US20020013358A1 - Indole derivatives - Google Patents

Indole derivatives Download PDF

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US20020013358A1
US20020013358A1 US09/450,462 US45046299A US2002013358A1 US 20020013358 A1 US20020013358 A1 US 20020013358A1 US 45046299 A US45046299 A US 45046299A US 2002013358 A1 US2002013358 A1 US 2002013358A1
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eletriptan hydrobromide
monohydrate
eletriptan
hydrobromide monohydrate
migraine
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Christopher Ian Dallmann
Ronald James Ogilvie
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Pfizer Inc
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Pfizer Inc
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Assigned to PFIZER INC. reassignment PFIZER INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DALLMANN, CHRISTOPHER IAN, OGILVIE, RONALD JAMES
Publication of US20020013358A1 publication Critical patent/US20020013358A1/en
Priority to US10/376,385 priority Critical patent/US7238723B2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • 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
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention relates to indole derivatives. More specifically the present invention relates to eletriptan hydrobromide monohydrate, to processes for the preparation thereof, to processes for its conversion to anhydrous eletriptan hydrobromide, and to the uses of, and to compositions containing, said monohydrate.
  • Eletriptan 3-([1-methylpyrrolidin-2(R)-yl]methyl)-5-(2-phenylsulphonylethyl)-1H-indole, has the formula:
  • Eletriptan is classified as a 5-HT 1B/1D receptor agonist and is particularly useful for the treatment of migraine and for the prevention of migraine recurrence.
  • WO-A-99/01135 discloses a pharmaceutical formulation including eletriptan hemisulphate and caffeine.
  • WO-A-96/06842 describes the anhydrous polymorphic alpha-and beta-hydrobromide salt forms of eletriptan.
  • the problem addressed by the invention disclosed therein is to obtain a salt form of eletriptan that is, inter alia, stable and essentially non-hygroscopic in nature. That problem is solved by the provision of a stable, anhydrous, alpha-form of eletriptan hydrobromide.
  • anhydrous beta-form of eletriptan hydrobromide that is also described therein is stated not to be a viable option for the development of a suitable solid dosage form of the drug because it is unstable and has a tendency to undergo polymorphic conversion to the alpha-form previously described on attempted further processing.
  • the problem addressed by the present invention is to provide a further stable, non-hygroscopic, crystalline form of eletriptan hydrobromide which has acceptable solubility and dissolution characteristics, and which can be economically prepared and processed to provide suitable solid dosage forms of the drug.
  • Eletriptan hydrobromide monohydrate has the formula (I):
  • Eletriptan hydrobromide monohydrate is, most advantageously, stable under normal conditions and essentially non-hygroscopic. Also included within the scope of the present invention are radiolabelled derivatives and any other isotopic variations of eletriptan hydrobromide monohydrate.
  • WO-A-96/06842 does not disclose the preparation of eletriptan hydrobromide monohydrate.
  • the anhydrous alpha-form of eletriptan hydrobromide mentioned therein is essentially non-hygroscopic under normal conditions as is demonstrated by the described hygroscopicity test results. These results show that it absorbs a maximum of 1.23% by weight of water on standing for 4 weeks at 40° C. and 90% relative humidity, that is under extreme conditions (an absorption of 3.9% by weight of water by anhydrous eletriptan hydrobromide would be required to form eletriptan hydrobromide monohydrate in this experiment).
  • Eletriptan hydrobromide monohydrate has been made available by the surprising finding that treatment of a solution of eletriptan in water, or in a suitable organic solvent containing a sufficient amount of water to facilitate formation of the required monohydrate, with hydrogen bromide or a suitable source thereof, e.g. ammonium bromide, produces said monohydrate.
  • the present invention therefore provides a process for the preparation of eletriptan hydrobromide monohydrate from eletriptan.
  • Preferred organic solvents for use in this process include water-miscible or -immiscible organic solvents such as tetrahydrofuran (THF), acetone, methyl ethyl ketone, 1,2-dimethoxyethane, methyl isobutyl ketone, ethyl acetate and a C 1 -C 4 alkanol (e.g. isopropanol).
  • Most preferred organic solvents are THF and acetone.
  • the solution of eletriptan may be treated with hydrogen bromide either in gaseous form or in the form of a suitable solution, e.g. dissolved in water, acetic acid, acetone or THF.
