METHOD FOR PREPARING ESCITALOPRAM BIS-HYDROXYNAPHTOATE CRYSTAL FORM A

Abstract

Provided herein is a method for preparing an Escitalopram bis-hydroxynaphthoate ((S)-(+)-1-(3+(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydro-5-cyanisobenzofuranone) crystal form A. Said method is ecofriendly and non pollutive, and the obtained Escitalopram bis-hydroxynaphthoate crystal form A is highly pure and easy to reproduce.

Claims

1. A method for preparing a crystal form A of a compound of formula I, comprising: dissolving escitalopram oxalate in a reaction solvent to obtain an escitalopram oxalate solution; and adding a solution of a pamoate salt dropwise to precipitate the crystal form A of the compound of formula I ##STR00002##

2. The method according to claim 1, wherein the reaction solvent is water.

3. The method according to claim 1, wherein dissolving is carried out at a temperature of 0-70° C.

4. The method according to claim 3, wherein dissolving is carried out at a temperature of 25-35° C.

5. The method according to claims 1-4, wherein the pamoate salt is disodium pamoate.

6. The method according to claims 1-5, wherein a solvent of the solution of the pamoate salt is a mixed solvent of water and ethanol.

7. The method according to claim 6, wherein a volume ratio of water and ethanol in the mixed solvent is 7:3-3:7.

8. The method according to claim 1, wherein during adding the solution of the pamoate salt dropwise, a temperature of the escitalopram oxalate solution is 25-35° C.

9. The method according to claim 8, wherein during adding the solution of the pamoate salt dropwise, the temperature of the escitalopram oxalate solution is 30° C.

10. The method according to claim 1, wherein a mass ratio of escitalopram oxalate and the pamoate salt is 1:0.9-1:1.2.

11. The method according to claim 1, wherein the crystal form A of the compound of formula I has a X-ray powder diffraction spectrum, showing characteristic peaks at 8.9±0.2°, 11.3±0.2°, 13.2±0.2°, 18.4±0.2°, 20.6±0.2° and 21.9±0.2°.

12. The method according to claim 6, wherein a volume ratio of water and ethanol in the mixed solvent is 1.2:1-1:1.2.

13. The method according to claim 6, wherein a volume ratio of water and ethanol in the mixed solvent is 1:1.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to illustrate the examples of the present application and the technical solution of the prior art more clearly, the following is a brief description of the drawings that need to be used in the examples and the prior art. It is obvious that the drawings in the following description are only some of the examples of the present invention and according to these drawings, other drawings can be obtained by those skilled in the art without any inventive efforts.

[0020] FIG. 1 is an XRPD spectrum of escitalopram pamoate crystal form A prepared according to Example 1.

[0021] FIG. 2 is a HPLC spectrum of escitalopram pamoate crystal form A prepared according to Example 1.

[0022] FIG. 3 is the relevant datas of the HPLC spectrum of escitalopram pamoate crystal form A prepared according to Example 1.

DETAILED DESCRIPTION OF THE INVENTION

[0023] In order to make the technical problems, technical solutions and beneficial effects of the present application more clear, the application is further explained below in combination with specific examples. In the following examples, unless otherwise indicated, specific conditions of all of the test methods are generally carried out according to the conventional conditions or conditions recommended by manufacturers; raw materials and reagents are commercially available or prepared by using published information.

[0024] The data of X-ray powder diffraction used in the present application is determined by BRUKER D8 Advance from BRUKER Corp., Germany using Cu-Kα radiation; voltage and current: 40 kV, 40 mA; goniometer: Vertical goniometer, radius: 280 mm; slit: DS=2°, SS=½°, mask=15 mm, RS=5.0 mm; detector: LYNXEYE detector; scan patterns: continuous scan; scan range: 3-40°; count time per step: 0.2 s; total scan time: 390 s.

[0025] The HPLC detection conditions used in the present application are as follows: [0026] Instrument: High performance liquid chromatograph equipped with an UV detector [0027] Chromatographic Waters Symmetry C18 100×4.6 mm, 3.5 μm [0028] column: [0029] Mobile phase A 3.54 g/L sodium hydrogen phosphate solution, pH is adjusted to 7.0 with phosphoric acid [0030] Mobile phase B Methanol:Acetonitrile=1:1 (V/V) [0031] Mobile phase Mobile phase A:Mobile phase B=55:45 (% V/V) [0032] Detection 230 nm [0033] wavelength: [0034] Flow rate: 1.2 mL/min [0035] Sample size: 10 μL [0036] Column 40° C. [0037] temperature: [0038] Run time: 25 min

Example 1: Preparation of Escitalopram Pamoate Crystal Form A

[0039] 900 ml of water was added to 35 g of escitalopram oxalate sample, and was heated to 60° C. to completely dissolve it; 500 ml of water was added to 36.6 g of disodium pamoate to completely dissolve it at room temperature, then 500 ml of anhydrous ethanol was added and was mixed well. A water/ethanol mixed solution of disodium pamoate was added dropwise to escitalopram oxalate solution at 30° C. A solid was obtained immediately with good dispersion. After the addition was complete, the mixture was continuously stirred for 2 h and then filtered. The filter cake was washed with 500 ml of water, filtered with suction for 10 min and dried under vacuum. 59.5 g of escitalopram pamoate crystal form A sample was obtained. XRPD spectrum thereof was shown in FIG. 1; HPLC spectrum was shown in FIGS. 2 and 3; the purity was 99.87% by HPLC.

Example 2: Preparation of Escitalopram Pamoate Crystal Form A

[0040] 25 ml of water was added to 500 mg of escitalopram oxalate sample, and was heated to 30° C. to completely dissolve it; 12.5 ml of water was added to 520 g of disodium pamoate to completely dissolve it at room temperature, then 12.5 ml of anhydrous ethanol was added and was mixed well. A water/ethanol mixed solution of disodium pamoate was added dropwise to escitalopram oxalate solution at 30° C. A solid was obtained immediately with good dispersion. After the addition was complete, the mixture was continuously stirred for 2 h and then filtered. The filter cake was washed with 50 ml of water, filtered with suction for 10 min and dried under vacuum. 850 mg of escitalopram pamoate crystal form A was obtained. The purity was 99.86% by HPLC.

Example 3: Preparation of Escitalopram Pamoate Crystal Form A

[0041] 140 ml of water was added to 5 g of escitalopram oxalate sample, and was heated to 60° C. to completely dissolve it; 25 ml of water was added to 5.2 g of disodium pamoate to completely dissolve it at room temperature, then 25 ml of anhydrous ethanol was added and was mixed well. A water/ethanol mixed solution of disodium pamoate was added dropwise to escitalopram oxalate solution at 30° C. A solid was obtained immediately with good dispersion. After the addition was complete, the mixture was continuously stirred for 2 h and then filtered. The filter cake was washed with 50 ml of water, filtered with suction for 10 min and dried under vacuum. 8.5 g of escitalopram pamoate crystal form A sample was obtained. The purity was 99.81% by HPLC.

Example 4

[0042] 400 ml of water was added to 15 g of escitalopram oxalate sample, and was heated to 60° C. to completely dissolve it; 200 ml of water was added to 14.9 g of disodium pamoate, and then 100 ml of anhydrous ethanol was added and was mixed well. The solid was completely dissolved at room temperature. A water/ethanol mixed solution of disodium pamoate was added dropwise to escitalopram oxalate solution at 30° C. A solid was obtained immediately with a small amount of agglomeration. After the addition was complete, the agglomeration was obvious. The mixture was continuously stirred for 2 h and then filtered. The filter cake was washed with 50 ml of water, filtered with suction for 10 min and dried under vacuum. 25.5 g of escitalopram pamoate crystal form A sample was obtained. The purity was 99.74% by HPLC.

Example 5

[0043] 400 ml of water was added to 15 g of escitalopram oxalate sample, and was heated to 60° C. to completely dissolve it; 200 ml of water was added to 14.9 g of disodium pamoate, and then 100 ml of anhydrous ethanol was added and was mixed well. The solid was completely dissolved at room temperature. A water/ethanol mixed solution of disodium pamoate was added dropwise to escitalopram oxalate solution at 30° C. A solid was obtained immediately with a small amount of agglomeration. After the addition was complete, the agglomeration was obvious. The mixture was continuously stirred for 2 h and then filtered. The filter cake was washed with 50 ml of water, filtered with suction for 10 min and dried under vacuum. 25.5 g of escitalopram pamoate crystal form A sample was obtained. The purity was 99.71% by HPLC.

Example 6

[0044] 140 ml of water was added to 5 g of escitalopram oxalate sample, and was heated to 60° C. to completely dissolve it; 50 ml of water was added to 5.2 g of disodium pamoate to completely dissolve it at room temperature. Disodium pamoate solution was added dropwise to escitalopram oxalate solution at 30° C. A solid was obtained immediately with a small amount of agglomeration. After the addition was complete, the agglomeration was obvious. The mixture was continuously stirred for 2 h and then filtered. The filter cake was washed with 50 ml of water, filtered with suction for 10 min and dried under vacuum. 8.5 g of escitalopram pamoate crystal form A sample was obtained. The purity was 99.71% by HPLC.

[0045] The function of the above-mentioned examples is to explain the substantive content of the present application, it is not intended to limit the protection scope of the present application. Those skilled in the art should understand that the technical solutions of the present application can be modified or equivalently replaced without departing from the substance and protection scope of the technical solutions of the present application.