WO2006040643A2 - Formes polymorphes d'efavirenz et processus de leur fabrication - Google Patents

Formes polymorphes d'efavirenz et processus de leur fabrication Download PDF

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Publication number
WO2006040643A2
WO2006040643A2 PCT/IB2005/003013 IB2005003013W WO2006040643A2 WO 2006040643 A2 WO2006040643 A2 WO 2006040643A2 IB 2005003013 W IB2005003013 W IB 2005003013W WO 2006040643 A2 WO2006040643 A2 WO 2006040643A2
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Prior art keywords
efavirenz
characteristic
values
solution
polymorphic form
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WO2006040643A3 (fr
Inventor
Ramnik Sharma
Kumar Hari Bhushan
Ram Chander Aryan
Nitu Singh
Bhargav Pandya
Yatendra Kumar
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Ranbaxy Laboratories Ltd
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Ranbaxy Laboratories Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/18—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the present invention relates to novel polymorphic forms of efavirenz.
  • the novel polymorphic forms are designated as Forms ⁇ , ⁇ , ⁇ , ⁇ l, ⁇ 2, ⁇ , ⁇ , N, O, and P of efavirenz.
  • the present invention further relates to an amorphous form of efavirenz.
  • the invention also relates to processes for the preparation and pharmaceutical compositions useful in the treatment of HTV-I infection with the novel polymorphic forms of efavirenz.
  • efavirenz of Formula I is an HTV-I specific, non- nucleoside, reverse transcriptase inhibitor. Efavirenz in combination with other antiretro viral agents is indicated for the treatment of HIV-I infection.
  • US Patent No. 6,673,372 discloses polymorphic forms of efavirenz designated as Form 2 and Form 5.
  • a polymorphic Form ⁇ of efavirenz having an X-ray powder diffraction (XRPD) pattern wherein characteristic 2 ⁇ values are obtained at 6.80, 12.76, 21.88 and 26.48.
  • XRPD X-ray powder diffraction
  • Embodiments of the polymorph may have one or more of the following features.
  • Form ⁇ may further include characteristic 2 ⁇ values at 3.4, 11.96, 13.0, 13.16, 13.64, 14.36, 15.12, 15.92, 16.5, 17.2, 18.14, 19.06, 19.56, 19.84, 20.32, 20.70, 21.16, 22.22, 23.04, 23.50, 23.98, 24.34, 24.70, 24.86, 25.18, 25.76, 26.06, 27.52, 28.10, 28.88, 30.40, 31.04, 31.44, 32.32, 32.52, 32.90, 33.48, 34.46 and 38.02.
  • Embodiments of the polymorph may have one or more of the following features.
  • Form ⁇ may further include the characteristic 2 ⁇ values at 10.24, 12.30, 15.20, 16.40, 17.60, 18.56, 19.08, 19.82, 20.34, 20.62, 21.36, 22.86, 23.52, 24.52, 24.78, 25.62, 26.10, 26.78, 28.24, 28.64, 29.12, 31.04, 31.60, 33.10, 33.52, 34.54, 34.76, 35.56, 36.14, 36.58, 37.50, 38.30, 38.66, 39.54 and 39.68.
  • a polymorphic Form ⁇ of efavirenz having an XRPD pattern wherein characteristic 2 ⁇ values are obtained at 6.10, 18.44, 21.30, and 22.20.
  • Embodiments of the polymorph may have one or more of the following features.
  • Form ⁇ may further include the characteristic 2 ⁇ values at 9.82, 10.98, 12.24, 12.68, 13.10, 14.16, 15.72, 16.20, 16.90, 18.0, 18.76, 19.22, 19.40, 19.78, 20.12, 20.70, 21.92, 23.20, 23.38, 24.12, 24.70, 25.04, 26.22, 26.58, 27.30, 27.96, 28.10, 28.44, 28.54, 29.02, 29.48, 30.82, 31.02, 31.58, 32.02, 32.46, 32.78, 32.94, 37.78 and 37.96.
  • a polymorphic Form ⁇ l of efavirenz having an XRPD pattern wherein characteristic 2 ⁇ values are obtained at 6.14, 6.26, 21.24, and 24.94.
  • Embodiments of the polymorph may have one or more of the following features.
  • Form ⁇ l may further include characteristic 2 ⁇ values at 10.50, 11.00, 12.28, 13.08, 13.26, 14.24, 15.30, 15.64, 16.68, 16.94, 17.90, 18.32, 18.54, 19.26, 19.70, 20.16, 21.98, 22.10, 22.32, 23.16, 24.56, 25.62, 26.06, 26.42, 27.26, 27.50, 28.18, 28.74, 29.26, 29.62, 30.84, 31.64, 32.38, and 37.40.
  • a polymorphic Form 72 of efavirenz having an XRPD pattern wherein characteristic 2 ⁇ values are obtained at 21.18, 21.74, 22.04, and 31.64.
  • Embodiments of the polymorph may have one or more of the following features.
  • Form ⁇ 2 may further include characteristic 2 ⁇ values at 12.12, 12.38, 12.98, 13.16, 15.64, 16.90, 17.22, 18.14, 18.42, 18.76, 19.34, 19.48, 19.90, 20.06, 20.32, 23.08, 23.30, 23.98, 24.42, 24.60, 24.94, 25.34, 26.14, 26.36, 27.06, 27.30, 28.04, 28.38, 28.98, and 29.24.
  • a polymorphic Form ⁇ of efavirenz having an XRPD pattern wherein characteristic 2 ⁇ values are obtained at 9.98, 20.40, 22.66, and 28.12.
  • Embodiments of the polymorph may have one or more of the following features.
  • Form ⁇ may further include characteristic 2 ⁇ values at 4.98, 11.26, 11.64, 12.06, 14.88, 15.02, 16.64, 17.18, 17.54, 18.06, 18.66, 19.02, 19.72, 20.78, 21.18, 21.58, 21.72, 22.10, 23.40, 23.86, 24.32, 24.74, 25.30, 25.82, 26.04, 26.42, 26.76, 27.60, 28.44, 29.04, 29.82, 37.66, and 37.78.
