Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
  • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
  • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
  • C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
• • 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

Definitions

• the present invention relates to a novel crystal line polymorph o f Endoxifen citrate and process for the preparation thereof.
• Endoxifen chemically " named N-desmethyl-4-hydroxytamoxifen is an active metabolite of tamoxifen, a breast cancer.
• WO 2009/120999A2 discloses the following method of preparing Endoxifen:
• WO 2008/070463 discloses the fol lowing method of preparing Endox i
• New crystalline polymorph of a drug substance may display d i fferent melting point, hygroscopicity, stability, solubility and/or dissolution rale, crysta!linity, crystal habits, bioavailability and formulation handling characteristics, which are among the numerous properties that need to be considered in preparing medicament that can be effectively administered. Therefore, the regulatory agencies require a definitive control of polymorphic form of the active component in solid pharmaceutical dosage forms. The present inventors have also made their efforts to make an amorphous form of Endoxifen citrate.
• Endoxifen citrate that have better thermal stabi lity and material flow character, lower water contents, and offer advantages for preparing reproducible pharmaceutical formulations.
• the new polymorphic form of Endoxifen citrate of the present invention helps fulfill this and other needs.
• the present invention provides hot only novel polymorph of Endoxifen citrate but also provides the characterization data for analysis of this form .
• the main object of the present invention is to provide a novel crystalline polymorphic form of Endoxifen citrate.
• Another object of the present invention is to provide a novel , crystalline polymorphic form of Endoxifen citrate which is characterized by an XRD pattern comprising 2 theta value at about 10.8 degree two-theta ⁇ 0.2.
• Another object of the present invention is to provide a novel crystal line polymorphic form of Endoxi fen citrate which is characterized by an XRD pattern comprising 2 theta values at about 5.4, 1 0.8, 1 1 .7, 1 3.6, 14.5, 1 8.3, 19.4 and 21 .8 degree two-theta ⁇ 0.2.
• Another object of the present invention is to provide a crystal l ine form of Endoxifen citrate, which is characterized by X-ray powder diffraction pattern (XRPD) as depicted in figure 1 .
• XRPD X-ray powder diffraction pattern
• Another object of the present invention is to provide a crystal line form of Endoxifen citrate, which is characterized by differential scanning calorimetry (DSC) endotherm at about 129.50°C ⁇ 2.
• Another object of the present invention is to provide a process for preparation of crystalline form of Endoxi fen citrate.
• the present invention provides a., novel crystalline polymorphic form of Endoxifen citrate which is characterized by .an XRD pattern comprising 2 theta value at about 10.8 degree two-theta ⁇ 0.2.
• novel crystal l ine polymorph of Endoxi fen citrate o f the present invention further characterized by an XRD pattern comprising 2 theta values at about 5.4, 1 1 .7, 13.6, 14.5, 18.3, 19.4 and 21 .8 degree two-theta ⁇ 0.2.
• the present invention discloses a method. for preparing the said polymorph of Endoxifen citrate.
• Fig. 1 is X-ray Di fractogram (XRD) of crystalline form of Endoxifen citrate as per the present invention.
• Fig. 2 is Differential Scanning Calorimetry (DSC) of crystal l ine form of Endoxifen citrate as per the present invention.
• the present invention provides novel polymorphic form of Endoxifen citrate.
• polymorphic form is crystalline form.
• novel crystalline polymorph of Endoxifen citrate further characterized by an XRD pattern comprisi ng 2 theta values at about 5.4, 1 1 .7, 1.3.6, 1 4.5, 18.3, 19.4 and 21 .8 degree two-theta ⁇ 0.2.
• the present invention discloses novel crystalline polymorph of Endoxifen citrate, which is .characterized by an XRD pattern comprising 2 theta values at about 5.4, 10.8, 1 1 ; 7, 1 3.6, 1 4.5, 1 8:3, 1 9.4 and 21 .8 degree two-theta ⁇ 0.2.
• the crystalline form of Endoxifen citrate can be characterized by PXRD pattern as set forth in figure 1.
• the crystalline form of Endoxifen citrate can also be characterized by an endotherm at about 129.50°C ⁇ 2 in a DSC.
• the DSC thermogram of crystalline form ofEndoxifen citrate is as set forth in -figure 2.
• Endoxifen citrate can also be characterized by IR spectroscopy at about 3523, 3500, 3483, 3'332, 3307, 3142, 3022, 2970, 2931,. 2872, 2829, 2735, 2669, 2540, 2492, 2378, 2320, 2096, 2083, 2071, 2019, 1953, 1892, 1734, 1710, 1602, 1573, 1506, 1435, 1402, 1367, 1336, 1309, 1261, 1236, 1 1 74, 1 130, 1 105, 1076, 1 055, 1028, 991 , 923; 875, 840, 769, 73 1 , 704, 644, 609, 588, 563, 51 8, 486 and 426 cm " ' . ' «
