US20020183553A1 - Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof - Google Patents
Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof Download PDFInfo
- Publication number
- US20020183553A1 US20020183553A1 US10/000,428 US42801A US2002183553A1 US 20020183553 A1 US20020183553 A1 US 20020183553A1 US 42801 A US42801 A US 42801A US 2002183553 A1 US2002183553 A1 US 2002183553A1
- Authority
- US
- United States
- Prior art keywords
- venlafaxine
- purity
- base
- venlafaxine hydrochloride
- process according
- 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.)
- Abandoned
Links
- QYRYFNHXARDNFZ-UHFFFAOYSA-N venlafaxine hydrochloride Chemical compound [H+].[Cl-].C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 QYRYFNHXARDNFZ-UHFFFAOYSA-N 0.000 title claims abstract description 114
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 title claims abstract description 93
- 229960004688 venlafaxine Drugs 0.000 title claims abstract description 91
- 238000000034 method Methods 0.000 title claims abstract description 53
- 229960002416 venlafaxine hydrochloride Drugs 0.000 title abstract description 88
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 59
- 239000000203 mixture Substances 0.000 claims abstract description 34
- 238000004519 manufacturing process Methods 0.000 claims abstract description 14
- 239000002585 base Substances 0.000 claims description 52
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 49
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 39
- 239000013078 crystal Substances 0.000 claims description 28
- 238000001035 drying Methods 0.000 claims description 25
- 239000002904 solvent Substances 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 7
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 5
- 239000012456 homogeneous solution Substances 0.000 claims description 5
- SUQHIQRIIBKNOR-UHFFFAOYSA-N N,N-didesmethylvenlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN)C1(O)CCCCC1 SUQHIQRIIBKNOR-UHFFFAOYSA-N 0.000 claims description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical group COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 2
- 239000003637 basic solution Substances 0.000 claims 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 abstract description 46
- 238000002360 preparation method Methods 0.000 abstract description 30
- 239000012453 solvate Substances 0.000 abstract description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 38
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- 239000000243 solution Substances 0.000 description 18
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- 150000001875 compounds Chemical class 0.000 description 12
- 229940093499 ethyl acetate Drugs 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 12
- 239000000725 suspension Substances 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 239000012296 anti-solvent Substances 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000007789 gas Substances 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 230000003068 static effect Effects 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000000113 differential scanning calorimetry Methods 0.000 description 4
- 230000001376 precipitating effect Effects 0.000 description 4
- 239000000010 aprotic solvent Substances 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- NTKXIDDUCSFBBF-UHFFFAOYSA-N 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexan-1-ol;hydrochloride Chemical compound Cl.C1=CC(OC)=CC=C1C(CN)C1(O)CCCCC1 NTKXIDDUCSFBBF-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000003586 protic polar solvent Substances 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- ABOFFTILKMAVBR-UHFFFAOYSA-N COC1=CC=C(C(CN(C)C)C2(O)CCCCC2)C=C1.COC1=CC=C(C(CN)C2(O)CCCCC2)C=C1.Cl Chemical compound COC1=CC=C(C(CN(C)C)C2(O)CCCCC2)C=C1.COC1=CC=C(C(CN)C2(O)CCCCC2)C=C1.Cl ABOFFTILKMAVBR-UHFFFAOYSA-N 0.000 description 1
- 102100025490 Slit homolog 1 protein Human genes 0.000 description 1
- 101710123186 Slit homolog 1 protein Proteins 0.000 description 1
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
Images
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
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified 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
- C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified 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 amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
- C07C217/66—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified 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 amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain
- C07C217/70—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified 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 amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
-
- 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
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified 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
- C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified 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
- 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
- Venlafaxine ( ⁇ )-1-[2-(Dimethylamino)-1-(4-ethyoxyphenyl) ethyl] cyclo-hexanol, having the following formula I, is the first of a class of anti-depressants. Venlafaxine acts by inhibiting re-uptake of norepinephrine and serotonin, and is an alternative to the tricyclic anti-depressants and selective re-uptake inhibitors.
- U.S. Pat. No. 4,535,186 (the '186 patent) describes the process for the preparation of venlafaxine hydrochloride via the intermediate venlafaxine base.
- the entirety of the '186 patent is incorporated herein by reference.
- the '186 patent does not describe whether the venlafaxine so obtained is solid.
- venlafaxine is in the form of white crystals, with a purity of 99.3% or greater as confirmed by high pressure liquid chromatography (HPLC).
- crystalline venlafaxine can be prepared from venlafaxine hydrochloride by methylation of N,N-didesmethyl venlafaxine by means of a novel process.
- the present invention relates to an essentially pure venlafaxine.
- the present invention relates to an essentially pure venlafaxine hydrochloride.
- the present invention provides a process of preparing venlafaxine base from venlafaxine hydrochloride.
- the present invention provides a process of preparing venlafaxine base by alkylation of N,N-didesmethyl venlafaxine.