  • characteristic 2 ⁇ values are obtained at 7.18, 13.44
  • Form ⁇ may further include characteristic 2 ⁇ values at 11.32, 12.12, 12.64, 13.04, 13.86, 14.44, 15.12, 15.44, 16.38, 17.00, 18.92, 19.56, 20.08, 20.58, 21.80, 22.14, 23.92, 24.66, 25.42, 26.72, 27.32, 27.86, 28.02, 29.22, 29.96, 30.72, 31.74, 32.40, 32.74, and 39.06.
  • an amorphous form of efavirenz In another general aspect there is provided an amorphous form of efavirenz.
  • the amorphous form of efavirenz may be used in a pharmaceutical composition with one or more pharmaceutical agents and one or more additional therapeutic agents, and may be administered for the treatment of an HIV-I infection.
  • a polymorphic Form O of efavirenz having an XRPD pattern wherein characteristic 2 ⁇ values are obtained at 13.16, 19.58, 20.86, and 25.38.
  • Embodiments of the polymorph may have one or more of the following features.
  • Form O may further include characteristic 2 ⁇ values at 3.92, 7.88, 10.70, 11.20, 11.40, 12.04, 12.86, 13.80, 14.38, 15.08, 15.78, 16.46, 17.26, 17.46, 18.44, 20.20, 21.26, 21.50, 21.92, 22.14, 22.34, 22.96, 23.74, 24.58, 26.02, 26.48, 26.90, 27.24, 27.62, 27.86, 28.00, 28.64, and 28.96.
  • a polymorphic Form N of efavirenz having an XRPD pattern wherein characteristic 2 ⁇ values are obtained at 13.12, 18.40, 20.82, and 25.30.
  • Embodiments of the polymorph may have one or more of the following features.
  • Form N may further include characteristic 20 values at 3.9, 7.84, 10.66, 12.00, 12.80, 15.04, 15.74, 17.40, 19.54, 22.88, 23.68, 24.96, 25.96, 26.86, 27.16, 27.92 and 28.90.
  • a polymorphic Form P of efavirenz having an XRPD pattern wherein characteristic 2 ⁇ values are obtained at 13.12, 18.38, 20.80, and 25.28.
  • Embodiments of the polymorph may have one or more of the following features.
  • Form ⁇ may further include characteristic 2 ⁇ values at 3.90, 7.84, 8.68, 10.66, 10.82, 11.22, 11.42, 12.00, 12.42, 12.78, 13.66, 14.30, 14.42, 15.04, 15.22, 15.74, 16.34, 16.58, 16.84, 17.40, 17.90, 18.56, 19.52, 21.46, 21.74, 22.18, 22.88, 23.82, 24.34, 24.66, 25.94, 26.20, 26.86, 27.14, 27.92, 28.44 and 28.88.
  • a pharmaceutical composition comprising Forms ⁇ , ⁇ , ⁇ , ⁇ l, ⁇ 2, ⁇ , ⁇ , N, O, or P of efavirenz.
  • the pharmaceutical composition may further include one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition may further include one or more additional therapeutic agents.
  • a method of treating HIV-I infections comprising Forms ⁇ , ⁇ , ⁇ , ⁇ l, ⁇ 2, ⁇ , ⁇ , N,
  • the method includes administering to a mammal in need thereof a pharmaceutical composition comprising the one or more polymorphic Forms ⁇ , ⁇ , ⁇ , ⁇ l, ⁇ 2, ⁇ , ⁇ , N, O or P of efavirenz and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition administered may further include one or more additional therapeutic agents.
  • a process for preparation of polymorphic Form ⁇ of efavirenz includes dissolving efavirenz in a mixture of one or more halogenated hydrocarbons and one or more hydrocarbon organic solvents to form a solution; partially concentrating the solution; and isolating Form ⁇ of efavirenz from the reaction mass thereof.
  • Embodiments of the process may include one or more of the following features.
  • the one or more halogenated hydrocarbons may be dichloromethane, 1,1,1- trichloroethane, tetrachloroethylene and trichloroethylene.
  • the one or more hydrocarbon organic solvents may be C 5-7 alkane, petroleum ether and cycloalkane.
  • a process for the preparation of polymorphic Form ⁇ of efavirenz includes dissolving efavirenz in one or more water miscible alkanols to form a solution; adding the solution to a mixture of one or more water miscible alkanols and water to form a mixture; stirring the reaction mixture at a temperature between 2 0 C and 1O 0 C; and isolating Form ⁇ of efavirenz from the reaction mass thereof.
  • Embodiments of the process may include one or more of the following features.
  • the one or more water miscible alkanols may be methanol, ethanol, n- propanol, isopropanol or mixtures thereof.
  • a process for the preparation of polymorphic Form ⁇ of efavirenz includes dissolving efavirenz in one or more water miscible organic solvents to form a solution; treating the solution with a mixture of water, one or more water miscible organic solvents and one or more agents for lowering the freezing point of water to cause precipitation of a solid; treating the solid with water; and isolating Fo ⁇ n ⁇ of efavirenz from the reaction mass thereof.
  • Embodiments of the process may include one or more of the following features.
  • the one or more water miscible organic solvents may be methanol, ethanol, n-propanol and isopropanol.
  • the one or more agents for lowering the freezing point of water may be alkali metal salts or alkaline earth metal salts.
  • the alkali metal salt may sodium chloride.
  • the process includes dissolving efavirenz in one or more halogenated hydrocarbons to form a solution; adding the solution to a second organic solvent including C 5-7 alkane, cycloalkane, petroleum ether; and isolating Form ⁇ of efavirenz from the reaction mass thereof.
