KR20190005678A - Novel nicotinate salt of O-desmethylvenlafaxine and method for preparing the same - Google Patents

Abstract

The present invention relates to an O-desmethyl-venlafaxine nicotinate, a novel salt of O-desmethyl-venlafaxine, and to a manufacturing method thereof. The novel salt of the present invention has excellent stability, hygroscopicity and solubility to be stably formulated, and there is an advantage of long-term storage.

Description

De-methyl-venlafaxine and a method for preparing the same. [0002] The present invention relates to a novel nicotinate salt of O-desmethyl-venlafaxine,

The present invention relates to a novel salt of O-desmethyl-venlafaxine, O-desmethyl-venlafaxine nicotinate, a process for its preparation and a pharmaceutical composition comprising said novel salt.

(Venlafaxine) represented by the following general formula (1) represented by the following general formula (1), which is the first (1) inhibiting the reuptake of norepinephrine and serotonin, It is a class of antidepressants.

[Chemical Formula 1]

(O-desmethyl-venlafaxine; ODV) represented by the following formula (2) is a major metabolite of venlafaxine (Klamerus, KJ et al., &Quot; Introduction of the Composite Parameter to the Pharmacokinetics of Venlafaxine and its Active O-Desmethyl Metabolite ", J. Clin. Pharmacol. 32: 716-724 (1992)).

(2)

O-desmethyl-venlafaxine as a free base and its preparation method are described in International Patent Publication No. WO 2003-048104.

O-desmethyl-venlafaxine is a fumarate salt described in U.S. Patent Publication No. 4,535,186. However, it is known that O-desmethyl-venlafaxine fumarate salt is poor in permeability and is unsuitable for use as a drug.

It is known that O-desmethyl-venlafaxine succinate is suitable for use as a drug in consideration of solubility, permeability and bioavailability, and its polymorphism and preparation method are described in U.S. Patent No. 6,673,838. Also, crystal forms of O-desmethylvenlafaxine succinate are disclosed in International Patent Publication Nos. WO 2008-047167 and International Patent Publication WO 2008-017886.

Salt formation provides a means to change physico-chemical and biological and physiochemical properties without altering the chemical structure of the drug. Suitable salts can be determined according to the yield, rate, elution rate and amount of the crystal structure, and the solubility, hygroscopicity, stability and process profile of the salt can be considered important.

One of the important physical properties of pharmaceutical compositions is the solubility of the drug in aqueous solution. When the water solubility is less than 10 mg / mL, the rate of dissolution in the absorption process during the bioavailability may act as a rate limiting factor and may exhibit low bioavailability, and the polymorphs of different crystal forms or the same pharmaceutical composition may have different water solubilities. A compound having a low hygroscopicity is one of the important characteristics because it is excellent in stability and easy in processing and hygroscopicity.

Thus, the development of new solids of pharmaceutically useful compounds provides an opportunity to improve the performance characteristics of pharmaceuticals and expands the list of available materials for drug formulation scientists to design pharmaceutical formulations of drugs with different characteristics . In addition, improvements in physical properties such as solubility, stability, and hygroscopicity can increase permeability and bioavailability, and development of new salts is required continuously.

O-desmethyl-venlafaxine succinate, which is a known O-desmethyl-venlafaxine salt, has a problem of showing a relatively low solubility.

Therefore, development of O-desmethyl-venlafaxine salt having high solubility can improve the performance characteristics of medicines and can contribute to the design of pharmaceutical formulations of drugs having different characteristics. Therefore, to be.

It is an object of the present invention to provide a novel salt of O-desmethyl-venlafaxine, a method for producing the same, and an anti-depressant composition comprising the novel salt of O-desmethyl-venlafaxine.

Thus, the present inventors have completed the present invention by preparing O-desmethyl-venlafaxine nicotinate having high solubility compared to the conventionally known O-desmethyl-venlafaxin succinate and excellent physical properties such as stability, hygroscopicity and purity.

Accordingly, the present invention provides a pharmaceutical composition comprising O-desmethyl-venlafaxine nicotinate (nicotinate), a process for its preparation and the O-desmethyl-venlafaxine nicotinate.

