WO2002046140A1 - Nouvelles formes polymorphes cristallines d'hydrochlorure de venlafaxine et procede permettant leur fabrication - Google Patents

Nouvelles formes polymorphes cristallines d'hydrochlorure de venlafaxine et procede permettant leur fabrication Download PDF

Info

Publication number
WO2002046140A1
WO2002046140A1 PCT/IN2000/000121 IN0000121W WO0246140A1 WO 2002046140 A1 WO2002046140 A1 WO 2002046140A1 IN 0000121 W IN0000121 W IN 0000121W WO 0246140 A1 WO0246140 A1 WO 0246140A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydrochloride
mixture
venlafaxine hydrochloride
venlafaxine
formula
Prior art date
Application number
PCT/IN2000/000121
Other languages
English (en)
Inventor
Mahender Rao Siripragada
Vyas Krishnamurthi
Siva Lakshmi Devi Arikatla
Om Reddy Gaddam
Original Assignee
Dr. Reddy's Laboratories Ltd.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Dr. Reddy's Laboratories Ltd. filed Critical Dr. Reddy's Laboratories Ltd.
Priority to AU2001235970A priority Critical patent/AU2001235970A1/en
Priority to PCT/IN2000/000121 priority patent/WO2002046140A1/fr
Publication of WO2002046140A1 publication Critical patent/WO2002046140A1/fr

Links

Classifications

    • 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
    • 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
    • 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