  • a process for preparation of amorphous efavirenz includes dissolving efavirenz in one or more organic solvents to form a solution; recovering the solvent from the solution; and isolating amorphous efavirenz from the reaction mass thereof.
  • a process for the preparation of amorphous efavirenz is provided.
  • the process includes dissolving efavirenz in one or more water miscible organic solvents to form a solution; adding the solution to a second solution of one or more inorganic salts; and isolating amorphous efavirenz from the reaction mass thereof.
  • a process for the preparation of Form O of efavirenz includes dissolving efavirenz in one or more water miscible organic solvents to form a solution; removing the solvent from the solution to leave a product; grinding the product between two surfaces; and isolating Form O of efavirenz from the reaction mass thereof.
  • Embodiments of the process may include one or more of the following features.
  • the one or more water miscible organic solvents may be methanol, ethanol, isopropanol, acetonitrile, acetone, tetrahydrofuran and 1,4-dioxane.
  • a process for preparation of polymorphic Form N of efavirenz includes treating Form O of efavirenz with water, and isolating Form N of efavirenz from the reaction mass thereof.
  • a process for the preparation of polymorphic Form N of efavirenz may include one or more of the following features.
  • the one or more water miscible organic solvents may be methanol, ethanol, isopropanol, acetonitrile, acetone, tetrahydrofuran and 1,4-dioxane.
  • the process includes mixing Form ⁇ of efavirenz with a catalytic quantity of Form N of efavirenz to form a mixture; drying the mixture under vacuum for a sufficient time; and isolating Form N of efavirenz from the reaction mass thereof.
  • Embodiments of the process may include one or more of the following features.
  • the drying may be carried out at a temperature of 1O 0 C or less.
  • the drying may be carried out in a rotary evaporator and may be rotated at a speed of 10 to 100 revolutions per minute.
  • a process for the preparation of Form P of efavirenz includes dissolving efavirenz in one or more water miscible organic solvents to form a solution; adding the solution to a mixture of Form N in water; and isolating Form P of efavirenz from the reaction mass thereof.
  • Figure 1 is an XRPD of Form ⁇ of efavirenz.
  • Figure 2 is an DSC of Form ⁇ of efavirenz.
  • Figure 3 is an XRPD of Form ⁇ of efavirenz.
  • Figure 4 is a DSC of Form ⁇ of efavirenz.
  • Figure 5 is an XRPD of Form ⁇ of efavirenz.
  • Figure 6 is a DSC of Form ⁇ of efavirenz.
  • Figure 7 is an XRPD of Form ⁇ l of efavirenz.
  • Figure 8 is a DSC of Form ⁇ l of efavirenz.
  • Figure 9 is an XRPD of Form ⁇ 2 of efavirenz.
  • Figure 10 is a DSC of Form ⁇ 2 of efavirenz.
  • Figure 11 is an XRPD of Form ⁇ of efavirenz.
  • Figure 12 is an XRPD of Form ⁇ of efavirenz.
  • Figure 13 is a DSC of Form ⁇ of efavirenz.
  • Figure 14 is an XRPD of Form ⁇ of efavirenz.
  • Figure 15 is a DSC of Form ⁇ of efavirenz.
  • Figure 16 is an XRPD of amorphous form of efavirenz.
  • Figure 17 is an XRPD of Form O of efavirenz.
  • Figure 18 is an XRPD of Form N of efavirenz.
  • Figure 19 is an XRPD of Form N of efavirenz.
  • Figure 20 is a DSC of Form N of efavirenz.
  • Figure 21 is a FTIR of Form N of efavirenz.
  • Figure 22 is an XRPD of Form P of efavirenz.
  • the present invention relates to novel polymorphic forms of efavirenz.
  • the novel polymorphic forms are designated as Forms ⁇ , ⁇ , ⁇ , ⁇ l, ⁇ 2, ⁇ , ⁇ , N, O, and P of efavirenz.
  • the present invention further relates to an amorphous form of efavirenz.
  • the invention also relates to processes for their preparation and their use in pharmaceutical compositions useful in the treatment of HIV-I infection.
  • the present invention provides the novel polymorphic Form ⁇ of efavirenz having a typical XRPD pattern as depicted in Figure 1 of the accompanying drawing.
  • the XRPD of Form ⁇ shows characteristic 2 ⁇ values at 3.4, 6.8, 11.96, 12.76, 13.0, 13.16, 13.64, 14.36, 15.12, 15.92, 16.5, 17.2, 18.14, 19.06, 19.56, 19.84, 20.32, 20.70, 21.16, 21.88, 22.22, 23.04, 23.50, 23.98, 24.34, 24.70, 24.86, 25.18, 25.76, 26.06, 26.48, 27.52, 28.10, 28.88, 30.40, 31.04, 31.44, 32.32, 32.52, 32.90, 33.48, 34.46 and 38.02.
  • the novel polymorphic Form ⁇ has a characteristic differential scanning calorimetry (DSC) thermogram as depicted in Figure 2 of the accompanying drawings.
  • the DSC thermogram shows three characteristic endothermic peaks at 7O 0 C - 85 0 C, 85 0 C - 95 0 C and 13O 0 C - 145 0 C. Also provided herein is a process for the preparation of the novel polymorphic
  • Form ⁇ of efavirenz The process includes: a) dissolving efavirenz in a mixture of one or more halogenated hydrocarbons and one or more hydrocarbon organic solvents to form a solution; b) partially concentrating the solution; and c) isolating Form ⁇ of efavirenz from the reaction mass thereof.
  • the efavirenz starting material may be prepared by any method known in the art. Efavirenz is first dissolved in a mixture of one or more halogenated hydrocarbons and one or more hydrocarbon organic solvents.
  • the one or more halogenated hydrocarbon solvents may include dichloromethane, 1,1,1 -trichloroethane, tetrachloroethylene and trichloroethylene.
  • the one or more hydrocarbon organic solvents may include C 5-7 alkane, petroleum ether and cycloalkane.
  • the solution is partially concentrated under a vacuum. The reaction mixture is stirred and the precipitated compound is filtered off to get Form ⁇ of efavirenz having the characteristic XRPD ( Figure 1) and DSC ( Figure 2) patterns.
  • the process includes: a) treating efavirenz with one or more C 5-7 alkanes, petroleum ethers or C 5-7 cycloalkane solvents; and b) isolating Form ⁇ of efavirenz from the reaction mass thereof.
  • the efavirenz starting material may be prepared by any method known in the art.
  • the efavirenz is treated with one or more C 5-7 alkanes, petroleum ethers or C 5-7 cycloalkane solvents.
  • the reaction mixture is stirred at a lower temperature and the precipitated compound is filtered off to get Form ⁇ of efavirenz having the characteristic XRD ( Figure 1) and DSC ( Figure 2) patterns.
  • a novel polymorphic Form ⁇ of efavirenz having typical XRPD pattern as depicted in Figure 3 of the accompanying drawing.
  • the XRPD of Form ⁇ shows characteristic 2 ⁇ values at 10.24, 11.18, 11.68, 12.30, 15.20, 16.40, 17.60, 18.56, 19.08, 19.82, 20.34, 20.62, 20.98, 21.36, 22.86, 23.52, 24.52, 24.78, 25.62, 26.10, 26.78, 27.38, 28.24, 28.64, 29.12, 31.04, 31.60, 33.10, 33.52, 34.54, 34.76, 35.56, 36.14, 36.58, 37.50, 38.30, 38.66, 39.54 and 39.68.
  • the novel polymorphic form ⁇ has a characteristic DSC thermogram as depicted in Figure 4 of the accompanying drawing.
  • the DSC thermogram shows two characteristic endothermic peaks at 105 0 C - HO 0 C and at 135 0 C - 14O 0 C.
  • the process includes: a) dissolving efavirenz in one or more water miscible organic solvents to form a solution; b) adding the solution to a mixture of one or more water miscible organic solvents and water to form a mixture; c) stirring the reaction mixture at a temperature of about O 0 C or less; and d) isolating Form ⁇ of efavirenz from the reaction mass thereof.
  • the efavirenz starting material may be prepared by any method known in the art.
  • the efavirenz is first dissolved in one or more water miscible organic solvents to form a solution.
  • the solution is added to a mixture of one or more water miscible organic solvents and water to form a mixture.
  • the resultant mixture is stirred at a temperature of about O 0 C or less.
  • the one or more water miscible organic solvents may include methanol, ethanol, acetone, acetonitrile, dimethylsulfoxide, dimethylformamide and dioxane.
  • the novel polymorphic Form ⁇ of efavirenz having typical XRPD pattern as depicted in Figure 5 of the accompanying drawing.
  • the XRPD of Form ⁇ shows characteristic 20 values at 6.10, 9.82, 10.98, 12.24, 12.68, 13.10, 14.16, 15.72, 16.20, 16.90, 18.0, 18.44, 18.76, 19.22, 19.40, 19.78, 20.12, 20.70, 21.30, 21.92, 22.20, 23.20, 23.38, 24.12, 24.70, 25.04, 26.22, 26.58, 27.30, 27.96, 28.10, 28.44, 28.54, 29.02, 29.48, 30.82, 31.02, 31.58, 32.02, 32.46, 32.78, 32.94, 37.78 and 37.96.
  • the novel polymorphic Form ⁇ has characteristic DSC thermogram as depicted in Figure 6 of the accompanying drawing.
  • the DSC thermogram shows two characteristic endothermic peaks at 75 0 C - 95 0 C and at 12O 0 C - 14O 0 C.
  • a process for the preparation of the novel polymorphic Form ⁇ of efavirenz includes: a) dissolving efavirenz in one or more polar aprotic solvents to form a solution; b) adding the solution to a salt solution; and c) isolating Form ⁇ of efavirenz from the reaction mass thereof.
  • the efavirenz starting material may be prepared by any method known in the art.
  • the efavirenz is first dissolved in one or more polar aprotic solvents to form a solution.
  • the solution is added to a salt solution.
  • the resultant mass is stirred and filtered off.
  • the product obtained is dried under vacuum at about 35 0 C - 4O 0 C to get Form ⁇ of efavirenz having the characteristic XRPD ( Figure 5) and DSC ( Figure 6) patterns.
  • the novel polymorphic Form ⁇ l of efavirenz having typical XRPD pattern as depicted in Figure 7 of the accompanying drawings.
  • the XRPD of Form ⁇ l shows characteristic 2 ⁇ values at 6.14, 6.26, 10.50, 11.00, 12.28, 13.08, 13.26, 14.24, 15.30, 15.64, 16.68, 16.94, 17.90, 18.32, 18.54, 19.26, 19.70, 20.16, 21.24, 21.98, 22.10, 22.32, 23.16, 24.56, 24.94, 25.62, 26.06, 26.42, 27.26, 27.50, 28.18, 28.74, 29.26, 29.62, 30.84, 31.64, 32.38 and 37.40.
  • the novel polymorphic Form ⁇ l has characteristic DSC thermogram as depicted in Figure 8 of the accompanying drawings.
  • the DSC thermogram shows one characteristic endothermic peak at 13O 0 C - 142 0 C.
  • a process for the preparation of novel polymorphic Form ⁇ l of efavirenz includes: a) dissolving efavirenz in one or more lower alkanols to form a solution; b) adding the solution to a mixture of one or more lower alkanols and salt solution; c) stirring the resultant reaction mass for a period not exceeding 1 hour; and d) isolating Form ⁇ l of efavirenz from the reaction mass thereof.
  • the efavirenz starting material may be prepared by any method known in the art.
  • the efavirenz is first dissolved in one or more lower alkanols to form a solution.
  • the solution is added to a mixture of one or more lower alkanols and water.
