EP2081885A2 - Procedes ameliores servant a preparer de la venlafaxine sous forme de base et des sels de celle-ci - Google Patents

Procedes ameliores servant a preparer de la venlafaxine sous forme de base et des sels de celle-ci

Info

Publication number
EP2081885A2
EP2081885A2 EP07858939A EP07858939A EP2081885A2 EP 2081885 A2 EP2081885 A2 EP 2081885A2 EP 07858939 A EP07858939 A EP 07858939A EP 07858939 A EP07858939 A EP 07858939A EP 2081885 A2 EP2081885 A2 EP 2081885A2
Authority
EP
European Patent Office
Prior art keywords
approximately
venlafaxine
pharmaceutically acceptable
solvates
hydrates
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.)
Withdrawn
Application number
EP07858939A
Other languages
German (de)
English (en)
Inventor
Carmen Arnalot Aguilar
Iolanda CHAMORRO GUTIÉRREZ
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Medichem SA
Original Assignee
Medichem SA
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 Medichem SA filed Critical Medichem SA
Publication of EP2081885A2 publication Critical patent/EP2081885A2/fr
Withdrawn legal-status Critical Current

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
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • 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

Definitions

  • the invention relates generally to an improved process for manufacturing venlafaxine base and/or salts thereof.
  • Venlafaxine is a commercially marketed pharmaceutically active substance known to be useful for the treatment of major depressive disorder and is marketed as the hydrochloride salt of the racemtc form thereof under the name Effexor ® .
  • Venlafaxine is the international common name for ( ⁇ )-l-[2-(dimethylamino)-l-(4-methoxyphenyl)ethyl] cyclohexanol, which has an empirical formula of Q7H27NO2 and is represented in Formula I.
  • Venlafaxine and its pharmaceutically acceptable salts are described in U.S. Patent No. 4,535,186. This patent describes three processes for preparing venlafaxine as illustrated below in Scheme 1 :
  • venlafaxine can also be prepared from N,N-didesmethyl venlafaxine in the presence of a salt of formic acid.
  • the salt of formic acid can be added to the reaction mixture or can be obtained in situ using an excess of formaldehyde and formic acid in the presence of a suitable amount of an alkali or alkaline earth metal hydroxide.
  • venlafaxine is included in pharmaceutical compositions, it is necessary to obtain a product with a very high purity and having very low impurity levels; the presence of impurities in the product may be a problem for formulation in that impurities may involve adverse effects on the safety and shelf life of a formulation.
  • the invention relates generally to an improved process for manufacturing venlafaxine base and/or salts thereof.
  • aqueous formic acid and aqueous formaldehyde some amounts of the impurity 1 -[2-(dimethyIamino)- 1 -(3-hydroxymethyl-4-methoxyphenyl)ethyl] cyclohexanol (Formula III) are formed.
  • Another aspect of the invention includes identification of an impurity that can be formed during the preparation of venlafaxine from N,N-didesmethylvenlafaxine.
  • an impurity that can be formed during the preparation of venlafaxine from N,N-didesmethylvenlafaxine.
  • the amount of impurity of Formula III produced during the process is higher when an excess of formic acid and/or formaldehyde is used for the reaction.
  • Another aspect of the invention includes a process for preparing venlafaxine from N,N-didesmethylvenlafaxine with optimized molar ratios of reactants in order to obtain a product with a high purity in a high yield by avoiding the formation of large amounts of impurities during the synthetic procedure.
  • Another aspect of the invention includes monitoring the products obtained from the reaction of N,N-didesmethyl venlafaxine (i.e., Formula H, Scheme 1) with formic acid and formaldehyde for the presence of impurities.
  • the invention includes monitoring the products of this process for the presence of the impurity represented by Formula III.
  • the invention further includes using the venlafaxine obtained in the above reaction to produce pharmaceutically acceptable salts, hydrates and/or solvates thereof.
  • an acid addition salt is prepared; more preferably the hydrochloride salt is prepared.
  • Another aspect of the invention includes preparing venlafaxine having less than approximately 0.02 % of the impurity of Formula III.
  • the invention includes an improved method for producing venlafaxine.
  • This process includes preparation of venlafaxine from N,N-didesmethylvenlafaxine hydrochloride using formic acid and formaldehyde and controlling the amount of the different reagents used to assure that levels of the main impurities (e.g., the impurity represented by Formula III) that can be formed in this reaction are minimized.
  • the main impurities e.g., the impurity represented by Formula III
  • the invention further includes a process for preparing venlafaxine with optimized reactant molar ratios in order to obtain a product with a high purity in a high yield by avoiding the formation of large amounts of impurities (e.g., the impurity represented by Formula III) during the synthetic procedure.
  • the preferred molar ratio of N,N- didesmethylvenlafaxine hydrochloride: formic acid: alkaline metal salt: formaldehyde is in the range of approximately 1.00: 4.90: 1.05: 2.00 to approximately 1.00: 7.60: 1.15: 3.10. The most preferred ratio is approximately 1.00: 5.34: 1.10: 2.14.
  • the invention further includes using the venlafaxine obtained by the above-described processes to produce pharmaceutically acceptable salts, hydrates and/or solvates.