Definitions

  • the present invention relates to novel crystalline polymorphic Forms of
  • Nenlafaxine hydrochloride and a process for their preparation.
  • the present invention relates to two polymorphic Forms of Nenlafaxine hydrochloride.
  • Nenlafaxine hydrochloride, ⁇ , ⁇ -dimethyl-2-(l-hydroxycyclohex-l-yl)-2-(4-methoxy phenyl)ethyl arnine hydrochloride has the formula (I) given below:
  • Nenlafaxine hydrochloride being flexible molecule, is a putative candidate for conformational polymorphism.
  • Nenlafaxine facilitates neurotransmission in the brain by blocking both presynaptic reuptake of serotonin and noradrenaline.
  • Nenlafaxine exists as a racemic mixture. The (-) enantiomer and the (+) enantiomer inhibits, respectively, reuptake of noradrenaline and serotonin.
  • Nenlafaxine is presented as its hydrochloride in tablet form.
  • the Forms 1, 2 and mixture of Form 1 and 2 of Nenlafaxine hydrochloride are also useful as antidepressant drug. Background of Invention
  • Polymorphism is very common among pharmaceutical substances. It is commonly defined as the ability of any substance to exist in two or more crystalline phases that in the packing arrangement and / or conformation of the molecules in the crystal lattice. Quite often drug substances encapsulate solvent molecules when crystallized. These solvates / hydrates are referred to as pseudopolymorphs. Occasionally even amorphous forms are also encountered. Different polymorphs / pseudopolymorphs differ in their physical properties such as melting point, solubility, chemical reactivity etc. These can appreciably influence pharmaceutical properties such as dissolution rate and bioavailability. It is therefore important to evaluate the polymorphism of drug substances. Rantidine, Sulfafhiazole, Indomethacin etc., are some of the important examples of pharmaceuticals that exhibit polymorphism.
  • a series of 2- phenyl-2-(l-hydroxycycloalkyl)emylamine derivatives were prepared by G. E. Morris Husbands et al of American home products and were examined for antidepressant activity. Neurotransmitter uptake inhibition was highest for 2- phenyl- 2- (1-hydroxycyclohexyl) ethylamine group of compounds in which the aryl ring has a halogen or methoxy substitution at the 3- and / or 4- positions, particularly 1-(1- (3,4-dichlorophenyl)-2-(dimethylamino)ethyl) cyclohexanol and l-(2- (dimethylamino)-l-(4-methoxy phenyl)ethyl)cyclohexanol (venlafaxine) showed acute and rapid onset of antidepressant activity.
  • Nenlafaxine hydrochloride can exist in any of the several novel crystalline forms, polymorphic forms that differ from each other in their stability, physical properties, spectral data and methods bf preparation.
  • Two polymorphs of these novel polymorphic forms and their mixture, that are prepared and characterized, during our research work, are described in this application and are referred to as Form 1, 2 and mixture of Form 1 and 2.
  • the present invention provides three novel polymorphic forms of Venlafaxine hydrochloride.
  • the present invention also provides a process for preparing the three novel polymorphic Forms namely Form 1, 2 and mixture of Form 1 and 2.
  • Nenlafaxine hydrochloride A saturated solution of Nenlafaxine hydrochloride in dioxane at reflux temperature on cooling gives Form 1 of Nenlafaxine hydrochloride.
  • recrystallization of Nenlafaxine hydrochloride from a mixture of ethyl acetate and methanol at subambient temperature yields Form 2.
  • Recrystallization of Nenlafaxine hydrochloride from medium polar solvents at reflux temperature or from a mixture of polar solvents and medium polar solvents yields a mixture of Form 1 and 2.
  • the present invention provides three novel crystalline polymorphic Forms of Nenlafaxine hydrochloride, which are characterized by differential scanning calorimetry.
  • the thermal characteristics of the Forms are presented in Table 1.
  • the DSC thermograms of the Forms are depicted in figures 1, 2 and 3.
  • Multiplot of DSC thermograms of these Forms are shown in figure 4.
  • the present invention provides three novel crystalline polymorphic Forms of Nenlafaxine hydrochloride, which are further characterized by infrared spectrum in potassium bromide pellet.
  • the characteristic absorption bands (cm ⁇ l) of the Forms are listed in Table 2.
  • the infrared spectra of the Forms are depicted in figures 5 - 7.
  • Table-2 The FT-IR absorption maxima (cnr*)
  • the present invention provides three novel crystalline polymorphic Forms of Nenlafaxine hydrochloride, which are further characterized by powder X-ray diffraction.