  • the resultant mass is stirred for a period not exceeding 1 hour followed by filtration.
  • the sticky product obtained gradually solidifies which is then dried under vacuum at about 3O 0 C to get Form ⁇ l of efavirenz having the characteristic XRPD ( Figure 7) and DSC ( Figure 8) patterns.
  • the novel polymorphic Form ⁇ 2 of efavirenz having typical XRPD pattern as depicted in Figure 9 of the accompanying drawings.
  • the XRPD of Form ⁇ 2 shows characteristic 20 values at 12.12, 12.38, 12.98, 13.16, 15.64, 16.90, 17.22, 18.14, 18.42, 18.76, 19.34, 19.48, 19.90, 20.06, 20.32, 21.18, 21.74, 22.04, 23.08, 23.30, 23.98, 24.42, 24.60, 24.94, 25.34, 26.14, 26.36, 27.06, 27.30, 28.04, 28.38, 28.98, 29.24 and 31.64.
  • the novel polymorphic Form od has characteristic DSC thermogram as depicted in Figure 10 of the accompanying drawings.
  • the DSC thermogram shows one characteristic endothermic peak at 13O 0 C - 14O 0 C.
  • a process for the preparation of novel polymorphic Form ⁇ 2 of efavirenz includes: a) dissolving efavirenz in one or more lower alkanols to form a solution; b) adding the solution to a mixture of one or more lower alkanols and salt solution; c) stirring the resultant mass for a period over about 1.5 hours; and d) isolating Form ⁇ 2 of efavirenz from the reaction mass thereof.
  • the efavirenz starting material may be prepared by any method known in the art.
  • the efavirenz is first dissolved in one or more lower alkanols.
  • the solution is added to a mixture of one or more lower alkanols and water.
  • the resultant mass is stirred for a period over about 1.5 hours and then filtered.
  • the product obtained is dried under vacuum at about 3O 0 C - 35 0 C to get Form ⁇ 2 of efavirenz having the characteristic XRPD ( Figure 9) and DSC ( Figure 10) patterns.
  • the novel polymorphic Form ⁇ has characteristic DSC thermogram as depicted in Figure 13 of the accompanying drawings
  • the DSC thermogram shows two characteristic endothermic peaks at 92 0 C - 105 0 C and 135 0 C - 142 0 C.
  • the process includes: a) dissolving efavirenz in one or more water miscible organic solvents to form a solution; b) adding the solution to a mixture of one or more water miscible alkanols and water to form a mixture; c) stirring the reaction mixture at a temperature between about 2 0 C and about 1O 0 C; and d) isolating Form ⁇ of efavirenz from the reaction mass thereof.
  • the efavirenz starting material may be prepared by any method known in the art.
  • the efavirenz is first dissolved in one or more water miscible alkanols to form a solution.
  • the solution is added to a mixture of one or more water miscible alkanols and water to form a mixture.
  • the resultant mixture is stirred at a temperature about 2 0 C and about 1O 0 C.
  • the mass is filtered and the product obtained is dried under vacuum at about 3O 0 C -35 0 C to get Form ⁇ of efavirenz having the characteristic XRPD ( Figure 11) and DSC ( Figure 13) patterns.
  • Also provided in the present invention is a process for the preparation of polymorphic Form ⁇ of efavirenz.
  • the process includes: a) dissolving efavirenz in one or more water miscible organic solvents to form a solution; b) treating the solution a mixture of water, one or more water miscible organic solvents and one or more agents for lowering the freezing point of water to precipitate out a solid; c) treating the solid with water; and d) isolating Form ⁇ of efavirenz from the reaction mass thereof.
  • the efavirenz starting material may be prepared by any method known in the art.
  • the efavirenz is dissolved in one or more water miscible alkanols to form a solution.
  • the solution is added to a mixture of water, one or more water miscible organic solvents and one or more agents for lowering the freezing point of water.
  • the water miscible organic solvents may include methanol, ethanol, n-propanol and isopropanol.
  • the agent for lowering the freezing point of water may be an alkali metal salt or an alkaline earth metal salt.
  • the resultant mixture is stirred at a temperature of about -1O 0 C or less.
  • the novel polymorphic Form ⁇ of efavirenz having typical XRPD pattern as depicted in Figure 14 of the accompanying drawing.
  • the XRPD of Form ⁇ shows characteristic 2 ⁇ values at 7.18, 11.32, 12.12, 12.64, 13.04, 13.44, 13.86, 14.44, 15.12, 15.44, 16.38, 17.00, 18.92, 19.56, 20.08, 20.58, 21.80, 22.14, 22.94, 23.92, 24.66, 25.42, 26.02, 26.72, 27.32, 27.86, 28.02, 29.22, 29.96, 30.72, 31.74, 32.40, 32.74 and 39.06.
  • the novel polymorphic Form ⁇ has the characteristic DSC thermogram as depicted in Figure 15 of the accompanying drawings.
  • the DSC thermogram shows two characteristic endothermic peaks at 85 0 C - 95 0 C and 135 0 C - 142 0 C.
  • the process includes: a) dissolving efavirenz in one or more halogenated hydrocarbons to form a solution; b) adding the solution to a second organic solvent including one or more of C 5-7 alkane, cycloalkane, and petroleum ether; and c) isolating Form ⁇ of efavirenz from the reaction mass thereof.
  • the efavirenz starting material may be prepared by any method known in the art.
  • the efavirenz is first dissolved in one or more halogenated hydrocarbons including dichloromethane, chloroform, ethylene dichloride, ethylene dibromide and mixtures thereof.
  • the solution is added to a second organic solvent including one or more of C 5-7 alkane, C 5-7 cycloalkane, and petroleum ether.
  • the resultant mixture is stirred at a low temperature of about -5O 0 C to 15 0 C.
  • the reaction mass can be partially concentrated to about half of its volume to effect precipitation. Addition of seed of Form ⁇ of efavirenz can also be effectively employed to improve the crystallization.