- the present invention provides crystalline venlafaxine base, wherein the venlafaxine base is white crystal with about 97% purity.
- the present invention provides crystalline venlafaxine base, wherein the venlafaxine base is white crystal with about 98% purity.
- the present invention provides crystalline venlafaxine base, wherein the venlafaxine base is white crystal with about 99% purity.
- the present invention provides crystalline venlafaxine base, wherein the venlafaxine base is white crystal with about 99.3% purity.
- the present invention provides crystalline venlafaxine base, wherein the venlafaxine base is white crystal with about 99.5% purity.
- the present invention relates to a process for the preparation of an essentially pure venlafaxine hydrochloride via the solid venlafaxine.
- the present invention relates to two novel polymorphs of venlafaxine hydrochloride denominated as Form I and Form II as well as solvate forms of venlafaxine hydrochloride denominated as Form III and Form IV.
- the present invention provides a process for preparation of the anhydrous Form I by dissolving the compound in water and precipitating it by adding DMF (dimethyl formamide) or MEK (methylethylketone).
- the present invention provides a process for preparation of the solvate Form III by dissolving the compound in a protic solvent such as water, ethanol or methanol and precipitating it by adding an aprotic solvent like acetone, ethylacetate, isopropylether or tert-butylmethylether (MTBE).
- a protic solvent such as water, ethanol or methanol
- an aprotic solvent like acetone, ethylacetate, isopropylether or tert-butylmethylether (MTBE).
- the present invention provides a process for preparation of the solvate Form III by dissolving the compound in chloroform and precipitating it by adding hexane or toluene.
- the present invention provides processes for preparation of the solvate Form III by crystallizing the compound in absolute ethanol or isopropyl alcohol.
- the present invention provides processes for preparation of the solvate Form III by triturating the compound in aprotic solvents such as ethyl acetate, isopropyl ether or hexane.
- aprotic solvents such as ethyl acetate, isopropyl ether or hexane.
- the present invention provides processes for preparation of the solvate Form IV by crystallizing the compound in DMF (dimethyl formamide) and DMSO (dimethyl sulfoxide), or by dissolving the compound in water and precipitating it by adding DMSO.
- DMF dimethyl formamide
- DMSO dimethyl sulfoxide
- the present invention provides a process for preparing venlafaxine hydrochloride from venlafaxine base.
- the present invention provides a process of preparing venlafaxine hydrochloride comprises the step of forming a mixture of venlafaxine, preferably venlafaxine base, in acetone and exposing the mixture in gaseous hydrochloric acid (HCl).
- a process of preparing venlafaxine hydrochloride comprises the step of forming a mixture of venlafaxine, preferably venlafaxine base, in acetone and exposing the mixture in gaseous hydrochloric acid (HCl).
- HCl hydrochloric acid
- Preferable pH is about 6 to about 7.5. Most preferable pH is about 7.
- the present invention provides a process of preparing venlafaxine hydrochloride comprises exposing a homogeneous solution of venlafaxine/acetone in gaseous hydrochloric acid (HCl).
- HCl gaseous hydrochloric acid
- the present invention provides a process of preparing venlafaxine hydrochloride comprises exposing a homogeneous solution of venlafaxine/isopropanol in gaseous hydrochloric acid (HCl).
- HCl gaseous hydrochloric acid
- the present invention provides preparing a homogenous solution of venlafaxine in a solution where venlafaxine is substantially insoluble or limited solubility, preferably acetone or isopropanol.
- the present invention provides processes for preparing venlafaxine Form I and Form II.
- the present invention provides a process for preparing venlafaxine hydrochloride comprising the steps of: 1) preparing a mixture (or a homogeneous solution) of venlafaxine, preferably venlafaxine base, with acetone; and 2) exposing the mixture in gaseous hydrochloric acid (HCl).
- the present invention provides a process for preparing venlafaxine hydrochloride comprising the steps of: 1) preparing a mixture of venlafaxine in isopropanol; and 2) exposing the mixture in gaseous hydrochloric acid at a range of pH.
- the pH ranges from about pH 5 to about pH 8.
- Preferably the pH ranges from about pH 6 to about pH 7.5.
- Most preferably the pH is at about pH 7.
- the present invention provides venlafaxine hydrochloride, where the venlafaxine hydrochloride is white crystal with about 99.92% purity.
- the present invention provides a process for preparing venlafaxine hydrochloride Form I comprises triturating venlafaxine hydrochloride with acetone followed by drying upon stirring under reduced pressure and crystallizing venlafaxine hydrochloride.
- the present invention provides venlafaxine hydrochloride Form I as prepared by a process comprises triturating venlafaxine hydrochloride with acetone followed by drying upon stirring under reduced pressure and crystallizing venlafaxine hydrochloride.
- the present invention provides a process for preparing venlafaxine hydrochloride Form I comprises triturating venlafaxine hydrochloride with isopropanol followed by drying upon stirring under reduced pressure and crystallizing venlafaxine hydrochloride.