In a specific embodiment, the O-desmethyl-venlafaxin nicotinate of the present invention has a structure of the following formula (III) and has peaks at 11.2, 12.5, 18.4, 19.0, 19.7, 20.5 and 22.9 + 0.2 degrees two theta, PXRD patterns with peaks at 7.9, 11.0, 11.2, 12.5, 16.8, 18.4, 19.0, 19.7, 20.2, 20.5, 21.3 and 22.9 + 0.2 degrees two theta; The stability, the non-hygroscopicity and the solubility are equivalent to or superior to the conventional O-desmethyl-benzlafaxin succinate monohydrate, which is characterized by showing a PXRD pattern as shown in Fig. In particular, the solubility is about 7 to 11 times better than the succinate salt of O-desmethyl-venlafaxine nicotinate.

 (3)

In another specific embodiment, the present invention provides a method for the preparation of a pharmaceutical composition comprising: (a) providing a mixture of O-desmethyl-venlafaxine, nicotinic acid, and a reaction solvent; (b) heating the mixture to obtain a solution; (c) cooling the solution to a temperature of from 40 캜 to 50 캜 to obtain an O-desmethyl-venlafaxine nicotinate suspension; And (d) cooling the suspension to obtain O-desmethyl-venlafaxine nicotinate crystalline, characterized in that the O-desmethyl-venlafaxin nicotinate Or a pharmaceutically acceptable salt thereof has characteristic peaks at angles 2θ at 11.2, 12.5, 18.4, 19.0, 19.7, 20.5 and 22.9 ± 0.2 °, preferably at 7.9, 11.0, 11.2, 12.5, 16.8, 18.4 , 19.0, 19.7, 20.2, 20.5, 21.3, and 22.9 +/- 0.2 degrees, respectively, of the O-desmethyl-venlafaxin nicotinate.

According to the present invention, O-desmethyl-venlafaxin nicotinate exhibits high solubility compared to O-desmethyl-venlafaxine succinate monohydrate which has excellent purity, stability and non-hygroscopicity but is used as a conventional raw material drug. .

This provides an opportunity to improve the performance characteristics of pharmaceuticals by providing novel salts with good physical properties and allows pharmaceutical scientists to expand the list of available materials to design pharmaceutical formulations of drugs with other characteristics will be.

Figure 1 shows the PXRD pattern of crystalline O-desmethyl-venlafaxine nicotinate prepared according to one embodiment of the present invention.
Figure 2 shows a differential scanning calorimetry (DSC) analysis of crystalline O-desmethyl-venlafaxine nicotinate prepared according to one embodiment of the present invention.
Figure 3 shows a hydrogen nuclear magnetic resonance (NMR) analysis of crystalline O-desmethyl-venlafaxin nicotinate prepared according to one embodiment of the present invention.

Hereinafter, the present invention will be described in more detail.

In one embodiment, the present invention provides O-desmethyl-venlafaxine nicotinate or a pharmaceutically acceptable salt thereof.

The O-desmethyl-venlafaxin nicotinate is also called the chemical name 4- (2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl) phenolnicotinate and is represented by the following formula 3:

(3)

O-desmethyl-venlafaxine nicotinate is present as an enantiomer, and the present invention encompasses racemic mixtures as well as their stereoisomerically pure forms. The term "O-desmethyl-venlafaxin nicotinate" as used herein means racemic or stereomerically pure forms unless otherwise stated.

The O-desmethyl-venlafaxine nicotinate may be characterized in that it forms crystals.

Desirably, the O-desmethyl-venlafaxin nicotinate may have a ratio of O-desmethyl-venlafaxine to nicotinic acid of 1: 1 and the characteristic peaks represented by angles 2? Are 11.2, 12.5, 18.4, 19.0, 19.7, 20.5 and 22.9 ± 0.2 ° and preferably at 7.9, 11.0, 11.2, 12.5, 16.8, 18.4, 19.0, 19.7, 20.2, 20.5, 21.3 and 22.9 ± 0.2 °, In a differential scanning calorimetry (DSC) analysis, the onset is 148.75 ° C and can have an endothermic peak at 150.26 ° C ± 1.5 ° C.

Desirably, the O-desmethyl-venlafaxin nicotinate may have a 1: 1 ratio of O-desmethyl-venlafaxine and nicotinic acid, a purity of 99.90% or more, and an anhydrous content of 0.09% of water.

Further, in a specific embodiment of the present invention, a stability test is conducted to determine whether the O-desmethyl-venlafaxine nicotinate exhibits a purity change of 0.01% or less under accelerated conditions for 34 days, and O-desmethyl-venlafaxine succinate monohydrate And it was found that the O-desmethyl-venlafaxine nicotinate was less restricted by storage conditions due to an increase in the amount of the suppositories and could be stored for a long period of time.

