WO2006010078A2 - Forme polymorphe de chlorhydrate de naratriptane - Google Patents

Forme polymorphe de chlorhydrate de naratriptane Download PDF

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Publication number
WO2006010078A2
WO2006010078A2 PCT/US2005/024435 US2005024435W WO2006010078A2 WO 2006010078 A2 WO2006010078 A2 WO 2006010078A2 US 2005024435 W US2005024435 W US 2005024435W WO 2006010078 A2 WO2006010078 A2 WO 2006010078A2
Authority
WO
WIPO (PCT)
Prior art keywords
naratriptan hydrochloride
hydrochloride
naratriptan
crystalline form
methyl
Prior art date
Application number
PCT/US2005/024435
Other languages
English (en)
Other versions
WO2006010078A3 (fr
Inventor
Aminul Islam
Katam Sahadev
Madadi Vijaypal Reddy
Ruturaj Vijay Kulkarni
Mohammed Mohosin Layek
Chandan Bhar
Original Assignee
Dr. Reddy's Laboratories Ltd.
Dr. Reddy's Laboratories, Inc.
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 Dr. Reddy's Laboratories Ltd., Dr. Reddy's Laboratories, Inc. filed Critical Dr. Reddy's Laboratories Ltd.
Publication of WO2006010078A2 publication Critical patent/WO2006010078A2/fr
Publication of WO2006010078A3 publication Critical patent/WO2006010078A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a new crystalline form of N-Methyl-3-(1- methyl-4-piperidinyl)-1 H-indole-5-ethanesulfonamide hydrochloride having the formula I.
  • the present invention also relates to a process for preparing the crystalline form and a pharmaceutical composition comprising the crystalline form.
  • N-Methyl-3-(1-methyl-4-piperidinyl)-1 H-indole-5- ethanesulfonamide hydrochloride is also known by the name "naratriptan hydrochloride.”
  • Naratriptan hydrochloride is the active ingredient in pharmaceutical products being sold using the trademark AMERGE, for treating migraine.
  • the AMERGE products are tablets for oral administration, containing either 1.11 or 2.78 mg of naratriptan hydrochloride, equivalent respectively to 1 and 2.5 mg of naratriptan.
  • N-Methyl-3-(1-methyl-4-piperidinyl)-1 H-indole-5- ethanesulfonamide hydrochloride of this invention is useful in the treatment of migraine.
  • polymorphism means that the substances exist in more than one form, such as one or more different crystalline forms, a noncrystalline (amorphous) form, solvates containing stoichiometric or nonstocihiometric amounts of a solvent, etc.
  • the subject of polymorphism has become very interesting in the field of pharmaceuticals, since different polymorphic forms tend to have different stabilities, solubilities, and processing properties, and frequently one of polymorphic forms of a given drug may exhibit superior bioavailability and consequently show a higher activity when compared to the other polymorphs.
  • the invention provides naratriptan hydrochloride having an X-ray diffraction pattern substantially in accordance with Fig. 1.
  • the invention provides naratriptan hydrochloride having a differential scanning calorimetry curve substantially in accordance with Fig. 2
  • the invention provides naratriptan hydrochloride having an infrared absorption spectrum substantially in accordance with Fig. 3.
  • the invention provides a process for preparing a crystalline form of naratriptan hydrochloride, comprising:
  • Fig. 1 is an X-ray powder diffraction pattern of the new crystalline form of naratriptan hydrochloride.
  • Fig. 2 is a differential scanning calorimeter thermogram of the new crystalline form of naratriptan hydrochloride.
  • Fig. 3 is a Fourier transform infrared absorption spectrum of the new crystalline form of naratriptan hydrochloride.
  • Fig. 4 is a table showing the X-ray powder diffraction peaks and calculated d- values for the new crystalline form of naratriptan hydrochloride.
  • the new crystalline form is characterized by the following data, obtained from a representative sample:
  • Infrared absorption (in KBr) peaks at about: 523, 582, 586, 638, 694, 763, 779, 807, 858, 889, 923, 955, 959 , 1067, 1109, 1158, 1232, 1274, 1315, 1349, 1404, 1429, 1452, 1474, 1543, 1577, 1652, 2361 , 2559, 2693, 2965, 3228 crr ⁇ 1 (a representative spectrum being shown as Figure 3)
  • the X-ray powder diffraction ("XRD") pattern was obtained using Cu K-alpha 1 radiation.
  • the instrument was equipped with fine focus X-ray tube.
  • the tube voltage and amperage were set at 50 KV and 34 mA respectively.
  • the divergence and scattering slits were set at 1/2 degree and receiving slit at 015 mm.
  • Diffracted radiation was detected by a scintillation counter detector, and a 0 to 20 continuous scan at 3 degrees/minute from 3 to 45 degrees was used.
  • a standard was analyzed to check the instrumental alignment, then the data were collected and analyzed using samples prepared for analysis by placing them in a standard sample holder From the XRD pattern, d-values were calculated, as summarized in Fig. 4.
  • DSC Differentional scanning calorimetry
  • IR infrared spectrum in the solid state as a potassium bromide dispersion using a Perkin- Elmer 1650 Fourier transform infrared spectrophotometer.
  • the starting compound can be dissolved at an elevated temperature, up to the boiling point of the solvent, to maximize the solution concentration.
  • the temperature chosen for dissolving the compound must not be so high that the compound degrades.
  • additional steps can be performed to increase product yield, and/or to enhance purity of the product.
  • a greater or lesser amount of solvent will frequently be removed, such as by evaporation, to increase solute concentration and minimize the amount of solute that remains in solution at the crystallization temperatures.
  • the impurity level of the solution before crystallization such as by absorption of the impurities using an absorbent such as activated charcoal.
  • the charcoal can be mixed with the solution, and then removed by filtration or other separation means, or the solution can be passed through a stationary bed of the charcoal.
  • the time for crystallization will vary, depending on the solution concentration, the temperature chosen, and the use of techniques such as seeding. Selection of the crystallization time for optimal yields can be determined by simple experimentation and is well within the ordinary skill in the art.
  • composition means a composition suitable for human pharmaceutical use, comprising at least one active ingredient and at least one pharmaceutical excipient.
  • the pharmaceutical composition containing the crystalline form of naratriptan hydrochloride may be in the forms normally employed, such as: tablets, capsules, powders, syrups, solutions, suspensions and the like, optionally containing flavoring agents, sweeteners, etc., in suitable solid or liquid carriers or diluents; and in suitable sterile media to form injectable solutions or suspensions.
  • Such compositions typically contain from 0.5 to 25 %, preferably 0.5 to 15 % by weight of active ingredient, the remainder of the composition being pharmaceutically acceptable excipients.
  • the crystalline form of the formula I as defined above is clinically administered to mammals, including man, via either oral, nasal, pulmonary, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, or intranasalmeans. Administration by the oral route is preferred, being more convenient and avoiding the possible pain and irritation of injection.
  • Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions.
  • the active ingredient will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage.
  • the polymorphic form can be combined with a suitable solid or liquid carrier or diluents to form capsules, tablets, powders, syrups, solutions, suspensions and the like.
  • the pharmaceutical compositions may, if desired, contain additional components such as flavorants, sweeteners, other excipients and the like.
  • the crystalline form can be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
  • solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or salts with base of the compounds.
  • Aqueous solutions with the active ingredient dissolved in polyhydroxylated castor oil may also be used for injectable solutions.
  • the injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.
  • the preparation may contain the crystalline form of the present invention dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
  • the carrier may contain additives such as solubilizing agents, such as propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin or preservatives such as parabenes.
  • Tablets, dragees or capsules having talc and / or a carbohydrate carried binder or the like are particularly suitable for any oral application.
  • carriers for tablets, dragees or capsules include lactose, corn starch and / or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet production method is exemplified using the following ingredients: 1) Active ingredient 1.1 g
  • the ingredients 1-4 are uniformly moistened with an aqueous solution of ingredient 5 and granulated after drying under reduced pressure.
  • Ingredient 6 is added and granules are compressed by a tableting machine to prepare 1000 tablets, each containing 2.78 mg of the active ingredient.
  • the compound N-Methyl-3-(1-methyl-4-piperidinyl)-1 H-indole-5- ethanesulfonamide hydrochloride can be prepared by any of a number of processes, and the present invention is not dependent on a particular synthetic method. Further, any polymorphic form of the compound is suitable for use to prepare the crystalline form of this invention. The crystallization of the polymorphic form of this invention can be performed as a final step in a synthesis of the compound, and it is not always necessary to isolate a product having another polymorphic form before performing the crystallization.
  • naratriptan hydrochloride The crystalline form of naratriptan hydrochloride was prepared by dissolving 90 grams of N-MethyI-3-(1-methyl-4-piperidinyl)-1 H-indole-5-ethanesulfonamide hydrochloride in a mixture of 1080 ml of methanol and 1620 ml of water. 9 grams of activated charcoal were added and the mixture was stirred for 60 to 90 minutes at a temperature 50 to 60 0 C, then filtered through a celite bed at 40 to 5O 0 C to remove the charcoal. The bed was washed with 200 ml of a 2:3 mixture of methanol and water.
  • the solution was concentrated under reduced pressure at a temperature of 40 to 5O 0 C to a volume of 450 to 500 ml .
  • the solution was cooled to a temperature 5 to 10 0 C and stirred for 40 to 60 minutes.
  • Solids were isolated by filtration and washed with 180 ml of methanol, then dried in a vacuum oven under 500 to 600 mm Hg pressure for 3 to 5 hours at a temperature of 50 to 6O 0 C to give 80 grams of the crystalline form of N-methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5- ethanesulfonamide hydrochloride having the XRD pattern of Fig. 1 , the DSC curve of Fig. 2, and the infrared absorption spectrum of Fig. 3.
  • the table of Fig. 4 was prepared to summarize the data from the XRD pattern, and includes calculated d-spacing values for the new crystalline form.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Selon l'invention, du chlorhydrate de naratriptane à nouvelle forme cristalline est préparé au cours d'un processus qui consiste à fournir une solution de chlorhydrate de naratriptane dans un solvant polaire, à refroidir ladite solution à des températures comprises entre 0 et 20°C afin de former des cristaux, et à isoler le chlorhydrate de naratriptane.
PCT/US2005/024435 2004-07-08 2005-07-08 Forme polymorphe de chlorhydrate de naratriptane WO2006010078A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN657/CHE/2004 2004-07-08
IN657CH2004 2004-07-08

Publications (2)

Publication Number Publication Date
WO2006010078A2 true WO2006010078A2 (fr) 2006-01-26
WO2006010078A3 WO2006010078A3 (fr) 2006-10-05

Family

ID=35785777

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2005/024435 WO2006010078A2 (fr) 2004-07-08 2005-07-08 Forme polymorphe de chlorhydrate de naratriptane

Country Status (1)

Country Link
WO (1) WO2006010078A2 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5786473A (en) * 1993-09-29 1998-07-28 Glaxo Group Limited Process for the preparation of n-methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethanesulphonamide
US20030181432A1 (en) * 2000-06-29 2003-09-25 Lancaster Robert William Process for preparing and harvesting crystalline particles

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5786473A (en) * 1993-09-29 1998-07-28 Glaxo Group Limited Process for the preparation of n-methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethanesulphonamide
US20030181432A1 (en) * 2000-06-29 2003-09-25 Lancaster Robert William Process for preparing and harvesting crystalline particles

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BRITTAIN H.G.: 'Polymorphism in Pharmaceutical Solids' 1999, MARCEL DEKKER, INC., page 2, AND 183 - 226, XP002350313 *

Also Published As

Publication number Publication date
WO2006010078A3 (fr) 2006-10-05

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