WO2009027766A2 - Nouvelles formes solides cristallines de la base o-desvenlafaxine - Google Patents

Nouvelles formes solides cristallines de la base o-desvenlafaxine Download PDF

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WO2009027766A2
WO2009027766A2 PCT/IB2007/004654 IB2007004654W WO2009027766A2 WO 2009027766 A2 WO2009027766 A2 WO 2009027766A2 IB 2007004654 W IB2007004654 W IB 2007004654W WO 2009027766 A2 WO2009027766 A2 WO 2009027766A2
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base form
desmethylvenlafaxine
solvent
desvenlafaxine
xrd
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PCT/IB2007/004654
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WO2009027766A3 (fr
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Monica Benito Velez
Iolanda Chamorro
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Medichem, S.A.
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • 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 invention relates generally to crystalline polymorphic forms of O- desmethylvenlafaxine base, designated herein as O-desmethylvenlafaxine base Forms A and B, and methods for preparing and obtaining the same.
  • Desvenlafaxine (Compound I, below) is an active pharmaceutical substance with an empirical formula of Ci6H 2 5NO 2 and a molecular weight of 263.38.
  • Desvenlafaxine which can also be referred to as desmethylvenlafaxine, l-[(2-dimethylamino)-l-(4-hydroxyphenyl) ethyl]cyclohexanol and/or O-desmethylvenlafaxine, is the major active metabolite of venlafaxine, an active pharmaceutical ingredient indicated for the treatment of major depressive disorder, and has been shown to inhibit norepinephrine and serotonin uptake.
  • U.S. Patent No. 4,535,186 discloses (see Example 26) one process for preparing desvenlafaxine.
  • desvenlafaxine is synthesized by the process illustrated in Scheme 1 :
  • U.S. Patent No. 5,043,466 describes an improved synthetic process for preparing desvenlafaxine.
  • desvenlafaxine is obtained by using hydrocarbon solvents as the reaction medium during the condensation reaction with cyclohexanone.
  • Further methods for preparing O-desmethylvenlafaxine are described in WO 00/32555, U.S. Patent Application Publication No. 2002/022662A1 and WO 02/064543A2.
  • Additional alternative processes for preparing desvenlafaxine are described in the literature. These alternative processes generally proceed via the demethylation of venlafaxine.
  • O-desmethylvenlafaxine including the fumarate, succinate and formate salts
  • U.S. Patent No.4,535, 186 reports the preparation of O-desmethylvenlafaxine fumarate salt. More recently, the preparation of several polymorphic forms of the succinate salt have been reported in U.S. Patent No. 6,673,838 B2. Additionally, U.S. Patent Application Publication No.2006/0058552 discloses the preparation of the formate salt.
  • International patent publication No. WO 2007/120925 discloses new polymorphic forms of O-desmethylvenlafaxine base, referred to therein as Forms C, and D. Further, International patent publication No. WO 2007/120925 discloses a method for preparing O- desmethylvenlafaxine base form A that includes crystallizing O-desmethylvenlafaxine base from a selected solvent from the group of ethanol, tetrahydrofuran (THF), isopropyl alcohol (IPA) and a mixture of IPA and water.
  • THF tetrahydrofuran
  • IPA isopropyl alcohol
  • IPA isopropyl alcohol
  • WO 2007/120925 to prepare O-desmethylvenlafaxine base form A make use of large amounts of organic solvents (see Examples 3 and 4).
  • the use of large amounts of organic solvents to prepare crystalline O-desmethylvenlafaxine base form A is not desirable, especially for industrial scale implementation.
  • Polymorphism is very common among pharmaceutical substances and is commonly defined as the ability of any substance to exist in two or more crystalline phases that have a different arrangement and/or conformation of the molecules in the crystal lattice. Different polymorphs typically differ in their physical properties such as melting point, solubility, chemical reactivity, etc. Thus, the particular characteristics of the respective polymorphs can appreciably influence pharmaceutical properties such as dissolution rate and bioavailability. It would be desirable, therefore, to identify and isolate new polymorphic forms of O- desmethylvenlafaxine base.
  • O-desmethylvenlafaxine base is poorly soluble in a number of solvents, it would be desirable to have reliable and efficient processes for producing O-desmethylvenlafaxine base in one or more of its polymorphic forms, which make use of small amounts of solvents, and which might be suitable for industrial implementation.
