CN107056691B

CN107056691B - Method for preparing etoricoxib crystal form V

Info

Publication number: CN107056691B
Application number: CN201710474511.0A
Authority: CN
Inventors: 刘超; 常繁; 彭显峰; 戴萍
Original assignee: SICHUAN SUNRISE BIOPHARM Ltd
Current assignee: SICHUAN SUNRISE BIOPHARM Ltd
Priority date: 2017-06-21
Filing date: 2017-06-21
Publication date: 2020-03-10
Anticipated expiration: 2037-06-21
Also published as: CN107056691A

Abstract

The invention discloses a method for preparing etoricoxib crystal form V, which comprises the steps of dissolving etoricoxib in a proper solvent, adding a little acid to induce crystallization, filtering and drying to obtain the etoricoxib crystal form V.

Description

Method for preparing etoricoxib crystal form V

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a method for preparing etoricoxib crystal form V, a pharmaceutical composition and medical application.

Background

Etoricoxib is a selective inhibitor of cyclooxygenase-2, has the functions of resisting inflammation, reducing fever and easing pain, and has the following chemical structure.

Currently, film-coated tablets of etoricoxib are marketed in various countries of the united kingdom, spain, australia, china, etc., primarily for clinical use as non-steroidal anti-inflammatory drugs.

The crystal form of etoricoxib has great influence on the properties of the medicine, and the patent WO2001092230A1 discloses the properties and preparation methods of eight crystal forms of etoricoxib, including crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, hemihydrate, sesquihydrate and amorphous state, and the properties and preparation methods are confirmed by Differential Scanning Calorimetry (DSC) spectrum and X-diffraction powder spectrum (XRPD). However, the preparation of the crystal form v in this patent is described briefly, and the inventors repeatedly repeated the preparation method of the crystal form v and found that it is difficult to reproduce.

Patent WO2001037833 discloses methods for the preparation of etoricoxib form i, form ii, form iii and form iv and related XRPD patterns, but does not mention the preparation of form v.

In addition, patent WO2005085199a1 discloses a preparation method of etoricoxib crystal form ix, crystal form x, crystal form xi, crystal form xii, crystal form XIII, crystal form XIV, crystal form XV and crystal form XVI, and the XRD property thereof is confirmed. However, no mention is made of the process for the preparation of form v.

The prior documents mentioned above have conducted much research on the crystal form of etoricoxib, but mention is less made of the preparation of the crystal form V which can be used in pharmaceutical preparations, only WO2001092230a1 discloses a very simplified method, and it is difficult to obtain the crystal form V reproducibly through several trial and error experiments by the present inventors. Therefore, through a large amount of researches, the inventor surprisingly discovers that the etoricoxib crystal form V can be simply and rapidly prepared by adding a small amount of acid in the etoricoxib crystallization process, the preparation method is simple to operate, good in repeatability and high in yield, and is suitable for industrial production, and the prepared crystal form also meets the pharmaceutical requirements.

Disclosure of Invention

The invention aims to provide a method for preparing etoricoxib crystal form V, which can be used for very easily preparing the etoricoxib crystal form V by adding a small amount of acid into an etoricoxib dissolving solution. The method has the advantages of simple process operation, good reproducibility, high yield, suitability for industrial production, high purity of the crystal form V and suitability for medicinal requirements.

The crystal form V of etoricoxib has characteristic absorption peaks at 2 theta values of 6.40, 12.86, 13.28, 17.79, 19.65, 20.93, 21.35, 22.00, 22.93, 23.45, 24.05, 26.26, 26.84, 29.05 and 31.24 +/-0.2 degrees in an X-diffraction powder pattern.

The method for preparing the etoricoxib crystal form V comprises the steps of adding etoricoxib into 5-10 times of organic solvent by volume, heating to 55-70 ℃ for dissolution, keeping the temperature between 50-70 ℃, adding a little acid, stirring for 0.4-0.6h, slowly cooling for crystallization, filtering, and drying to obtain the etoricoxib crystal form V, wherein the molar mass of the acid is less than 1% of that of the etoricoxib, and preferably not more than 0.5%.