- the present invention provides venlafaxine hydrochloride Form I as prepared by a process comprises triturating venlafaxine hydrochloride with isopropanol followed by drying upon stirring under reduced pressure and crystallizing venlafaxine hydrochloride.
- the present invention provides venlafaxine hydrochloride Form I, where the venlafaxine hydrochloride Form I is white crystal with about 99.95% purity.
- the present invention provides a process for preparing venlafaxine hydrochloride Form II comprises triturating venlafaxine hydrochloride with acetone or isopropanol followed by drying in a tray under reduced pressure and crystallizing venlafaxine hydrochloride.
- the present invention provides venlafaxine hydrochloride Form II as prepared by a process of triturating venlafaxine hydrochloride with acetone or isopropanol followed by drying in a tray under reduced pressure and crystallizing venlafaxine hydrochloride.
- the present invention provides venlafaxine hydrochloride Form II, where the venlafaxine hydrochloride Form II is white crystal with about 99.95% purity.
- FIG. 1 represents the Differential Scanning Calorimetry (DSC) curve of Venlafaxine Hydrochloride Form I.
- FIG. 2 represents the powder x-ray diffractogram (PXRD) of Venlafaxine Hydrochloride Form I.
- FIG. 3 represents the DSC curve of Venlafaxine Hydrochloride Form II.
- FIG. 4 represents the PXRD of Venlafaxine Hydrochloride Form II.
- FIG. 5 represents the DSC curve of Venlafaxine Hydrochloride Form III.
- FIG. 6 represents the PXRD of Venlafaxine Hydrochloride Form III.
- FIG. 7 represents the DSC curve of Venlafaxine Hydrochloride Form IV.
- FIG. 8 represents the PXRD of Venlafaxine Hydrochloride Form IV.
- FIG. 9 represents the PXRD of crystalline Venlafaxine Base.
- FIG. 10 represents the schematic process for preparing Venlafaxine Hydrohloride from Venlafaxine Base in the presence of Hydrochloride Acid (HCl) gas and acetone.
- Hydrochloride Acid HCl
- DMF dimethyl formamide
- MEK methylethylketone
- MTBE tert-butylmethylether
- DMSO dimethyl sulfoxide
- DSC Differential Scanning Calorimetry
- PXRD powder x-ray diffractogram
- IPA isopropyl alcohol
- HCl hydrochloric acid
- the present invention relates to essentially pure venlafaxine which, surprisingly, can be obtained in the form of free base.
- the venlafaxine base exists in a solid crystalline form.
- An essentially pure venlafaxine is prepared by adding sodium hydroxide to an aqueous solution of venlafaxine hydrochloride. Another preferable alkali solution is potassium hydroxide. The resulting mixture was extracted by an organic solvent. The extraction can be performed using ethyl acetate, heptane, hexane and a mixture thereof. The extraction solvent is preferably ethyl acetate. The combined organic layers are dried, preferably over anhydrous sodium sulfate, and evaporated. The residue is then crystallized from hexane or heptane.
- the crystals so obtained are filtered off, washed with cold hexane or heptane and dried to give solid venlafaxine, with purity of 99.3% or greater.
- the purity of solid venlafaxine is generally greater than about 97%, preferably greater than about 98% and most preferably greater than about 99%.
- the solid venlafaxine is further reacted with hydrochloric acid and crystallized to yield an essentially pure venlafaxine hydrochloride.
- N,N-didesmethyl venlafaxine (20 mmole) was added to water (480 mL), formic acid (88.5%, 5.2 grams, ⁇ 100 mmole), formaldehyde (35.8%, 5 grams, 62 mmole) at room temperature. The obtained mixture was stirred under reflux conditions during 21 hours and cooled to room temperature. The pH was adjusted to about 11 with 32% aqueous solution of NaOH. Potassium hydroxide can be equivalently used to adjust to pH to about 11. The pH-adjusted mixture was extracted with toluene (50 mL ⁇ 5).
- the present invention provides a process for the purification of venlafaxine hydrochloride comprising basifying the venlafaxine hydochloride.
- the present invention provides a process for the purification of venlafaxine hydochloride further comprising crystallizing the venlafaxine.
- the present invention provides a process for the purification of venlafaxine hydochloride further comprising reacting the venlafaxine so prepared with hydrochloric acid and crystallization to regenerate venlafaxine hydrochloride in a higher state of purity.
- the purity of venlafaxine hydrochloride is generally greater than about 97%, preferably greater than 98% and most preferably greater than about 99%.
- Venlafaxine hydrochloride is obtained according to the process as described in U.S. Pat. No. 4,535,186, which is incorporated herewith in reference.
- the present invention relates to a novel polymorphic form of venlafaxine hydrochloride, denominated Form I.
- This crystal form is characterized by unique strong X-ray peaks at about 10.2, 15.5, 20.3, 21.7 ⁇ 0.2 degrees two-theta, and medium peaks at 6.7, 13.5, 18.2, 19.8, 22.6, 25.6, 28.1, 35.1 ⁇ 0.2 degrees two-theta.