  • the invention relates generally to crystalline polymorphic forms of O- desmethylvenlafaxine base, designated herein as O-desmethylvenlafaxine base Forms A and B, and methods for preparing and obtaining the same.
  • O-desmethylvenlafaxine base Forms A and B cannot be distinguished by their melting point, but they can be distinguished by their X-Ray diffraction patterns.
  • the invention includes a process for preparing an anhydrous polymorph of O- desmethylvenlafaxine base Form A that includes crystallizing the desired Form A from a solution comprising O-desmethylvenlafaxine and/or a solvent or precipitating from a mixture of an organic water-miscible solvent with water.
  • the preferred crystallizing solvents are alcohol, ester, ether solvents or combinations thereof.
  • the preferred organic water-miscible solvents are ether, nitrile, amide, or sulphoxide solvents. It also has been found that Form A appears to be the kinetic product of crystallization of O-desmethylvenlafaxine base, which can be converted to the thermodynamic product Form B upon treating Form A in the crystallization solvent.
  • the process for preparing O-desmethylvenlafaxine base Form B includes suspending O- desmethylvenlafaxine base Form A in a ketone, alcohol, ether, ester or nitrile solvent for a period of time enough to allow the formation of O-desmethylvenlafaxine base Form B.
  • Figure 1 illustrates the X-ray powder diffraction (XRD) of O-desmethylvenlafaxine base Form A obtained in Example 3;
  • Figure 2 illustrates the X-ray powder diffraction (XRD) of O-desmethylvenlafaxine base Form B obtained in.Example 28; and Figure 3 illustrates the X-ray powder diffraction (XRD) of O-desmethylvenlafaxine succinate obtained in Example 37.
  • XRD X-ray powder diffraction
  • One aspect of the invention includes new crystalline polymorphic forms of O- desmethylvenlafaxine base (designated herein as O-desmethylvenlafaxine Forms A and B) and methods for obtaining thereof.
  • Another aspect of the invention includes crystalline Form A and Form B of O- desmethylvenlafaxine base characterized by their X-ray powder diffraction patterns (XRD).
  • XRD X-ray powder diffraction patterns
  • O-desmethylvenlafaxine base Form A can be prepared by one or more crystallizations of O-desmethylvenlafaxine base with an alcohol, ester or ether solvent(s), nitrile solvents or mixtures thereof.
  • Preferred alcohol solvents include, for example, ethanol, 2-propanol, 2-butanol and 1-butanol.
  • Preferred ester solvents include, for example, ethyl acetate.
  • Preferred ether solvents include, for example, tetrahydrofuran.
  • Preferred nitrile solvents include, for example, acetonitrile.
  • O-desmethylvenlafaxine base Form A can be prepared by one or more precipitations from a mixture of ether, nitrile, amide or sulphoxide solvents with water.
  • Preferred ether solvents include, for example, tetrahydrofuran, and 1,4- dioxane.
  • Preferred nitrile solvents include, for example, acetonitrile.
  • Preferred amide solvents include, for example, dimethylacetamide, dimethylformamide, l-methyl-2-pyrrolidone, and 1- formylpiperidine.
  • Preferred sulphoxide solvents include, for example, dimethylsulphoxide.
  • O-desmethylvenlafaxine base Form B can be prepared by one or more treatments of O-desmethylvenlafaxine base Form A with an alcohol, ketone, ether, ester or nitrile solvent, or mixtures thereof.
  • Preferred alcohol solvents include, for example, methanol, ethanol and 2-propanol.
  • Preferred ketone solvents include, for example, acetone.
  • Preferred ether solvents include, for example, tetrahydrofiiran.
  • Preferred ester solvents include, for example, ethyl acetate.
  • Preferred nitrile solvents include, for example, acetonitrile.
  • Another aspect of the invention includes the use of O-desmethylvenlafaxine base Form A, Form B or mixtures thereof for preparing and obtaining pharmaceutically acceptable salts of O-desmethylvenlafaxine.
  • Another aspect of the invention includes the use of O-desmethylvenlafaxine base Form A, Form B or mixtures thereof for preparing and obtaining O-desmethylvenlafaxine succinate.