  • the invention includes producing an acid addition salt of venlafaxine; more preferably, the invention includes producing the hydrochloride salt of venlafaxine (i.e., venlafaxine hydrochloride).
  • Another aspect of the invention includes identification of one impurity that can be formed during the preparation of venlafaxine.
  • this impurity is formed when an excess of reagents is used to prepare venlafaxine from N,N-didesmethylvenlafaxine of Formula II.
  • This impurity has been identified and is represented herein by Formula III.
  • the invention further includes a method for preparing a compound of Formula III, which includes reacting venlafaxine base with a large excess of formic acid and formaldehyde heated under reflux.
  • Another aspect of the invention includes monitoring the products obtained when venlafaxine is prepared from N,N-didesmethylvenlafaxine of Formula II using formic acid and formaldehyde for the presence of the impurity represented by Formula III.
  • Another aspect of the invention includes a process for preparing venlafaxine hydrochloride by reacting an ethyl acetate solution of venlafaxine base with HCl gas in isopropanol until the pH is adjusted to between approximately 3 and approximately 4.
  • the invention further includes a process for preparing venlafaxine hydrochloride of high purity, wherein the venlafaxine hydrochloride is more than approximately 99.5% pure when analyzed by reverse phase high performance liquid chromatography (HPLC) and more preferably wherein the venlafaxine hydrochloride is more than approximately 99.9% pure when analyzed by reverse phase HPLC.
  • HPLC reverse phase high performance liquid chromatography
  • Another aspect of the invention includes venlafaxine hydrochloride having a purity of at least approximately 99.5% when analyzed by reverse phase HPLC, and more preferably wherein the venlafaxine hydrochloride is more than approximately 99.9 % pure when analyzed by reverse phase HPLC.
  • Another aspect of the invention includes venlafaxine having less than approximately 0.1% of individual impurities, preferably less than approximately 0.05%, more preferably less than approximately 0.02% of individual impurities.
  • Another aspect of the invention includes venlafaxine having less than approximately 0.05%, more preferably less than approximately 0.02% of the impurity represented by Formula HI.
  • Another aspect of the invention includes a process for recrystallizing venlafaxine hydrochloride with at least one of methanol, isopropanol and ethyl acetate and mixtures thereof.
  • Another aspect of the invention includes venlafaxine hydrochloride having less than approximately 100 ppm of residual methanol content as determined by gas chromatography.
  • Another aspect of the invention includes venlafaxine hydrochloride having less than approximately 100 ppm of residual isopropanol content as determined by gas chromatography.
  • Another aspect of the invention includes venlafaxine hydrochloride having less than approximately 550 ppm of residual ethyl acetate content as determined by gas chromatography.
  • Another aspect of the invention includes venlafaxine hydrochloride having a defined particle size distribution wherein approximately 10% of the total volume (D )0 ) is made of particles having a diameter below approximately 10 ⁇ m, approximately 50% of the total volume(Dso) is made of particles having a diameter below approximately 35 ⁇ m and approximately 90% of the total volume (D») is made of particles having a diameter below approximately 80 ⁇ m.
  • Another aspect of the invention includes venlafaxine hydrochloride particles having a specific surface area higher than approximately 0.5 m 2 /g and more preferably, venlafaxine hydrochloride particles having specific surface area of approximately 1.2 to approximately 2.8 m 2 /g.
  • Another aspect of the invention includes a powder composition including venlafaxine hydrochloride, wherein the venlafaxine hydrochloride has a particle size distribution in which approximately 10% of the total volume is made of particles having a diameter below approximately 10 ⁇ m, approximately 50% of the total volume is made of particles having a diameter below approximately 35 ⁇ m and approximately 90% of the total volume is made of particles having a diameter below approximately 80 ⁇ m.
  • a "powder composition” means a powder that consists entirely of venlafaxine or that contains venlafaxine in intimate or non- intimate mixture with one or more other substances and/or excipient materials.
  • Another aspect of the invention includes a dosage form that includes venlafaxine hydrochloride, wherein the venlafaxine hydrochloride has a particle size distribution in which approximately 10% of the total volume is made of particles having a diameter below approximately 10 ⁇ m, approximately 50% of the total volume is made of particles having a diameter below approximately 35 ⁇ m and approximately 90% of the total volume is made of particles having a diameter below approximately 80 ⁇ m.
  • the chromatographic separation was carried out in a Kromasil C 8, S ⁇ m, 25 cm x 4.6 mm. I.D column at room temperature ( ⁇ 20-25° C).
  • the chromatograph was equipped with a 22S nm detector, and the flow rate is 1.2 mL per minute at room temperature.
  • Test samples (20 ⁇ l) were prepared by dissolving the appropriate amount of sample to obtain 1 mg per mL concentration in the mobile phase.
  • Chromatographic separation is carried out in a VOCOL capillary column of 3 ⁇ m film thickness, 105 m x 0.53 mm i.d. column.
