[go: up one dir, main page]

WO2008149154A2 - Nouveaux sels et nouvelles formes polymorphiques - Google Patents

Nouveaux sels et nouvelles formes polymorphiques Download PDF

Info

Publication number
WO2008149154A2
WO2008149154A2 PCT/GB2008/050413 GB2008050413W WO2008149154A2 WO 2008149154 A2 WO2008149154 A2 WO 2008149154A2 GB 2008050413 W GB2008050413 W GB 2008050413W WO 2008149154 A2 WO2008149154 A2 WO 2008149154A2
Authority
WO
WIPO (PCT)
Prior art keywords
tegaserod
crystalline form
peaks
salt
acid
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/GB2008/050413
Other languages
English (en)
Other versions
WO2008149154A3 (fr
Inventor
Abhay Gaitonde
Bindu Manojkumar
Sandeep Sonawane
Dattatrey Kokane
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Generics UK Ltd
Mylan Pharmaceuticals Pvt Ltd
Original Assignee
Generics UK Ltd
Mylan Development Centre Pvt Ltd
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 Ltd, Mylan Development Centre Pvt Ltd filed Critical Generics UK Ltd
Publication of WO2008149154A2 publication Critical patent/WO2008149154A2/fr
Publication of WO2008149154A3 publication Critical patent/WO2008149154A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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 various novel salts of tegaserod and to novel polymorphic forms of various salts of tegaserod.
  • the invention further relates to processes for the preparation of these novel salts and novel polymorphic forms.
  • the invention also relates to pharmaceutical compositions comprising these novel salts or novel polymorphs, and to uses of said compositions for treating patients suffering from gastrointestinal disorders.
  • Tegaserod chemically named 2-[(5-methoxy-li ⁇ -indol-3-yl)methylene]-IV-pentylhydrazine- carboximidamide, 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 pseudoobstruction, irritable bowel syndrome and gastro-oesophageal reflux.
  • Tegaserod as the maleate salt is marketed for the short-term treatment of irritable bowel syndrome in women whose primary bowel symptom is constipation.
  • Tegaserod represented by formula (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 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 suggested is a process for preparing tegaserod salts by reacting a specific crystalline form of tegaserod base with hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, oxalic, maleic, fumaric, citric, tartaric, mandelic or camphor sulphonic acid.
  • WO 2006/116953 does not actually disclose tegaserod mandelate or tegaserod camphor sulphonate.
  • Another process suggested is a method of preparing the maleate, fumarate, tartrate, citrate, mesylate, lactate, succinate, oxalate, hydrochloride, salicylate, glutarate, adipate, hydrobromide, sulphate and hydrogen sulphate from a hydrogen halide salt of tegaserod.
  • 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.
  • the present invention provides various novel salts of tegaserod and novel polymorphic forms of various salts of tegaserod, including polymorphic forms of tegaserod succinate, tartrate, malonate, camphor sulphonate (camsylate), mandelate, oxalate and fumarate.
  • 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.
  • novel salts of tegaserod and novel crystalline forms of tegaserod salts 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.
  • a novel polymorphic form of tegaserod succinate with a characteristic XRD spectrum having peaks at 2 ⁇ values 5.1, 5.9 and 10.3 + 0.2 degree; preferably having major peaks with 2 ⁇ values at 5.10, 5.85 and 10.30.
  • a second aspect of the present invention is a polymorphic form of tegaserod succinate characterized by a DSC with an endothermic peak at about 136°C and a TGA loss of about 2.1% (preferably about 2.12%, preferably about 2.119%).
  • a novel polymorphic form of tegaserod tartrate with a characteristic XRD spectrum having at least five peaks (preferably at least six, seven, eight, nine, ten, or eleven peaks) selected from peaks at 2 ⁇ values 14.9, 16.4, 17.9, 18.8, 20.0, 20.8, 21.4, 22.3, 23.9, 27.2 and 29.0 ⁇ 0.2 degree; preferably having major peaks with 2 ⁇ values at 14.92, 16.42, 17.90, 18.77, 19.98, 20.84, 21.41, 22.28, 23.94, 27.16 and 29.04.