  • the characteristic powder diffraction peaks are expressed in degrees 2 ⁇ .
  • the positions of the peaks (2 ⁇ ) for all the Forms are presented in Table 3.
  • the powder X-ray diffractograms of these Forms are depicted in figures 8-10. Multiplot of X-ray diffractograms of these Forms are shown in figure 11.
  • the present invention provides two polymo ⁇ hs of Nenlafaxine hydrochloride that are further characterized by the crystal parameters obtained from the single crystal X-ray diffraction analysis.
  • the crystal parameters for Form 1 and Form 2 are presented in Table 4. Table 4. Crystal data
  • the invention also provides polymorphs of Nenlafaxine hydrochloride that are further characterized by the atomic positions and other structural .parameters obtained from the single crystal X-ray diffraction analysis.
  • the results of X-ray structure determination of Form - 1 and Form - 2 are given in Tables 5 and 6 respectively.
  • the bond distances and bond angles of the two Forms are compared in Table 7 and 8 respectively.
  • the molecular structure for Form 1 and Form 2 are depicted in figure 12 and 13 respectively.
  • Angles are in degrees. Estimated standard deviations in the least significant figure given in parentheses.
  • the DSC thermogram of Form 1 has characteristic melting endotherm at 211 °C (Fig. 1) with an onset temperature at 208 °C followed by a decomposition endotherm at 245 °C.
  • Form 2 has a characteristic melting endotherm at 221 °C (Fig. 2) with an onset temperature at 216 °C followed by a decomposition endotherm at 255 °C.
  • the mixture of Form 1 and 2 has two endotherms at 211 °C and 219 °C (Fig. 3) which are due to the melting of Form 1 and 2 respectively.
  • the endotherm at 251 °C corresponds to the decomposition of the compound.
  • Form 1 exhibits absorption at 3365 and 3324 cm'l, while Form 2 has only broad abso ⁇ tion at 3352 cm-l (Fig. 14).
  • Form 1 has a peak at 3003 cm"! while in Form 2, it is at 3016 c ⁇ rl (Fig. 14). Form 1 absorbs at 2944 and 2923 cm-1 while Form 2 absorbs only at 2936 cnrl
  • Form 1 displays peaks at 2675, 2587, 2522 and 2484 cm" 1 while Form 2 has peaks at
  • Form 1 shows peaks at 830 and 818 cm _ l while Form 2 has peaks at 837 and 811 cm"l respectively (Fig. 16).
  • Form 1 shows two peaks at 770 and 735 cm'l while Form 2 has three peaks at 778,
  • Form 1 shows peaks at 594, 547 and 528 cm-1 w ile Form 2 has peaks at 581, 553 and 523 cm'l respectively (Fig. 16).
  • Form 2 As the thermodynarnically stable form at room temperature since the most dense crystal at a given temperature is considered to be the most thermodynarnically stable (cf. J. Haleblian and W. McCrone, J. Pharm. Sci., 58(8), 911 (1969)). Further Form 2 has higher melting point than Form 1. , ,
  • the results of a single crystal X-ray analysis are limited to, as the name implies, the sole crystal placed in the X-ray beam.
  • the results from powder diffraction represents the contribution from many crystalline particles in the sample exposed to X-rays.
  • Powder X-ray diffraction pattern can be computed from the results of single crystal analysis. This pattern can be compared with the experimental powder X-ray pattern. Comparison of the calculated and experimental diffraction patterns will confirm if the results of the two techniques are the same.
  • the computed powder X-ray diffraction patterns of the Form 1 and Form 2 of Nenlafaxine hydrochloride are displayed in figure 17 and 18 respectively. These calculated pattern match reasonably well with their respective experimental pattern viz., figures 8 and 9.
  • the primary powder X-ray diffraction pattern provides an unambiguous description of each of two polymo ⁇ hs of Nenlafaxine hydrochloride.
  • Infrared abso ⁇ tion bands (cm"l): 3352, 3016, 2936, 2857, 2835, 2583, 2515, 2480, 1614, 1582, 1514, 1473, 1439, 1401, 1385, 1367, 1307, 1275, 1247, 1179, 1169, 1153, 1141, 1110, 1083, 1062, 1043, 1035, 982, 972, 957, 929, 909, 837, 811, 778, 768, 740, 581, 553, 523 (Fig. 6)
  • Infrared abso ⁇ tion bands (cm" 1 ): 3353, 3326, 3016, 2943, 2856, 2851, 2832, 2585, 2519, 2483, 1613, 1583, 1513, 1473, 1441, 1403, 1387, 1366, 1303, 1275, 1246, 1179, 1153, 1141, 1109, 1081, 1062, 1040, 971, 958, 929, 909, 831, 818, 769, 736, 592, 525 (Fig. 7) X-ray powder diffraction peaks (2 ⁇ ): 6.72, 8.34, 10.20, 12.68, 13.50, 15.00, 15.42, 15.94.
  • step (ii) dissolving the compound obtained in step (i) in a medium polar or polar organic solvent at the reflux temperature
  • the medium polar or polar organic solvents are selected from 1,4-dioxane, 1,3-dioxane, and tetrahydrofuran and isopropanol.