  • Another aspect of the invention includes the use of O-desmethylvenlafaxine base Form A or Form B or mixtures thereof for preparing and obtaining O-desmethylvenlafaxine formate.
  • DSC Differential Scanning Calorimetry
  • Chromatographic separation was performed in a Kromasil C8, 5 ⁇ m, 25 cm x 4.6 mm I.D. column at room temperature ( ⁇ 20-25° C).
  • the mobile phase was prepared by mixing 1600 g Of(NH 4 )H 2 PO 4 buffer solution
  • the chromatograph was equipped with a 225 nm detector, and the flow rate was 1.2 mL per minute.
  • Test samples (20 ⁇ L) were prepared by dissolving a sufficient quantity of sample in order to obtain a 1 mg per mL concentration in the mobile phase.
  • Venlafaxine base (40 g, 144 mmol) was added into a solution of 13.05 g (241 mmol) of NaOMe and 51.8 mL (43.7 g, 216 mmol) of dodecanethiol in 400 mL of N 5 N- dimethylacetamide, at room temperature, under an argon atmosphere.
  • the reaction mixture was heated and stirred while the formed methanol was removed from the mixture by distillation until the inner temperature was raised gradually to 150° C. At this point, the distillation apparatus was replaced with a reflux condenser, and the reaction mixture was boiled for about 20 additional hours, until all the starting material disappeared (by TLC).
  • the reaction mixture was cooled to room temperature and poured into 1500 mL of water (exothermic reaction), the pH of the mixture was adjusted to 9.6 with 1 : 1 aqueous HCl solution, and the resulting precipitate was filtered and washed with 200 mL water.
  • the wet material was suspended in 100 mL of methyl /er/-butyl ether (MTBE), filtered and washed with 2 * 50 mL of MTBE, and dried in vacuo at 40° C.
  • the obtained product (27.0 g, 71.1%)) was recrystallized from approximately 1200 mL of ethyl acetate to yield 23.1 g (55.4%) of white crude product.
  • the wet solid was characterized by XRD as O-desmethylvenlafaxine base Form A.
  • Analytical data XRD: Form A.
  • the diffractogram was substantially identical to the diffractogram shown in Figure 1. Melting Point: 219.6-220.8° C.
  • O-desmethylvenlafaxine base (0.15 g) was dissolved in 3.75 mL of ethanol at reflux. The solution was heated at this temperature for one hour. The solution was hot filtered, and then it was allowed to cool to room temperature while stirring. The wet solid was collected by filtration and characterized by means of XRD as O-desmethylvenlafaxine base Form A. Analytical data: XRD: Form A. Diffractogram shown in Figure 1.
  • O-desmethylvenlafaxine base (1.5 g) was dissolved in 34 mL of ethanol at reflux. The solution was hot filtered, and the solution was again heated to reflux for 5 minutes. The solution was allowed to cool to room temperature while stirring for 2 hours. The solid was collected by filtration and characterized by means of XRD as O-desmethylvenlafaxine base Form A. The solid was dried at 100° C for 5 hours. The analysis by XRD confirmed it was O-desmethylvenlafaxine base Form A. Analytical data: XRD: Form A. The diffractogram was substantially identical to the diffractogram shown in Figure 1.
  • EXAMPLE 5 O-desmethylvenlafaxine base (0.15 g) was dissolved in 4.25 mL of 2-propanol at reflux. The solution was heated at this temperature for one hour and was allowed to cool to room temperature while stirring. The wet solid was collected by filtration and characterized by means of XRD as O-desmethylvenlafaxine base Form A. Analytical data: XRD: Form A. The diffractogram was substantially identical to the diffractogram shown in Figure 1. EXAMPLE 6
  • O-desmethylvenlafaxine (0.15 g) was dissolved in 3.5 itiL of 2-butanoI at 90° C for 1 hour. The solution was hot filtered and heated again at 90° C for a few minutes and was then allowed to cool to room temperature while stirring for 1.5 hours. The wet solid was filtered and characterized by XRD as O-desmethylvenlafaxine base Form A. Analytical data: XRD: Form A. The diffractogram was substantially identical to the diffractogram shown in Figure 1.
