WO2010088865A2

WO2010088865A2 - New salts of desvenlafaxine and a method of their preparation

Info

Publication number: WO2010088865A2
Application number: PCT/CZ2010/000010
Authority: WO
Inventors: Ludek Ridvan; Petr Hruby; Stanislav Radl; Hana Brusova; Lukas Krejcik; Tomas Pekarek; Natalia Csokova; Anna Zerzanova
Original assignee: Zentiva KS
Current assignee: Zentiva KS
Priority date: 2009-02-06
Filing date: 2010-02-03
Publication date: 2010-08-12
Anticipated expiration: 2011-08-06
Also published as: EA019449B1; CZ200969A3; US8779005B2; UA103368C2; EP2393770A2; EA201190137A1; CZ301820B6; US20120041227A1; WO2010088865A3

Abstract

The invention deals with new salts of the desvenlafaxine base of formula (I) with oxalic acid, the new salts being the hydrogen oxalate of formula (II) in the proportion of desvenlafaxine : oxalic acid of 1 : 1 and hemioxalate of formula (III) in the proportion of desvenlafaxine : oxalic acid of 2 : 1.

Description

NEW SALTS OF DESVENLAFAXINE AND A METHOD OF THEIR PREPARATION

Technical Field

The invention deals with new salts of the desvenlafaxine base of formula (I) with oxalic acid, to a method of their preparation and use.

These new salts are first the hydrogen oxalate of formula (II), i.e. a salt in the desvenlafaxine oxalic acid proportion of 1 : 1 ,

and also the hemioxalate of formula (III), i.e. a salt in the desvenlafaxine : oxalic acid proportion of 2:1.

Background Art

Desvenlafaxine in the form of hydrogen succinate of formula (JV), i.e. a salt with the molar proportion of desvenlafaxine base : succinic acid of 1:1, was approved for treatment of depression and vasomotoric symptoms related to the menopause (Drugs of the Future 2006, 31(4), 304-309).

Patent no. US 4,535,186 in Example 19 describes preparation of desvenlafaxine by debenzylation of the starting "O-benzyldesvenlafaxine", Scheme L

Desvenlafaxine base

O-B enzyldes venlafaxine

Scheme 1

Desvenlafaxine prepared in this manner in the free base form is transformed by the effect of fumaric acid in an acetone - ethanol mixture to a salt characterized by the melting point of 140- 142 ⁰C.

Other patented procedures (e.g. US 7,026,508, US 6,673,838, WO 03/048104, WO 2007/071404, WO 2007/120923) describe preparation of the desvenlafaxine base by demethylation of venlafaxine; Scheme 2. Thiolates or trialkylborohydrides, for example, are used as demethylation agents.

Desvenlafaxine

Venlafaxine base

Scheme 2

Patent no. WO 00/76955 in Example 1 describes transformation of the crude base of Desvenlafaxine to the hydrogen fumarate hydrate of formula (V), i.e. a salt with the molar proportion of desvenlafaxine base : fumaric acid of 1:1 : from a methanol/acetone mixture with a small addition of water. The salt is characterized by the melting point of 145-150 °C.

Patents nos. US 7,026,508 and US 6,673,838 mention that the hydrogen fumarate has unsuitable physical and chemical properties, e.g. solubility. For this reason this patent claims the hydrogen succinate, including its several polymorphous forms and hemisuccinate. Patent no. US 7,001,920 describes preparation of desvenlafaxine formate, which also has more suitable physical and chemical properties than the hydrogen fumarate according to the authors.

Disclosure of Invention

The present invention deals with new salts of desvenlafaxine, which exhibit physical and chemical properties suitable for use as an active pharmaceutical substance. These new salts are the hydrogen oxalate of formula (II), i.e. a salt with the. proportion of desvenlafaxine : oxalic acid of 1 :1,

as well as the hemioxalate of formula (III), i.e. a salt with the proportion of desvenlafaxine oxalic acid of 2:1.