• Another embodiment of the present invention is to provide a process for the preparation of novel crystal line form of Endoxi fen citrate by the reaction of Endoxifen base with citric acid to give Endoxifen citrate salt.
• Endox i fen Citrate obtained can be uri fied / recr stallized from a solvent or mixture thereof.
• Endoxifen base used in the preparatio of Endoxifen citrate can be E-isomer or Z-isomer or mixture thereof.
• Endoxifen is mixture of E- and Z-isomers of Endoxifen.
• Citric acid used in the above step (a) of the reaction may be either anhydrous or hydrous.
• citric acid used is anhydrous.
• the above reaction step (a) can be carried out at room temperature or higher temperature. After that, the reaction mixture can be cooled to room temperature or lower temperature followed by filtration of reaction mass to obtain crude solid Endoxifen citrate, which may be further washed with water and methanol .
• Puri fication / recrystallization of crude- Endoxifen citrate step (b) can be carried out in presence of suitable solvent or mixture thereo f, wherein solvent is selected from either organic or an inorganic solvent.
• Organic solvent includes but not limited to alcoholic solvents, hydrocarbon solvents, ester solvents or ether solvents.
• Alcoholic solvent i ncl udes but not limited to methanol, ethanol, propanol, butanol, isobutanol. pentanol or hexanol.
• alcoholic solvent is methanol.
• the purification step (b) can be carried out at room temperature or higher temperature. Activated charcoal can be added ' for the above step (b) in order to remove any color impurities.
• the reaction itiixture can be fi ltered and washed with methanol to give pure crystalline form of Endoxifen citrate.
• novel crystalline polymorph of the present invention is prepared by reacting the solution of Endoxifen base ((Z)-4-( l - (4-(2-(methylamino)ethoxy)plienyl)-2-phenyIbut- l -en- l -yl)phenol) with a solution of anhydrous citric acid to give Endoxifen citrate salt.
• Endoxifen citrate salt obtained is purified with methanol and charcoal .
• the above reaction step (a) can be carried out at room temperature or higher temperature. After that, the reaction mixture can be cooled to room temperature or lower temperature followed by filtration of reaction mass. The obtained Endoxifen citrate solid can be washed with water and methanol to give crude Endoxifen citrate.
• Purification / recrystal lization of crude Endoxi fen citrate step (b) can be earned out in presence of methanol and activated charcoal at room temperature or higher temperature.
• the reaction mixture can be fi ltered and washed with methanol to give pure crystalline form of Endoxifen citrate.
• Endoxifen base used in the present invention can be prepared by any of the known prior art process, for example as disclosed in examples of the present invention.
• Identification of solids obtained by the present invention can be made by methods known in the art, such as X-Ray Di ffraction, Di fferential Scanning Calorimetry (DSC) and Infrared Spectroscopy (IR). It should be understood that operator, instrument and other simi lar changes may result in some margin of error with respect to analytical characterization of the solid.
• the reaction mass was fi ltered and the obtained solid was washed with ethyl acetate (200 ml) urgive Endoxi fen base ( 140 gm).
• Endoxifen base ( 1 40 gm) and ethyl acetate ( 1 50 ml) were charged i n a RBF.
• the reaction mass was filtered and washed with ethyl acetate ( 1 50 m l) to give residue of Endoxifen base (80 gm).
• Endoxifen base residue (80 gm) and isopropyl alcohol (600 m l) were charged in a RBF.
• n-heptane ( 1700 ml) was added to the reaction mass at room temperature.
• the reaction mass was filtered off to obtain 40 gm of Endoxifen base solid.
• Endoxifen base (40 gm) prepared from example 1 and chlorobenzene (250 ml) was charged in a RBF. Thus formed reaction mixture was heated to. 60-70°C and then cooled to room temperature. The reaction mixture was filtered to obtai n 25 gm of pure Endox ifen base.
• Citric acid (75 gm) and water (150 ml) were charged in a RBF.
• the obtained solution was heated at a temperature of 30-50 o C, followed by addition of Endoxi fen (25 gm). A fter completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was filtered to obtain 30 gm of Endoxifen citrate solid.
• Endoxifen citrate (30 gm) prepared from example 3 and methanol (400 ml) were taken in a RBF. The reaction mixture was heated to 60-70°C fol lowed by cooling to room temperature. The reaction mixture was filtered; solid thus obtained was dried to give 24 g of title compound.

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

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Cited By (9)

Citations (4)

• 2014
  • 2014-03-03 WO PCT/IN2014/000136 patent/WO2014141292A2/en active Application Filing
  • 2014-03-03 IN IN646MU2013 patent/IN2013MU00646A/en unknown

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