  • O-desmethylvenlafaxine (0.15 g) was dissolved in 3.75 mL of ethanol at reflux. The solution was hot filtered, 0.6 mL of ethanol was added, and the solution was heated again at reflux for a few minutes until complete dissolution. The solution was cooled in an ice bath for 30 minutes, and the resulting wet solid was filtered and characterized by XRD as O- desmethylvenlafaxine base Form A. Analytical data: XRD: Form A. The diffractogram was substantially identical to the diffractogram shown in Figure 1. EXAMPLE 8
  • O-desmethylvenlafaxine (0.15 g) was dissolved in 4.25 mL of 2-propanol at reflux. The solution was quickly hot filtered and was cooled in an ice bath for 30 minutes. The wet solid was filtered and characterized by XRD as O-desmethylvenlafaxine base Form A. Analytical data: XRD: Form A. The diffractogram was substantially identical to the diffractogram shown in Figure 1.
  • O-desmethylvenlafaxine (0.15 g) was dissolved in 3 mL of tetrahydrofiiran at reflux. The solution was hot filtered and heated again at reflux for a few minutes until complete dissolution. The solution was cooled in an ice bath for 30 minutes, and the wet solid was filtered and characterized by XRD as O-desmethylvenlafaxine base Form A. Analytical data: XRD: Form A. The diffractogram was substantially identical to the diffractogram shown in Figure 1.
  • O-desmethylvenlafaxine (0.15 g) was dissolved in 3.5 mL of tetrahydrofiiran at reflux and then 4 mL of water was added to the hot solution. The mixture was cooled to room temperature while stirring. One hour later the wet solid was filtered and characterized by XRD as O-desmethylvenlafaxine base Form A. Analytical data: XRD: Form A. The diffractogram was substantially identical to the diffractogram shown in Figure 1.
  • O-desmethylvenlafaxine (0.15 g) was dissolved in 3.75 mL of ethanol at reflux. The solution was hot filtered, and heated again to reflux for complete dissolution. Next, 4 mL of water was added and the mixture was allowed to cool to room temperature while stirring for 1 hour. The wet solid was collected by filtration and characterized by XRD as O- desmethylvenlafaxine base Form A. Analytical data: XRD: Form A. The diffractogram was substantially identical to the diffractogram shown in Figure 1. EXAMPLE 12
  • O-desmethylvenlafaxine (0.15 g) was dissolved in 4 mL of 2-propanol at reflux. The solution was hot filtered, and heated again to reflux for complete dissolution. Next, 4 mL of water was added and the mixture was allowed to cool to room temperature while stirring for 1 hour. The wet solid was collected by filtration and characterized by XRD as O-desmethylvenlafaxine base Form A. Analytical data: XRD: Form A. The diffractogram was substantially identical to the diffractogram shown in Figure 1.
  • O-desmethylvenlafaxine (0.15 g) was dissolved in 2.3 mL of 1 ,4-dioxane at reflux. The solution was hot filtered and heated again to reflux for complete dissolution. Next, 4 mL of water was added, and the mixture was allowed to cool to room temperature while stirring for 1 hour. The wet solid was collected by filtration and characterized by XRD as O-desmethylvenlafaxine base Form A. Analytical data: XRD: Form A. The diffractogram was substantially identical to the diffractogram shown in Figure 1.
  • EXAMPLE 14 O-desmethylvenlafaxine (0.15 g) was suspended in 1.5 mL of acetonitrile and 1.5 mL of water. The mixture was heated at 90° C for 1 hour and was allowed to cool to room temperature while stirring for 1.5 hour. The wet solid was collected by filtration and characterized by XRD as O-desmethylvenlafaxine base Form A. Analytical data: XRD: Form A. The diffractogram was substantially identical to the diffractogram shown in Figure 1.
  • EXAMPLE 15 O-desmethylvenlafaxine (0.15 g) was dissolved in 2.6 mL of dimethylacetamide at room temperature. The solution was filtered, 2.6 mL of water was added, and the mixture was stirred for 1 hour. The wet solid was collected by filtration and characterized by XRD as O-desmethylvenlafaxine base Form A. Analytical data: XRD: Form A. The diffractogram was substantially identical to the diffractogram shown in Figure 1.
