IMPROVED PROCESSES FOR PREPARING VENLAFAXINE BASE AND SALTS

THEREOF

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to United States Provisional Application No.60/830,616, filed July 14, 2006, which is expressly incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION Field of the Invention

The invention relates generally to an improved process for manufacturing venlafaxine base and/or salts thereof.

Relevant Background

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.

(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 :

Scheme 1

The processes of Scheme 1 are based on introducing the cyclohexanol residue by reacting cyclohexanone with an enolate anion of an arylacetic acid, or of an appropiate derivative thereof, and then further elaborating the carboxylic group derivative or analogue thereof in order to obtain the N,N-dimethylaminomethyl group.

The Journal of Medicinal Chemistry, Vol. 33, No. 10, pp. 2899-2905 ( 1990) " discloses the preparation of venlafaxine using formaldehyde and formic acid.

International Application WO 02/45658 discloses the preparation of venlafaxine free base from N,N-didesmethylvenlafaxine hydrochloride in water. The N,N- didesmethylvenlafaxine hydrochloride is reacted with aqueous sodium hydroxide, aqueous formic acid and aqueous formaldehyde to give venlafaxine, which is extracted with heptane.

According to International Application WO 2005/058796, 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.

In view of the foregoing, it is important to develop a simplified process for preparing venlafaxine that yields venlafaxine of high quality and in high yields. Given that 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.

SUMMARY OF THE INVENTION

The invention relates generally to an improved process for manufacturing venlafaxine base and/or salts thereof. In particular, it has been observed that during the N,N-dimethylation with 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.

(III)

Another aspect of the invention includes identification of an impurity that can be formed during the preparation of venlafaxine from N,N-didesmethylvenlafaxine. In particular, it has been observed that 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. Preferably, 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. Preferably, 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 various embodiments of the invention having thus been generally described, several examples will hereafter be discussed to illustrate the inventive aspects more fully.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Reference will now be made in detail to the preferred embodiments of the invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.

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 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. In particular, 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. Preferably, 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. In particular, 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.

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 μm, approximately 50% of the total volume(Dso) is made of particles having a diameter below approximately 35 μm and approximately 90% of the total volume (D») is made of particles having a diameter below approximately 80 μm.

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 μm, approximately 50% of the total volume is made of particles having a diameter below approximately 35 μm and approximately 90% of the total volume is made of particles having a diameter below approximately 80 μm. 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 μm, approximately 50% of the total volume is made of particles having a diameter below approximately 35 μm and approximately 90% of the total volume is made of particles having a diameter below approximately 80 μm.

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit or scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.

The following examples are for illustrative purposes only and are not intended, nor should they be interpreted, to limit the scope of the invention.

Specific Examples

General Experimental Conditions:

1. HPLC Method 1

In the examples described below, the following analytical chromatographic HPLC method is used:

The chromatographic separation was carried out in a Kromasil C 8, S μm, 25 cm x 4.6 mm. I.D column at room temperature (~20-25° C).

The mobile phase A was prepared by mixing 1490 g Of(NH ₄ )H ₂ PO ₄ buffer solution (pH = 4.4) and 398.3 g of acetonitrile. The pH of the mixture should be 4.9, and was adjusted accordingly as necessary. The mobile phase was mixed and filtered through 0.22 μm nylon filter under vacuum.

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 μl) were prepared by dissolving the appropriate amount of sample to obtain 1 mg per mL concentration in the mobile phase.

2. Gas Chromatography Method and Solutions

Chromatographic separation is carried out in a VOCOL capillary column of 3 μm 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. Helium is used as carrier gas at a pressure of 20 psi with a split Samples were heated for 30 minutes at 85° C in the head space device. After heating, the vials were pressurized with helium at 18 psi for 0.3 minutes. The sample loop was filled for 0.15 minutes (loop volume = 1 mL) and then injected for 0.5 minutes.

Solutions: a. Standard Propanol Solution (100 ppm):

The stock solution of propanol was prepared so as to contain 1000 μg/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 μg/mL and 20 μg/mL of propanol in water. b. Standard Methanol Solution (100 ppm):

The stock solution of methanol was prepared so as to contain 95 μg/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 μg/mL of methanol. c. Standard Ethylacetate Solution (100 ppm):

The stock solution of ethylacetate was prepared so as to contain 99 μg/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 μg/mL of ethylacetate.

Test Solutions:

The test solutions were prepared by mixing approximately 100 mg of venlafaxine hydrochloride in 5 mL of water.

Procedure:

The vials containing samples were sealed with suitable crimp caps and analyzed by head space using the above-described conditions.

3. Particle Size Distribution:

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.

For particle size characterization, the notation D _x means that approximately X% by volume of the particles have a diameter less than a specified diameter. Thus, for example, D ₉₀ < 10.00 μm means that approximately 90% of the particles by volume in a composition

preferably have a diameter less than approximately 10.00 μm. 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.

4. Specific Surface Method:

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).

Example 1: Preparation of l-[2-(dimethylamino)-l-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride

Step 1: Preparation of Venlafaxine Base

In a suitable reactor, 23 kg of deionized water was charged and cooled to 0-10° C. Thereafter, 1.19 kg (21.21 mol) of potassium hydroxide was combined with the water, and the reactor was heated to room temperature (-20-25° C). Next, 5.5 kg (19.24 mol) of aminomethoxyfeniletilciclohexanol hydrochloride was charged, and the mixture was stirred for 30 minutes at room temperature. Thereafter, the suspension was charged 5.56 kg (102.67 mol, 85 %) of formic acid followed by 3.34 kg (41.14 mol, 37%) of formaldehyde. After combining the reactants, 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%

Thereafter, the reactor contents were cooled to 5-10° C, and 29.3 kg (32.5 L) of ethyl acetate was charged with continuous stirring. The temperature was adjusted to 8-12° C, and 4.97 kg (62.11 mol, 3.25 L) of a 50% aqueous sodium hydroxide was added with continuous stirring to adjust the pH to approximately 11-12. The reaction mixture was then stirred for 30 minutes. The resulting aqueous and organic phase were then separated, and the aqueous phase was extracted with 14.6 kg (16.20L) of ethyl acetate. Residual water and possible presence of mechanical particles were then eliminated. The organics phases were dried over with anhydrous sodium sulphate (1.1 kg), and the solution was filtered. A sample of the obtained organic solution (4 kg; yield= 99.53%) was titrated to assay and verify the content of 1 -[2-(Dimethylamino)-l -(4- methoxyphenyl)ethyl]cyclohexanol (Le., venlafaxine base; Assay= 9.84%).

Step 2: Preparation of Venlafaxine Hydrochloride

The organic solution containing 5.31 kg of venlafaxine base obtained in Step 1 (above) was cooled to 5-10° C, and 3.8 L (solution 5 N) of dry HCl gas in isopropanol was slowly added with stirring to adjust the pH to less than 4. The reactor 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 charged in another suitable reactor. 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 3: Preparation of Venlafaxine Hydrochloride Form I

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 μm screen and blended for 2 hours.

Analytical data: HPLC purity: 99.97 %; Residual solvents (as determined by gas chromatography): methanol < 100 ppm, isopropanol < 100 ppm, ethyl acetate 513 ppm: Particle size: D _t0 < 3.2 μm, D ₅₀ < 32.6 μm, and D ₉ O < 71.2 μm; Titration 99,8%; specific surface area 1.5477 ± 0.0822 m ² /g.

Example 2: Preparation of l-[2-(dimethyIamino)-l-(3-hydroxymcthyl-4 methoxy phenyl)etbyl]cyclohexanol (Formula III)

In a suitable 500 mL flask at room temperature under a nitrogen atmosphere were charged 2Og (0.072 mol) of venlafaxine base, 157.3 mL (188.8 g, 3.486 mol) of formic acid (85%) and 141.3 mL (152.6g, 1.880 mol) of formaldehyde (37%). After combining the reactants, the resulting solution was heated to reflux (approximately 100° C) for approximately 90 hours. Thereafter, the mixture was distilled under reduced pressure until a residue was obtained. To the residue was added 400 mL of water and 250 mL(331.25 g) of dichloromethane with continuous stirring. The mixture was then basified with a 50% aqueous sodium hydroxide solution with continuous stirring to adjust the pH to approximately 11-12.

Next, 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 resulting organic phase was next distilled under reduced pressure to yield 47.37 g of a yellow residue. This mixture of products was chromatographed on 12O g of Silica gel F60 with (1) ethyl acetate, (2) ethyl acetate/methanol (50:5) and (3) ethyl acetate/methanol (50:20). The resulting six fractions obtained with the column were combined with ethyl acetate and then distilled under reduced pressure. Then, 30 mL (27.03 g) of ethyl acetate was charged to the residue obtained (6.06 g). The suspension was stirred and 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.

Analytical data: HPLC purity: 97.82 %; elemental analysis: Calculated for Ci ₈ H ₂₉ NO ₃ • ( Vi H ₂ O): C 68.32 %, H 9.56%, N 4.43%. Found: C 68.29 %, H 9.63%, N 4.32%; he ¹ H-NMR (CD ₃ OD, 300 MHz), δ(ppm) of the byproduct is characterized as follows : 7.22 (d, J= 2.4 Hz, 1 H, phenyl 2-H), 7.10 (dd, J= 8.4, 2.4, 1 H, phenyl 6-H), 6.87 (d, J= 8.4, 1 H, phenyl 5-H), 4.61 (s, 2 H, ArCH ₂ OH), 3.81 (s, 3 H, OCH ₃ ), 2.86 (dd, J= 7.8, 6.9, Ar-CH), 3.17 (dd, J= 12.9, 8.1, 1 H, CH ₂ N), 2.59 (dd, J= 12.6, 6.6, 1 H), 2.26 (s, 6 H, N(CHj) ₂ ), 0.87-1.70 (complex signal, 10 H, cyclohexyl H); The ¹³ C-NMR (CD ₃ OD, 75.4 MHz), δ(ppm) of the byproduct is characterized as follows: 157.0 ( C, Ar-C4), 133.4 (C, Ar-Cl and Ar-C3), 129.9 (C), 130.4 (CH, Ar-C2 and Ar-C6), 129.8 (CH), 110.7 (CH, Ar- C5), 75.5 (C, cyclohexyl Cl), 61.7 (CH ₂ , CH ₂ OH), 60.4 (CH ₂ , CH ₂ N(CRj) ₂ ), 55.8 (CH ₃ , OCH ₃ ), 53.8 (CH, Ar-CH), 45.8 (CH ₃ , N(CH ₃ ) ₂ ), 38.3 (CH ₂ , Cyclohexyl C2 and C6), 33.4 (CH ₂ ), 27.0 (CH ₂ , cyclohexyl C4), 22.6 (2 CH ₂ , cyclohexyl C3 and C5).

Although the invention has been described and illustrated with a certain degree of particularity, it is understood that the present disclosure has been made only by way of example, and that numerous changes in the conditions and order of steps can be resorted to by those skilled in the art without departing from the spirit and scope of the invention.

u