  • the cooling in step (iii) is effected by allowing the solution to attain room temperature on its own or with mild coolants like cold water / water at room temperature.
  • a process for the preparation of novel polymo ⁇ hic Form-2 of Nenlafaxine hydrochloride of the formula I which comprises: (i) synthesizing Nenlafaxine hydrochloride by employing known methods, (ii) dissolving the compound obtained in step (i) in an organic polar solvent and adding an organic solvent of medium polarity at 0 to 10° C,
  • step (iii) is effected using ice, ice-salt mixture, dry ice and liquid nitrogen.
  • a process for the preparation of mixture of Form 1 and Form 2 of Nenlafaxine hydrochloride of the formula I which comprises: (i) " synthesizing Nenlafaxine hydrochloride by employing known methods, (ii) dissolving the compound obtained in step (i) in an organic polar solvent at. room temperature,
  • the organic polar solvents are selected from methanol, ethanol and isopropanol.
  • the medium polar organic solvent employed are selected from acetonitrile, methyl isobutyl ketone, ethylacetate, n-butyl acetate and diisopropyl ether.
  • an alternate process for the preparation of mixture of Form 1 and Form 2 of Nenlafaxine hydrochloride of the formula I having the characteristics described earlier, which comprises:
  • the organic solvents are selected from isopropanol, acetonitrile, methyl isobutyl ketone, ethylacetate, n-butyl acetate and diisopropyl ether.
  • step (iii) is effected using ice, ice-salt mixture, dry ice and liquid nitrogen.
  • the present invention provides a pharmaceutical composition, containing the polymo ⁇ hic forms of Nenlafaxine hydrochloride the formula (I) as defined above, in combination with the usual pharmaceutically employed carriers, diluents and the like, useful for the treatment and / or prophylaxis of depression, anxiety, neuropathy.
  • the pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavourants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions.
  • Such compositions typically contain from 1 to 25 %, preferably 1 to 15 % by weight of active ingredient, the remainder of the composition being pharmaceutically acceptable carriers, diluents or solvents.
  • polymo ⁇ hic forms of the formula (I) as defined above are clinically administered to mammals, including man, via either oral, nasal, pulmonary, transdermal or parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment.
  • Administration by the oral route is preferred, being more convenient and avoiding the possible pain and irritation of injection.
  • the patient cannot swallow the medication, or abso ⁇ tion following oral administration is impaired, as by disease or other abnormality, it is essential that the drug be administered parenterally.
  • the dosage is in the range of about 0.01 to about 100 mg / kg body weight of the subject per day or preferably about 0.01 to about 30 mg / kg body weight per day administered singly or as a divided dose.
  • the optimum dosage for the individual subject being treated will be determined by the person responsible for treatment, generally smaller doses being administered initially and thereafter increments made to determine the most suitable dosage.
  • Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions.
  • the active ingredient will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above.
  • the polymo ⁇ hic form can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like.
  • the pharmaceutical compositions may, if desired, contain additional components such as flavourants, sweeteners, excipients and the like.
  • the polymo ⁇ hic form can be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
  • solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water- soluble pharmaceutically-acceptable acid addition salts or salts with base of the compounds.
  • Aqueous solutions with the active ingredient dissolved in polyhydroxylated castor oil may also be used for injectable solutions.
  • the injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.
  • the preparation may contain the polymo ⁇ hic forms of the present invention dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
  • the carrier may contain additives such as solubilizing agents, such as propylene glycol, surfactants, abso ⁇ tion enhancers such as lecithin (phosphatidylcholine) or cyclodextrin or preservatives such as parabenes.
  • Tablets, dragees or capsules having talc and / or a carbohydrate carried binder or the like are particularly suitable for any oral application.
  • carriers for tablets, dragees or capsules include lactose, corn starch and / or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • Tablet Production Example a) 1) Active ingredient 30 g
