A process for the preparation of escitalopram diphosphate form A

Abstract

The application relates to a novel preparation method of eslicarbazepine acetate crystal form A ((S)-(+)-1-〔3-(dimethylamino)propyl〕-1-(4-fluorophenyl)-1,3-dihydro-5-cyanoisobenzofuran acetate), which is environment-friendly and pollution-free, and eslicarbazepine acetate crystal form A prepared by the method has high purity and good repeatability.

Description

[0001] This application claims priority to Chinese patent application No. 201811212608.5, filed with the Patent Office of China on October 18, 2018, entitled “A New Process for the Preparation of High-Purity Escitalopram Pamoate”, the entire contents of which are incorporated herein by reference. Technical Field

[0002] The present application belongs to the field of medical technology, and in particular relates to a method for preparing escitalopram pamoate ((S)-(+)-1-〔3-(dimethylamino)propyl〕-1-(4-fluorophenyl)-1,3-dihydro-5-cyanoisobenzofuran pamoate) crystal form A. Background Art

[0003] Escitalopram, chemical name: (S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-cyanoisobenzofuran. Escitalopram oxalate was jointly developed by Forest Laboratories (USA) and Lundbeck (Denmark). It was first marketed in Switzerland and other European and American countries in March 2002 and received FDA approval in August. Escitalopram is a serotonin reuptake inhibitor (SSRI) with a unique serotonin isosite binding mechanism and high selectivity for serotonin receptors. It is used for the treatment of major depression and maintenance depression.

[0004] Patients with major depression are often non-compliant, making it difficult to assess whether they have received the correct dose of medication. Therefore, it is essential to formulate escitalopram oxalate into a low-solubility, sustained-release salt form by replacing the acid group.

[0005] Patent document EP0347066 discloses escitalopram pamoate crystalline form A and a preparation method thereof, wherein the solvent used is methanol and the starting materials are escitalopram free base and pamoic acid.

[0006] The above-mentioned method for preparing escitalopram pamoate uses a solvent, methanol, which is somewhat toxic. Therefore, using a less toxic or even non-toxic solvent to prepare escitalopram pamoate has become a technical problem that needs to be solved urgently by technicians. Summary of the Invention

[0007] Through continuous research, the inventors of this application have discovered a novel method for preparing escitalopram pamoate Form A. This method utilizes water and ethanol as solvents, resulting in an environmentally friendly and pollution-free preparation method that overcomes the solvent toxicity issues present in prior art. Furthermore, the escitalopram pamoate Form A prepared by this method has a purity exceeding 99.5%.

[0008] The specific plan is as follows:

[0009] The present application provides a method for preparing escitalopram pamoate (compound of Formula I) crystal form A, comprising dissolving escitalopram oxalate in a reaction solvent to obtain an escitalopram oxalate solution; and dropwise adding the pamoate solution thereto to precipitate escitalopram pamoate crystal form A.

[0010]

[0011] In some embodiments of the present application, the X-ray powder diffraction pattern of Form A of the compound of Formula I has 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°.

[0012] In some embodiments of the present application, the reaction solvent is water.

[0013] In some embodiments of the present application, the dissolution temperature is 0-70°C.

[0014] In some embodiments of the present application, the dissolution temperature is 25-35°C.

[0015] In some embodiments of the present application, the pamoate salt is disodium pamoate.

[0016] In some embodiments of the present application, the solvent of the pamoate solution is a mixed solvent of water and ethanol; preferably, in the mixed solvent, the mixing ratio of water and ethanol is: 7:3-3:7, preferably 1.2:1-1:1.2, and more preferably 1:1.

[0017] In some embodiments of the present application, during the process of adding the pamoate solution dropwise, the temperature of the escitalopram oxalate solution is 25-35°C.

[0018] In some embodiments of the present application, during the process of dropwise adding the pamoate solution, the temperature of the escitalopram oxalate solution is 30°C.