In a specific example of the present invention, the hygroscopicity test was conducted to confirm that the O-desmethyl-venlafaxin nicotinate did not show a decrease in stability with respect to moisture and was easy to process, and a solubility evaluation was performed to evaluate the O -Desmethyl-venlafaxine nicotinate crystals was about 7 to 11 times greater than that of the control group O-desmethyl-venlafaxine succinate monohydrate.

Thus, it was confirmed that the O-desmethyl-venlafaxin nicotinate of the present invention is remarkably superior in physicochemical stability, non-hygroscopicity and solubility to the known O-desmethyl-benzlafaxin succinate monohydrate. Thus, the O-desmethyl-venlafaxin nicotinate of the present invention can be usefully used as an active ingredient of an antidepressant.

In yet another aspect,

(a) providing a mixture of O-desmethyl-venlafaxine, nicotinic acid, and a reaction solvent;

(b) heating the mixture to obtain a solution;

(c) cooling the solution to a temperature of from 40 캜 to 50 캜 to obtain an O-desmethyl-venlafaxine nicotinate suspension; And

(d) cooling said suspension to obtain crystalline O-desmethyl-venlafaxine nicotinate crystals, comprising the steps of:

The crystalline form of O-desmethyl-venlafaxine nicotinate has characteristic peaks at angles 2θ at 11.2, 12.5, 18.4, 19.0, 19.7, 20.5 and 22.9 ± 0.2 °, preferably 7.9, 11.0, 11.2, 12.5, Desmethyl-venlafaxine nicotinate crystal form characterized in that it exhibits an X-ray powder diffraction pattern having the following powders at 16.8, 18.4, 19.0, 19.7, 20.2, 20.5, 21.3 and 22.9 ± 0.2 °.

Each step will be described in detail below.

In step (a) above, O-desmethyl-venlafaxine may preferably be in the form of a free base. In the production process of the present invention, the O-desmethyl-venlafaxine free base may be prepared by a method described in International Publication WO 2003-048104 or commercially available, and commercially available niacin acid may also be used .

The amount of nicotinic acid used in (a) may be 0.8 to 2.0 equivalents based on 1 equivalent of O-desmethyl-venlafaxine free base, but is not limited thereto. The nicotinic acid may more preferably be used in an amount of 0.95 equivalents.

The reaction solvent of (a) may be at least one selected from the group consisting of C1-C4 alcohols and organic solvents, and the C1-C4 alcohol may be ethanol, methanol, isopropanol, propanol or butanol, Ethanol, and the organic solvent may be used alone or in combination with at least one organic solvent selected from the group consisting of ethyl acetate, acetone, tetrahydrofuran, methyl tert-butyl ether and diethyl ether. Preferably in a mixture of ethanol and ethyl acetate, and the ratio of ethanol to ethyl acetate can be used from 1:10 to 4:10, but is not limited thereto. More preferably, ethanol: ethyl acetate may be used in a ratio of 3:10. The amount of the solvent used is 1 to 30 times by volume, preferably 5 to 15 times by volume per 1 weight of O-desmethyl-venlafaxine free base.

In the step (b), the reaction for the production of O-desmethyl-venlafaxine nicotinate is carried out by heating the mixture to obtain a solution. The temperature for the reaction is 30 ° C to reflux temperature (75 ° C), preferably 50 ° C to reflux temperature (75 ° C), and the complete dissolution temperature is 65 ° C to reflux temperature (75 ° C).

In the next step (c), the temperature of the O-desmethyl-venlafaxin nicotinate solution produced in step (b) is lowered to precipitate the O-desmethyl-venlafaxin nicotinate solution to obtain a suspension, wherein the salt (O-desmethyl-venlafaxin nicotinate) May be carried out at 40 캜 to 50 캜, preferably at 45 캜 for 20 minutes to 1 hour.

In step (d), the suspension of O-desmethyl-venlafaxin nicotinate produced in step (c) is cooled. The temperature of the cooling process is 0 ° C to 30 ° C, preferably 0 ° C to room temperature 25 ° C), and the solid may be formed by the cooling process, and the solid may be O-desmethyl-venlafaxine nicotinate crystal form, and the suspension is cooled to 0 ° C to room temperature (25 ° C) The yield can be significantly increased.