  • amorphous efavirenz having an XRPD pattern as shown in Figure 16 of the accompanying drawings.
  • the amorphous efavirenz may be prepared by the following process: a) dissolving efavirenz in one or more water miscible organic solvents to form a solution; b) adding the solution to a second solution of one or more inorganic salts; and c) isolating amorphous efavirenz from the reaction mass thereof.
  • the efavirenz starting material may be prepared by any method known in the art.
  • the efavirenz is first dissolved in one or more organic solvents.
  • the solution is added to a second solution of one or more inorganic salts to form a mixture.
  • the resultant mixture is stirred at a temperature of about -5O 0 C to 15 0 C.
  • the reaction mass may be partially concentrated to about half of its volume under cooling to effect precipitation. After complete precipitation of solids, the mass is filtered, washed and the product obtained is dried to get amorphous efavirenz having the characteristic XRPD ( Figure 16) pattern.
  • the inorganic salt may include one or more of water soluble salts of magnesium, potassium, calcium or sodium. Chloride salts of calcium, potassium and sodium may also be used.
  • Also provided in the present invention is a process for the preparation of amorphous efavirenz.
  • the process includes: a) dissolving efavirenz in one or more organic solvents to form a solution; b) recovering the solvent from the solution; and c) isolating amorphous efavirenz from the mass thereof.
  • the efavirenz starting material is dissolved in one or more organic solvents and the solution is concentrated optionally under a vacuum.
  • the organic solvent may be dichloromethane or methanol.
  • the residue obtained is further dried and recovered to get amorphous efavirenz.
  • the polymorphic Form O of efavirenz which exhibits a typical XRPD pattern as depicted in Figure 17 of the accompanying drawings.
  • the XRPD of Form O of efavirenz shows characteristic 2 ⁇ values at 3.92, 7.88, 10.70, 11.20, 11.40, 12.04, 12.86, 13.16, 13.80, 14.38, 15.08, 15.78, 16.46, 17.26, 17.46, 18.44, 19.58, 20.20, 20.86, 21.26, 21.50, 21.92, 22.14, 22.34, 22.96, 23.74, 24.58, 25.38, 26.02, 26.48, 26.90, 27.24, 27.62, 27.86, 28.00, 28.64 and 28.96.
  • the process includes: a) dissolving efavirenz in one or more water miscible organic solvents to form a solution; b) removing the solvent from the solution; c) grinding the product obtained in step b) between two surfaces; and d) isolating Form O of efavirenz from the reaction mass thereof.
  • the efavirenz starting material may be prepared by any method known in the art.
  • the efavirenz is dissolved in one or more water miscible organic solvents including methanol, ethanol, isopropanol, acetonitrile, acetone, tetrahydrofuran and 1,4-dioxane or mixtures thereof.
  • the solvent may be removed from the resultant solution optionally under vacuum and the product obtained is then subjected to grinding between two surfaces, which can be further dried under vacuum to get Form O of efavirenz.
  • the polymorphic Form N of efavirenz exhibits a typical X-Ray Powder diffraction (XRPD) pattern as depicted in Figure 18 of the accompanying drawing.
  • the XRPD of Form N exhibits characteristic 2 ⁇ values at 7.84, 13.12, 15.04, 18.40, 19.54, 20.82, 25.30 and 25.96.
  • Form N of efavirenz is further characterized by a XRPD pattern comprising 2 ⁇ values at 3.9, 7.84, 10.66, 12.00, 12.80, 13.12, 15.04, 15.74, 17.40, 18.40, 19.54, 20.82, 22.88, 23.68, 24.96, 25.30, 25.96, 26.86, 27.16, 27.92 and 28.90.
  • FTIR Fourier Transform Infrared
  • the DSC thermogram shows two characteristic endothermic peaks at 85 0 C - 100 0 C and 132 0 C - 144 0 C.
  • a process for the preparation of Form N of efavirenz includes: a) treating Form O of efavirenz with water; and b) isolating Form N of efavirenz from the reaction mass thereof.
  • Form O of Efavirenz is stirred in water at a low temperature for sufficient time to produce Form N.
  • the resultant mixture is filtered and dried optionally under vacuum to get Form N of efavirenz having the characteristic XRPD ( Figure 18) pattern.
  • Also provided in the present invention is a process for the preparation of polymorphic Form N of efavirenz.
  • the process includes: a) mixing Form ⁇ of efavirenz with a catalytic quantity of Form N of efavirenz to form a mixture; b) drying the mixture under a vacuum for sufficient time; and c) isolating Form N of efavirenz from the reaction mass thereof.
  • the starting compounds such as Form ⁇ and Form N of efavirenz can be prepared by the methods provided in the present invention.
  • Form ⁇ of efavirenz is mixed with catalytic quantity of Form N of efavirenz.
  • the mixture is placed in a flask and a vacuum is applied to the mixture for sufficient time to effect the formation of Form N.
  • the vacuum can be applied so as to obtain a pressure of 5 rnmHg or less.
  • the process can also be accompanied by the rotation of the flask.
  • the flask can be rotated at a speed of 10 to 100 revolutions per minute.
  • the process is carried out at a temperature of about 1O 0 C or less. Further drying is optionally carried out under vacuum at 3O 0 C to 45 0 C.
  • Form N of efavirenz having characteristic XRPD ( Figure 19) pattern is isolated from the reaction mass.
  • polymorphic Form P of efavirenz having the typical XRPD pattern as depicted in Figure 22 of the accompanying drawing.
  • the XRPD of Form P of efavirenz shows characteristic 2 ⁇ values at 8.6 and 24.66.
  • the polymorphic Form P is further characterized by an XRPD pattern comprising 2 ⁇ values at 3.90, 7.84, 8.68, 10.66, 10.82, 11.22, 11.42, 12.00, 12.42, 12.78, 13.12, 13.66, 14.30, 14.42, 15.04, 15.22, 15.74, 16.34, 16.58, 16.84, 17.40, 17.90, 18.38, 18.56, 19.52, 20.80, 21.46, 21.74, 22.18, 22.88, 23.82, 24.34, 24.66, 25.28, 25.94, 26.20, 26.86, 27.14, 27.92, 28.44 and 28.88.