[0019] In some embodiments of the present application, the mass ratio of escitalopram oxalate to pamoate is 1:0.9-1:1.2. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In order to more clearly illustrate the embodiments of the present application and the technical solutions of the prior art, the following briefly introduces the drawings required for use in the embodiments and the prior art. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without any creative work.

[0021] Figure 1 This is the XRPD spectrum of escitalopram pamoate Form A prepared in Example 1.

[0022] Figure 2 This is the HPLC spectrum of escitalopram pamoate Form A prepared in Example 1.

[0023] Figure 3 The data are related to the HPLC spectrum of escitalopram pamoate Form A prepared in Example 1. DETAILED DESCRIPTION

[0024] In order to make the technical problems, technical solutions and beneficial effects solved by this application more clearly understood, the present application is further described below in conjunction with specific examples. In the following examples, unless otherwise stated, the specific conditions of the test methods described are generally implemented according to conventional conditions or conditions recommended by the manufacturer; raw materials and reagents are obtained commercially or prepared using public information.

[0025] The X-ray powder diffraction data used in this application were measured using a BRUKER D8 Advance from Bruker, Germany, using Cu-Kα radiation; voltage and current: 40 kV, 40 mA; goniometer: vertical goniometer, radius 280 mm; slit: DS = 2°, SS = 1 / 2°, mask = 15 mm, RS = 5.0 mm; detector: LYNXEYE detector; scanning mode: continuous scanning; scanning range: 3-40°; counting time per step: 0.2 s; total scanning time: 390 s.

[0026] The HPLC detection conditions used in this application are as follows:

[0027]

[0028]

[0029] Example 1: Preparation of Escitalopram Pamoate Form A

[0030] Weigh 35g of escitalopram oxalate sample, add 900ml of water, and heat to 60°C to completely dissolve it; weigh 36.6g of disodium pamoate, add 500ml of water, and completely dissolve it at room temperature, then add 500ml of anhydrous ethanol and mix evenly. Add the water / ethanol mixed solution of disodium pamoate dropwise to the escitalopram oxalate aqueous solution at 30°C, and solids will appear immediately and disperse well. After the addition is complete, continue stirring for 2h and then filter. Wash the filter cake with 500ml of water, filter for 10min, and vacuum dry. Obtain 59.5g of escitalopram pamoate crystal form A sample. Its XRPD spectrum is as follows Figure 1 As shown; HPLC spectrum as Figure 2 and Figure 3 As shown; the purity was 99.87% as determined by HPLC.

[0031] Example 2: Preparation of Escitalopram Pamoate Form A

[0032] Weigh 500 mg of escitalopram oxalate sample, add 25 ml of water, and heat to 30°C to completely dissolve. Weigh 520 mg of disodium pamoate, add 12.5 ml of water, and completely dissolve at room temperature. Then, add 12.5 ml of anhydrous ethanol and mix thoroughly. Add the water / ethanol mixture of disodium pamoate dropwise to the escitalopram oxalate aqueous solution at 30°C. Solids will immediately appear and disperse well. Continue stirring for 2 hours after the addition is complete, then filter. Wash the filter cake with 50 ml of water, filter with suction for 10 minutes, and dry under vacuum. This yields 850 mg of escitalopram pamoate Form A sample. HPLC analysis indicates a purity of 99.86%.

[0033] Example 3: Preparation of Escitalopram Pamoate Form A

[0034] Weigh 5g of escitalopram oxalate sample, add 140ml of water, and heat to 60°C to completely dissolve. Weigh 5.2g of disodium pamoate, add 25ml of water, and completely dissolve at room temperature. Then, add 25ml of anhydrous ethanol and mix thoroughly. Add the water / ethanol mixture of disodium pamoate dropwise to the escitalopram oxalate aqueous solution at 30°C. Solids will immediately appear and disperse well. Continue stirring for 2 hours after the addition is complete, then filter. Wash the filter cake with 50ml of water, filter with suction for 10 minutes, and dry under vacuum. This yields 8.5g of escitalopram pamoate Form A sample. HPLC analysis indicates a purity of 99.81%.