  • a fourth aspect of the present invention is a polymorphic form of tegaserod tartrate characterized by a DSC with an endothermic peak at about 154°C and a TGA loss of about 0.7% (preferably about 0.66%).
  • a fifth aspect of the present invention provides tegaserod malonate or a tautomeric form thereof and/or a pharmaceutically acceptable solvate or hydrate thereof.
  • a novel polymorphic form of tegaserod malonate with a characteristic XRD spectrum having at least four peaks (preferably five peaks) selected from peaks at 2 ⁇ values 5.3, 5.7, 10.5, 15.8 and 26.3 ⁇ 0.2 degree; preferably having major peaks with 2 ⁇ values at 5.3, 5.7, 10.5, 15.8 and 26.3.
  • a seventh aspect of the present invention is a polymorphic form of tegaserod malonate characterized by a DSC with an endothermic peak at about 182°C (preferably about 182.6°C) and a TGA loss of about 1.9% (preferably about 1.922%).
  • An eighth aspect of the present invention provides tegaserod camphor sulphonate or an isomer and/or a tautomeric form thereof and/or a pharmaceutically acceptable solvate or hydrate thereof.
  • a novel polymorphic form of tegaserod camphor sulphonate with a characteristic XRD spectrum having at least five peaks (preferably at least six, seven, eight, nine, ten, fifteen, twenty, twenty-five, thirty, thirty-five, forty, or forty-six peaks) selected from peaks at 2 ⁇ values 5.1, 6.3, 7.1, 9.0, 10.1, 12.0, 12.7, 13.3, 13.9, 14.3, 14.6, 15.0, 15.3, 16.1, 16.3, 17.1, 18.0, 18.4, 18.7, 19.1, 19.6, 20.3, 20.1, 21.3, 21.9, 22.2, 22.6, 23.1, 23.8, 24.2, 24.5, 24.7, 25.5, 25.9, 26.8, 27.7, 28.3, 28.9, 29.5,
  • a polymorphic form of tegaserod camphor sulphonate characterized by a DSC with an endothermic peak at about 91 0 C (preferably about 91.92°C) and a TGA loss of about 7.8% (preferably about 7.78%).
  • An eleventh aspect of the present invention provides tegaserod mandelate or an isomer and/or a tautomeric form thereof and/or a pharmaceutically acceptable solvate or hydrate thereof.
  • a novel polymorphic form of tegaserod mandelate with a characteristic XRD spectrum having at least four peaks (preferably at least five, six, or seven peaks) selected from peaks at 2 ⁇ values 5.1, 15.1, 18.7, 20.0, 20.4, 23.5 and 24.9 + 0.2 degree; preferably having major peaks with 2 ⁇ values at 5.1, 15.1, 18.7, 20.0, 20.4, 23.5 and 24.9.
  • a polymorphic form of tegaserod mandelate characterized by a DSC with two endothermic peaks at about 108 0 C (preferably about 108.32 0 C) and about 152°C (preferably about 151.74°C), and a TGA loss of about 2.4%.
  • a novel polymorphic form of tegaserod oxalate with a characteristic XRD spectrum having at least four peaks (preferably at least five, six, or seven peaks) selected from peaks at 2 ⁇ values 4.3, 6.3, 8.7, 18.9, 21.8, 25.1 and 29.0 ⁇ 0.2 degree; preferably having major peaks with 2 ⁇ values at 4.3, 6.3, 8.72, 18.88, 21.76, 25.08 and 28.97.
  • a novel polymorphic form of tegaserod oxalate characterized by a DSC with an endothermic peak at about 110 0 C and a TGA loss of about 5.7% (preferably about 5.72%).
  • a novel polymorphic form of tegaserod fumarate with a characteristic XRD spectrum having at least five peaks (preferably at least six, seven, eight, nine, ten, fifteen, twenty, or twenty- four peaks) selected from peaks at 2 ⁇ values 4.2, 5.9, 8.3, 11.9, 14.2, 14.9, 16.6, 18.4, 19.0, 19.3, 20.0, 20.2, 20.7, 21.2, 22.4, 23.9, 24.5, 25.6, 26.0, 26.8, 27.5, 28.4, 29.0 and 30.1 ⁇ 0.2 degree; preferably having major peaks with 2 ⁇ values at 4.2, 5.9, 8.3, 11.9, 14.2, 14.9, 16.6, 18.4, 19.0, 19.3, 20.0, 20.2, 20.7, 21.2, 22.4, 23.9, 24.5, 25.6, 26.0, 26.8, 27.5, 28.4, 29.0 and 30.1.
  • a novel polymorphic form of tegaserod fumarate characterized by a DSC with an endothermic peak at about 182°C (preferably about 181.83°C) and a TGA loss of about 3.7% or about 3.8% (preferably about 3.78%).
  • the tegaserod malonate of the present invention may exist in one or more polymorphic, tautomeric, hydrate and/or solvate forms.
  • the present invention embraces all polymorphic forms and their mixtures, all tautomeric forms and their mixtures, all hydrate forms and their mixtures, and all solvate forms and their mixtures.
  • the tegaserod malonate of the present invention has a chemical purity of greater than 95%