  • the process includes: a) dissolving efavirenz in one or more water miscible organic solvents to form a solution; b) adding the solution to a mixture of Form N in water; and c) isolating Form P of efavirenz from the reaction mass thereof.
  • the efavirenz starting material may be prepared by any method known in the art.
  • a solution of efavirenz may be prepared in one or more water miscible organic solvents including methanol, ethanol, isopropanol, acetonitrile, acetone, tetrahydrofuran, 1,4- dioxane, and mixtures thereof.
  • the solution is then added to a mixture of Form N in water.
  • the precipitated solids are filtered and dried suitably to get Form P of efavirenz.
  • compositions of Forms ⁇ , ⁇ , ⁇ , ⁇ l, ⁇ 2, ⁇ , ⁇ , N, O and P of efavirenz.
  • the pharmaceutical compositions may include one or more pharmaceutically acceptable excipients.
  • the method includes administering to a mammal in need thereof a therapeutically effective amount of one or more of polymorphic Forms ⁇ , ⁇ , ⁇ , ⁇ l, ⁇ 2, ⁇ , ⁇ , N, O and P of efavirenz.
  • Powder XRPD of the samples were determined by using X-Ray Diffractometer, Rigaku Corporation, RU-H3R, Goniometer CN2155A3, X-Ray tube with Cu target anode, Divergence slits 1 0, Receiving slit 0.15mm, Scatter slit 1°, Power: 40 KV, 100 rnA, Scanning speed: 2 deg/min step: 0.02 deg, Wavelength: 1.5406 A.
  • FT-IR of the samples were determined by using as the instrument a Perkin
  • Efavirenz (1.0 gm) was dissolved in dichloroniethane (4 ml) and hexane (50 ml) was added to the solution obtained. 25 ml of the reaction mixture was evaporated under vacuum at 4O 0 C and 5 ml under vacuum at 25 0 C. The reaction mixture was stirred for 10 minutes and the precipitated compound was filtered off to get the title compound.
  • Efavirenz (5.0 gm) was dissolved in cyclohexane by heating to 55 0 C. The solution was cooled to 45 0 C and was seeded with Form ⁇ . The solution was further cooled to 25 0 C and again seeded with Form ⁇ . The resultant mass was stirred at 7 0 C for 20 minutes and filtered to get the title compound.
  • Efavirenz (5 gm) was dissolved in methanol (5 ml) under stirring. This solution was added drop-wise into a pre-cooled mixture of water (150 ml) and methanol (15 ml) while maintaining the temperature below -6 0 C. The resultant mass was stirred at -5 0 C for about 3 hours and the separated solids were filtered. The solids were dried in a vacuum oven at a temperature of 30° to 35 0 C for 6 hours to get the title compound.
  • Efavirenz (1.0 gm) was dissolved in N,N-dimethylformarnide (1.0 ml) under stirring. This solution was added drop-wise into a sodium chloride solution (15%) at 25 0 C. The resultant mass was stirred at the same temperature for about 5 hours and the separated solid was filtered and washed with water. The solid was dried in a vacuum oven at a temperature of 35 0 Qo 4O 0 C for 2 hours to get the title compound.
  • Efavirenz (1.0 gm) was dissolved in methanol (1.0 ml) under stirring. This solution was added drop-wise into a pre-cooled mixture of 15% sodium chloride in water (30 ml) and methanol (3 ml) while maintaining the temperature below -8 0 C. The resultant mass was stirred at -5 0 C for about 10 minutes followed by filtration and washing with water. The sticky compound solidified after 2 hours was dried in vacuum oven at 3O 0 C for 6 hrs to get the title compound.
  • EXAMPLE 6 PREPARATION OF FORM ⁇ 2 OF EFAVIRENZ Efavirenz (1.0 gm) was dissolved in methanol (1.0 ml) under stirring. This solution was added drop-wise into a pre-cooled mixture of 15% sodium chloride in water (30 ml) and methanol (3 ml) while maintaining the temperature below -8 0 C. The resultant mass was stirred at -8 0 C to 5 0 C for about 3 hours followed by filtration and washing with water. The solid was dried in a vacuum oven at a temperature of 30°Cto 35 0 C for 6 hours to get the title compound.
  • Efavirenz (10.0 gm) was dissolved in methanol (10.0 ml) under stirring. This solution was added drop-wise into a pre-cooled mixture of water (150 ml) and methanol (15 ml) while maintaining the temperature below -6 0 C. The resultant mass was stirred at 2 0 C to 3 0 C for about 3 hours and the separated solid was filtered. The solid was dried in a vacuum oven at a temperature of 3 O 0 CtO 35 0 C for 6 hours to get the title compound.
  • Form ⁇ seed (0.1 gm) was added to a pre-cooled n-pentane (60 ml) at -15 0 C followed by the addition of a solution of efavirenz (3 gm) in dichloromethane (3 ml). The mass was cooled further to -4O 0 C, stirred for 45 minutes at -4O 0 C to -35 0 C and filtered to get the title compound.
  • Efavirenz (5 gm) was dissolved in dichloromethane (50 ml) and the solvent was recovered under vacuum. The resultant residue was kept under vacuum for a further 1 to 2 hours at 4O 0 C. The product was removed and dried at 25 0 C under vacuum to get the title compound.
  • EXAMPLE 16 PREPARATION OF FORM O OF EFAVIRENZ Efavirenz (20 gm) was dissolved in methanol (200 ml) at 25 0 C. Methanol was recovered completely from the resulting solution under vacuum at 38 0 C. The product obtained was further dried under vacuum at 25 0 C for 15 hours. The resulting material was ground further to obtain the title compound.
