution was then cooled to about 30 0 C within about 45 minutes.
  • the XRPD data confirmed that the solid obtained was crystalline form 1 according to the invention.
  • the DSC data confirmed that the crystalline form was polymorphically pure.
  • Tegaserod free base was heated in ethyl acetate (10 volumes) to about 78°C until a clear solution was obtained. The solution was cooled to about 26°C within 1 hour and stirred at that temperature for a further 30 minutes. The mixture was filtered and the precipitated solid was washed with ethyl acetate (3 volumes) and dried under vacuum at 45°C for about 2 hours (molar yield: 65%).
  • Tegaserod free base was added to acetone (5 volumes) and a clear solution was obtained.
  • Chilled water (5 volumes) at a temperature of between about 5-10 0 C was added to precipitate out a solid and the resultant slurry was stirred at 26°C for 30 minutes. The mixture was filtered and the residue was washed with water (5 volumes). The washed solid was then dried under vacuum at 45°C for 2 hours (molar yield: 72%).
  • the XRPD data confirmed that the solid obtained was crystalline form 2 according to the invention.
  • the DSC data confirmed that the crystalline form was polymorphically pure.
  • Tegaserod free base was heated in 1-butanol (5 volumes) to 45°C until a clear solution was obtained. The solution was then cooled to about 26°C within about 45 minutes. Chilled water (5 volumes) at a temperature of between about 5-10 0 C was added to precipitate a solid and the resultant slurry was stirred at that temperature for 30 minutes. The mixture was filtered and the residue was washed with water (5 volumes). The washed solid was then dried under vacuum at 45°C for 2 hours (molar yield: 26%).
  • the XRPD data confirmed that the solid obtained was crystalline form 2 according to the invention.
  • the DSC data confirmed that the crystalline form was polymorphically pure.
  • Tegaserod free base was added to 2-ethoxyethanol (5 volumes) and a clear solution was obtained.
  • Chilled water (5 volumes) at a temperature of between about 5-10 0 C was added to precipitate out a solid and the resultant slurry was stirred at 26°C for 30 minutes. The mixture was filtered and the residue was washed with water (5 volumes). The washed solid was then dried under vacuum at 45°C for 2 hours (molar yield: 88%).
  • the XRPD data confirmed that the solid obtained was crystalline form 2 according to the invention.
  • the DSC data confirmed that the crystalline form was polymorphically pure.
  • Tegaserod free base was dissolved in allyl alcohol (5 volumes) and a clear solution was obtained. Chilled water (5 volumes) at a temperature of between about 5-10 0 C was added to precipitate out a solid and the resultant slurry was stirred at 26°C for 30 minutes. The mixture was filtered and the residue was washed with water (5 volumes). The washed solid was then dried under vacuum at 45°C for 2 hours (molar yield: 78%). The XRPD data confirmed that the solid obtained was crystalline form 3 according to the invention. The DSC data confirmed that the crystalline form was polymorphically pure.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur de nouvelles formes cristallines à base de tégasérode et sur des procédés pour la préparation de ces nouvelles formes cristallines. L'invention porte également sur des compositions pharmaceutiques comprenant ces nouvelles formes cristallines et sur des utilisations desdites compositions dans le traitement de patients souffrant de troubles gastro-intestinaux.
PCT/GB2008/050677 2008-08-07 2008-08-07 Nouvelles formes polymorphes WO2010015794A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/GB2008/050677 WO2010015794A1 (fr) 2008-08-07 2008-08-07 Nouvelles formes polymorphes

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/GB2008/050677 WO2010015794A1 (fr) 2008-08-07 2008-08-07 Nouvelles formes polymorphes

Publications (1)

Publication Number Publication Date
WO2010015794A1 true WO2010015794A1 (fr) 2010-02-11

Family

ID=39855334

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2008/050677 WO2010015794A1 (fr) 2008-08-07 2008-08-07 Nouvelles formes polymorphes

Country Status (1)

Country Link
WO (1) WO2010015794A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005058819A2 (fr) * 2003-12-16 2005-06-30 Teva Pharmaceutical Industries Ltd. Formes polymorphiques de la base du tegaserod et des sels de celui-ci
WO2005105740A2 (fr) * 2004-04-26 2005-11-10 Teva Pharmaceutical Industries Ltd. Préparation de tégasérode et de maléate de tégasérode
US20060178519A1 (en) * 2004-12-23 2006-08-10 Venkataraman Sundaram Process for preparing tegaserod
WO2006116953A1 (fr) * 2005-05-02 2006-11-09 Zentiva, A.S. Procede de preparation de tegaserod et de sels sélectionnés dérivés de ce composé
WO2007119109A2 (fr) * 2005-10-06 2007-10-25 Medichem, S.A. Compositions et procédés utiles pour la préparation de maléate de tégaserod

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005058819A2 (fr) * 2003-12-16 2005-06-30 Teva Pharmaceutical Industries Ltd. Formes polymorphiques de la base du tegaserod et des sels de celui-ci
WO2005105740A2 (fr) * 2004-04-26 2005-11-10 Teva Pharmaceutical Industries Ltd. Préparation de tégasérode et de maléate de tégasérode
US20060178519A1 (en) * 2004-12-23 2006-08-10 Venkataraman Sundaram Process for preparing tegaserod
WO2006116953A1 (fr) * 2005-05-02 2006-11-09 Zentiva, A.S. Procede de preparation de tegaserod et de sels sélectionnés dérivés de ce composé
WO2007119109A2 (fr) * 2005-10-06 2007-10-25 Medichem, S.A. Compositions et procédés utiles pour la préparation de maléate de tégaserod

Similar Documents

Publication Publication Date Title
US20110263649A1 (en) Crystalline form of lenalidomide and a process for its preparation
US6710184B2 (en) Crystalline solids of carvedilol and processes for their preparation
MX2007016179A (es) Formas cristalinas de o-desmetilvenlafaxina.
WO2005105740A2 (fr) Préparation de tégasérode et de maléate de tégasérode
US20070112057A1 (en) Polymorphic forms of tegaserod maleate
WO2008149154A2 (fr) Nouveaux sels et nouvelles formes polymorphiques
CA2694835C (fr) Nouvelle forme cristalline
WO2006037042A1 (fr) Forme de cristal de fexofenadine et ses processus de preparation
US20110251254A1 (en) Novel salt of tegaserod
WO2010015794A1 (fr) Nouvelles formes polymorphes
WO2009063247A1 (fr) Nouvelles formes cristallines
WO2009141571A1 (fr) Nouveau polymorphe d'hydrochlorure de tegaserod
WO2009141573A1 (fr) Nouveau polymorphe d'adipate de tegaserod
WO2009092993A1 (fr) Nouveau sel de tégasérod
WO2008149139A2 (fr) Nouvelles formes polymorphes
WO2008149137A2 (fr) Benzoate de tégasérod et formes polymorphes
WO2009053732A1 (fr) Nouveau sel
WO2008149136A1 (fr) Bésylate de tégasérod et formes polymorphes
WO2008149138A1 (fr) Maléate de tégasérod et formes polymorphiques
WO2009141572A1 (fr) Nouveau polymorphe
WO2008149140A2 (fr) Nouvelles formes polymorphes
WO2009063248A2 (fr) Nouvelles formes cristallines
US20070043099A1 (en) Crystalline forms of carvedilol and processes for their preparation
WO2009053750A2 (fr) Nouvelles formes cristallines et amorphes
WO2009053733A2 (fr) Nouvelles formes cristallines

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08788648

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08788648

Country of ref document: EP

Kind code of ref document: A1