  • O-desmethylvenlafaxine (0.15 g) was dissolved in 5 mL of dimethylformamide at room temperature. The solution was filtered, 5 mL of water was added, and the mixture was stirred for 1 hour. The wet solid was collected by filtration and characterized by XRD as O-desmethylvenlafaxine base Form A. Analytical data: XRD: Form A. The diffractogram was substantially identical to the diffractogram shown in Figure 1.
  • O-desmethylvenlafaxine (0.15 g) was dissolved in 4.5 mL of dimethylsulfoxide at room temperature. The solution was filtered, 4.5 mL of water was added, and the mixture was stirred for 1 hour. The wet solid was collected by filtration and characterized by XRD as O-desmethylvenlafaxine base Form A. Analytical data: XRD: Form A. The diffractogram was substantially identical to the diffractogram shown in Figure 1.
  • O-desmethylvenlafaxine (0.15 g) was dissolved in 1 mL of dimethylacetamide at 80° C for 15 minutes. Next, ImL of water was added, and the resulting mixture was allowed to cool to room temperature while stirring for 1 hour. The solid was filtered and washed with water. The wet solid was characterized by XRD as O-desmethylvenlafaxine base Form A. Analytical data: XRD: Form A. The diffractogram was substantially identical to the diffractogram shown in Figure 1. EXAMPLE 19
  • O-desmethylvenlafaxine (0.15 g) was dissolved in 1 mL of dimethylformamide at 80° C for 15 minutes. Next, 2 mL of water was added, and the resulting mixture was allowed to cool to room temperature while stirring for 1 hour. The solid was filtered and washed with water. The wet solid was characterized by XRD as O-desmethylvenlafaxine base Form A. Analytical data: XRD: Form A. The diffractogram was substantially identical to the diffractogram shown in Figure 1. EXAMPLE 20
  • O-desmethylvenlafaxine (0.15 g) was dissolved in 1 mL of dimethylsulfoxide at 80° C for 15 minutes. Next, 2 mL of water was added, and the resulting mixture was allowed to cool to room temperature while stirring for 1 hour. The solid was filtered and washed with water. The wet solid was characterized by XRD as O-desmethylvenlafaxine base Form A. Analytical data: XRD: Form A. The diffractogram was substantially identical to the diffractogram shown in Figure 1. EXAMPLE 21
  • O-desmethylvenlafaxine (0.15 g) was dissolved in 0.8 mL of l-methyl-2- pyrrolidone at 80° C for 15 minutes. Next, 2 mL of water was added, and the resulting mixture was allowed to cool to room temperature while stirring for 1 hour. The solid was filtered and washed with water. The wet solid was characterized by XRD as O- desmethylvenlafaxine base Form A. Analytical data: XRD: Form A. The diffractogram was substantially identical to the diffractogram shown in Figure 1.
  • O-desmethylvenlafaxine (0.15 g) was dissolved in 1 mL of 1 -formylpiperidine at 80° C for 15 minutes. Next, 2 mL of water was added, and the resulting mixture was allowed to cool to room temperature while stirring for 1 hour. The solid was filtered and washed with water. The wet solid was characterized by XRD as O-desmethylvenlafaxine base Form A. Analytical data: XRD: Form A. The diffractogram was substantially identical to the dif ⁇ ractogram shown in Figure 1.
  • O-desmethylvenlafaxine base (32.98 g) was suspended in 136 g (172 mL) of methanol, the suspension was heated to reflux temperature and maintained at this temperature 30 minutes. The resulting suspension was cooled to and maintained at 20-25° C for one hour and was filtered. The resulting solid was washed with 17 g (22 mL) of methanol and two portions of 22 g of deionized water. A wet white solid was obtained (45.6 g) that was dried at 60° C under vacuum to yield 31.5 g of O-desmethylvenlafaxine base (yield: 95.51 %). Analytical data: HPLC purity: 99.8 %; assay: 99.9 %, XRD: Form A. The diffractogram was substantially identical to the diffractogram shown in Figure 1.
  • O-desmethylvenlafaxine base Form A (0.1 g) was suspended in 1 mL of acetone and stirred at room temperature for 7 days. The solid was filtered and characterized by means of XRD as Form B. The solid was dried at 50° C for 15 hours under vacuum and was characterized again by XRD as O-desmethylvenlafaxine base Form B. Analytical data: XRD: Form B. The diffractogram was substantially identical to the diffractogram shown in Figure 2. Melting point: 220.5-221.3° C.