  • any form of eletriptan hydrobromide other than the monohydrate, including mixtures thereof, may be converted to eletriptan hydrobromide monohydrate by crystallisation from water, or from a suitable organic solvent containing a sufficient amount of water to facilitate formation of the required monohydrate.
  • suitable organic solvents include acetone, THF, 1,2-dimethoxyethane and a C 1 -C 4 alkanol, e.g. methanol.
  • any hydrated form of eletriptan hydrobromide including eletriptan hydrobromide monohydrate, or mixtures thereof, may be converted to anhydrous eletriptan hydrobromide under suitable dehydration conditions.
  • suitable conditions include reslurry in, or crystallisation from, a suitable organic solvent, optionally with heating. Small amounts of water are tolerated in the organic solvent used in this process.
  • dehydration conditions may optionally involve distillation or azeotropic distillation of the organic solvent used to remove the water associated with the hydrate.
  • Preferred organic solvents for use in this process include toluene, acetone, THF and acetonitrile.
  • organic solvents include ethanol, n-propanol, isopropanol, t-butanol, industrial methylated spirit, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, n-butyl acetate, cyclohexane, t-amyl alcohol, xylene and dichloromethane.
  • this conversion may be effected by drying the hydrate, e.g. eletriptan hydrobromide monohydrate, either under reduced pressure and/or at elevated temperatures, or in a low-humidity environment.
  • Eletriptan hydrobromide monohydrate may be used for the treatment of a disease or condition for which a selective agonist of 5-HT 1 receptors, and particularly of 5-HT 1B/1D receptors, is indicated.
  • Such conditions include migraine, recurrent migraine, hypertension, depression, emesis, anxiety, an eating disorder, obesity, drug abuse, cluster headache, pain, chronic paroxysmal hemicrania and headache associated with a vascular disorder.
  • Eletriptan hydrobromide monohydrate can be administered alone but it will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • eletriptan hydrobromide monohydrate can be administered orally or sublingually in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, which may be formulated as immediate- or controlled-release, or fast-dissolving, compositions.
  • Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine, disintegrants such as starch, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, glyceryl benhenate and talc may be included.
  • excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine
  • disintegrants such as starch, croscarmellose sodium and certain complex silicates
  • granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, glyceryl benhenate and talc may be included.
  • Solid compositions of a similar type may also be employed as fillers in gelatin capsules.
  • Preferred excipients in this regard include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • eletriptan hydrobromide monohydrate may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
  • Eletriptan hydrobromide monohydrate can also be injected parenterally, for example, intravenously, intraperitoneally, intrathecally, intraventricularly, intrasternally, intracranially, intramuscularly or subcutaneously, or it may be administered by infusion techniques. It is best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • the aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
  • suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.
  • the daily dosage level of eletriptan hydrobromide monohydrate will usually be from 0.1 to 4 mg/kg (in single or divided doses).
  • tablets or capsules of eletriptan hydrobromide monohydrate may contain from 5 to 240 mg, preferably from 5 to 100 mg, of active compound for administration singly or two or more at a time, as appropriate.
  • the physician in any event will determine the actual dosage which will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient.
  • the above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.
  • Eletriptan hydrobromide monohydrate can also be administered intranasally or by inhalation and is conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container or a nebuliser with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A [trade mark] or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (H
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurised container or nebuliser may contain a solution or suspension of the active compound, e.g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate.
  • Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of eletriptan hydrobromide monohydrate and a suitable powder base such as lactose or starch.
  • eletriptan hydrobromide monohydrate may be administered intranasally by delivery from a non-pressurised unit or multi-dose, pump-type device.
  • eletriptan hydrobromide monohydrate can be administered in the form of a suppository or pessary, or it may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder. Eletriptan hydrobromide monohydrate may also be transdermally administered by the use of a skin patch.
  • eletriptan hydrobromide monohydrate can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
  • a suitable lotion or cream suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyidodecanol, benzyl alcohol and water.
  • Suitable formulations of eletriptan hydrobromide monohydrate are similar to those disclosed in WO-A-92/06973, WO-A-96/06842 and WO-A-99/01135.
  • Preferred formulations of eletriptan hydrobromide monohydrate, particularly for use in the prevention of migraine recurrence, include dual-, sustained-, controlled-, delayed- or pulsed-release formulations.
  • Sustained-release dosage forms are designed to release eletriptan hydrobromide monohydrate to the gastro-intestinal tract of a patient over a sustained period of time following administration of the dosage form to the patient.
  • Suitable dosage forms include:
  • a matrix containing the active compound may be formed into a multiparticulate and/or coated with an impermeable coating provided with an aperture.
  • Pulsed-release formulations are designed to release the active compound in pulses over a sustained period of time following administration of the dosage form to the patient. The release may then be in the form of immediate- or sustained-release. Delay in release may be achieved by releasing the drug at particular points in the gastro-intestinal tract or by releasing drug after a pre-determined time. Pulsed-release formulations may be in the form of tablets or multiparticulates or a combination of both. Suitable dosage forms include:
  • capsules containing an erodible plug e.g. see U.S. Pat. No. 5,474,784.
  • Dual-release formulations can combine the active compound in immediate-release form with additional active compound in sustained-release form.
  • a bilayer tablet can be formed with one layer containing eletriptan hydrobromide monohydrate in an immediate-release form and the other layer containing eletriptan hydrobromide monohydrate embedded in a matrix from which it is released by diffusion or erosion.
  • Dual-release formulations can also combine the active compound in immediate-release form with additional active compound in pulsed-release form.
  • a capsule containing an erodible plug could liberate active compound initially and after a predetermined period of time further active compound may be delivered in immediate- or sustained-release form.
  • Preferred drug dual release profiles include
  • Delayed-release formulations are designed to release the active compound a predetermined time after administration.
  • the release from delayed-release formulations may be in the form of immediate-release or sustained-release.
  • Controlled-release formulations impart control with respect to the rate of release or the time of release, or both, of the active compound and include sustained-, pulsed-, dual- and delayed-release formulations.
  • Eletriptan (2 kg) was dissolved in acetone (24.2 L) and filtered. The mixture was diluted with further acetone (7.4 L) and water (2.36 L) added. A chilled ( ⁇ 5° C.) mixture of a solution of 48% by weight hydrogen bromide in water (0.863 kg) and acetone (12.4 L) was added in portions over about a 6 hour period whilst maintaining the temperature below 25° C. throughout the addition. Full transfer of the hydrogen bromide solution was ensured by washing the residues into the reaction mixture using further acetone (2.4 L). The resulting slurry was granulated and chilled prior to collection of the product obtained by filtration. The product was washed carefully with acetone and then dried under reduced pressure and at ambient temperature in the presence of a water reservoir to provide eletriptan hydrobromide monohydrate (1.75 kg, 70%). This material was then milled before further use.
  • Eletriptan (1.9 kg) was dissolved in a solution of 97.5:2.5, by volume, THF:water (30 L) and filtered. A solution of hydrogen bromide (ca. 48% by weight) in water (0.87 kg) was added to the solution at 15-25° C. A dense crystalline slurry was formed. The slurry was heated under reflux for approximately one hour. The slurry was cooled to from 15 to 20° C. and granulated for a minimum of 1 hour. The product was filtered and washed with THF (10 L) to provide eletriptan hydrobromide monohydrate (2.3 kg).
  • Eletriptan (25 g) was dissolved in a solution of 95:5, by volume, THF:water and filtered. A solution of hydrogen bromide (ca. 48% by weight) in water (10.7 g) was added to the solution at 15-25° C. A dense crystalline slurry was formed. The slurry was heated under reflux for approximately one hour. The slurry was cooled to from 15 to 25° C. The product was filtered and washed with THF (50 ml) to produce eletriptan hydrobromide monohydrate (28.4 g, 96%).
  • Eletriptan hydrobromide (4.91 g) was dissolved in a mixture of acetone (10 ml) and water (1.85 ml) by heating under reflux. The mixture was treated with acetone (63.6 ml), dropwise over about 20 minutes, and then cooled to ambient temperature. The mixture was granulated overnight (16 hours), cooled to 0-5° C. and granulated at this temperature for a further hour. The resulting solid was filtered, washed with acetone (3 ml) and then dried under reduced pressure and at ambient temperature to give eletriptan hydrobromide monohydrate (4.8 g).
  • FIG. 6 shows the DSC thermogram obtained for this product by the method of paragraph (b) of the Analytical section below. This was consistent with that previously obtained for the alpha-form of anhydrous eletriptan hydrobromide described in WO-A-96/06842.
  • FIG. 7 shows the DSC thermogram obtained for this product by a similar method to that of paragraph (b) of the Analytical section below except that a 10 mg weight of sample and a heating rate of 40° C./minute were used.