  • the chromatograph is equipped with a FID detector and a Head Space injection auxiliary device.
  • the oven temperature is programmed as follows: Initial 0-16 minutes 70° C, then the temperature is raised to 150° C (ramp rate 25° C/minute) and is maintained at 150° C for 3 minutes, then raised again to 240° C with a ramp of 30° C per minute.
  • the injector and detector temperatures are men set at 220° C and 250° C, respectively.
  • the stock solution of propanol was prepared so as to contain 1000 ⁇ g/mL of propanol in water by diluting a quantitatively known volume of propanol. The stock solution of propanol was then diluted quantitatively with water to obtain solutions containing 40 ⁇ g/mL and 20 ⁇ g/mL of propanol in water.
  • Standard Methanol Solution 100 ppm
  • the stock solution of methanol was prepared so as to contain 95 ⁇ g/mL of methanol in water by diluting quantitatively a known quantity of methanol.
  • the stock solution of methanol was men diluted quantitatively to obtain a solution containing 1.9 ⁇ g/mL of methanol.
  • the stock solution of ethylacetate was prepared so as to contain 99 ⁇ g/mL of ethylacetate in water by diluting quantitatively a known quantity of ethylacetate. The stock solution was then diluted quantitatively with water to obtain a solution containing 2 ⁇ g/mL of ethylacetate.
  • test solutions were prepared by mixing approximately 100 mg of venlafaxine hydrochloride in 5 mL of water.
  • the vials containing samples were sealed with suitable crimp caps and analyzed by head space using the above-described conditions.
  • the particle size for venlafaxine hydrochloride was measured using a Malvern light scattering particle size analyzer using a 2 milliwatt Helium/Neon laser and a Fourier Transform lens system to focus the scattered laser light onto a photosensitive detector.
  • the sample was run using a 2.40 mm lens and a MSl Small Volume Sample Dispersion Unit with a stirred cell.
  • Samples for analysis were prepared by dispersing a weighed amount of venlafaxine hydrochloride (appproximately 0.1 g) in 20 mL of dispersant. The suspension was sonicated for 2 minutes and delivered drop-wise to a previously filled and background- corrected measuring cell until the obscuration reached the desired level. The sample was measured as quickly as possible after stabilization of the obscuration.
  • the notation D x means that approximately X% by volume of the particles have a diameter less than a specified diameter.
  • D 90 ⁇ 10.00 ⁇ m means that approximately 90% of the particles by volume in a composition preferably have a diameter less than approximately 10.00 ⁇ m.
  • the values of Dm, D 50 and Dg 0 were specifically listed, each one being the mean of the six values available for each characterization parameter.
  • the BET (Brunauer, Emmett and Teller) specific surface for venlafaxine was measured using Micromeritics ASAP2010 equipment. Samples for analysis were degassed at 150° C under vacuum, and the determination of the adsorption of N 2 at 77° K was measured for relative pressures in the range of 0.07-0.2 for a weighed amount of venlafaxine (approximately 0.2 g).
  • the reactor was heated to reflux (approximately 100° C) with continuous stirring and maintained at this temperature for 15 hours.
  • the reaction mixture was measured by HPLC Method 1 for the presence of the impurity of Formula III. According to his measurement, the amount of the impurity was less than 0.02%
  • Step 2 Methanol (4.2 kg; 3.3L) and ethyl acetate (4.78 kg; 4.31 L) were charged over the wet solid of Step 2 (above). Thereafter, seed crystals of venlafaxine hydrochloride Form I were added to the suspension. The mixture was then heated to reflux and maintained at this temperature for 30 minutes. The suspension was then cooled to 0-5° C and maintained at this temperature for approximately 1 hour. Thereafter, the suspension was filtered, and the collected wet solid was dried under vacuum at 60 ⁇ 5° C until constant weight to yield 5.25 kg (16.73 mol, 86.92 %) of venlafaxine hydrochloride. The solid was then milled and sieved through a 500 ⁇ m screen and blended for 2 hours.
  • the mixture was then basified with a 50% aqueous sodium hydroxide solution with continuous stirring to adjust the pH to approximately 11-12.
  • the reaction mixture was stirred, the resulting aqueous and organic phases were separated, and the aqueous phase was extracted with 200 mL (265 g) of dichloromethane.
  • the organic phase was dried over with anhydrous sodium sulphate, and the solution was filtered.
  • the collected wet solid was treated with 50 mL (39.6 g) of methanol, and the obtained solution was filtered to remove any mechanical particles.
  • the methanol was then removed by distillation under reduced pressure, and 15 mL (13.5g) of ethyl acetate was charged to the residue.
  • the resulting suspension was then cooled to 0-5° C.
  • the resulting solid was then filtered, washed with 4 mL (3.6g) of ethyl acetate and dried at 40° C to yield 4 g of l-[2- (dimethylamino)- 1 -(3-hydroxy methyl-4-methoxyphenyl)ethyl] cyclohexanol.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne d'une façon générale un procédé amélioré servant à fabriquer de la venlafaxine sous forme de base et/ou des sels de celle-ci.
EP07858939A 2006-07-14 2007-07-13 Procedes ameliores servant a preparer de la venlafaxine sous forme de base et des sels de celle-ci Withdrawn EP2081885A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US83061606P 2006-07-14 2006-07-14
PCT/IB2007/003757 WO2008038146A2 (fr) 2006-07-14 2007-07-13 Procédés améliorés servant à préparer de la venlafaxine sous forme de base et des sels de celle-ci