- the DSC thermogram of Form I includes an endotherm at about 210-213 degrees due to melting.
- the present invention relates to a novel polymorphic form of venlafaxine hydrochloride, denominated Form II.
- This crystal form is characterized by unique strong X-ray peaks at about 12.8, 20.5, 21.3 ⁇ 0.2 degrees two-theta, and medium peaks at 6.8, 8.5, 10.3,13.6, 15.6, 16.5, 19.8, 19.9, 21.9, 25.2, 28.7, 31.2, 31.7, 35.3 ⁇ 0.2 degrees two-theta.
- the DSC thermogram of Form II includes an endotherm at about 210-213 degrees due to melting; a phase transformation is often observed with a resulting peak at about 219-222 degrees. This transformation may occur at different extents and probably is concomitant to a sublimation phenomenon.
- the present invention relates to a novel solvate crystal form of venlafaxine hydrochloride, denominated Form III.
- This crystal form is characterized by unique strong X-ray peaks at about 7.4, 14.9, 26.5 ⁇ 0.2 degrees two-theta, and medium peaks at about 12.9, 16.4, 17.5, 18.6, 18.9, 20.5, 21.4, 38.2 ⁇ 0.2 degrees two-theta.
- the DSC thermogram of Form III includes a broad endotherm due to desolvatation, a small endotherm in the range of approximately 180-200 degrees and an endotherm at about 212 degrees, due to melting.
- This solvated form may include water, or methanol, ethanol or hexane.
- the loss on drying values range between about 5.6%-6.0% for the compounds that contain methanol or ethanol, about 4.6% for the compound that contains isopropyl alcohol, and about 5.5% for the compound that contains hexane.
- the present invention relates to a novel solvate crystal form of venlafaxine hydrochloride, denominated Form IV.
- This crystal form is characterized by unique strong X-ray peaks at about 10.3, 20.3 ⁇ 0.2 degrees two-theta, and medium peaks at about 6.8, 13.5, 15.6, 21.8, 27.2, 35.2 ⁇ 0.2 degrees two-theta.
- the DSC thermogram of Form IV includes a broad endotherm due to desolvatation, and an endotherm at about 212 degrees due to melting.
- This solvated crystal form may include DMSO or DMF.
- the loss on drying value, as determined in the TGA, is about 41% in the compound crystallized in DMSO, and about 33% in the compound crystallized in DMF. These values—about 41% and 33%—correspond to the stoichiometric values of 3 molecules of DMSO and 2 molecules of DMF per molecule of Venlafaxine hydrochloride. From this we deduce that solvated Form IV may be a trisolvate of DMSO and disolvate of DMF.
- the present invention discloses processes for preparation of the different polymorphic forms of venlafaxine hydrochloride.
- Form III can form solvates with different solvents, such as ethanol, methanol, or isopropanol.
- venlafaxine hydrochloride is dissolved in protic solvents (i.e., solvents that have a hydroxide [—OH] group) like water, ethanol or methanol, and an aprotic solvent (i.e., a solvent that lacks a hydroxide [—OH] group) such as acetone, ethyl acetate, isopropyl ether or tert-butylmetylether (MTBE) is added to produce solvate Form III.
- protic solvents i.e., solvents that have a hydroxide [—OH] group
- an aprotic solvent i.e., a solvent that lacks a hydroxide [—OH] group
- MTBE tert-butylmetylether
- Heating rate 10° C./min
- Heating rate 10° C./min
- Venlafaxine hydrochloride was dissolved in water under reflux. Acetone was added. The suspension formed is refluxed additional ten minutes and exposed at room temperature overnight. Afterward the suspension is filtered, washed with about 2 mL of the same mixture of solvents. The solid obtained is crystallized in Form III. Further drying in a rotavapor under a reduced pressure ( ⁇ 10 mbar) over about 45 minutes at about 60 degrees produced Form I.
- Venlafaxine hydrochloride was dissolved in methanol under reflux. Ethyl acetate, or isopropyl ether, or MTBE was added. The suspension formed is refluxed additional ten minutes and exposed at room temperature overnight. Afterward the suspension is filtered, washed with 2 ml of the same mixture of solvents. The solid obtained is crystallized in Form III. Further drying in a rotavapor under a reduced pressure ( ⁇ 10 mbar) over about 45 minutes at about 60 degrees produced Form I.
- Venlafaxine hydrochloride was dissolved in the solvent under reflux. The antisolvent was added. The suspension formed is refluxed additional ten minutes and exposed at room temperature overnight. Afterward the suspension is filtered, washed with 2 ml of the same mixture of solvents. The solid obtained is crystallized in Form III. Further drying in a rotavapor under a reduced pressure ( ⁇ 10 mbar) over about 45 minutes at about 60 degrees produced mixtures of Form II, or Form I., or a mixture of the two forms.
- Venlafaxine hydrochloride (2 grams) was dissolved in ethanol (8 mL) or in isopropyl alcohol (10 mL) under reflux and the solution was left overnight at room temperature. The crystallized material was filtered and washed with 2 ml of the same solvent. The solid obtained is crystallized in Form III. Further drying in a rotavapor under a reduced pressure ( ⁇ 10 mbar) over about 45 minutes at about 60 degrees produced Form II, or Form I, or a mixture of the two forms.
- Venlafaxine hydrochloride (2 grams) was dissolved in DMF or DMSO (8 ml) under reflux and the solution was left overnight at room temperature. The crystallized material was filtered and washed with 2 ml of the same solvent. The solid obtained is crystallized in Form III. Further drying in a rotavapor under a reduced pressure ( ⁇ 10 mbar) over about 45 minutes at about 60 degrees produced Form II, or Form I, or a mixture of the two forms.
- Venlafaxine hyrdrochloride was dissolved in water under reflux. The antisolvent was added. The suspension formed is refluxed additional ten minutes and exposed at room temperature overnight. Afterward the suspension is filtered, washed with 2 mL of the same mixture of solvents. The solid obtained is crystallized in Form I. Further drying in a rotavapor under a reduced pressure ( ⁇ 10 mbar) over about 45 minutes at about 60 degrees produced Form I.
- Venlafaxine hydrochloride was dissolved in methanol at about 0-5° C. The antisolvent was added. The suspension formed is stirred for 30 minutes. Afterward the suspension is filtered, washed with 2 ml of the same mixture of solvents. The solid obtained is crystallized in Form II. Further drying in a rotavapor under a reduced pressure ( ⁇ 10 mbar) over about 45 minutes at about 60 degrees produced Form II.
- the present invention provides a process for preparing venlafaxine hydrochloride.
- the process comprises exposing venlafaxine base to gaseous hydrochloric acid (HCl).
- FIG. 10 The schematic process for preparing venlafaxine hydrochloride from venlafaxine base is illustrated in FIG. 10.
- the theoretical yield of the product is about 31.34 grams (i.e., 100 mmol).
- a 1-L double-jacketed reactor equipped with a mechanical stirrer, a thermometer, a pH-electrode and PTFE deep tube was charged with venlafaxine base (about 27.7 grams) and acetone (about 526 grams). The mixture was stirred for about 20 min at room temperature until a homogeneous solution was achieved.
- the crude venlafaxine hydrochloride (about 15.0 grams) was triturated with acetone (about 60.0 grams) for about 1 hour at about 60° C. and for about 1 hour at about 0° C., filtered off, washed on filter with cold acetone (about 120 grams) and dried in a tray under reduced pressure at about 50° C. (water bath) to a constant weight to give about 14.8 grams (about 93.2%) of venlafaxine hydrochloride as white crystals with purity of about 99.95% by HPLC.
- Venlafaxine base (1 Kg) was dissolved in isopropanol (6 L). Hydrochloric acid (gas) was bubbled until a pH ranging from about pH 5 to about pH 8 was achieved, at ⁇ 20° C. Preferably, the pH ranges from pH about 6 to pH about 7.5. Most preferably, the pH is at about pH 7. The reaction mixture was heated to clear solution and cooled gradually to 10° C. The precipitate was filtered and washed with isopropanol and dried in vacuum.
- Hydrochloric acid gas
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Priority Applications (20)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/000,428 US20020183553A1 (en) | 2000-10-19 | 2001-11-30 | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof |
CNA2007101970607A CN101219962A (zh) | 2001-11-30 | 2002-11-20 | 结晶文拉法辛碱、新的盐酸文拉法辛多晶型物及它们的制备方法 |
CNA028276485A CN1617848A (zh) | 2001-11-30 | 2002-11-20 | 结晶文拉法辛碱、新的盐酸文拉法辛多晶型物及它们的制备方法 |
IL16217102A IL162171A0 (en) | 2001-11-30 | 2002-11-20 | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof |
PCT/US2002/037268 WO2003048082A2 (en) | 2001-11-30 | 2002-11-20 | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof |
CA002468728A CA2468728A1 (en) | 2001-11-30 | 2002-11-20 | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof |
AU2002365874A AU2002365874A1 (en) | 2001-11-30 | 2002-11-20 | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof |
HU0700037A HUP0700037A2 (en) | 2001-11-30 | 2002-11-20 | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof |
JP2003549277A JP2005511668A (ja) | 2001-11-30 | 2002-11-20 | 結晶性ベンラファキシン塩基及びベンラファキシン塩酸塩の新規多形、並びにそれらの製法 |
ZA200404080A ZA200404080B (en) | 2001-11-30 | 2002-11-20 | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof |
PL02374273A PL374273A1 (en) | 2001-11-30 | 2002-11-20 | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof |
KR10-2004-7008012A KR20040068163A (ko) | 2001-11-30 | 2002-11-20 | 결정질 벤라팍신 염기 및 벤라팍신 히드로클로라이드의신규한 다형태, 이의 제조 방법 |
EP02791279A EP1474379A4 (de) | 2001-11-30 | 2002-11-20 | Kristalline venlafaxinbase und neue polymorphe von venlafaxinhydrochlorid, verfahren zu deren herstellung |
MXPA04005193A MXPA04005193A (es) | 2001-11-30 | 2002-11-20 | Base de venlafaxina cristalina y polimorfos nuevos de hidrocloruro de venlafaxina, procesos para la preparacion de los mismos. |
IS7289A IS7289A (is) | 2001-11-30 | 2004-05-27 | Kristallaður venlafaxínbasi og nýir fjölgervingarvenlafaxínhýdróklóríðs, aðferðir til að framleiðaþá |
US10/863,958 US20040220278A1 (en) | 2000-10-19 | 2004-06-08 | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof |
HR20040565A HRP20040565A2 (en) | 2001-11-30 | 2004-06-17 | Crystalline venlafaxine base and novel polymorphsof venlafaxine hidrochloride, processes for preparing thereof |
NO20042732A NO20042732L (no) | 2001-11-30 | 2004-06-29 | Krystallinsk venlafaksin-base og nye polymorfe former av venlafaksin-hydroklorid samt fremgangsmater for fremstilling derav |
US10/961,337 US6924393B2 (en) | 2000-10-19 | 2004-10-07 | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof |
US12/075,875 US20080167498A1 (en) | 2000-10-19 | 2008-03-13 | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US24157700P | 2000-10-19 | 2000-10-19 | |
US25886100P | 2000-12-29 | 2000-12-29 | |
US27872101P | 2001-03-26 | 2001-03-26 | |
US29246901P | 2001-05-21 | 2001-05-21 | |
US10/000,428 US20020183553A1 (en) | 2000-10-19 | 2001-11-30 | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/045,510 Continuation-In-Part US20020143211A1 (en) | 2000-10-19 | 2001-10-19 | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochlorid, processes for preparing thereof |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/863,958 Division US20040220278A1 (en) | 2000-10-19 | 2004-06-08 | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof |
US10/961,337 Division US6924393B2 (en) | 2000-10-19 | 2004-10-07 | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
US20020183553A1 true US20020183553A1 (en) | 2002-12-05 |
Family
ID=21691493
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/000,428 Abandoned US20020183553A1 (en) | 2000-10-19 | 2001-11-30 | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof |
US10/863,958 Abandoned US20040220278A1 (en) | 2000-10-19 | 2004-06-08 | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof |
US10/961,337 Expired - Fee Related US6924393B2 (en) | 2000-10-19 | 2004-10-07 | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof |
US12/075,875 Abandoned US20080167498A1 (en) | 2000-10-19 | 2008-03-13 | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof |
Family Applications After (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/863,958 Abandoned US20040220278A1 (en) | 2000-10-19 | 2004-06-08 | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof |
US10/961,337 Expired - Fee Related US6924393B2 (en) | 2000-10-19 | 2004-10-07 | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof |
US12/075,875 Abandoned US20080167498A1 (en) | 2000-10-19 | 2008-03-13 | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof |
Country Status (16)
Country | Link |
---|---|
US (4) | US20020183553A1 (de) |
EP (1) | EP1474379A4 (de) |
JP (1) | JP2005511668A (de) |
KR (1) | KR20040068163A (de) |
CN (2) | CN1617848A (de) |
AU (1) | AU2002365874A1 (de) |
CA (1) | CA2468728A1 (de) |
HR (1) | HRP20040565A2 (de) |
HU (1) | HUP0700037A2 (de) |
IL (1) | IL162171A0 (de) |
IS (1) | IS7289A (de) |
MX (1) | MXPA04005193A (de) |
NO (1) | NO20042732L (de) |
PL (1) | PL374273A1 (de) |
WO (1) | WO2003048082A2 (de) |
ZA (1) | ZA200404080B (de) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030105359A1 (en) * | 2000-10-31 | 2003-06-05 | Van Der Schaaf Paul Adriaan | Crystalline forms of venlafaxine hydrochloride |
US20030109585A1 (en) * | 2001-12-05 | 2003-06-12 | Wyeth | Novel crystalline polymorph of venlafaxine hydrochloride and methods for the preparation thereof |
US20030114536A1 (en) * | 2001-12-05 | 2003-06-19 | Wyeth | Venlafaxine hydrochloride monohydrate and methods for the preparation thereof |
WO2003082806A1 (en) * | 2002-03-28 | 2003-10-09 | Synthon B.V. | Venlafaxine base |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CZ20031298A3 (cs) * | 2000-10-19 | 2003-10-15 | Teva Pharmaceutical Industries Ltd. | Způsob přípravy krystalické báze venlafaxinu a nových polymorfů hydrochloridu venlafaxinu |
DE10359154A1 (de) * | 2003-12-16 | 2005-07-28 | Krka Tovarna Zdravil, D.D. | Verfahren zur Herstellung von Venlafaxin und Venlafaxinhydrochlorid der Form I |
US7456317B2 (en) * | 2005-12-01 | 2008-11-25 | Auspex Pharmaceuticals | Substituted phenethylamines with serotoninergic and/or norepinephrinergic activity |
EP1824815A2 (de) * | 2005-10-19 | 2007-08-29 | Teva Pharmaceutical Industries Ltd. | Verfahren zur herstellung von hochreinem 1-[2-dimethylamino-(4-methoxyphenyl)ethyl]cyclohexanol-hydrochlorid |
US20080234257A1 (en) * | 2007-03-15 | 2008-09-25 | Auspex Pharmaceuticals, Inc. | Substituted phenethylamines with serotoninergic and/or norepinephrinergic activity |
CN101279926A (zh) * | 2008-05-22 | 2008-10-08 | 杭州盛美医药科技开发有限公司 | 盐酸文拉法辛晶型FormⅠ的制备方法 |
IN2015DN01662A (de) | 2012-09-18 | 2015-07-03 | Auspex Pharmaceuticals Inc | |
TWI788702B (zh) | 2013-11-15 | 2023-01-01 | 美商阿克比治療有限公司 | {[5-(3-氯苯基)-3-羥基吡啶-2-羰基]胺基}乙酸之固體型式,其組合物及用途 |
PL3265085T3 (pl) | 2015-03-06 | 2022-11-07 | Auspex Pharmaceuticals, Inc. | Sposoby leczenia zaburzeń związanych z nieprawidłowymi ruchami mimowolnymi |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL63968A (en) * | 1980-10-01 | 1985-10-31 | Glaxo Group Ltd | Form 2 ranitidine hydrochloride,its preparation and pharmaceutical compositions containing it |
US4535186A (en) * | 1983-04-19 | 1985-08-13 | American Home Products Corporation | 2-Phenyl-2-(1-hydroxycycloalkyl or 1-hydroxycycloalk-2-enyl)ethylamine derivatives |
US4611078A (en) * | 1983-10-26 | 1986-09-09 | American Home Products Corporation | Substituted phenylacetonitriles |
US6197828B1 (en) * | 1998-12-01 | 2001-03-06 | Sepracor, Inc. | Derivatives of (+)-venlafaxine and methods of preparing and using the same |
CZ20031298A3 (cs) * | 2000-10-19 | 2003-10-15 | Teva Pharmaceutical Industries Ltd. | Způsob přípravy krystalické báze venlafaxinu a nových polymorfů hydrochloridu venlafaxinu |
US6906087B2 (en) | 2000-10-31 | 2005-06-14 | Ciba Specialty Chemicals Corpation | Crystalline forms of venlafaxine hydrochloride |
AU2001235970A1 (en) | 2000-12-07 | 2002-06-18 | Dr. Reddy's Research Foundation | Novel crystalline polymorphic forms of venlafaxine hydrochloride and a process for their preparation |
ATE411986T1 (de) * | 2001-04-10 | 2008-11-15 | Alembic Ltd | Zwischenprodukt zur herstellung von 1-ä2- dimethylamino-1-(4-methoxyphenyl)-ethylü- cyclohexanol |
AU2002348266A1 (en) * | 2001-12-05 | 2003-06-23 | Wyeth | Novel crystalline polymorph of venlafaxine hydrochloride and methods for the preparation thereof |
WO2003050074A1 (en) * | 2001-12-13 | 2003-06-19 | Cadila Healthcare Limited | Manufacture of venlafaxine hydrochloride and crystalline polymorphs thereof |
-
2001
- 2001-11-30 US US10/000,428 patent/US20020183553A1/en not_active Abandoned
-
2002
- 2002-11-20 PL PL02374273A patent/PL374273A1/xx not_active Application Discontinuation
- 2002-11-20 WO PCT/US2002/037268 patent/WO2003048082A2/en active Search and Examination
- 2002-11-20 CN CNA028276485A patent/CN1617848A/zh active Pending
- 2002-11-20 KR KR10-2004-7008012A patent/KR20040068163A/ko not_active Application Discontinuation
- 2002-11-20 IL IL16217102A patent/IL162171A0/xx unknown
- 2002-11-20 CA CA002468728A patent/CA2468728A1/en not_active Abandoned
- 2002-11-20 ZA ZA200404080A patent/ZA200404080B/en unknown
- 2002-11-20 EP EP02791279A patent/EP1474379A4/de not_active Withdrawn
- 2002-11-20 JP JP2003549277A patent/JP2005511668A/ja active Pending
- 2002-11-20 AU AU2002365874A patent/AU2002365874A1/en not_active Abandoned
- 2002-11-20 CN CNA2007101970607A patent/CN101219962A/zh active Pending
- 2002-11-20 HU HU0700037A patent/HUP0700037A2/hu unknown
- 2002-11-20 MX MXPA04005193A patent/MXPA04005193A/es active IP Right Grant
-
2004
- 2004-05-27 IS IS7289A patent/IS7289A/is unknown
- 2004-06-08 US US10/863,958 patent/US20040220278A1/en not_active Abandoned
- 2004-06-17 HR HR20040565A patent/HRP20040565A2/xx not_active Application Discontinuation
- 2004-06-29 NO NO20042732A patent/NO20042732L/no not_active Application Discontinuation
- 2004-10-07 US US10/961,337 patent/US6924393B2/en not_active Expired - Fee Related
-
2008
- 2008-03-13 US US12/075,875 patent/US20080167498A1/en not_active Abandoned
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030105359A1 (en) * | 2000-10-31 | 2003-06-05 | Van Der Schaaf Paul Adriaan | Crystalline forms of venlafaxine hydrochloride |
US6906087B2 (en) * | 2000-10-31 | 2005-06-14 | Ciba Specialty Chemicals Corpation | Crystalline forms of venlafaxine hydrochloride |
US20050256205A1 (en) * | 2000-10-31 | 2005-11-17 | Schaaf Paul Adriaan V D | Crystalline forms of venlafaxine hydrochloride |
US7045661B2 (en) | 2000-10-31 | 2006-05-16 | Ciba Specialty Chemicals Corporation | Crystalline forms of venlafaxine hydrochloride |
US20030109585A1 (en) * | 2001-12-05 | 2003-06-12 | Wyeth | Novel crystalline polymorph of venlafaxine hydrochloride and methods for the preparation thereof |
US20030114536A1 (en) * | 2001-12-05 | 2003-06-19 | Wyeth | Venlafaxine hydrochloride monohydrate and methods for the preparation thereof |
US20050272822A1 (en) * | 2001-12-05 | 2005-12-08 | Wyeth | Venlafaxine hydrochloride monohydrate and methods for the preparation thereof |
US20060074131A1 (en) * | 2001-12-05 | 2006-04-06 | Wyeth | Novel crystalline polymorph of venlafaxine hydrochloride and methods for the preparation thereof |
US7030164B2 (en) * | 2001-12-05 | 2006-04-18 | Wyeth | Crystalline polymorph of venlafaxine hydrochloride and methods for the preparation thereof |
WO2003082806A1 (en) * | 2002-03-28 | 2003-10-09 | Synthon B.V. | Venlafaxine base |
Also Published As
Publication number | Publication date |
---|---|
HUP0700037A2 (en) | 2007-05-02 |
CN1617848A (zh) | 2005-05-18 |
KR20040068163A (ko) | 2004-07-30 |
PL374273A1 (en) | 2005-10-03 |
IS7289A (is) | 2004-05-27 |
US6924393B2 (en) | 2005-08-02 |
US20080167498A1 (en) | 2008-07-10 |
EP1474379A4 (de) | 2006-06-07 |
JP2005511668A (ja) | 2005-04-28 |
NO20042732L (no) | 2004-06-29 |
CA2468728A1 (en) | 2003-06-12 |
MXPA04005193A (es) | 2005-02-22 |
WO2003048082A3 (en) | 2004-08-26 |
ZA200404080B (en) | 2007-12-27 |
CN101219962A (zh) | 2008-07-16 |
WO2003048082A2 (en) | 2003-06-12 |
IL162171A0 (en) | 2005-11-20 |
US20050049304A1 (en) | 2005-03-03 |
EP1474379A2 (de) | 2004-11-10 |
AU2002365874A1 (en) | 2003-06-17 |
HRP20040565A2 (en) | 2005-08-31 |
US20040220278A1 (en) | 2004-11-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20080167498A1 (en) | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof | |
US20020143211A1 (en) | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochlorid, processes for preparing thereof | |
US11739057B2 (en) | Polymorphic forms of Belinostat and processes for preparation thereof | |
US11780810B2 (en) | Intermediates for optically active piperidine derivatives and preparation methods thereof | |
US7728173B2 (en) | Processes for preparing venlafaxine and venlafaxine hydrochloride of form I | |
ZA200302768B (en) | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof | |
EP4063351A1 (de) | Verfahren zur herstellung von chinolinderivatverbindungen | |
US20050171145A1 (en) | Process for the preparation of 2-(ethoxymethyl)-tropane derivatives | |
EP4071139A1 (de) | Kristallines lofexidin hydrochlorid | |
US6384244B2 (en) | Process for preparing cis- aminochromanols | |
EP2938595B1 (de) | Verfahren zur synthese eines hydrazin zur behandlung des papillomavirus | |
WO2009118758A2 (en) | Novel crystalline forms of desvenlafaxine succinate | |
US20020095047A1 (en) | Process for preparing hydroxychomanones and CIS-aminochromanols |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: TEVA PHARMACEUTICAL INDUSTRIES LTD., ISRAEL Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:DOLITZKY, BEN-ZION;ARONHIME, JUDITH;WIZEL, SHLOMIT;AND OTHERS;REEL/FRAME:013903/0114;SIGNING DATES FROM 20020411 TO 20020430 |
|
AS | Assignment |
Owner name: TEVA PHARMACEUTICAL USA, INC., PENNSYLVANIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:TEVA PHARMACEUTICAL INDUSTRIES, LTD.;REEL/FRAME:013916/0749 Effective date: 20030302 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |