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WO2009053750A2 - Nouvelles formes cristallines et amorphes - Google Patents

Nouvelles formes cristallines et amorphes Download PDF

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Publication number
WO2009053750A2
WO2009053750A2 PCT/GB2008/050988 GB2008050988W WO2009053750A2 WO 2009053750 A2 WO2009053750 A2 WO 2009053750A2 GB 2008050988 W GB2008050988 W GB 2008050988W WO 2009053750 A2 WO2009053750 A2 WO 2009053750A2
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WO
WIPO (PCT)
Prior art keywords
tegaserod
tartrate
process according
amorphous
crystalline form
Prior art date
Application number
PCT/GB2008/050988
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English (en)
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WO2009053750A3 (fr
Inventor
Abhay Gaitonde
Bindu Manojkumar
Sandeep Sonawane
Dattatrey Kokane
Vikas Padalkar
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
Publication of WO2009053750A2 publication Critical patent/WO2009053750A2/fr
Publication of WO2009053750A3 publication Critical patent/WO2009053750A3/fr

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    • 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 amorphous and crystalline forms of the tartrate salt of tegaserod, and to processes for the preparation of these novel forms.
  • the invention also relates to pharmaceutical compositions containing these novel forms, and to uses of said compositions to provide methods of 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 (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.
  • 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 novel crystalline forms of the tartrate salt of tegaserod. There is also provided a novel amorphous form of the tartrate salt.
  • polymorphism influences every aspect of the solid state properties of an API and one of the important aspects of polymorphism in pharmaceuticals is the possibility of interconversion from one crystalline or amorphous form to another. It is important that stable crystalline or amorphous 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.
  • a novel crystalline form of tegaserod tartrate designated form 3, with a characteristic XRD spectrum having two or more peaks (preferably three or more, four or more, or all five peaks) with 2 ⁇ values at 3.82, 6.08, 7.61, 19.15, 24.64 ⁇ 0.2 °2 ⁇ .
  • a novel crystalline form of tegaserod tartrate designated form 3, having an XRPD trace substantially as shown in figure 1. - A -
  • a novel crystalline form of tegaserod tartrate designated form 3, characterized by a DSC with endothermic peaks at about 90 0 C and about 156°C, preferably at about 89.75°C and about 155.71°C, all ⁇ 2°C.
  • a novel crystalline form of tegaserod tartrate designated form 3, having a DSC trace substantially as shown in figure 2.
  • a process for the preparation of tegaserod tartrate crystalline form 3 comprising the steps of:
  • step (b) causing tegaserod tartrate form 3 to precipitate from the solution or suspension obtained in step (a); and (c) isolating the tegaserod tartrate form 3.
  • tegaserod tartrate is dissolved in step (a).
  • the solvent used in step (a) is acetonitrile.
  • the acetonitrile is heated to between about 70-90 0 C, preferably to about 82°C.
  • the tegaserod tartrate form 3 is caused to precipitate by cooling the solution or suspension obtained in step (a) to between about 20- 30 0 C.
  • the tegaserod tartrate form 3 is isolated by filtration.
  • the filtered tegaserod tartrate form 3 is washed, preferably with acetonitrile, preferably about 5 volumes.
  • the tegaserod tartrate form 3 is dried, particularly preferred is drying under reduced pressure, preferably a vacuum, preferably until a constant weight is achieved. Preferably the drying occurs at about 20-50 0 C, preferably about 45°C.
  • a novel crystalline form of tegaserod tartrate designated form 4, with a characteristic XRD spectrum having two or more peaks (preferably three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or all ten peaks) with 2 ⁇ values at 3.77, 7.34, 14.85, 17.07, 18.38, 18.79, 21.00, 24.18, 24.96, 25.28 ⁇ 0.2 °2 ⁇ .
  • a novel crystalline form of tegaserod tartrate designated form 4, having an XRPD trace substantially as shown in figure 3.
  • a novel crystalline form of tegaserod tartrate designated form 4, characterized by a DSC with endothermic peaks at about 98°C and about 148°C, preferably at about 97.78°C and about 148.13°C, all ⁇ 2°C.
  • a novel crystalline form of tegaserod tartrate designated form 4, having a DSC trace substantially as shown in figure 4.
  • step (b) causing tegaserod tartrate form 4 to precipitate from the solution or suspension obtained in step (a); and (c) isolating the tegaserod tartrate form 4.
  • tegaserod tartrate is dissolved in step (a).
  • the solvent one of the solvents or each solvent(s) used in step (a) is a C 1 -C 6 alcohol, preferably a C 1 -C 2 alcohol, preferably a primary alcohol, preferably the solvent is ethanol.
  • the solvent is ethanol.
  • the ethanol is heated to between about 70-90 0 C, preferably about 78°C.
  • the tegaserod tartrate form 4 is caused to precipitate by cooling the solution or suspension obtained in step (a), preferably to about 20-30 0 C.
  • the tegaserod tartrate form 4 is isolated by filtration.
  • the filtered tegaserod tartrate form 4 is washed, preferably with ethanol, preferably about 2 volumes.
  • the tegaserod tartrate form 4 is dried, particularly preferred is drying under reduced pressure, preferably under vacuum, preferably until a constant weight is achieved.