In the above-mentioned method of the present invention, the acid is selected from the group consisting of a lower fatty acid, an inorganic acid and a sulfonic acid, wherein the lower fatty acid is formic acid, acetic acid, propionic acid, butyric acid or isobutyric acid. The inorganic acid is hydrochloric acid, sulfuric acid or phosphoric acid. The sulfonic acid is methanesulfonic acid or p-toluenesulfonic acid, and the dosage of the acid is not more than 0.5% of the molar mass of etoricoxib.

In the above process of the present invention, the solvent is selected from one or more of benzene, toluene, xylene, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, sec-butyl acetate, tert-butyl acetate, amyl acetate, acetone, methyl isobutyl ketone and butanone, and preferably, the solvent is toluene, ethyl acetate, isopropyl acetate or acetone.

In a preferred embodiment, the method for preparing etoricoxib crystal form V comprises the steps of adding etoricoxib into 5-10 times of volume of organic solvent, heating to 55-70 ℃ for dissolution, keeping the temperature between 50-70 ℃, adding a little acid, stirring for about 0.4-0.6h, preferably about 0.5h, slowly cooling for crystallization, filtering and drying, wherein the organic solvent is toluene, ethyl acetate, isopropyl acetate or acetone, the acid is selected from acetic acid, propionic acid, hydrochloric acid and p-toluenesulfonic acid, and the amount of the added acid is less than 1% of the molar mass of the etoricoxib, and more preferably less than or equal to 0.5%.

The term "volume-by-volume amount" refers to the amount of solvent by volume that is a multiple of the mass of solute, e.g., 5 to 20 volume-by-volume amounts refers to the amount of solvent by volume (L or ml) that is 5 to 20 times the mass (kg or g) of solute etoricoxib (L/kg or ml/g).

In the above embodiment, the amount of the solvent is preferably 5 times the volume amount.

The invention also aims to provide a pharmaceutical composition containing the etoricoxib crystal form V obtained by the method of the invention and a pharmaceutically acceptable carrier.

The etoricoxib crystal form obtained by the method is used for preparing medicines for treating inflammation and pain.

After the polymorphic form V of the etoricoxib prepared by the method is prepared into a tablet (the pharmaceutical excipients which are the same as those of the marketed products are adopted), XRD of the tablet and XRD of the marketed products (ARCOXIA tablets) are measured, and XRD patterns of the tablet and the marketed products are compared, so that the XRD patterns of the tablet and the marketed products are basically consistent, and the polymorphic form V of the etoricoxib prepared by the preparation method is basically the same as the crystal forms of the raw materials of the marketed products. Accordingly, the polymorphic form of etoricoxib prepared by the present invention can be used for the manufacture and use of formulations, suitable pharmaceutical formulations include tablets, capsules, orally disintegrating tablets, dispersible tablets and the like.

Drawings

Figure 1 XRPD pattern of etoricoxib polymorph form V obtained in example 1.

Figure 2 DSC and TGA profiles of etoricoxib polymorph form V obtained in example 1.

Detailed Description

The following examples are intended to further illustrate the nature of the invention, but not to limit the scope thereof.

Example 1

Adding 50g of etoricoxib crude product into 250mL of toluene with 5 times volume of the etoricoxib crude product, heating to 70 ℃ for dissolving, keeping the temperature at 60 ℃, adding a little acetic acid (the amount is about 0.1% of the molar mass of the etoricoxib), stirring for about 0.5h, slowly cooling for crystallization, filtering and drying to obtain 45.3g of etoricoxib crystal form V. The melting point is measured: 134.5 to 138.3 ℃.

The X-ray powder diffractogram (XRD pattern) of the obtained crystal form was measured by a Cu target X-ray powder diffractometer, as shown in FIG. 1, and the 2. theta. values and relative intensity I% of characteristic absorption peaks thereof are shown in Table 1.

Table 1 XRPD determination of etoricoxib polymorphic absorption peaks 2 theta values and relative intensity I%

Differential Scanning Calorimetry (DSC) and thermogravimetric analysis (TGA) of the obtained crystal form were carried out by using TGA and DSC 2 LF1100/155 test instruments (TGA DSC 40-350 ℃ C. 10 ℃/min), and the results are shown in FIG. 2.

