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WO2009118758A2 - Nouvelles formes cristallines de succinate de desvenlafaxine - Google Patents

Nouvelles formes cristallines de succinate de desvenlafaxine Download PDF

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Publication number
WO2009118758A2
WO2009118758A2 PCT/IN2009/000191 IN2009000191W WO2009118758A2 WO 2009118758 A2 WO2009118758 A2 WO 2009118758A2 IN 2009000191 W IN2009000191 W IN 2009000191W WO 2009118758 A2 WO2009118758 A2 WO 2009118758A2
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WO
WIPO (PCT)
Prior art keywords
reaction mixture
crystalline form
desmethylvenlafaxine
succinate
desmethylvenlafaxine succinate
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/IN2009/000191
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English (en)
Other versions
WO2009118758A3 (fr
Inventor
Rajamannar Thennati
Rajeev Budhdev Rehani
Nischalkumar Vinodbhai Patel
Riteshkumar Rajnikant Kansara
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.)
Sun Pharmaceutical Industries Ltd
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Sun Pharmaceutical Industries Ltd
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Filing date
Publication date
Application filed by Sun Pharmaceutical Industries Ltd filed Critical Sun Pharmaceutical Industries Ltd
Publication of WO2009118758A2 publication Critical patent/WO2009118758A2/fr
Anticipated expiration legal-status Critical
Publication of WO2009118758A3 publication Critical patent/WO2009118758A3/fr
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/64—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/10—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to novel crystalline forms of the succinate salt of 4-[2- (dimethylamino)-l-(l-hydroxycyclohexyl)ethyl]phenol, a compound of formula I, also known as O -desmethylvenlafaxine or desvenlafaxine.
  • Form II of the '838 patent is also a crystalline monohydrate, which exhibits a DSC endotherm at 127 0 C and which when analyzed by XRPD has characteristic 2-theta peaks at 13.18, 14.04, 14.35, 14.66, 16.68, 17.67, 19.24, 25.13 and 31.78.
  • Crystalline Form III of the '838 patent is reported to be a hydrate (between a hemihydrate and a monohydrate), which when analyzed by XRPD exhibits characteristic 2-theta peaks at 13.74, 22.55 and 32.42.
  • Crystalline Form IV of the '838 patent is an anhydrous form with a DSC endotherm at 145 0 C, and which when analyzed by XRPD exhibits characteristic 2-theta peaks at 11.29, 17.22, 19.64, 20.91, 21.61, 28.86, 29.80, 30.60, 36.85 and 37.70.
  • the amorphous form of desvenlafaxine succinate reported in the '838 patent exhibits a DSC endotherm at 120 C.
  • Polymorphism is often characterized as the ability of a substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice.
  • Polymorphs and/or solvates of a pharmaceutical solid can have different chemical and physical properties, including melting point, chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure,, density, sensitivity to conditions such as humidity, light, heat, flowability and compressibility. These properties can have a direct effect on the ability to process and/or manufacture the drug substance and the drug product, as well as on drug product stability, dissolution, and bioavailability. Thus, polymorphism can affect the quality, safety, and efficacy of the drug product.
  • the discovery of new polymorphic forms provides an opportunity to improve performance characteristics of a pharmaceutical product. There is need in the art for polymorphic forms of O-desmethylvenlafaxine succinate.
  • the present invention provides crystalline Form V of O-desmethylvenlafaxine succinate, wherein the crystalline form exhibits an X-Ray Powder Diffraction pattern having characteristic peaks expressed in degrees 20 ( ⁇ 0.2° 2 ⁇ ) at 12.15, 13.17, 14.67, 15.8, 19.69, 20.45, 22.27, 24.40, 26.43, 28.44 and 33.69.
  • the present invention provides a process for preparing crystalline Form V of O- desmethylvenlafaxine succinate comprising the steps of a. combining O-desmethylvenlafaxine, succinic acid and toluene to form a reaction mixture; b. heating the reaction mixture; and c. cooling the reaction mixture of step b to obtain crystalline Form V of O-desmethylvenlafaxine succinate.
  • the present invention provides a process for preparing crystalline Form VI of O- desmethylvenlafaxine succinate comprising the steps of a. combining 0-desmethylvenlafaxine, succinic acid, cyclohexane and acetonitrile to form a reaction mixture; b. heating the reaction mixture; and c. cooling the reaction mixture of step b to obtain crystalline Form VI of 6>-desmethylvenlafaxine succinate.
  • the present invention provides a process for preparing crystalline Form VII of O- desmethylvenlafaxine succinate comprising the steps of a. combining Odesmethylvenlafaxine, succinic acid and toluene to form a reaction mixture; b. heating the reaction mixture; c. adding acetonitrile to the reaction mixture: of step 'b' at elevated temperatures; and d. cooling the reaction mixture of step 'c' to obtain crystalline Form VII of 0-desmethylvenlafaxine succinate.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising crystalline Form V of O-desmethylvenlafaxine succinate, and pharmaceutically acceptable, carrier, diluent or excipient.
  • the present invention provides new crystalline forms of 0-desmethylvenlafaxine succinate, designated herein as Form V, Form VI and Form VII.
  • the present invention provides a crystalline Form V wherein the crystalline form exhibits an X-Ray Powder Diffraction pattern having characteristic peaks expressed in degrees 2 ⁇ ( ⁇ 0.2° 2 ⁇ ) at 12.15, 13.17, 14.67, 15.91, 19.69, 20.45, 22.27, 24.40, 26.43, 28.44 and 33.69.