  • the drying occurs at about 20-50 0 C, preferably about 45°C.
  • a novel crystalline form of tegaserod tartrate designated form 5, with a characteristic XRD spectrum having two or more peaks (preferably three or more, four or more, five or more, six or more, or all seven peaks) with 2 ⁇ values at 4.04, 4.41, 6.21, 7.82, 19.39, 24.75, 25.39 ⁇ 0.2 °2 ⁇ .
  • a novel crystalline form of tegaserod tartrate designated form 5, having an XRPD trace substantially as shown in figure 5.
  • a novel crystalline form of tegaserod tartrate designated form 5, characterized by a DSC with an endothermic peak at about 157°C + 2°C, preferably at about 156.93°C ⁇ 2°C.
  • a fourteenth aspect according to the invention there is provided a novel crystalline form of tegaserod tartrate, designated form 5, having a DSC trace substantially as shown in figure 6.
  • a fifteenth aspect of the present invention there is provided a process for the preparation of tegaserod tartrate crystalline form 5 according to the invention comprising the steps of:
  • step (a) dissolving or suspending tegaserod tartrate, or tegaserod and tartaric acid, in one or more solvent(s); (b) causing tegaserod tartrate form 5 to precipitate from the solution or suspension obtained in step (a);
  • tegaserod tartrate is dissolved in step (a).
  • the solvent, one of the solvents or each solvent(s) used in step (a) is a C 1 -C 6 alcohol, preferably a C 3 -C 6 alcohol, preferably a secondary or tertiary alcohol, preferably the solvent is tert- butanol.
  • the tert-butanol is heated to between about 70-90 0 C, preferably about 82°C.
  • the tegaserod tartrate form 5 is caused to precipitate by cooling the solution or suspension obtained in step (a), preferably to about 20-30 0 C.
  • the tegaserod tartrate form 5 is isolated by filtration.
  • the filtered tegaserod tartrate form 5 is washed, preferably with tert-butanol, preferably about 5 volumes.
  • the tegaserod tartrate form 5 is dried, particularly preferred is drying under reduced pressure, preferably under vacuum, preferably until a constant weight is achieved.
  • the drying occurs at about 20-50 0 C, preferably about 45°C.
  • a novel crystalline form of tegaserod tartrate designated form 6, with a characteristic XRD spectrum having two or more peaks (preferably three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, or all fifteen peaks) with 2 ⁇ values at 3.9, 4.9, 7.6, 9.7, 12.5, 14.0, 14.6, 16.3, 18.0, 19.2, 19.5, 20.5, 23.0, 24.5 and 27.1 ⁇ 0.2 °2 ⁇ .
  • the novel crystalline form 6 of tegaserod tartrate has a characteristic XRD spectrum having two or more peaks (preferably three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, or all fifteen peaks) with 2 ⁇ values at 3.9, 4.9, 7.6, 9.7, 12.5, 14.03, 14.64, 16.27, 17.99, 19.18, 19.53, 20.52, 23.00, 24.48 and 27.05 ⁇ 0.2 °2 ⁇ .
  • a novel crystalline form of tegaserod tartrate designated form 6, with a characteristic XRD spectrum having peaks with 2 ⁇ values at 3.91 and 4.94 ⁇ 0.2 °2 ⁇ .
  • a novel crystalline form of tegaserod tartrate designated form 6, having an XRPD trace substantially as shown in figure 7.
  • a novel crystalline form of tegaserod tartrate designated form 6, characterized by a DSC with endothermic peaks at about 105 0 C and about 158°C, preferably at about 104.66 0 C and about 157.71°C, all ⁇ 2°C.
  • a novel crystalline form of tegaserod tartrate designated form 6, having a DSC trace substantially as shown in figure 8.
  • a process for the preparation of tegaserod tartrate crystalline form 6 according to the invention comprising the steps of:
  • step (b) causing tegaserod tartrate form 6 to precipitate from the solution or suspension obtained in step (a);
  • tegaserod tartrate is dissolved in step (a).
  • the solvent used in step (a) is dimethyl formamide (DMF).
  • DMF dimethyl formamide
  • the tegaserod tartrate form 6 is caused to precipitate by stirring at between about 20-35 0 C, preferably at about 26°C, preferably for about 1 hour.
  • the tegaserod tartrate form 6 is isolated by filtration.
  • the filtered tegaserod tartrate form 6 is washed, preferably with DMF.
  • the filtered tegaserod tartrate form 6 is dried, particularly preferred is drying under reduced pressure, preferably under vacuum, preferably until a constant weight is achieved.
  • drying occurs at about 20-50 0 C, preferably about 45°C.
  • a novel amorphous form of tegaserod tartrate According to a twenty-first aspect of the present invention there is provided a novel amorphous form of tegaserod tartrate.
  • a novel amorphous form of tegaserod tartrate having an XRPD trace substantially as shown in figure 9.
  • a novel amorphous form of tegaserod tartrate characterized by a DSC with an endothermic peak at about 120 0 C + 2°C, preferably at about 119.79°C ⁇ 2°C.
  • step (b) causing amorphous tegaserod tartrate to precipitate from the solution or suspension obtained in step (a); and (c) isolating the amorphous tegaserod tartrate.
  • tegaserod tartrate is dissolved in step (a).
  • the solvent one of the solvents or each solvent(s) used in step (a) is a C 1 -C 6 alcohol, preferably a C 3 -C 6 alcohol, preferably a primary alcohol, preferably the solvent is 1-butanol. Preferably about 25 volumes of 1-butanol are used.
  • the 1-butanol is heated to between about 50-60 0 C, preferably about 55°C.
  • the amorphous form is caused to precipitate by cooling the solution or suspension in step (b), preferably to about 20-30 0 C.
  • the amorphous form is isolated by filtration.
  • the filtered amorphous form is washed, preferably with 1-butanol, preferably about 5 volumes.
  • the filtered amorphous form is dried, particularly preferred is drying under reduced pressure, preferably under vacuum, preferably until a constant weight is achieved.
  • tegaserod tartrate 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 amorphous forms of tegaserod tartrate according to the above described aspects and embodiments have a chemical purity of greater than 90%, 95%, 96%, 97%, 98%, 99% or 99.9% (as measured by HPLC).
  • the crystalline or amorphous forms of tegaserod tartrate according to the above described aspects and embodiments have a polymorphic purity of greater than 90%, 95%, 96%, 97%, 98%, 99% or 99.9% (as measured by XRPD or DSC).
  • the tegaserod tartrate is obtained on an industrial scale, preferably in batches of 0.5kg, lkg, 5kg, 10kg, 50kg, 100kg, 500kg or more.
  • a twenty-sixth aspect according to the invention provides a pharmaceutical composition comprising any of the crystalline or amorphous forms of the present invention or prepared by any of the processes of the present 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 from the list comprising heartburn, bloating, postoperative ileus, abdominal pain and discomfort, epigastric pain, nausea, vomiting, regurgitation, intestinal pseudo-obstruction, irritable bowel syndrome and gastro-oesophageal reflux (preferably irritable bowel syndrome), comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of any of the crystalline or amorphous forms of the present invention or prepared by any of the processes of the present invention, or a therapeutically or prophylactically effective amount of a pharmaceutical composition of the present invention.
  • the patient is a mammal, preferably a human.
  • a gastrointestinal disorder for example, for use in the treatment or prevention of a gastrointestinal disorder.
  • the disorder is irritable bowel syndrome.
  • a twenty-ninth aspect provides the use of any of the crystalline or amorphous forms of the present invention or prepared by any of the processes of the present invention in the manufacture of a medicament for use in the treatment or prevention of a gastrointestinal disorder.
  • 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 tartrate form 3.
  • Figure 2 describes the DSC of tegaserod tartrate form 3.
  • Figure 3 describes the XRPD of tegaserod tartrate form 4.
  • Figure 4 describes the DSC of tegaserod tartrate form 4.
  • Figure 5 describes the XRPD of tegaserod tartrate form 5.
  • Figure 6 describes the DSC of tegaserod tartrate form 5.
  • Figure 7 describes the XRPD of tegaserod tartrate form 6.
  • Figure 8 describes the DSC of tegaserod tartrate form 6.
  • Figure 9 describes the XRPD of amorphous tegaserod tartrate.
  • Figure 10 describes the DSC of amorphous tegaserod tartrate.
  • the terms 'polymorph', 'polymorphic form', 'crystalline' and 'crystalline form' are used interchangeably.
  • the term 'reduced pressure' refers to an atmospheric pressure of below about 100 mbar, preferably below about 15 mbar, and the term 'vacuum' as used herein refers to an atmospheric pressure of below about 10 mbar.
  • 'XRD spectrum' and 'X-ray diffraction pattern' are used interchangeably herein and preferably refer to an X-ray powder diffraction (XRPD) trace, spectrum or pattern.
  • XRPD X-ray powder diffraction
  • the present invention provides novel polymorphs of tegaserod tartrate, a novel amorphous form of tegaserod tartrate, processes for their preparation and compositions comprising said crystalline and amorphous forms.
  • the processes disclosed are simple and amenable to scale up and are capable of providing these novel forms in consistent purity.
  • Particularly preferred embodiments comprise tegaserod tartrate form 3, form 4, form 5, form 6 or the amorphous form respectively, wherein each of the novel forms according to the invention comprises less than 10%, preferably less than 5%, more preferably less 1%, most preferably less than 0.1% of other forms of tegaserod irrespective of the scale of preparation.
  • the other forms include but are not limited to amorphous forms, hydrates, crystalline forms which are not the subject of this invention and, for example, an embodiment relating to tegaserod tartrate form 3 according to the present embodiment will comprise less than 10%, preferably less than 5%, more preferably less 1%, most preferably less than 0.1% of other forms of tegaserod including tegaserod tartrate forms 4-6 or the amorphous form.
  • a preferred process according to the invention for preparing any of the crystalline or amorphous forms of tegaserod tartrate disclosed herein and as claimed below comprises adding tegaserod tartrate, or tegaserod and tartaric acid, preferably tegaserod tartrate, to an organic solvent.
  • the solvent type is dependent on the crystalline or amorphous form desired.
  • form 3 is obtained from acetonitrile
  • form 4 is obtained from ethanol
  • form 5 is obtained from tert-butanol
  • form 6 is obtained from DMF
  • the amorphous form according to the invention is preferably obtained from 1-butanol.
  • the tegaserod tartrate can be completely or only partially dissolved and the process still falls within the scope of the invention.
  • the solvent is heated.
  • the solution is heated until the solution is clear.
  • the novel crystalline or amorphous form according to the invention is caused to precipitate from the tegaserod tartrate solution.
  • the precipitation is caused by cooling the solution until the precipitate is no longer soluble and is forced out of solution and a slurry is formed.
  • the solution is cooled to between about 20-35 0 C.
  • 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 most preferably is washed with acetonitrile when form 3 is prepared, ethanol when form 4 is prepared, tert-butanol when form 5 is prepared, DMF when form 6 is prepared and 1- butanol when the amorphous form is prepared, and dried.
  • the product is dried at a temperature that does not induce conversion of the crystalline or amorphous forms respectively or causes the resultant form to degrade.
  • the inventors have found that drying the product at between about 20-50 0 C, preferably about 45°C, is advantageous.
  • the solid product is dried under reduced atmospheric pressure, preferably until a constant weight is obtained.
  • the solid product is dried under vacuum.
  • a further embodiment of the invention comprises pharmaceutical compositions of the novel polymorphic or amorphous form(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 polymorphic or amorphous form(s) and uses of the pharmaceutical compositions to provide methods of treating patients suffering from gastrointestinal disorders comprising providing to a patient a pharmaceutically effective amount of these novel polymorphic or amorphous form(s).
  • Illustrative of the invention is a pharmaceutical composition comprising a novel polymorph or amorphous form of tegaserod tartrate according to the invention and one or more pharmaceutically acceptable excipient(s).
  • a further embodiment of the invention is a process for preparing a pharmaceutical composition comprising mixing a novel polymorph or amorphous form of tegaserod tartrate according to the invention and one or more pharmaceutically acceptable excipient(s).
  • Said composition may comprise solid pharmaceutical compositions which in certain embodiments may comprise tablets including for example dispersible tablets, capsules containing pellets, mini-tablets, powders or mixtures thereof, caplets, or any of the solid dosage forms that are within the repertoire of the skilled formulation scientist.
  • the invention comprises liquid formulations which may be prepared by mixing the crystalline or amorphous forms according to the invention with a pharmaceutically suitable liquid carrier or solvent.
  • 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 tartrate or amorphous form according to the invention.
  • a novel polymorph or amorphous form of tegaserod tartrate according to the invention substantially free of other crystalline or amorphous forms for the preparation of a medicament for treating a 5-HT 4 receptor mediated disorder in a subject in need thereof, preferably the purity is in the order of tegaserod tartrate form 3, form 4, form 5, form 6 or the amorphous form comprising less than 10%, preferably less than 5%, more preferably less 1%, most preferably less than 0.1% of other forms of tegaserod.
  • 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.
  • 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, crospovid
  • 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 or amorphous 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 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 but are not limited to other 5-HT 4 receptor agonists such as prucalopride, RS 67333 (l-(4-amino-5- chloro-2-methoxyphenyl)-3-(l-n-butyl-4-piperidinyl)-l-propanone), RS 67506 (l-(4-amino- 5-chloro-2-methoxyphenyl) -3- [1 - [2- [(methylsulphonyl) amino] ethyl] -4-piperidinyl] - 1 - propanone), cisapride, renzapride, norcisapride, mosapride, zacopride, tegaserod, SB 205149, SC 53116, BIMU 1, and BIMU 8; proton pump inhibitors such as omeprazole, rabeprazole, pantoprazole, and
  • the following examples describe specific methods for preparing crystalline and amorphous forms of tegaserod tartrate according to the invention.
  • the starting material comprises Ig of tegaserod tartrate.
  • Tegaserod tartrate was added to 1-butanol (25 volumes) and heated to about 55°C and then cooled to about 25-30 0 C for about 15 minutes. The slurry was filtered and washed with 1- butanol (5 volumes) and dried at about 45°C under vacuum until a constant weight was achieved. XRPD and DSC analysis data (see figures 9 and 10) confirmed that the product obtained was the novel amorphous form of tegaserod tartrate.
  • Tegaserod tartrate was dissolved in 25 volumes of acetonitrile and heated to 82°C. The solution was cooled to between 25-30 0 C for about 15 minutes. The resultant slurry was filtered, washed with 5 volumes of acetonitrate, and dried under vacuum at about 45°C until a constant weight was achieved.
  • Tegaserod tartrate was mixed in 20 volumes of ethanol and heated to 78°C. The reaction mixture was cooled to between 25-30 0 C for about 15 minutes. The resultant slurry was filtered, washed with 2 volumes of ethanol, and then dried under vacuum at 45°C until a constant weight was achieved.
  • Tegaserod tartrate was mixed in 25 volumes of tert-butanol and heated to 82°C. The reaction mixture was cooled to between 25-30 0 C for about 15 minutes. The resultant slurry was filtered, washed with 5 volumes of tert-butanol, and then dried under vacuum at 45°C until a constant weight was achieved. XRPD and DSC analysis data (see figures 5 and 6) confirmed that the product obtained was the novel polymorph form 5 of tegaserod tartrate.