  • a mixture of Form ⁇ (48 gm) and Form N (10.1 gm) of efavirenz was loaded in a 2 L rotary evaporator flask and 4 Teflon coated magnetic beads were added.
  • a high vacuum (0 to 2 mmHg) was applied to the rotary evaporator and the evaporator flask was dipped into ice water bath at O 0 C to 2 0 C.
  • the rotary evaporator flask was rotated at 20 rpm for 5 minutes and the speed was increased to 60 to 80 rpm.
  • the rotation at 60 to 80 rpm under vacuum was continued for 5 hours at O 0 C to 2 0 C.
  • the solid was isolated from the walls of the flask and kept in vacuum oven at 38 0 C for 15 hours to get the title compound.
  • the various novel polymorphic Forms ⁇ , ⁇ , ⁇ , ⁇ l, ⁇ 2, ⁇ , ⁇ , N, O, and P of efavirenz, and the amorphous form of efavirenz may be combined with one or more pharmaceutical excipients and carriers to form a dosage form suitable for administration to a patient in need thereof, such as a patient in need of treatment of an HIV-I infection.
  • the dosage form may be any conventionally used dosage form, such as a tablet, capsule, injection, intravenous, inhalation, powder, dispersible tablet, etc.
  • the dosage forms of these novel polymorphic forms of efavirenz may further include one or more additional therapeutic agents suitable for the treatment of an HIV-I infection.

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Abstract

La présente invention concerne de nouvelles formes polymorphes d'éfavirenz. Les nouvelles formes polymorphes sont désignées comme formes d'éfavirenz a, ß, ?, ?1, ?2, ?, d, N, O et P. La présente invention concerne aussi une forme amorphe d'éfavirenz. L'invention concerne également des processus de leur préparation et de leur utilisation dans des compositions pharmaceutiques visant le traitement de l'infection par VIH-1.
PCT/IB2005/003013 2004-10-11 2005-10-10 Formes polymorphes d'efavirenz et processus de leur fabrication Ceased WO2006040643A2 (fr)

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IN2167/DEL/2004 2004-10-29
IN2166/DEL/2004 2004-10-29
IN2165/DEL/2004 2004-10-29
IN2166DE2004 2004-10-29
IN2164DE2004 2004-10-29
IN2164/DEL/2004 2004-10-29
IN433/DEL/2005 2005-02-28
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008108630A1 (fr) * 2007-03-02 2008-09-12 Ultimorphix Technologies B.V. Formes polymorphes de l'efavirenz
WO2009011567A1 (fr) * 2007-07-16 2009-01-22 Ultimorphix Technologies B.V. Formes cristallines d'efavirenz
WO2009026257A2 (fr) 2007-08-17 2009-02-26 Teva Pharmaceutical Industries Ltd. Procédés et compositions pour contrôler la biodisponibilité de médicaments faiblement solubles
WO2009087679A3 (fr) * 2007-12-24 2010-01-21 Matrix Laboratories Limited Procédé de préparation de formes polymorphes de (s)-6-chloro-(cyclopropyléthynyl)-1,4-dihydro-4-(trifluorométhyl)-2h-3,1-benzoxazin-2-one
WO2011032634A1 (fr) 2009-09-16 2011-03-24 Archimica Gmbh Sels d'éfavirenz, leur procédé de préparation et de libération du sel
EP2471783A1 (fr) 2010-12-23 2012-07-04 Esteve Química, S.A. Nouvelle forme polymorphe de l'éfavirenz
US8383811B2 (en) 2008-12-22 2013-02-26 Hetero Research Foundation Process for preparing efavirenz polymorph

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5965729A (en) * 1997-02-05 1999-10-12 Merck & Co., Inc. Process for the crystallization of a reverse transcriptase inhibitor using an anti-solvent
US6673372B1 (en) * 1998-06-11 2004-01-06 Bristol-Myers Squibb Pharma Company Crystalline Efavirenz

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008108630A1 (fr) * 2007-03-02 2008-09-12 Ultimorphix Technologies B.V. Formes polymorphes de l'efavirenz
WO2009011567A1 (fr) * 2007-07-16 2009-01-22 Ultimorphix Technologies B.V. Formes cristallines d'efavirenz
WO2009026257A2 (fr) 2007-08-17 2009-02-26 Teva Pharmaceutical Industries Ltd. Procédés et compositions pour contrôler la biodisponibilité de médicaments faiblement solubles
WO2009087679A3 (fr) * 2007-12-24 2010-01-21 Matrix Laboratories Limited Procédé de préparation de formes polymorphes de (s)-6-chloro-(cyclopropyléthynyl)-1,4-dihydro-4-(trifluorométhyl)-2h-3,1-benzoxazin-2-one
US20100274007A1 (en) * 2007-12-24 2010-10-28 Matrix Laboratories Limited Process for preparing polymorphic forms of (s)-6-chloro-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2h-3,1-benzoxazin-2-one
US8318930B2 (en) 2007-12-24 2012-11-27 Matrix Laboratories Limited Process for preparing polymorphic forms of (S)-6-chloro-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one
US8383811B2 (en) 2008-12-22 2013-02-26 Hetero Research Foundation Process for preparing efavirenz polymorph
WO2011032634A1 (fr) 2009-09-16 2011-03-24 Archimica Gmbh Sels d'éfavirenz, leur procédé de préparation et de libération du sel
DE102009041443A1 (de) 2009-09-16 2011-03-31 Archimica Gmbh Salze des 6-Chlor-4-(cyclopropylethinyl)-1,4-dihydro-4-(trifluormethyl)-2H-3,1-benzoxazin-2-ons und deren Synthese, Aufreinigung und Anwendung als Vorstufen für Efavirenz
EP2471783A1 (fr) 2010-12-23 2012-07-04 Esteve Química, S.A. Nouvelle forme polymorphe de l'éfavirenz

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