  • This showed the product to be a mixture of the alpha- and beta-forms of anhydrous eletriptan hydrobromide, both as disclosed in WO-A-96/06842, the former with an endotherm maximum at 176° C. and the latter with an endotherm maximum at 161° C. No evidence for the presence of eletriptan hydrobromide monohydrate was detected in this DSC analysis.
  • Eletriptan hydrobromide monohydrate was blended with lactose for 10 minutes and then microcrystalline cellulose and croscarmellose sodium added. The mixture was blended for 20 minutes and screened through a 500 micron screen. The screened material was blended for a further 20 minutes and a first portion of magnesium stearate (0.75% w/w) added. The mixture was roller compacted and blended for 20 minutes then a second portion of magnesium stearate (0.50% w/w) added. The mixture was compressed into tablets each containing a 80 mg dose of eletriptan.
  • the tablets were then film-coated using Opadry Orange (trade mark) film coat (OY-LS-23016) as a 12% solids system at 3.0% w/w followed by Opadry Clear (trade mark) overcoat (YS-2-19114-A) as a 5% solution at 0.5% w/w.
  • Opadry Orange trade mark
  • OY-LS-23016 Opadry Clear film coat
  • YS-2-19114-A Opadry Clear
  • the powder X-ray diffraction (PXRD) pattern was determined using a Siemens D5000 powder X-ray diffractometer fitted with an automatic sample changer, a theta-theta goniometer, automatic beam divergence slits, a secondary monochromator and a scintillation counter.
  • the sample was prepared for analysis by packing the powder sample into a 12 mm diameter, 0.25 mm deep cavity that had been cut into a silicon wafer specimen mount.
  • the analysis was performed with the goniometer running in step-scan mode set for a 5 second count per 0.02° step over a two-theta range of 2° to 55°.
  • FIG. 1 shows the PXRD pattern obtained.
  • Table 1 shows the peak listings for FIG. 1 in which dA° is a measurement of the interplanar spacing and I/I i is a measurement of the relative intensity.
  • DSC Differential scanning calorimetry
  • FIG. 2 shows the DSC thermogram obtained.
  • the DSC thermogram of FIG. 2 shows a broad endotherm at 103° C. due to the dehydration of the monohydrate followed by a melting endotherm at 135° C.
  • FIG. 3 shows the moisture sorption isotherm obtained for eletriptan hydrobromide monohydrate. This isotherm shows that above 6%RH the sample remains as a monohydrate but at 0%RH the material has lost all of the 3.8% w/w of water associated with its monohydrate molecular structure. Once the monohydrate has formed there is very little additional moisture sorbed and within the range 10 to 90% RH less than 0.3% w/w of water is sorbed. These data illustrate that eletriptan hydrobromide monohydrate is essentially non-hygroscopic.
  • Infrared (IR) spectroscopy was performed with a Nicolet 800 FT-IR spectrometer fitted with a d-TGS detector. The spectrum was acquired at 2 cm ⁇ 1 resolution from a KBr disc preparation of the sample.
  • FIGS. 4 and 5 show the IR spectra obtained.
  • Table 2 gives the peak listing for FIGS. 4 and 5 in which the wavenumber (cm ⁇ 1 ) of each peak is recorded.
  • TABLE 2 Peak position and intensity data from FIGS. 4 and 5 cm ⁇ 1 % T 406.9 76.26 429.6 58.71 456.6 70.18 473.9 74.14 497.1 61.84 529.2 47.58 553.9 61.60 566.4 55.54 592.2 64.48 601.1 62.96 606.2 64.21 642.2 50.81 665.0 62.00 667.3 61.99 689.1 44.63 729.5 41.77 747.8 42.52 767.2 55.12 793.0 61.03 807.2 52.47 822.0 61.96 841.2 77.97 852.8 82.78 870.1 72.30 876.3 75.82 890.9 81.30 926.3 75.29 937.9 82.07 948.9 83.39 970.5 80.26 985.0 74.49

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050245591A1 (en) * 2003-07-23 2005-11-03 Pfizer Inc. Process
US20080287519A1 (en) * 2007-05-01 2008-11-20 Marioara Mendelovici Amorphous eletriptan hydrobromide and process for preparing it and other forms of eletriptan hydrobromide
US20080319205A1 (en) * 2007-05-29 2008-12-25 Roman Bednar Process for preparing 5-bromo-3-[(R)-1-methyl-pyrrolidin-2-ylmethyl]-1H-indole
US20130023672A1 (en) * 2010-01-19 2013-01-24 Srinivasa Rao Venturi PROCESS FOR PREPARING ELETRIPTAN HYDROBROMIDE HAVING a-FORM

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0018968D0 (en) * 2000-08-02 2000-09-20 Pfizer Ltd Particulate composition
JP2006522790A (ja) 2003-04-11 2006-10-05 ファイザー・インク エレトリプタンと重炭酸ナトリウムを含む医薬組み合わせ物
GB0317229D0 (en) * 2003-07-23 2003-08-27 Pfizer Ltd Improved process
EP2225224A2 (en) * 2007-12-17 2010-09-08 Actavis Group PTC EHF Novel hemioxalate salt of eletriptan
WO2010097703A1 (en) * 2009-02-25 2010-09-02 Actavis Group Ptc Ehf Highly pure eletriptan or a pharmaceutically acceptable salt thereof substantially free of eletriptan n-oxide impurity
WO2010116386A2 (en) * 2009-04-08 2010-10-14 Biophore India Pharmaceuticals Pvt. Ltd. Novel polymorph of eletriptan hydrobromide and process for the preparation thereof
WO2014063752A1 (en) 2012-10-26 2014-05-01 Synthon Bv Process for making crystalline form alpha of eletriptan hydrobromide
CN103893112A (zh) * 2012-12-31 2014-07-02 重庆圣华曦药业股份有限公司 氢溴酸依来曲普坦注射液
CN107954947A (zh) * 2016-10-14 2018-04-24 北京莱瑞森医药科技有限公司 沃替西汀氢溴酸盐晶型c及其制备方法

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3952741A (en) * 1975-01-09 1976-04-27 Bend Research Inc. Controlled release delivery system by an osmotic bursting mechanism
FR2624732B1 (fr) * 1987-12-21 1991-02-15 Synthelabo Formulation pharmaceutique a liberation prolongee
US5474784A (en) * 1990-03-02 1995-12-12 British Technology Group Limited Dispensing device
US5545644A (en) * 1990-10-15 1996-08-13 Pfizer Inc. Indole derivatives
RU2095360C1 (ru) 1990-10-15 1997-11-10 Пфайзер Инк. Производные индола, их оптические изомеры и фармацевтически приемлемые соли
US5464633A (en) * 1994-05-24 1995-11-07 Jagotec Ag Pharmaceutical tablets releasing the active substance after a definite period of time
GB9417310D0 (en) * 1994-08-27 1994-10-19 Pfizer Ltd Therapeutic agents
GB9510223D0 (en) * 1995-05-20 1995-07-19 Pfizer Ltd Therapeutic agent
TW448172B (en) * 1996-03-08 2001-08-01 Pharmacia & Upjohn Co Llc Novel hydroxamic acid derivatives useful for the treatment of diseases related to connective tissue degradation
US5998462A (en) * 1996-12-16 1999-12-07 Allelix Biopharmaceuticals Inc. 5-alkyl indole compounds
GB9704498D0 (en) * 1997-03-05 1997-04-23 Glaxo Wellcome Spa Chemical compound
PL337803A1 (en) 1997-07-03 2000-09-11 Pfizer Pharmaceutic agents containing eletriptane hemisulphate and caffeine

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050245591A1 (en) * 2003-07-23 2005-11-03 Pfizer Inc. Process
US7164030B2 (en) * 2003-07-23 2007-01-16 Pfizer Inc. Process
US20080287519A1 (en) * 2007-05-01 2008-11-20 Marioara Mendelovici Amorphous eletriptan hydrobromide and process for preparing it and other forms of eletriptan hydrobromide
EP2093224A1 (en) 2007-05-01 2009-08-26 Plus Chemicals B.V. Process for preparing eletriptan hydrobromide form beta
EP2093225A1 (en) 2007-05-01 2009-08-26 Plus Chemicals B.V. Process for preparing crystalline eletriptan hydrobromide form ß
US20080319205A1 (en) * 2007-05-29 2008-12-25 Roman Bednar Process for preparing 5-bromo-3-[(R)-1-methyl-pyrrolidin-2-ylmethyl]-1H-indole
US20130023672A1 (en) * 2010-01-19 2013-01-24 Srinivasa Rao Venturi PROCESS FOR PREPARING ELETRIPTAN HYDROBROMIDE HAVING a-FORM
US8754239B2 (en) * 2010-01-19 2014-06-17 Sms Pharmaceuticals Limited Process for preparing eletriptan hydrobromide having α-form

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