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Abstract

La présente invention concerne de nouvelles formes amorphes et cristallines d'un sel de tartrate de tégasérod ainsi que des procédés de préparation de ces nouvelles formes. L'invention concerne également des compositions pharmaceutiques contenant ces nouvelles formes ainsi que les utilisations desdites compositions dans des méthodes de traitement de patients souffrant de troubles gastro-intestinaux.
PCT/GB2008/050988 2007-10-24 2008-10-24 Nouvelles formes cristallines et amorphes WO2009053750A2 (fr)

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IN2106MU2007 2007-10-24

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0297651A1 (fr) 1987-06-29 1989-01-04 Duphar International Research B.V Dérivés d'indole annulaires
US5510353A (en) 1991-03-22 1996-04-23 Sandoz Ltd. Certain aminoguanidine compounds, pharmaceutical compositions containing them and their use in treating gastrointestinal motility disorders and disorders associated with cephalic pain
WO1999017755A2 (fr) 1997-10-07 1999-04-15 Glaxo Group Limited Medicaments
WO2006116953A1 (fr) 2005-05-02 2006-11-09 Zentiva, A.S. Procede de preparation de tegaserod et de sels sélectionnés dérivés de ce composé

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008149154A2 (fr) * 2007-06-05 2008-12-11 Generics [Uk] Limited Nouveaux sels et nouvelles formes polymorphiques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0297651A1 (fr) 1987-06-29 1989-01-04 Duphar International Research B.V Dérivés d'indole annulaires
US5510353A (en) 1991-03-22 1996-04-23 Sandoz Ltd. Certain aminoguanidine compounds, pharmaceutical compositions containing them and their use in treating gastrointestinal motility disorders and disorders associated with cephalic pain
WO1999017755A2 (fr) 1997-10-07 1999-04-15 Glaxo Group Limited Medicaments
WO2006116953A1 (fr) 2005-05-02 2006-11-09 Zentiva, A.S. Procede de preparation de tegaserod et de sels sélectionnés dérivés de ce composé

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