The invention includes :

(a) Preparation of desvenlafaxine hydrogen oxalate;

(b) Preparation of desvenlafaxine demioxalate;

(c) Re-crystallization of desvenlafaxine hydrogen oxalate;

(d) Re-crystallization of desvenlafaxine hemioxalate; (e) Use of desvenlafaxine hydrogen oxalate as an active pharmaceutical substance; (f) Use of desvenlafaxine hemioxalate as an active pharmaceutical substance;

Preparation of a salt of a biologically active substance represents the possibility of influencing its physical and chemical properties without intervening in the chemical structure. In selection of the crystalline salt the ease and yield of its preparation must be taken into account. It is also necessary to evaluate the properties such as solubility, stability, hygroscopicity, etc. Literature mentions (see e.g. US 6,673,838) that if the solubility of a salt in water is lower than 10 mg/ml, dissolving may represent a speed limiting step during in vivo absorption, which may result in a reduction of biological availability of the active substance. The comparison of biological availabilities of desvenlafaxine hydrogen fumarate and hydrogen succinate mentioned in US _.

6,673,838, Example 13, may serve as an example. Biological availability demonstrated by absorption of desvenlafaxine in the intestine of a test rat is roughly three times higher in the case of the hydrogen succinate than in the case of hydrogen fumarate.

This result corresponds to our results of measurement of equilibrium solubility as well as dissolution speed of desvenlafaxine hydrogen succinate and hydrogen fumarate. Desvenlafaxine hydrogen succinate dissolves in water approximately twice as fast as the hydrogen fumarate; the equilibrium concentration in water is about 6 times higher in the case of hydrogen succinate than in the case of hydrogen fumarate.

We have surprisingly found out that desvenlafaxine forms stable crystalline salts with oxalic acid both in the proportion of 1 :1 (hydrogen oxalate) and in the proportion of 2:1 (hemioxalate), whose physical and chemical properties are considerably different from desvenlafaxine hydrogen fumarate and hydrogen succinate. The salt desvenlafaxine hydrogen oxalate can be generally prepared by mixing of one equivalent of desvenlafaxine base and one equivalent of oxalic acid and subsequent crystallization of the salt. The salt desvenlafaxine hemioxalate can be generally prepared by mixing of two equivalents of desvenlafaxine base and one equivalent of oxalic acid and subsequent crystallization of the salt. Another possibility consists in dissolving of one equivalent of desvenlafaxine hydrogen oxalate and one equivalent of desvenlafaxine base and subsequent crystallization of the salt.

Known salts of desvenlafaxine usually crystallize in the form of hydrates, e.g. the hydrogen fumarate or hydrogen succinate are described as monohydrates. Similarly, the newly prepared desvenlafaxine hydrogen oxalate crystallizes in the form of a hydrate, or rather monohydrate. Desvenlafaxine hemioxalate surprisingly crystallizes not only as a hydrate or dehydrate, but also as an anhydrous salt.

Suitable solvents for the preparation of a salt of desvenlafaxine with oxalic acid and subsequent crystallization include organic solvents with a content of water of 0 % to 50 % by weight, preferably 0.1 to 25% by weight. Organic solvents suitable for crystallization include the group or Cl to C4 alcohols, C3 to C6 ketones, C4 to C6 ethers or cyclic ethers, or other water- miscible solvents, such as dimethyl sulfoxide or dimethyl formamide. Out of less lipophilic solvents (e.g. methanol or ethanol) these salts can be crystallized without addition of water. In the case of other solvents (e.g. 2-propanol or tetrahydrofuran, dioxan) it is advisable to use an adequate addition of water to achieve an acceptable volume of the solvent and crystallization yield.

The results of measurement of the dehydration temperature by the TGA method and of the melting temperature by the DSC method (Table 1) of desvenlafaxine salts show that the dehydration and meting temperatures are different in the case of oxalates from the other known salts of desvenlafaxine.

Table 1. Temperatures of dehydration (TGA) and melting (DSC) of desvenlafaxine salts

Solubility of the particular form in water is a very important parameter for biological availability of the active substance. It is characterized by equilibrium solubility on one hand, which is defined as the quantity of the substance dissolved in a certain volume in the equilibrium state (the commonly used unit is mg/ml) and the dissolution rate on the other hand, which is defined as the quantity of the substance dissolved from a certain area per certain time unit (i.e. true dissolution, the commonly used unit is mg/cm²/min). In all the new salts of desvenlafaxine with oxalic acid both these characteristics achieve relatively high values, higher than with the previously described salts (Tables 2 and 3). This means that very good solubility in water characterized by high values of the dissolution rate constants and of equilibrium solubilities is a convenient property of these new salts of desvenlafaxine.

Table 2. Rate constants of dissolution of desvenlafaxine salts

Table 3. Equilibrium solubilities of desvenlafaxine salts

So it is obvious that the new salts of desvenlafaxine with oxalic acid exhibit such physical and chemical properties that make them suitable for use as active pharmaceutical substances. Convenient properties of the salts of desvenlafaxine with oxalic acid mainly include high solubility in water, which is necessary for the preparation of a dosage form with good biological availability. Other convenient properties include chemical and physical stabilities of these salts.

Brief Description of Drawings:

Figure 1 : X-ray diffraction pattern of desvenlafaxine base (characteristic peaks: 12.11; 13.19; 15.86; 20.38 and 22.40° 2Θ)

Figure 2: X-ray diffraction pattern of desvenlafaxine hydrogen oxalate hydrate 1:1, form A (characteristic peaks: 5.24; 9.54; 10.05; 10.50; 11.69; 15.14; 18.96; 26.48° 2Θ)

Figure 3: X-ray diffraction pattern of anhydrous desvenlafaxine hemioxalate 2:1, form B (characteristic peaks: 7.34; 8.49; 9.19; 11.22; 12.94; 14.70; 17.06; 19.12; 22.48 °2Θ)

Figure 4: X-ray diffraction pattern of desvenlafaxine hemioxalate trihydrate 2:1, form C (characteristic peaks: 7.09; 8.43; 9.10; 11.02; 12.61; 14.19; 16.95; 22.10° 20)

Figure 5: X-ray diffraction pattern of desvenlafaxine hydrogen succinate (characteristic peaks: 5.16; 10.34; 15.0; 16.61; 20.73 and 25.98° 2Θ) Figure 6: DSC record of desvenlafaxine base

(characteristic temperatures: Tonset = 225 ⁰C and Tpeak = 227 ⁰C)

Figure 7: DSC record of desvenlafaxine hydrogen oxalate hydrate 1:1, form A (characteristic temperatures: Tonset = 77 ⁰C and Tpeak = 86 ⁰C)

Figure 8: DSC record of anhydrous desvenlafaxine hemioxalate 2:1, form B (characteristic temperatures: Tonsetl = 174 ⁰C and Tpeakl = 181 ⁰C; Tonset2 = 215 ⁰C and Tpeak2 = 217 ⁰C)

Figure 9: DSC record of desvenlafaxine hemioxalate trihydrate 2:1, form C

(characteristic temperatures: Tonsetl = 154 ⁰C and Tpeakl = 163 ⁰C; Tonset2 = 215 ⁰C and Tpeak2 ^:

217 ⁰C)

Figure 10: DSC record of desvenlafaxine hydrogen succinate (characteristic temperatures: Tonset = 120 ⁰C and Tpeak = 125 ⁰C)