  • crystalline Form V has an XRPD pattern substantially identical to that shown in Figure .1. Peak locations and intensities for the XRPD pattern in Figure 1 are provided in Table 1 below.
  • the crystalline Form V of O-desmethylvenlafaxine succinate of the present invention has a moisture content of about 2%.
  • the crystalline Form V of O-desmethylvenlafaxine succinate of the present invention is a stable crystalline compound. It retains the powder XRPD pattern upto atleast 12 months from the date of its manufacturing, when packed in glass vial and stored below 25 0 C, preferably between 10 to 25 0 C. Further more there was no significant change in the initial chemical purity after storage.
  • the present invention provides a process for preparing crystalline form V of O-desmethylvenlafaxine succinate.
  • Crystalline Form V of O- desmethylvenlafaxine succinate may be prepared by a process comprising combining O- desmethylvenlafaxine and succinic acid in a hydrocarbon solvent preferably an aromatic hydrocarbon preferably toluene and isolating the crystalline form V of O- desmethylvenlafaxine succinate from the reaction mixture.
  • the crystalline Form V of O-desmethylvenlafaxine succinate is prepared by a process comprising the steps of a. combining 0-desmethylvenlafaxine, succinic acid and toluene to form a reaction mixture; b. heating the reaction mixture; and c. cooling the reaction mixture of step b to obtain crystalline Form V of 0-desmethylvenlafaxine succinate.
  • the ratio of O-desmethylvenlafaxine to toluene is in the range of 10 to 100.
  • the reaction mixture is heated at or below reflux temperatures, preferably at reflux temperature. Most preferred temperature at which the reaction mixture is heated is in the range of 105 to 110 0 C.
  • the time for which the reflux may be carried is 2 to 6 hours preferably 4 hours.
  • the reaction mixture is cooled to 25 -35 0 C, preferably to about 25-30 0 C and further maintained for a sufficient period of time to obtain crystalline form V of (9-desmethylvenlafaxine succinate.
  • the cooled reaction mixture is maintained preferably for a period of 10 to 30 hours, more preferably for a period of 20 to 22 hours.
  • the reaction mixture is stirred, vigorously.
  • the formed crystals of Form V may be separated from the liquid medium by any method known in the art such as filtration or centrifugation and the obtained crystals may be optionally dried.
  • the crystalline Form V is separated by filtration and dried at about 50 0 C, under vacuum-
  • the present invention provides a crystalline Form VI of O- desmethylvenlafaxine succinate wherein the crystalline form exhibits an XRPD pattern having characteristic peaks expressed in degrees 2 ⁇ ( ⁇ 0.2° 2 ⁇ ) at 5.73, 11.19, 15.05, 15.58, 17.03, 17.61, 18.00, 19.86, 20.28, 21.20, 22.07, 24.28, 25.59, 26.36, 26.71 and 27.58.
  • the crystalline Form VI has an XRPD pattern substantially identical to that shown in Figure 2. Peak locations and intensities for the XRPD pattern in Figure 2 are provided in Table 2 below. Table 2
  • the present invention provides a process for preparing crystalline Form VI of O-desmethylvenlafaxine succinate.
  • Crystalline Form VI of O- desmethylvenlafaxine succinate may be prepared by a process comprising combining O- desmethylvenlafaxine, a hydrocarbon solvent preferably cyclohexane, a nitrile preferably acetonitrile and succinic acid and isolating the crystalline Form VI of O- desmethylvenlafaxine succinate from the reaction mixture.
  • crystalline Form VI of Odesmethylvenlafaxine succinate is prepared by a process comprising the steps of a. combining O-desmethylvenlafaxine, succinic acid, cyclohexane and acetonitrile to form a reaction mixture; b. heating the reaction mixture; and c. cooling the reaction mixture of step b to obtain crystalline Form VI of O-desmethylvenlafaxine succinate.
  • the ratio of cyclohexane to acetonitrile is in the range of (1 : 1) to about (10:1) preferably about 6:1.
  • the reaction mixture is heated at or below reflux temperatures, preferably to at about reflux temperature.
  • the time for which the reflux may be carried is 2 to 8 hours preferably 4 hours.
  • the reaction mixture is partially concentrated before cooling
  • the reaction mixture or the reaction mixture obtained after partial concentration is cooled to 20 -35 0 C, preferably to about 25-30 0 C and further maintained for a sufficient period of time to obtain crystalline Form VI of O- desmethylvenlafaxine succinate.
  • the cooled reaction mixture is maintained preferably for a period of 30 to 60 hours, more preferably for a period of 40 to 48 hours.
  • the reaction mixture is stirred.
  • the obtained crystalline form may be recovered by any method known in the art.
  • the crystalline form is filtered and dried at about 40 o 1 ,C.
  • the present invention provides a crystalline Form VII of O- desmethylvenlafaxine succinate wherein the crystalline Form exhibits an X-Ray Powder Diffraction pattern having characteristic peaks expressed in degrees 2 ⁇ ( ⁇ 0.2° 2 ⁇ ) at 10.78, 14.37, 14.72, 16.69, 17.21, 17.67, 20.11, 25.16, 25.88, 27.61and 30.33.
  • the crystalline Form VII has an XRPD pattern substantially identical to that shown in Figure 3. Peak locations and intensities for the XRPD pattern in Figure 3 are provided in Table 3 below.
  • the crystalline Form VII of O-desmethylvenlafaxine succinate of the present invention is a stable crystalline compound. It retains the powder XRPD pattern upto atleast 12 months from the date of its manufacturing, when packed in glass vial and stored below 25 0 C, preferably between 10 to 25 0 C. Further more there was no significant change in the initial chemical purity after storage.