Example 2

Adding 500g of etoricoxib crude product into 2500mL of isopropyl acetate with 5 times volume amount, heating to 70 ℃ for dissolution, keeping the temperature between 68 and 70 ℃, adding a little acetic acid (the amount is about 0.5 percent of the molar mass of etoricoxib), stirring for about 0.4 to 0.5h, slowly cooling for crystallization, filtering, and drying to obtain 467.6g of etoricoxib crystal form V. The melting point is measured: 135.5 to 137.4 ℃.

Example 3

Adding 45g of the crude etoricoxib product into 420mL of ethyl acetate with volume of 7 times, heating to 65 ℃ for dissolution, keeping the temperature at about 65 ℃, adding a little propionic acid (the amount is about 0.01 percent of the molar mass of the etoricoxib), stirring for about 0.4-0.6h, slowly cooling for crystallization, filtering, and drying to obtain the etoricoxib crystal form V43.5 g. The melting point is measured: 134.8 to 138.0 ℃.

Example 4

Adding 40g of etoricoxib crude product into 400mL of acetone with the volume of 10 times, heating to 55 ℃ for dissolving, keeping the temperature at 50 ℃, adding a little hydrochloric acid (the amount is about 0.9% of the molar mass of etoricoxib), stirring for about 0.5h, slowly cooling for crystallization, filtering and drying to obtain 35.2g of etoricoxib crystal form V. The melting point is measured: 135.7 to 137.8 ℃.

Example 5

480g of etoricoxib crude product is added into toluene with 10 times volume of the etoricoxib crude product, the mixture is heated to 70 ℃ for dissolution, a little propionic acid (the amount is about 0.1 percent of the molar mass of the etoricoxib) is added at the temperature of about 55-60 ℃, the mixture is stirred for about 0.4-0.6h, the mixture is slowly cooled and crystallized, filtered and dried, and the polymorphic etoricoxib crystal form V432.2 g is obtained. The melting point is measured: 134.8-136.6 ℃.

Example 6

Adding 500g of etoricoxib crude product into 5 times volume of isopropyl acetate, heating to 70 ℃ for dissolution, keeping the temperature between 65 and 70 ℃, adding a little of p-toluenesulfonic acid (the amount is about 0.05 percent of the molar mass of etoricoxib), stirring for about 0.5h, slowly cooling for crystallization, filtering, and drying to obtain the polymorphic etoricoxib crystal form V467.2 g. The melting point is measured: 135.4 to 137.2 ℃.

The XRPD of the crystalline forms obtained by the methods of examples 2-5 was determined as in example 1 and the XRPD characteristics were substantially the same as in figure 1 with error.

Claims

1. A method for preparing etoricoxib crystal form V comprises the steps of adding etoricoxib into 5-10 times of the volume of an organic solvent, heating to 55-70 ℃ for dissolution, keeping the temperature between 50-70 ℃, adding a little acid, stirring for 0.4-0.6h, slowly cooling for crystallization, filtering and drying to obtain the specific etoricoxib crystal form V, wherein the use amount of the acid is less than 1% of the use amount of the etoricoxib, and the XRPD of the crystal form V has a characteristic peak shown in figure 1 in terms of mole.

2. The method of claim 1, wherein the acid is selected from the group consisting of lower fatty acids, mineral acids, and sulfonic acids.

3. The method of claim 2, wherein the inorganic acid is hydrochloric acid, sulfuric acid, or phosphoric acid.

4. The method of claim 2, wherein the lower fatty acid is formic acid, acetic acid, propionic acid, butyric acid, or isobutyric acid.

5. The process of claim 2, wherein the sulfonic acid is methanesulfonic acid or p-toluenesulfonic acid.

6. The process of claim 1, wherein the solvent is selected from one or more of benzene, toluene, xylene, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, sec-butyl acetate, tert-butyl acetate, amyl acetate, acetone, methyl isobutyl ketone, and methyl ethyl ketone.

7. The process of claim 6, wherein the solvent is toluene, ethyl acetate, isopropyl acetate or acetone.

8. The method of claim 1 wherein the amount of acid is less than or equal to 0.5% by moles of the amount of etoricoxib.