  • O-desmethylvenlafaxine base Form A (0.080 g) was suspended in 0.8 mL of acetone. The mixture was seeded with Form B and stirred at room temperature for 1 day. The wet solid was filtered and characterized by means of XRD as O-desmethylvenlafaxine base Form B. Analytical data: XRD: Form B. The diffractogram was substantially identical to the diffractogram shown in Figure 2.
  • O-desmethylvenlafaxine base Form A (0.75 g) was suspended in 7.5 mL of acetone and stirred at room temperature for 7 days. The wet solid was filtered and characterized by means of XRD as O-desmethylvenlafaxine base Form B. Analytical data: XRD: Form B. The diffractogram was substantially identical to the diffractogram shown in Figure 2.
  • O-desmethylvenlafaxine base Form A (0.1 g) was suspended in 1 mL of methanol and stirred at room temperature for 7 days. The wet solid was filtered and characterized by means of XRD as O-desmethylvenlafaxine base Form B. Analytical data: XRD: Form B. The diffractogram was substantially identical to the diffractogram shown in Figure 2. Melting point: 220.3-221.3° C.
  • EXAMPLE 28 O-desmethylvenlafaxine base Form A (0.3 g) was suspended in 3 mL of methanol and stirred at room temperature for 7 days. The wet solid was filtered and characterized by means of XRD as O-desmethylvenlafaxine base Form B. Analytical data: XRD: Form B. The diffractogram was substantially identical to the diffractogram shown in Figure 2.
  • EXAMPLE 29 O-desmethylvenlafaxine base Form A (0.3 g) was suspended in 3 mL of methanol and stirred at room temperature for 7 days. The wet solid was filtered and characterized by means of XRD as O-desmethylvenlafaxine base Form B. Analytical data: XRD: Form B. The diffractogram was substantially identical to the diffractogram shown in Figure 2. EXAMPLE 29
  • O-desmethylvenlafaxine base Form A (0.1 g) was suspended in 1 mL of ethanol and stirred at room temperature for 7 days. The solid was filtered and characterized by means of XRD as Form B. The solid was dried at 50° C for 15 hours under vacuum and characterized again by XRD as O-desmethylvenlafaxine base Form B. Analytical data: XRD: Form B. Diffractogram shown in Figure 2.
  • O-desmethylvenlafaxine base Form A (0.3 g) was suspended in 3 mL of ethanol and stirred at room temperature for 7 days. The wet solid was filtered and analyzed by means of XRD as O-desmethylvenlafaxine base Form B. Analytical data: XRD: Form B. The diffractogram was substantially identical to the diffractogram shown in Figure 2.
  • O-desmethylvenlafaxine base Form A (1.5 g) was suspended in 15 mL of ethanol and stirred at room temperature for 4 days. The wet solid was filtered and characterized by means of XRD as O-desmethylvenlafaxine base Form B. Analytical data: XRD: Form B. The diffractogram was substantially identical to the diffractogram shown in Figure 2.
  • O-desmethylvenlafaxine base Form A (0.1 g) was suspended in 1 mL of 2-propanol and stirred at room temperature for 7 days. The wet solid was filtered and characterized by means of XRD as O-desmethylvenlafaxine base Form B. Analytical data: XRD: Form B. The diffractogram was substantially identical to the diffractogram shown in Figure 2.
  • O-desmethylvenlafaxine base Form A (0.3 g ) was suspended in 3 mL of 2-propanol and stirred at room temperature for 7 days. The wet solid was filtered and characterized by means of XRD as O-desmethylvenlafaxine base Form B. Analytical data: XRD: Form B. The diffractogram was substantially identical to the diffractogram shown in Figure 2.
  • O-desmethylvenlafaxine base Form A (0.1 g) was suspended in 1 mL of ethyl acetate and stirred at room temperature for 7 days. The wet solid was filtered and characterized by means of XRD as O-desmethylvenlafaxine base Form B. Analytical data: XRD: Form B. The diffractogram was substantially identical to the diffractogram shown in Figure 2. Melting point: 220.7-221.2° C.
  • O-desmethylvenlafaxine base Form A (0.1 g) was suspended in 1 mL of tetrahydrofuran and stirred at room temperature for 7 days. The wet solid was filtered and characterized by means of XRD as O-desmethylvenlafaxine base Form B. Analytical data: XRD: Form B. The diffractogram was substantially identical to the diffractogram shown in Figure 2.
  • O-desmethylvenlafaxine base Form A (0.1 g) was suspended in 1 mL of acetonitrile and stirred at 50° C for 4 days. The suspension was allowed to cool to room temperature. The wet solid was filtered and characterized by means of XRD as O-desmethylvenlafaxine base Form B. Analytical data: XRD: Form B. The diffractogram was substantially identical to the diffractogram shown in Figure 2.
  • O-desmethylvenlafaxine base Form A (0.3 g) was suspended in 3 mL of acetonitrile and stirred at room temperature for 7 days. The wet solid was filtered and characterized by means of XRD as O-desmethylvenlafaxine base Form B. Analytical data: XRD: Form B. The diffractogram was substantially identical to the diffractogram shown in Figure 2.
  • O-desmethylvenlafaxine base Form A (140 g) obtained following the procedure described in Example 1 was suspended in 1183 mL of acetone and 374 mL of water. The white suspension obtained was stirred for 30 minutes at room temperature. A suspension of 65 g of succinic acid in 132.6 mL of acetone and 42.25 mL of water was added, and the reaction mixture was heated at 58 0 C and stirred at this temperature for 30 minutes to obtain a solution. The solution was filtered at 44°.C to remove insoluble particles and was stirred at 30-34° C for 3 hours until a suspension appeared.

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Abstract

L'invention concerne de manière générale des formes polymorphes cristallines de la base O-desméthylvenlafaxine, appelées formes A et B de la base O-desméthylvenlafaxine, ainsi que des méthodes permettant de préparer et d'obtenir lesdites formes.
PCT/IB2007/004654 2006-12-22 2007-12-21 Nouvelles formes solides cristallines de la base o-desvenlafaxine WO2009027766A2 (fr)

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US87658006P 2006-12-22 2006-12-22
US60/876,580 2006-12-22

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WO2009027766A2 true WO2009027766A2 (fr) 2009-03-05
WO2009027766A3 WO2009027766A3 (fr) 2009-04-23

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Cited By (3)

* 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
CN114478271A (zh) * 2021-12-13 2022-05-13 植恩生物技术股份有限公司 琥珀酸去甲文拉法辛制备方法
CN114478271B (zh) * 2021-12-13 2024-05-31 植恩生物技术股份有限公司 琥珀酸去甲文拉法辛制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030045583A1 (en) * 2001-02-12 2003-03-06 American Home Products Corporation Novel succinate salt of O-desmethyl-venlafaxine
US20060058552A1 (en) * 2002-06-10 2006-03-16 Wyeth Novel formate salt of O-desmethyl-venlafaxine
WO2007120925A2 (fr) * 2006-04-17 2007-10-25 Teva Pharmeceutical Industries Ltd. Formes cristallines du o-desmethylvenlafaxine
WO2008035369A2 (fr) * 2006-06-30 2008-03-27 Alembic Limited Nouvelle forme de o-desméthyl venlafaxine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030045583A1 (en) * 2001-02-12 2003-03-06 American Home Products Corporation Novel succinate salt of O-desmethyl-venlafaxine
US20060058552A1 (en) * 2002-06-10 2006-03-16 Wyeth Novel formate salt of O-desmethyl-venlafaxine
WO2007120925A2 (fr) * 2006-04-17 2007-10-25 Teva Pharmeceutical Industries Ltd. Formes cristallines du o-desmethylvenlafaxine
WO2008035369A2 (fr) * 2006-06-30 2008-03-27 Alembic Limited Nouvelle forme de o-desméthyl venlafaxine

Cited By (3)

* 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
CN114478271A (zh) * 2021-12-13 2022-05-13 植恩生物技术股份有限公司 琥珀酸去甲文拉法辛制备方法
CN114478271B (zh) * 2021-12-13 2024-05-31 植恩生物技术股份有限公司 琥珀酸去甲文拉法辛制备方法

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AR064507A1 (es) 2009-04-08
WO2009027766A3 (fr) 2009-04-23

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