  • the present invention provides a process for preparing crystalline Form VII of O-desmethylvenlafaxine succinate.
  • Crystalline Form VII of O- desmethylvenlafaxine succinate may be prepared by a process comprising combining desvenlafaxine, a hydrocarbon solvent preferably toluene and succinic acid and heating followed by addition of nitrile solvent preferably acetonitrile and isolating the crystalline Form VII of O-desmethylvenlafaxine succinate from the reaction mixture.
  • crystalline Form VII of O-desmethylvenlafaxine succinate is prepared by a process comprising the steps of a. combining O-desmethylvenlafaxine, succinic acid and toluene to form a reaction mixture; b heating the reaction mixture; c. adding acetonitrile to the reaction mixture of step 'b' at elevated temperatures; and d. cooling the reaction mixture of step 'c' to obtain crystalline Form VII of O-desmethylvenlafaxine succinate.
  • O-desmethylvenlafaxine, toluene and succinic acid are heated at or below reflux temperatures, preferably to at about reflux temperature.
  • the time for which the reflux may be carried is 1 to 4 hours preferably 2 hours.
  • the acetonitrile may be added to the reaction mixture at elevated temperature in the range of 85-95 C.
  • the acetonitrile is added to the reaction mixture at 90 0 C.
  • the refluxing reaction mixture Prior to adding acetonitrile the refluxing reaction mixture is cooled gradually to, 90 0 C.
  • the amount of acetonitrile used is in the range of 5 to 20 volumes.
  • the reaction mixture is maintained in the temperature range of 80-90 0 C for a period of 0.5 to 1 hour.
  • the reaction mixture is cooled to 25 -35 0 C, preferably to about 25-30 0 C and further maintained for a sufficient period of time to obtain crystalline form VII of desvenlafaxine succinate.
  • the cooled reaction mixture is maintained preferably for a period of 20 to 35 hours, more preferably for a period of 24 to 30 hours.
  • the reaction mixture is stirred while cooling.
  • the formed crystals of Form VII may be separated from the liquid medium by any method known in the art such as filtration or centrifugation and the obtained crystals may be optionally dried.
  • the crystalline Form VII is separated by filtration and dried at about 40 0 C.
  • the present invention provides pharmaceutical compositions comprising the above crystalline forms of O-desmethylvenlafaxine succinate and pharmaceutically acceptable, carrier, diluent or excipient.
  • present invention provides pharmaceutical compositions comprising the crystalline Form V of O-desmethylvenlafaxine succinate and pharmaceutically acceptable, carrier, diluent or excipient.
  • novel crystalline forms of O-desmethylvenlafaxine succinate of the present invention may be formulated into conventional dosage forms such as, for example, conventional release tablets, sustained release preparations, pills, suspensions, emulsions, granules, capsules, suppositories, injection preparations, and the like.
  • the dosage forms may be obtained by using pharmaceutically acceptable excipients, in amounts and manner conventional to the pharmaceutical art.
  • novel crystalline forms of 0-desmethylvenlafaxine succinate of the present invention may be used alone or in combination with one or more other therapeutically active agents.
  • the present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and are not intended to limit the scope of the invention.
  • X-ray diffraction data were acquired using a PANalyticalX'pert PRO X-ray diffractometer model.
  • K 01 I.54060 A 0 , voltage 45 kV, current 40 mA, Xray source : Cu..
  • the water content measurements were carried out using a METTLER TOLEDO Model: DL31Karl Fischer Titrator according to standard procedures.
  • O-desmethylvenlafaxine (free base) and succinic acid were mixed in a 1 :1 molar concentration in 600 ml of toluene, and the reaction mixture was heated to reflux temperature for 4 hours. The reaction mixture was then cooled gradualy to about 25 to 3O 0 C, and maintained at that temperature for about 20 to 22 hours. The solid thus obtained was filtered and dried at about 5O 0 C to obtain crystalline form V of O-desmethylvenlafaxine succinate. The moisture content of the crystalline form V was found to be about 2%. . HPLC purity; > 98%.
  • O-desmethylvenlafaxine (free base) and succinic acid were dissolved in a 1 :1 molar concentration in a mixture of 60 parts cyclohexane and 10 parts acetonitrile.
  • the reaction mixture was heated to reflux temperature and maintained for about 4 hours at reflux conditions with partial concentration.
  • the reaction mixture was then cooled gradually to about 25 to 3O 0 C under stirring for about 48 hours.
  • the solid thus obtained was filtered and dried at about 4O 0 C to obtain crystalline form VI of O-desmethylvenlafaxine succinate. HPLC purity; > 98%.
  • Odesmethylvenlafaxine (free base) and succinic acid were dissolved in a 1:1 molar concentration in 60 parts of toluene.
  • the reaction mixture was heated to reflux temperature and maintained for about 2 hours at reflux conditions.
  • the reaction mixture was then cooled gradually to about 85 0 C, and 10 parts of acetonitrile was added to the reaction mixture.
  • the reaction mixture was maintained at about 85°C for about 45 minutes.
  • the reaction mixture was then cooled gradually to about 25 to 30 0 C under stirring for about 30 hours.
  • the solid thus obtained was filtered and dried at about 40 0 C to obtain crystalline form VII of 0-desmethylvenlafaxine succinate. HPLC purity; > 98%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

La présente invention concerne une forme cristalline V de succinate de O-desméthylvenlafaxine, caractérisée en ce que la forme cristalline présente un profil de diffraction des rayons X sur poudre ayant des pics caractéristiques exprimés en degrés 2θ (±0,2° 2θ) à 12,15, 13,17, 14,67, 15,8, 19,69, 20,45, 22,27, 24,40, 26,43, 28,44 et 33,69.
PCT/IN2009/000191 2008-03-24 2009-03-23 Nouvelles formes cristallines de succinate de desvenlafaxine Ceased WO2009118758A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN175/MUM/2008 2008-03-24
IN617/MUM/2008 2008-03-24
IN175MU2008 2008-03-24
IN617MU2008 2008-03-24

Publications (2)

Publication Number Publication Date
WO2009118758A2 true WO2009118758A2 (fr) 2009-10-01
WO2009118758A3 WO2009118758A3 (fr) 2011-05-26

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012046250A2 (fr) 2010-10-08 2012-04-12 Cadila Healthcare Limited Formes polymorphes de succinate de o-desméthylvenlafaxine

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4220243B2 (ja) * 2001-02-12 2009-02-04 ワイス Ｏ−デスメチル−ベンラファキシンの新規コハク酸塩
WO2008156748A2 (fr) * 2007-06-15 2008-12-24 Teva Pharmaceutical Industries Ltd. Formes cristallines du succinate de o-desméthylvenlafaxine
TR200909798T1 (tr) * 2007-07-12 2010-05-21 Dr. Reddy's Laboratories Ltd. O-desmetilvenlafaksin.
WO2009010990A2 (fr) * 2007-07-16 2009-01-22 Matrix Laboratories Limited Procédé pour préparer des formes polymorphes de succinate de o-desméthylvenlafaxine
IN2008CH00818A (fr) * 2008-04-01 2009-10-09 Actavis Group Ptc Ehf

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012046250A2 (fr) 2010-10-08 2012-04-12 Cadila Healthcare Limited Formes polymorphes de succinate de o-desméthylvenlafaxine

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