In yet another embodiment, the present invention relates to a pharmaceutical composition comprising said O-desmethyl-venlafaxin nicotinate. Desmethyl-venlafaxine is known to be used as antidepressant as a norepinephrine and serotonin reuptake inhibitor, and its pharmaceutical composition containing O-desmethyl-venlafaxin nicotinate according to the present invention, which is a new pharmaceutically acceptable salt thereof May be for the prevention or treatment of depression. Preferably, the pharmaceutical composition according to the present invention may further comprise a pharmaceutically acceptable carrier, excipient and / or additive together with the O-desmethyl-venlafaxin nicotinate mentioned above, Or parenteral formulations.

Hereinafter, the present invention will be described in more detail with reference to the following Examples and Test Examples. However, these examples are only for illustrating the present invention, and the scope of the present invention is not limited by these examples.

Example  1. Crystalline O- Desmethyl - Venlafaxine Nicotinate  Produce

10 mg of O-desmethyl-venlafaxine free base (ChengDu Climb Pharmaceutical Technology Co. Ltd.) and 4.44 g of nicotinic acid (Sigma Aldrich / Catalog No. N41280-1KG) were added to 100 mL of ethyl acetate and 30 mL of ethanol to obtain a suspension . The suspension was completely dissolved by stirring at 72 占 폚 at reflux. The solution was slowly cooled to 45 and stirred at this temperature for 50 minutes to obtain a suspension. The suspension was cooled slowly to 25 and stirred for 1 hour, after which the resulting solids were separated by filtration. The solid was dried under reduced pressure (-760 mm Hg) at 35 ° C for 14 hours to give white crystalline O-desmethyl-venlafaxine nicotinate (10.05 g, 68.5%).

Example  2. Crystalline O- Desmethyl - Venlafaxine Nicotinate  Character analysis

2-1. Powder X-ray diffraction analysis

Powder X-ray diffraction (PXRD) analysis was performed on a Bruker D8 Advance X-ray diffractometer using Cu Kα radiation. The detector is Lynxeye, and the wavelength of the X-ray source is 1.5405 Å.

The O-desmethyl-venlafaxin nicotinate crystalline material prepared by the same method as in Example 1 had I / I0 (I: intensity of peak at each diffraction angle, I0: intensity of largest peak) of 40% or 20% And is shown in Fig. 1 as a value for the 2 &thetas; diffraction angle.

As shown in FIG. 1, the crystalline O-desmethyl-venlafaxin nicotinate crystals prepared in the same manner as in Example 1 had characteristic peaks at angles 2? Of 11.2, 12.5, 18.4, 19.0, 19.7, 20.5 and 22.9 ± 0.2 °, preferably at 7.9, 11.0, 11.2, 12.5, 16.8, 18.4, 19.0, 19.7, 20.2, 20.5, 21.3 and 22.9 ± 0.2 °.

2-2. Differential injection Calorimetric method  analysis

Differential Scanning Calorimetry (DSC) analysis was performed on a Mettler Toledo DSC823e calorimeter. The weight of about 3 to 5 mg of sample was accurately recorded and placed in a DSC pan and the pan was sealed and sealed. Each sample was heated at a rate of 5 / min under nitrogen at an initial temperature of 25 占 폚 to a final temperature of 350 占 폚. The reported temperatures are indicated as the onset temperature and the endothermic peak.

The DSC results of the crystalline O-desmethyl-venlafaxin nicotinate prepared by the same method as in Example 1 are shown in Fig. 2, with an onset of 148.75 ° C and an endothermic peak of 150.26 ° C.

2-3. Hydrogen Nuclear Magnetic Resonance (NMR) Spectrum Analysis

Hydrogen nuclear magnetic resonance (NMR) analysis was performed using a Bruker AVANCE II 400, analyzed by 16 scans and shown in FIG.

The spectrum of O-desmethyl-venlafaxin nicotinate crystalline prepared in Example 1 was expressed as -0.5 to 10 ppm.

As shown in FIG. 3, it was confirmed that O-desmethyl-venlafaxine nicotinate crystalline material prepared by the same method as in Example 1 had a 1: 1 ratio of O-desmethyl-venlafaxine base and nicotinic acid.

^{1 H NMR (400MHz, DMSO-} d 6): δ 9.03 (dd, J = 2.1, 0.8Hz, 1H), 8.65 (dd, J = 4.8, 1.8Hz, 1H), 8.20 (dt, J = 7.8, 1.9 Hz, 1H), 7.43 (ddd , J = 7.8, 4.8, 0.8Hz, 1H), 7.04 (d, J = 8.5Hz, 2H), 6.68 (d, J = 8.5Hz, 2H), 3.31 (dd, J 2H), 2.37 (s, 6H), 1.59-1.41 (m, 4H), 1.34-1.31 (m, 3H), 1.13-1.03 ), 0.95-0.86 (m, 1 H).

Test Example  1. Stability test (acceleration)

The drug stability test was conducted to determine the storage method and the period of use of the O-desmethyl-venlafaxin nicotinate crystalline substance prepared by the method of Example 1.

The stability of O-desmethyl-venlafaxin nicotinate crystalline and O-desmethyl-venlacomine succinate monohydrate (ChengDu Climb Pharmaceutical Technology Co. Ltd.) prepared by the method of Example 1 were compared. The sample was sealed in a PE bag and then packed in an aluminum bag. The stability test (temperature 40 ° C ± 2 ° C, relative humidity 75% ± 5%, sealing) under accelerated conditions was carried out according to ICH guidelines and purity was analyzed using liquid chromatography (HPLC) analysis. The results are shown in Table 1 below.

ODV-nicotinate ODV-succinate monohydrate Early 99.934% 99.871% 3 days 99.927% 99.824% 13th 99.927% 99.840% 20 days 99.929% 99.825% 34 days 99.927% 99.818%

As shown in Table 1, the O-desmethyl-venlafaxine nicotinate crystalline prepared by the method of Example 1 exhibited a purity change of 0.01% or less under accelerated conditions for 34 days, and O-desmethyl-venlafaxine succinate monohydrate Which is equivalent or more stable.

Thus, it can be seen that the crystalline O-desmethyl-venlafaxin nicotinate prepared by the method of Example 1 is very stable, and thus can be less restricted by storage conditions due to the increase in the amount of the flexible substance, and can be stored for a long period of time.

Test Example  2. Hygroscopicity test

Hygroscopicity is one of the important factors in the stability and processability of the compound. It is known that a compound having a low hygroscopicity tends to be excellent in stability and advantageous in processing.

The hygroscopicity test was performed on the O-desmethyl-venlafaxine nicotinate crystalline material prepared by the method of Example 1 as follows.

Specifically, the hygroscopicity test was conducted under the conditions of a temperature of 25 ° C ± 2 ° C, a relative humidity of 80% ± 2% for 24 hours, and moisture was measured using a Karl-Fischer moisture meter. The results are shown in Table 2 below.

ODV-nicotinate ODV-succinate monohydrate Early 0.09% 4.74% 24 hours 0.07% 4.74%

As shown in Table 2, moisture was measured after 24 hours under the above conditions. As a result, it was confirmed that neither O-desmethyl-venlafaxine nicotinate nor succinate monohydrate absorbed moisture.

Thus, it was found that the O-desmethyl-venlafaxine nicotinate crystalline material prepared by the method of Example 1 did not decrease in stability with respect to moisture and was easy to process.

Test Example  3: Solubility evaluation

One of the important physical properties of pharmaceutical compositions is the solubility of the drug in aqueous solution. When the solubility is low, the dissolution rate acts as a rate limiting factor in the absorption process in vivo administration, so that it can exhibit low bioavailability.

A comparative solubility test of the O-desmethyl-venlafaxin nicotinate crystalline, O-desmethyl-venlafaxine free base and O-desmethyl-venlafaxine succinate monohydrate prepared by the method of Example 1 was performed. The results are shown in Table 3 below.

pH Solubility (mg / ml) ODV-nicotinate ODV-succinate
Monohydrate 1.2 628.53 85.48 4.0 635.32 60.29 5.2 652.62 56.77 6.8 643.35 56.45 Purified water 647.88 50.90

As shown in Table 3, the solubility of O-desmethyl-venlafaxin nicotinate crystalline prepared by the method of Example 1 was about 7 to 11 times higher than that of the control group O-desmethyl-venlafaxine succinate monohydrate .

The excellent solubility of the crystalline O-desmethyl-venlafaxin nicotinate crystals prepared by the method of Example 1 can be seen as a significant improvement in the physicochemical properties of the drug. In particular, it exhibits good solubility at the full range of pH, so that it is expected that bioavailability will be improved by absorption of fast dissolution in the gastrointestinal tract. It is also anticipated that by providing drugs with high solubility, pharmaceutical researchers can help expand the list of available materials to design pharmaceutical formulations of drugs with different characteristics.

Claims (18)

O-desmethyl-venlafaxin nicotinate represented by the following formula 3:
(3)

. The o-desmethyl-venlafaxin nicotinate as claimed in claim 1, wherein the O-desmethyl-venlafaxin nicotinate forms crystals. The o-desmethyl-venlafaxin nicotinate according to claim 1, wherein the O-desmethyl-venlafaxin nicotinate is O-desmethyl-venlafaxin nicotinate, wherein the ratio of O-desmethyl-venlafaxine to nicotinic acid is 1: 1. 3. The method of claim 2, wherein the O-desmethyl-venlafaxin nicotinate exhibits an X-ray powder diffraction pattern having characteristic peaks at angles 2 &thetas; at 11.2, 12.5, 18.4, 19.0, 19.7, 20.5 and 22.9 +/- 0.2 DEG. O-desmethyl-venlafaxine nicotinate. 6. The composition of claim 2, wherein the O-desmethyl-venlafaxin nicotinate has characteristic peaks represented by angles 2? Of 7.9, Lt; / RTI > exhibits an X-ray powder diffraction pattern having an intensity of at least < RTI ID = 0.0 > 3. The O-desmethyl-venlafaxin nicotinate as claimed in claim 2, wherein the O-desmethyl-venlafaxin nicotinate has an endothermic peak at 150.26 DEG C +/- 1.5 DEG C in differential scanning calorimetry (DSC) analysis. (a) providing a mixture of O-desmethyl-venlafaxine, nicotinic acid, and a reaction solvent;
(b) heating the mixture to obtain a solution;
(c) cooling the solution to a temperature of from 40 캜 to 50 캜 to obtain an O-desmethyl-venlafaxine nicotinate suspension; And
(d) cooling the suspension to obtain crystalline O-desmethyl-venlafaxine nicotinate crystals. A method for preparing O-desmethyl-venlafaxin nicotinate crystal form according to claim 3,
(3)

. 8. The method according to claim 7, wherein the O-desmethyl-venlafaxin nicotinate crystal form has an X-ray powder diffraction pattern having characteristic peaks at angles 2 &thetas; at 11.2, 12.5, 18.4, 19.0, 19.7, 20.5 and 22.9 +/- 0.2 DEG ≪ / RTI > desmethyl-venlafaxine nicotinate crystal form. 8. The method according to claim 7, wherein the crystalline form of O-desmethyl-venlafaxin nicotinate has characteristic peaks represented by angles 2? Desmethyl-venlafaxine nicotinate crystal form exhibiting an X-ray powder diffraction pattern having an X-ray powder diffraction pattern at < RTI ID = 0.0 > 0.2. ≪ / RTI > 8. The method of claim 7, wherein the amount of nicotinic acid in (a) is from 0.8 to 2.0 equivalents per equivalent of O-desmethyl-venlafaxine. The method for producing O-desmethyl-venlafaxine nicotinate crystal form according to claim 7, wherein the reaction solvent (a) is at least one selected from the group consisting of C1-C4 alcohols and organic solvents. 12. The process according to claim 11, wherein the C1-C4 alcohol is ethanol, methanol, isopropanol, propanol or butanol. 12. The process according to claim 11, wherein the organic solvent is at least one selected from the group consisting of ethyl acetate, acetone, tetrahydrofuran, methyl tertiary butyl ether, and diethyl ether, to prepare an O-desmethyl-venlafaxine nicotinate crystal form Way. 8. The process for producing O-desmethyl-venlafaxine nicotinate crystal form according to claim 7, wherein the heating temperature of (b) is 30 to 75 占 폚. 8. The process according to claim 7, wherein in step (c), a suspension comprising O-desmethyl-venlafaxin nicotinate is prepared by lowering the temperature of the solution to 40 to 50 占 폚. O-desmethyl-venlafaxine nicotinate crystal form ≪ / RTI > 8. The method according to claim 7, wherein (d) the temperature of cooling the suspension is 0 to 30 占 폚. 8. The process according to claim 7, wherein the starting material O-desmethyl-venlafaxine of (a) is in its free base form. A pharmaceutical composition for preventing or treating depression, comprising O-desmethyl-venlafaxine nicotinate according to any one of claims 1 to 6.

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