  • the tegaserod malonate of the present invention has a polymorphic purity of greater than 95%, 96%, 97%, 98%, or
  • the tegaserod camphor sulphonate and the tegaserod mandelate of the present invention may exist in one or more enantiomeric, polymorphic, tautomeric, hydrate and/or solvate forms.
  • the present invention embraces all enantiomeric forms and their mixtures, all polymorphic forms and their mixtures, all tautomeric forms and their mixtures, all hydrate forms and their mixtures, and all solvate forms and their mixtures.
  • the tegaserod camphor sulphonate and the tegaserod mandelate of the present invention have a chemical purity of greater than 95%, 96%, 97%, 98%, or 99% (as measured by HPLC).
  • the tegaserod camphor sulphonate and the tegaserod mandelate of the present invention have a polymorphic purity of greater than 95%, 96%, 97%, 98%, or 99% (as measured by XRPD or DSC).
  • the tegaserod camphor sulphonate and the tegaserod mandelate of the present invention have an enantiomeric purity of greater than 95%, 96%, 97%, 98%, or 99% (as measured by chiral HPLC).
  • crystalline or polymorphic forms of tegaserod succinate, tegaserod tartrate, tegaserod oxalate and tegaserod fumarate 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.
  • the crystalline or polymorphic forms of tegaserod succinate, tegaserod tartrate, tegaserod oxalate and tegaserod fumarate of the present invention have a chemical purity of greater than 95%, 96%, 97%, 98%, or 99% (as measured by HPLC).
  • the crystalline or polymorphic forms of tegaserod succinate, tegaserod tartrate, tegaserod oxalate and tegaserod fumarate of the present invention have a polymorphic purity of greater than 95%, 96%, 97%, 98%, or 99% (as measured by XRPD or DSC).
  • 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 ratio of tegaserod : acid in all of the tegaserod salts of the present invention is from 1:2 to 2:1, preferably about 1:1.
  • a process for the preparation of a tegaserod salt or a crystalline form of a tegaserod salt comprising the steps of:
  • an appropriate acid means succinic, tartaric, malonic, camphor sulphonic, mandelic, oxalic or fumaric acid.
  • an appropriate tegaserod salt means tegaserod succinate, tartrate, malonate, camphor sulphonate, mandelate, oxalate or fumarate.
  • tegaserod and an appropriate acid are used in step (a).
  • the solvent used in step (a) is water or an organic solvent or a mixture thereof.
  • the organic solvent is an alcohol or ethyl acetate, preferably an alcohol, preferably a C 1 5 alcohol.
  • the alcohol is methanol, ethanol, 1-propanol, isopropanol, 1-butanol, isobutanol or tert-butanol, preferably methanol.
  • step (a) is carried out by (al) dissolving or suspending tegaserod in a solvent, and (a2) adding a solution or suspension of an appropriate acid.
  • the solvent used in step (al) is an organic solvent, preferably an alcohol or ethyl acetate, preferably an alcohol, preferably a C 1 5 alcohol.
  • the alcohol is methanol, ethanol, 1-propanol, isopropanol, 1-butanol, isobutanol or tert-butanol, preferably methanol.
  • tegaserod is suspended in the solvent in step (al).
  • the solvent used in step (a2) is water or an organic solvent or a mixture thereof. If an organic solvent is used, then it is preferably an alcohol, preferably a C 1 5 alcohol.
  • the alcohol is methanol, ethanol, 1-propanol, isopropanol, 1-butanol, isobutanol or tert-butanol, preferably methanol.
  • the acid is added as a solution of the acid, preferably in water or methanol.
  • the reaction mixture obtained in step (a) is stirred to increase the precipitation of the tegaserod salt or the crystalline form of the tegaserod salt. It is preferred that the stirring occurs at about 20-30 0 C preferably for about 0.5-2 hours.
  • the reaction mixture obtained in step (a) can be cooled (preferably to about 10-20 0 C preferably for about 0.5-2 hours) to increase the precipitation of the tegaserod salt or the crystalline form of the tegaserod salt.
  • an anti-solvent can be added to the reaction mixture obtained in step (a) to increase the precipitation of the tegaserod salt or the crystalline form of the tegaserod salt.
  • the tegaserod salt or the crystalline form of the tegaserod salt in step (b) is isolated by filtration, preferably by vacuum filtration. Most preferably the tegaserod salt or the crystalline form of the tegaserod salt is dried to constant weight.
  • the tegaserod salt or the crystalline form of the tegaserod salt is obtained on an industrial scale, preferably in batches of 0.5kg, lkg, 5kg, 10kg, 50kg, 100kg, 500kg or more.
  • a nineteenth aspect according to the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a tegaserod salt or a crystalline form of a tegaserod salt according to the invention and one or more pharmaceutically acceptable excipients.
  • the composition is a solid composition, most preferably a tablet or capsule composition.
  • a method of treating or preventing a gastrointestinal disorder selected form 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 pharmaceutically or prophylactically effective amount of a tegaserod salt or of a crystalline form of a tegaserod salt according to the invention.
  • a tegaserod salt or a crystalline form of a tegaserod salt according to the invention for use as a medicament, for example, for use in the treatment or prevention of gastrointestinal disorders.
  • the disorder is irritable bowel syndrome.
  • a twenty-second aspect provides the use of a tegaserod salt or of a crystalline form of a tegaserod salt according to the invention in the manufacture of a medicament for the treatment or prevention of 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, preferably irritable bowel syndrome.
  • Figure 1 describes the XRPD of tegaserod succinate according to the invention.
  • Figure 2 describes the DSC of tegaserod succinate according to the invention.
  • Figure 3 describes the TGA of tegaserod succinate according to the invention.
  • Figure 4 describes the XRPD of tegaserod tartrate according to the invention.
  • Figure 5 describes the DSC of tegaserod tartrate according to the invention.
  • Figure 6 describes the TGA of tegaserod tartrate according to the invention.
  • Figure 7 describes the XRPD of tegaserod malonate according to the invention.
  • Figure 8 describes the DSC of tegaserod malonate according to the invention.
  • Figure 9 describes the TGA of tegaserod malonate according to the invention.
  • Figure 10 describes the XRPD of tegaserod camphor sulphonate according to the invention.
  • Figure 11 describes the DSC of tegaserod camphor sulphonate according to the invention.
  • Figure 12 describes the TGA of tegaserod camphor sulphonate according to the invention.
  • Figure 13 describes the XRPD of tegaserod mandelate according to the invention.
  • Figure 14 describes the DSC of tegaserod mandelate according to the invention.
  • Figure 15 describes the TGA of tegaserod mandelate according to the invention.
  • Figure 16 describes the XRPD of tegaserod oxalate according to the invention.
  • Figure 17 describes the DSC of tegaserod oxalate according to the invention.
  • Figure 18 describes the TGA of tegaserod oxalate according to the invention.
  • Figure 19 describes the XRPD of tegaserod fumarate according to the invention.
  • Figure 20 describes the DSC of tegaserod fumarate according to the invention.
  • Figure 21 describes the TGA of tegaserod fumarate according to the invention.
  • the present invention provides novel tegaserod salts (namely tegaserod malonate, camphor sulphonate and mandelate) and novel polymorphs of tegaserod salts (namely polymorphs of tegaserod succinate, tartrate, malonate, camphor sulphonate, mandelate, oxalate and fumarate) and processes for their preparation.
  • novel tegaserod salts namely tegaserod malonate, camphor sulphonate and mandelate
  • novel polymorphs of tegaserod salts namely polymorphs of tegaserod succinate, tartrate, malonate, camphor sulphonate, mandelate, oxalate and fumarate
  • the processes disclosed are simple and amenable to scale up and are capable of providing these novel salts and polymorphs in consistent polymorphic and chemical purity of greater than 95% respectively, preferably greater than 96%, more preferably greater than 97%, particularly preferred is
  • the processes disclosed also provide the salts and polymorphs in consistent enantiomeric purity of preferably greater than 95%, preferably greater than 96%, preferably greater than 97%, preferably greater than 98%, and more preferably greater than 99%, irrespective of the scale of preparation.
  • a preferred process according to the invention for preparing any of the tegaserod salts or polymorphs according to the invention comprises adding tegaserod to methanol.
  • the tegaserod is in the form of the free base.
  • the tegaserod can be completely or only partially dissolved and the process still falls within the scope of the invention.
  • the appropriate acid depending on the desired salt preferably in solution, either in methanol or in alternative embodiments in water.
  • the acid to be added is malonic acid resulting in the malonate salt of tegaserod.
  • the resulting reaction mixture comprising methanol, tegaserod and the appropriate acid solution in certain embodiments can be stirred to increase the precipitation of the solid desired salt or polymorph. It is preferred that the stirring occurs 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 product obtained can then be isolated by any means common in the field or known to the skilled artisan.
  • 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 form to degrade. The inventors have found that drying the product at about 40 0 C is advantageous.
  • the solid product is dried under vacuum until a constant weight is obtained.
  • a further embodiment of the invention comprises pharmaceutical compositions of the novel salts or polymorphs with one or more pharmaceutically acceptable excipient(s).
  • Another aspect of the present invention is the pharmaceutical compositions containing the novel salts or 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 the novel salts or polymorphs.
  • Illustrative of the invention is a pharmaceutical composition made by mixing a tegaserod salt or polymorph 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 tegaserod salt or polymorph according to the invention and a pharmaceutically acceptable carrier.
  • 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 tegaserod salt or polymorph according to the invention.
  • a tegaserod salt or polymorph according to the invention for the preparation of a medicament for treating a 5-HT 4 receptor mediated disorder
  • HT 4 receptor mediated disorder in a subject in need thereof.
  • 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.
  • Eudragit ® polymethacrylates
  • 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 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.
  • 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.
  • 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 granulation.
  • 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.
  • 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 taken in 3.3 vol of methanol and added a solution of succinic acid
  • Tegaserod free base was taken in 3.3 vol of methanol and added a solution of tartaric acid (2eq) in 3.3 vol water. The reaction mixture was stirred at 25°C for 30 minutes and then filtered. The solid product was dried at 40 0 C under vacuum until a constant weight was obtained.
  • Tegaserod free base was taken in 3.3 vol of methanol and added a solution of malonic acid (2eq) in 3.3 vol water. The reaction mixture was stirred at 25°C for 30 minutes and then filtered. The solid product was dried at 40 0 C under vacuum until a constant weight was obtained.
  • Example 4 Tegaserod free base was taken in 3.3 vol of methanol and added a solution of D-(+)- camphor sulphonic acid (2eq) in 3.3 vol water. The reaction mixture was stirred at 25°C for 30 minutes and then filtered. The solid product was dried at 40 0 C under vacuum until a constant weight was obtained.
  • Tegaserod free base was taken in 3.3 vol of methanol and added a solution of S-mandelic acid (2eq) in 3.3 vol water. The reaction mixture was stirred at 25°C for 30 minutes and then filtered. The solid product was dried at 40 0 C under vacuum until a constant weight was obtained.
  • Tegaserod free base was taken in 3.3 vol of methanol and added a solution of oxalic acid (2eq) in 3.3 vol water. The reaction mixture was stirred at 25°C for 30 minutes and then filtered. The solid product was dried at 40 0 C under vacuum until a constant weight was obtained.
  • Example 7 Tegaserod free base was taken in 3.3 vol of methanol and added a solution of fumaric acid

Landscapes

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

Abstract

La présente invention concerne divers nouveaux sels de tégasérod et de nouvelles formes polymorphiques de sels de tégasérod, y compris des formes polymorphiques de succinate, de tartrate, de malonate, de sulfonate de camphre, de mandélate, d'oxalate et de fumarate de tégasérod. L'invention se rapporte en outre à des procédés de préparation de ces nouveaux sels et de ces nouvelles formes polymorphiques. Elle concerne également des compositions pharmaceutiques comprenant ces nouveaux sels ou ces nouveaux polymorphes, ainsi que les utilisations desdites compositions pour traiter des patients souffrant de troubles gastro-intestinaux.
PCT/GB2008/050413 2007-06-05 2008-06-05 Nouveaux sels et nouvelles formes polymorphiques Ceased WO2008149154A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1065MU2007 2007-06-05
IN1065/MUM/2007 2007-06-05

Publications (2)

Publication Number Publication Date
WO2008149154A2 true WO2008149154A2 (fr) 2008-12-11
WO2008149154A3 WO2008149154A3 (fr) 2009-07-23

Family

ID=39737123

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2008/050413 Ceased WO2008149154A2 (fr) 2007-06-05 2008-06-05 Nouveaux sels et nouvelles formes polymorphiques

Country Status (1)

Country Link
WO (1) WO2008149154A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009053750A3 (fr) * 2007-10-24 2009-08-06 Generics Uk Ltd Nouvelles formes cristallines et amorphes
WO2009053733A3 (fr) * 2007-10-24 2009-09-03 Generics [Uk] Limited Nouvelles formes cristallines

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HUT64023A (en) * 1991-03-22 1993-11-29 Sandoz Ag Process for producing aminoguanidine derivatives and pharmaceutical compositions comprising such compounds
CA2550886A1 (fr) * 2003-12-16 2005-06-30 Teva Pharmaceutical Industries Ltd. Formes polymorphiques de la base du tegaserod et des sels de celui-ci
WO2006116953A1 (fr) * 2005-05-02 2006-11-09 Zentiva, A.S. Procede de preparation de tegaserod et de sels sélectionnés dérivés de ce composé
EP1939176A1 (fr) * 2006-12-22 2008-07-02 Novartis AG Sels de Tegaserod

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009053750A3 (fr) * 2007-10-24 2009-08-06 Generics Uk Ltd Nouvelles formes cristallines et amorphes
WO2009053733A3 (fr) * 2007-10-24 2009-09-03 Generics [Uk] Limited Nouvelles formes cristallines

Also Published As

Publication number Publication date
WO2008149154A3 (fr) 2009-07-23

Similar Documents

Publication Publication Date Title
US7598396B2 (en) Crystalline solids of carvedilol and processes for their preparation
US20110263649A1 (en) Crystalline form of lenalidomide and a process for its preparation
JP2008546719A (ja) 結晶形のｏ−デスメチルベンラファキシン
WO2008149154A2 (fr) Nouveaux sels et nouvelles formes polymorphiques
US12441701B2 (en) Solid state forms of roluperidone and salts thereof
US20110251254A1 (en) Novel salt of tegaserod
WO2009063247A1 (fr) Nouvelles formes cristallines
WO2008149138A1 (fr) Maléate de tégasérod et formes polymorphiques
WO2008149136A1 (fr) Bésylate de tégasérod et formes polymorphes
WO2008149137A2 (fr) Benzoate de tégasérod et formes polymorphes
WO2008149140A2 (fr) Nouvelles formes polymorphes
WO2009092993A1 (fr) Nouveau sel de tégasérod
WO2008149139A2 (fr) Nouvelles formes polymorphes
WO2009141573A1 (fr) Nouveau polymorphe d'adipate de tegaserod
WO2009141571A1 (fr) Nouveau polymorphe d'hydrochlorure de tegaserod
WO2009141572A1 (fr) Nouveau polymorphe
WO2009053732A1 (fr) Nouveau sel
WO2010015794A1 (fr) Nouvelles formes polymorphes
WO2009063248A2 (fr) Nouvelles formes cristallines
WO2009053750A2 (fr) Nouvelles formes cristallines et amorphes
WO2009053754A2 (fr) Nouvelles formes cristallines
WO2009053733A2 (fr) Nouvelles formes cristallines
US20070043099A1 (en) Crystalline forms of carvedilol and processes for their preparation
WO2007139984A2 (fr) Polymorphes de chlorhydrate de duloxétine
AU2008252604A1 (en) Process for the preparation of form A of tegaserod

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: 08750808

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08750808

Country of ref document: EP

Kind code of ref document: A2