Figure 11 : TG record of desvenlafaxine base

Figure 12: TG record of desvenlafaxine hydrogen oxalate hydrate 1:1, form A

Figure 13: TG record of anhydrous desvenlafaxine hemioxalate 2:1, form B

Figure 14: TG record of desvenlafaxine hemioxalate trihydrate 2:1, form C

Figure 15: TG record of desvenlafaxine hydrogen succinate

Figure 16: IR record of desvenlafaxine base

(characteristic bands: v(CH) + v(OH) 2936, v(C=C) 1618, 1594, 1515 cm^"1)

Figure 17: IR record of desvenlafaxine hydrogen oxalate hydrate 1:1, form A (characteristic bands: v(CH) + v(OH) 2935, v(C=O) 1709, 1615, v(C=C) 1516, v(CO) 1217 cm^"1) Figure 18: IR record of anhydrous desvenlafaxine hemioxalate 2:1, form B (characteristic bands: v(CH) + v(OH) 2936, v(O0) 1608, v(OC) 1515, v(CO) 1278 cm^'1)

Figure 19: IR record of desvenlafaxine hemioxalate trihydrate 2:1, form C (characteristic bands: v(CH) + v(OH) 2935, v(C=O) 1620, v(C=C) 1515, v(CO) 1275 cm^"1)

Figure 20: IR record of desvenlafaxine hydrogen succinate

(characteristic bands: v(CH) + v(OH) 2931, v(C=O) 1651, v(C=C) 1603, 1516, v(CO) 1269 cm^"1)

The invention is explained in a more detailed way in the examples below. These examples exclusively have an illustrative character and do not limit the scope of the invention in any aspect.

Examples of Carrying out the Invention Desvenlafaxine base was prepared either by demethylation of venlafaxine in accordance with US 6,673,838, Example 5, or using the procedure described in Examples 1 and 2. Desvenlafaxine hydrogen fumarate was prepared in accordance with WO 00/76955, Example 1. Desvenlafaxine hydrogen succinate was prepared in accordance with US 6,673,83.8, Example 7.

Example 1 : Preparation of desvenlafaxine base

0-Benzyldes venlafaxine base (35 g) is stirred up in MeOH (300 ml). Ammonium formate (25 g) and 3% Pd/C (3.5 g) are added to the solution. The mixture is stirred at 60 °C for 2 hours. The pH of the reaction mixture is adjusted to 5 by addition of formic acid. The mixture is filtered through kieselguhr. The pH value of the filtrate is adjusted to 9.5 by dropwise addition of a 25% aqueous solution of ammonia. The suspension is then stirred at the laboratory temperature for 1 hour and then filtered. The filter cake is washed with water and dried. Yield 25 g (95 %); HPLC purity 99.4 %.

Example 2: Preparation of desvenlafaxine base G-B enzyldes venlafaxine base (70 g) is stirred up in MeOH (400 ml) and formic acid (12 ml) is added dropwise. Ammonium formate (25 g) and 10% Pd/C (2 g) are added to the solution. The mixture is stirred at 50 ⁰C for 4 hours. The pH of the .solution is adjusted to 5 by addition of formic acid. The mixture is filtered through kieselguhr. The pH value of the filtrate is adjusted to 9.5 by dropwise addition of a 25% aqueous solution of ammonia. The suspension is then stirred at the laboratory temperature for 1 hour and then filtered. The filter cake is washed with water and dried. Yield 49 g (93 %); HPLC purity 99.5 %.

Example 3 : Re-purification of desvenlafaxine base

Desvenlafaxine base (52 g, HPLC purity 99.2 %) is stirred up in MeOH (200 ml) and 2M hydrochloric acid is added dropwise up to the pH value of the solution of 4. The solution is stirred up with activated charcoal and filtered through kieselguhr. The pH value of the filtrate is adjusted to 9.6 by dropwise addition of a 2M solution of sodium hydroxide. The suspension is then stirred at 0 ⁰C for 1 hour and then filtered. The filter cake is washed with water and with cooled 2-ρropanol. Yield 49 g (94 %); HPLC purity 99.9 %.

Example 4: Preparation of desvenlafaxine hydrogen oxalate hydrate

Desvenlafaxine base (11.0 g; 42 mmol) and oxalic acid dihydrate (5.7 g; 45 mmol) are dissolved in a mixture of acetone (100 ml) and water (1 ml) at 50 °C and the almost clear solution is filtered through kieselguhr. Then, another part of acetone (100 ml) is added dropwise and the mixture is slowly cooled down to 0 °C. The crystals are aspirated and washed with acetone. Yield 12.9 g (83 %). ¹H NMR (250 MHz. OMSO-d₆): 0.96-1.58 (m, 1OH, CH₂), 2.61 (s, 6H, CH₃), 2.93 (dd, IH, CH), 3.42 (dd, IH, CH), 3.61 (dd, IH, CH), 6.73 (d, 2H, Ar), 7.04 (d, 2H, Ar).

Example 5: Preparation of desvenlafaxine hemioxalate trihydrate

Desvenlafaxine base (11.0 g; 42 mmol) and oxalic acid dihydrate (2.52 g; 20 mmol) are dissolved in a mixture of 2-propanol (60 ml) and water (10 ml) at 60 °C and the almost clear solution is filtered through kieselguhr. The mixture is slowly cooled down to 0 °C and stirred for 1 hour. The crystals are extracted and washed with 2-propanol. Yield 7.4 g (56 %). ¹H NMR (250 MHz, DMSO-^₅): 0.95-1.53 (m, 1OH, CH₂), 2.39 (s, 6H, CH₃), 2.80-2.96 (m, 2H, CH₂), 3.31 (dd, IH, CH), 6.69 (d, 2H, Ar), 7.11 (d, 2H, Ar).

Example 6: Preparation of anhydrous desvenlafaxine hemioxalate

Desvenlafaxine base (11.0 g; 42 mmol) and oxalic acid dihydrate (2.52 g; 20 mmol) are dissolved in methanol (60 ml) at 50 ⁰C. The mixture is slowly cooled down to 0 °C and stirred for 1 hour. The crystals are aspirated and washed with methanol. Yield 10.1 g (78 %). ¹H NMR (250 MHz, DMSO-d*): 0.95-1.53 (m, 1OH, CH₂), 2.39 (s, 6H, CH₃), 2.80-2.96 (m, 2H, CH₂), 3.31 (dd, IH, CH), 6.69 (d, 2H, Ar), 7.11 (d, 2H, Ar).

Example 7: Preparation of desvenlafaxine hemioxalate trihydrate by re-crystallization of anhydrous desvenlafaxine hemioxalate

Anhydrous desvenlafaxine hemioxalate (6.2 g; 10 mmol) is dissolved in a mixture of 2- propanol (30 ml) and water (3 ml) at 60 ⁰C. The mixture is slowly cooled down to 0 °C and stirred for 1 hour. The crystals are aspirated and washed with 2-propanol. Yield 5.8 g (86 %).

Example 8: Preparation of anhydrous desvenlafaxine hemioxalate by re-crystallization of desvenlafaxine hemioxalate trihydrate

Desvenlafaxine hemioxalate trihydrate (6.7 g; 10 mmol) is dissolved in methanol (50 ml) at 50

°C. The mixture is slowly cooled down to 0 °C and stirred for 1 hour. The crystals are aspirated and washed with methanol. Yield 5.6 g (90 %).

Measurement of the dissolution rate

The dissolution rate of desvenlafaxine salts (Table 2) in water at various pH values was measured in a Varian-Vankel System, USP Wood Apparatus (rotary disk method). A disk with the diameter of 5 mm was prepared by compression from about 0.2 g of the substance. Phosphate buffer of pH 6.8 or 0.01 M HCl at 37 °C was used as the aqueous medium. The concentration of the substance in the aqueous solution was measured by the spectrophotometric method using a Varian - Cary 50 apparatus at 217 run.

Measurement of equilibrium solubility Equilibrium solubility of desvenlafaxine salts (Table 3) was measured after 24-hour stirring of an excess of the salt (about 1 g) in water (10 ml) with various pH at 25 °C and subsequent filtration. Phosphate buffer of pH 6.8 or 0.01 M HCl was used as the aqueous medium. The concentration of the substance in the aqueous solution was measured by the spectrophotometric method using a Varian - Cary 50 apparatus at 227 nm.

X-ray Powder Diffraction

The presented patterns (Figs. 1, 2, 3, 4 and 5) were measured with an X'PERT PRO MPD

PANalytical diffractometer with a graphite monochromator, radiation used CuKα (λ=1.542 A), excitation voltage: 45 kV, anodic current: 40 mA, measurement range: 4 - 40° 2Θ, increment: 0,008° 2Θ, irradiated part of the sample 10 mm.

DSC (Differential Scanning Calorimetry) The presented records (Figs. 6, 7, 8, 9 and 10) were measured with a Perkin Elmer Pyris 1 apparatus with the sample load of 3 to 5 mm and with heating under nitrogen at the rate of 10 °C/min up to the final temperature of 250 °C.

TGA (Thermogravimetric Analysis) The presented records (Figs. 11, 12, 13, 14 and 15) were measured with a Perkin Elmer TGA6 apparatus with the sample load of 10 to 15 mg and with heating under nitrogen at the rate of 10°C/min up to the final temperature of 350 °C.

IR (Infrared Spectroscopy) The presented records (Figs. 16, 17, 18, 19 and 20) were obtained by accumulation of 64 scans with the resolution of 2 cm^"1 with an FT-IR Spectrometer Nicolet Nexus apparatus (Thermo, USA).

Claims

1. Salts of desvenlafaxine of formula (I)

with oxalic acid.

2. Desvenlafaxine hydrogen oxalate of formula (II).

3. Desvenlafaxine hemioxalate of formula (III) .

4. The salts of desvenlafaxine with oxalic acid according to claims 1-3, wherein the salt is in the hydrate form.

5. Desvenlafaxine hydrogen oxalate according to claim 2, wherein the salt is in the monohydrate form.

6. Desvenlafaxine hemioxalate according to claim 3, wherein the salt is in the trihydrate form.

7. Desvenlafaxine hemioxalate according to claim 3, wherein the salt is anhydrous.

8. Desvenlafaxine hydrogen oxalate according to claim 2, wherein the X-ray Powder Diffraction has the following characteristic peaks: 5.24; 10.50; 15.14; 26.48° 2Θ ± 0.2° 2Θ.

9. Desvenlafaxine hemioxalate according to claim 3, wherein the X-ray Powder Diffraction has the following characteristic peaks: 9.19; 14.70; 19.12; 22.48° 2Θ ± 0.2° 20.

10. Desvenlafaxine hemioxalate according to claim 3, wherein the X-ray Powder Diffraction has the following characteristic peaks: 9.10; 14.19; 16.95; 22.10° 2Θ ± 0.2° 20.

11. A method of preparation of the salts of desvenlafaxine with oxalic acid according to claims 1-7, characterized in that 0.9 to 2.1 equivalents of desvenlafaxine and 1 equivalent of oxalic acid are dissolved in an organic solvent or in a mixture of solvents and, after cooling or concentration, the solid substance is isolated.

12. The method according to claim 11, characterized in that the solvent is selected from the group consisting of an organic solvent and a mixture of organic solvents with a content of water of 0-50% by weight.

13. The method according to claim 11, characterized in that the solvent is selected from the group consisting of C1-C4 alcohols and ethers with a content of water of 0-

50% by weight.

14. The method according to claim 11, characterized in that the solvent is selected from the group consisting of tetrahydrofuran, dioxan, methanol, ethanol and 2-propanol with a content of water of 0-25% by weight.