Publications (1)

Publication Number Publication Date
EP2081885A2 true EP2081885A2 (fr) 2009-07-29

Family

ID=39230603

Family Applications (1)

Application Number Title Priority Date Filing Date
EP07858939A Withdrawn EP2081885A2 (fr) 2006-07-14 2007-07-13 Procedes ameliores servant a preparer de la venlafaxine sous forme de base et des sels de celle-ci

Country Status (4)

Country Link
EP (1) EP2081885A2 (fr)
AR (1) AR062064A1 (fr)
CA (1) CA2657912A1 (fr)
WO (1) WO2008038146A2 (fr)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000059851A1 (fr) * 1999-04-06 2000-10-12 Sepracor Inc. Derives de la venlafaxine et leurs procedes de preparation et utilisation
IL155400A0 (en) * 2000-10-19 2003-11-23 Teva Pharma Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride and processes for preparing thereof
WO2003050074A1 (fr) * 2001-12-13 2003-06-19 Cadila Healthcare Limited Fabrication de l'hydrochlorure venlafaxine et de polymorphes cristallins de celui-ci

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2008038146A3 *

Also Published As

Publication number Publication date
CA2657912A1 (fr) 2008-04-03
WO2008038146A2 (fr) 2008-04-03
WO2008038146A3 (fr) 2008-11-13
AR062064A1 (es) 2008-10-15

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