[0035] Example 4

[0036] Weigh 15g of escitalopram oxalate sample, add 400ml of water, and heat to 60°C to completely dissolve. Weigh 14.9g of disodium pamoate, add 200ml of water, and then add 120ml of anhydrous ethanol, and mix thoroughly. Dissolve completely at room temperature. Add the water / ethanol mixture of disodium pamoate dropwise to the escitalopram oxalate aqueous solution at 30°C. Solids will immediately form, with a small amount of agglomeration. After the addition is complete, significant agglomeration is observed. Stirring is continued for 2 hours, then filtered. The filter cake is washed with 50ml of water, filtered with suction for 10 minutes, and vacuum dried. This yields 25.5.5g of escitalopram pamoate Form A sample. HPLC analysis indicates a purity of 99.74%.

[0037] Example 5

[0038] Weigh 15g of escitalopram oxalate sample, add 400ml of water, and heat to 60°C to completely dissolve. Weigh 14.9g of disodium pamoate, add 200ml of water, and then add 100ml of anhydrous ethanol, and mix thoroughly. Dissolve completely at room temperature. Add the water / ethanol mixture of disodium pamoate dropwise to the escitalopram oxalate aqueous solution at 30°C. Solids will immediately form, with noticeable agglomeration. After the addition is complete, significant agglomeration is observed. Stirring is continued for 2 hours, followed by filtration. The filter cake is washed with 50ml of water, filtered with suction for 10 minutes, and vacuum dried. This yields 25.5g of escitalopram pamoate Form A. HPLC analysis indicates a purity of 99.71%.

[0039] Example 6

[0040] Weigh 5g of escitalopram oxalate sample, add 140ml of water, and heat to 60°C to completely dissolve. Weigh 5.2g of disodium pamoate, add 50ml of water, and completely dissolve at room temperature. Add the aqueous solution of disodium pamoate dropwise to the aqueous solution of escitalopram oxalate at 30°C. Solids will immediately form, with noticeable agglomeration. After the addition is complete, significant agglomeration is observed. Stirring is continued for 2 hours, followed by filtration. The filter cake is washed with 50ml of water, filtered with suction for 10 minutes, and dried under vacuum. This yields 8.5g of escitalopram pamoate Form A sample. HPLC analysis indicates a purity of 99.71%.

[0041] The above embodiments are intended to illustrate the substantive content of the present application, but are not intended to limit the scope of protection of the present application. Those skilled in the art should understand that the technical solutions of the present application can be modified or replaced by equivalents without departing from the essence and scope of protection of the technical solutions of the present application.

Claims

1. A method for preparing the crystalline form A of the compound of formula I, characterized in that: Escitalopram oxalate is dissolved in water to obtain an escitalopram oxalate solution; a pamoate solution is added dropwise thereto to precipitate a crystalline form A of the compound of formula I; wherein, during the addition of the pamoate solution, the temperature of the escitalopram oxalate solution is 25-35° C., and the solvent of the pamoate solution is a mixed solvent of water and ethanol in a volume ratio of 1:

1.

2. The preparation method according to claim 1, wherein The dissolving temperature is 0-70°C.

3. The preparation method according to claim 2, wherein The dissolution temperature is 25-35°C.

4. The preparation method according to claim 1, wherein The pamoate is disodium pamoate.

5. The preparation method according to claim 1, wherein During the dropwise addition of the pamoate solution, the temperature of the escitalopram oxalate solution was 30°C.

6. The preparation method according to any one of claims 1 to 4, characterized in that The mass ratio of escitalopram oxalate to pamoate is 1:0.9-1:1.

2.

7. The preparation method according to any one of claims 1 to 4, characterized in that In the X-ray powder diffraction pattern of Form A of the compound of Formula I, there are 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°.

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