  • the ingredients 1 to 3 are uniformly blended with water and granulated after, drying under reduced pressure.
  • the ingredient 4 and 5 are mixed well with the granules and compressed by a tabletting machine to prepare 1000 tablets each containing 30 mg of active ingredient.
  • ingredients 1-4 are uniformly moistened with an aqueous solution of 5 and granulated after drying under reduced .pressure.
  • Ingredient 6 is added and granules are compressed by a tabletting machine to prepare 1000 tablets containing 30 mg of ingredient 1.
  • Nenlafaxine hydrochloride was synthesized starting from p-methoxy phenyl acetonitrile. Condensation of cyclohexanone with p-methoxy phenyl acetonitrile in presence of butyl lithium produced 2-(4-methoxyphenyl)-2-(l- cyclohexanol)acetonitrile in good yield. Catalytic reduction of 2-(4-methoxy phenyl)-2-(l-cyclohexanol)acetonitrile in presence of RI1.AI2O3 yielded 2-(4- methoxyphenyl-2-(l-cyclohexanol)ethylamine.
  • Examples 2-5 illustrates the Process for the preparation of polymorphic Form-1 Venlafaxine hydrochloride Examples 2
  • Nenlafaxine hydrochloride (5 g) obtained in example 1 was heated in 1,4-dioxane (250 ml) at reflux temperature until complete dissolution, the hot solution was filtered and allowed to cool to room temperature slowly during a period of 8 hrs. The reaction mass was stirred for 20 hrs at room temperature and the solid formed was filtered and dried to yield 4.12 g (82.4 % yield) of > 99% pure polymo ⁇ hic Form-1 of Nenlafaxine hydrochloride of the formula (I).
  • Nenlafaxine hydrochloride (5 g) obtained in example 1 was dissolved in refluxing 1,4-dioxane (200 ml). The solution was filtered hot to remove the undissolved material and allowed to come to room temperature on its own. The crystalline compound was filtered after 30 hr to yield 4.1 g (82 % yield) of > 99% pure polymo ⁇ hic Form-1 of Nenlafaxine hydrochloride of the formula (I).
  • Example 4 Nenlafaxine hydrochloride (7.5 g) obtained in example 1 was added to 1,4-dioxane (200 ml) at its refluxing temperature. After 30 min the solution was filtered and cooled rapidly to room temperature. The compound was filtered after 24 hr and dried to yield 6.2 g (82.6 % yield) of > 99% pure polymo ⁇ hic Form-1 of Nenlafaxine hydrochloride of the formula (I).
  • Nenlafaxine hydrochloride (5 g) obtained in example 1 was dissolved in isopropanol (200 ml) at refluxing temperature. After 30 min the clear solution was filtered and cooled to room temperature. The compound was filtered after 26 hr of stirring at room temperature. The resultant compound was dried to yield 3.75 g (75 % yield) of pure polymo ⁇ hic Form-1 of Nenlafaxine hydrochloride of the formula (I).
  • Examples 6-7 illustrates the Process for the preparation of polymorphic Form-2 Venlafaxine hydrochloride Example 6
  • Nenlafaxine hydrochloride obtained in example 1 (5 g) was dissolved in methanol (8 ml) at 0 °C, then ethyl acetate (120 ml) was added and cooled between 0 to 5 °C. The fine needles were filtered after 24 hr and dried to yield 3.92 g (78.4% yield) of >99% pure polymo ⁇ hic Form-2 of Nenlafaxine hydrochloride of the formula (I).
  • Examples 8-10 illustrates the Process for the preparation of mixture of polymorphic Form 1 and 2 of Venlafaxine hydrochloride: Example 8
  • Venlafaxine hydrochloride obtained in example 1 (25 g) was dissolved in methanol (30 ml) between 25 - 30° C, then ethyl acetate was added till turbidity appeared. The solution was allowed to stand for 20 hr. The solid thus precipitated was filtered, washed with ethyl acetate and dried to yield fine crystalline mass of 23.6 g (yield 94.4%) of mixture of polymo ⁇ hic Form 1 and 2 of Venlafaxine hydrochloride of the formula (I).
  • Example 9 Venlafaxine hydrochloride obtained in example 1 (20 g) was taken in acetonitrile (200 ml) and heated under reflux for 1 hr. The hot solution was filtered and allowed to room temperature. The compound precipitated after 24 hr was filtered and dried to yield white crystalline mass of 17.4 g (yield 86.8%) of mixture of polymo ⁇ hic Form 1 and 2 of Venlafaxine hydrochloride of the formula (I).
  • Venlafaxine hydrochloride obtained in example 1 (20 g) was taken in isopropanol (150 ml) and heated under reflux with stirring until the compound dissolved completely. The solution was allowed to cool to room temperature while stirring was continued. The precipitated compound was filtered and dried to yield white fluffy solid of 16.3 g (81.5%) of mixture of polymo ⁇ hic Form 1 and 2 of Venlafaxine hydrochloride of the formula (I).

Abstract

L'invention concerne de nouvelles formes polymorphes cristallines d'hydrochlorure de venlafaxine et un procédé permettant leur fabrication. L'invention concerne également deux formes polymorphes d'hydrochlorure de venlafaxine. Hydrochlorure de venlafaxine, N, N-diméthyl-2-(1-hydroxycyclohex-1-y1)-2-(4-méthoxy phényl)éthyl amine hydrochlorure, dont la formule (I) est décrite ci-dessous.
PCT/IN2000/000121 2000-12-07 2000-12-07 Nouvelles formes polymorphes cristallines d'hydrochlorure de venlafaxine et procede permettant leur fabrication WO2002046140A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2001235970A AU2001235970A1 (en) 2000-12-07 2000-12-07 Novel crystalline polymorphic forms of venlafaxine hydrochloride and a process for their preparation
PCT/IN2000/000121 WO2002046140A1 (fr) 2000-12-07 2000-12-07 Nouvelles formes polymorphes cristallines d'hydrochlorure de venlafaxine et procede permettant leur fabrication

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2000/000121 WO2002046140A1 (fr) 2000-12-07 2000-12-07 Nouvelles formes polymorphes cristallines d'hydrochlorure de venlafaxine et procede permettant leur fabrication

Publications (1)

Publication Number Publication Date
WO2002046140A1 true WO2002046140A1 (fr) 2002-06-13

Family

ID=11076286

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2000/000121 WO2002046140A1 (fr) 2000-12-07 2000-12-07 Nouvelles formes polymorphes cristallines d'hydrochlorure de venlafaxine et procede permettant leur fabrication

Country Status (2)

Country Link
AU (1) AU2001235970A1 (fr)
WO (1) WO2002046140A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003042161A1 (fr) * 2001-11-13 2003-05-22 EGIS Gyógyszergyár Rt. Polymorphes de chlorhydrate de venlafaxine
WO2003050074A1 (fr) * 2001-12-13 2003-06-19 Cadila Healthcare Limited Fabrication de l'hydrochlorure venlafaxine et de polymorphes cristallins de celui-ci
WO2003050076A1 (fr) * 2001-12-05 2003-06-19 Wyeth Hydrochlorure de venlafaxine monohydrate et procedes de preparation de celui-ci
EP1334082A2 (fr) 2000-10-19 2003-08-13 Teva Pharmaceutical Industries Ltd. Base cristalline de venlafaxine et nouveaux polymorphes de chlorhydrate de venlafaxine, et preparation de ceux-ci
US6906087B2 (en) 2000-10-31 2005-06-14 Ciba Specialty Chemicals Corpation Crystalline forms of venlafaxine hydrochloride
US6924393B2 (en) 2000-10-19 2005-08-02 Teva Pharmaceutical Industries Ltd. Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof
US7030164B2 (en) 2001-12-05 2006-04-18 Wyeth Crystalline polymorph of venlafaxine hydrochloride and methods for the preparation thereof
JP2016188233A (ja) * 2010-10-01 2016-11-04 シャンドン リュイェ ファーマシューティカル カンパニー リミテッドＳｈａｎ Ｄｏｎｇ Ｌｕｙｅ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．， Ｌｔｄ． ４−［２−ジメチルアミノ−１−（１−ヒドロキシシクロヘキシル）エチル］フェニル４−メチルベンゾエートヒドロクロリドの多形体、それらを作製する方法及びそれらの使用
CN113831252A (zh) * 2020-06-24 2021-12-24 中国医学科学院药物研究所 咖啡酸文拉法辛及制备方法和其组合物与用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0112669A2 (fr) * 1982-12-13 1984-07-04 American Home Products Corporation Dérivés de phényléthylamines et leurs produits intermédiaires

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0112669A2 (fr) * 1982-12-13 1984-07-04 American Home Products Corporation Dérivés de phényléthylamines et leurs produits intermédiaires

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1334082A2 (fr) 2000-10-19 2003-08-13 Teva Pharmaceutical Industries Ltd. Base cristalline de venlafaxine et nouveaux polymorphes de chlorhydrate de venlafaxine, et preparation de ceux-ci
US6924393B2 (en) 2000-10-19 2005-08-02 Teva Pharmaceutical Industries Ltd. Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof
EP1334082A4 (fr) * 2000-10-19 2006-02-01 Teva Pharma Base cristalline de venlafaxine et nouveaux polymorphes de chlorhydrate de venlafaxine, et preparation de ceux-ci
US6906087B2 (en) 2000-10-31 2005-06-14 Ciba Specialty Chemicals Corpation Crystalline forms of venlafaxine hydrochloride
US7045661B2 (en) 2000-10-31 2006-05-16 Ciba Specialty Chemicals Corporation Crystalline forms of venlafaxine hydrochloride
WO2003042161A1 (fr) * 2001-11-13 2003-05-22 EGIS Gyógyszergyár Rt. Polymorphes de chlorhydrate de venlafaxine
WO2003050076A1 (fr) * 2001-12-05 2003-06-19 Wyeth Hydrochlorure de venlafaxine monohydrate et procedes de preparation de celui-ci
US7030164B2 (en) 2001-12-05 2006-04-18 Wyeth Crystalline polymorph of venlafaxine hydrochloride and methods for the preparation thereof
WO2003050074A1 (fr) * 2001-12-13 2003-06-19 Cadila Healthcare Limited Fabrication de l'hydrochlorure venlafaxine et de polymorphes cristallins de celui-ci
JP2016188233A (ja) * 2010-10-01 2016-11-04 シャンドン リュイェ ファーマシューティカル カンパニー リミテッドＳｈａｎ Ｄｏｎｇ Ｌｕｙｅ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．， Ｌｔｄ． ４−［２−ジメチルアミノ−１−（１−ヒドロキシシクロヘキシル）エチル］フェニル４−メチルベンゾエートヒドロクロリドの多形体、それらを作製する方法及びそれらの使用
CN113831252A (zh) * 2020-06-24 2021-12-24 中国医学科学院药物研究所 咖啡酸文拉法辛及制备方法和其组合物与用途

Also Published As

Publication number Publication date
AU2001235970A1 (en) 2002-06-18

Similar Documents

Publication Publication Date Title
KR101468827B1 (ko) 카베딜롤 인산염 및(또는) 그의 용매화물, 상응하는 조성물, 및(또는) 치료 방법
JP4288299B2 (ja) Ｌｔｂ４−アンタゴニスト活性を有するベンズアミジン誘導体及びその医薬としての使用
JPH06199743A (ja) 新規なセルトラリン結晶多形体およびその製法
JP2008509953A (ja) ４−［［（７ｒ）−８−シクロペンチル−７−エチル−５，６，７，８−テトラヒドロ−５−メチル−４−６−オキソ−２−ピペリジニル］アミノ］−３−メトキシ−ｎ−（１−メチル−４−ピペリジニル）ベンズアミドの水和物及び多形、その製造方法、並びにその薬物としての使用
EP1836154A1 (fr) Polymorphes du chlorhydrate de memantine
JPH0819065B2 (ja) ベンゾ融合シクロアルカンおよびオキサ‐およびチア‐シクロアルカントランス‐１，２‐ジアミン誘導体
MX2007016179A (es) Formas cristalinas de o-desmetilvenlafaxina.
EP3880663A1 (fr) Formes solides de daprodustat et leurs procédés de préparation
NZ330766A (en) Apo b-secretion/mtp inhibitor hydrochloride salt using isoquiniline derivatives
WO2021044437A1 (fr) Co-cristaux d'olaparib et leur procédé de préparation
US20080262029A1 (en) Acid and Base Salt Forms of Gaboxadol
WO2002046140A1 (fr) Nouvelles formes polymorphes cristallines d'hydrochlorure de venlafaxine et procede permettant leur fabrication
JP2008510715A (ja) アザビシクロヘキサンの新規多型
JP7237269B2 (ja) エスシタロプラムの新しい塩および固体形態
KR20200118098A (ko) 약제학적 화합물, 이의 염, 이의 제형, 그리고 이의 제조 방법 및 사용 방법
WO2019014412A1 (fr) Nouvelles formes polymorphes cristallines du bardoxolone méthyle
EP0699198B1 (fr) Derives de paroxetine a substitution n-benzoylmethyle
Caira et al. Thermal and structural properties of ambroxol polymorphs
EP0770612B1 (fr) Polymorphe crystallin de Terazosin et compositions pharmaceutiques le contenant
KR20110074574A (ko) 1-부틸-2-히드록시아르알킬 피페라진 유도체 및 항-우울증제로서의 그 용도
EP4320113A1 (fr) Formes solides de zavegepant et leur procédé de préparation
US20130245125A1 (en) HCl Polymorphs of 3-((2-(Dimethylamino)methyl(cyclohex-1-yl))phenol
HU178147B (en) Process for producing hexahydro-1,4-oxazepines
TWI834634B (zh) 醫藥化合物、其鹽類、其製劑及其等之製備和使用之方法
US20070281957A1 (en) Crystalline Forms of Levorphanol

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP