CN107417599B - Preparation method of etoricoxib crystal form - Google Patents
Preparation method of etoricoxib crystal form Download PDFInfo
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- CN107417599B CN107417599B CN201710474500.2A CN201710474500A CN107417599B CN 107417599 B CN107417599 B CN 107417599B CN 201710474500 A CN201710474500 A CN 201710474500A CN 107417599 B CN107417599 B CN 107417599B
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses a preparation method of an etoricoxib crystal form, which comprises the steps of adding specific crystal seeds into etoricoxib in a proper solvent to induce crystallization, filtering and drying to obtain an etoricoxib polycrystalline refined product.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method, a pharmaceutical composition and medical application of an etoricoxib polymorph.
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.
Etoricoxib is currently marketed in various countries in the uk, spain, australia, china and the like in the form of film-coated tablets, mainly for clinical use as a non-steroidal anti-inflammatory drug.
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, 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 XRD properties of the etoricoxib crystal form IX, crystal form X, crystal form XI, crystal form XIII, crystal form XIIV, crystal form XV and crystal form XVI are confirmed. However, no mention is made of the process for the preparation of form v.
The existing literature has carried out more researches on the crystal form of etoricoxib, but the preparation of the crystal form V which can be used for pharmaceutical preparations is less, only WO2001092230A1 discloses a simple preparation method, and the crystal form V is difficult to reproduce and obtain through multiple trial and error experiments of the inventor. Therefore, through a great deal of research, the inventor finds that the etoricoxib specific crystal seed is prepared by adding acid into an etoricoxib dissolving solution, and the etoricoxib crystal form V is prepared simply and rapidly by adding the specific crystal seed in the preparation process of the etoricoxib crystal form V. The preparation method is simple to operate, good in repeatability and high in yield, is suitable for industrial production, and the prepared crystal form also meets the requirement of medicine.
Disclosure of Invention
The invention provides a method for preparing etoricoxib crystal form V, which has the advantages of simple preparation process operation, good reproducibility and high yield by adding specific crystal seeds and is suitable for industrial production. Particularly, the inventor finds a specific crystal seed through a great deal of research and exploration, and the crystal seed is utilized to ensure that the etoricoxib crystal form V is very easy to prepare, has high purity and is very suitable for the requirement of medicinal use.
The preparation method of etoricoxib crystal form V comprises the steps of adding etoricoxib into an organic solvent, heating until etoricoxib is dissolved, keeping the temperature at 55-70 ℃, adding etoricoxib specific crystal seeds, stirring, slowly cooling for crystallization, filtering, and drying to obtain the etoricoxib crystal form, wherein the X-diffraction powder pattern of the obtained crystal form has 2 theta values of 6.49, 12.37, 12.98, 17.85, 19.74, 19.98, 21.00, 21.86, 22.96, 23.54, 24.11, 26.39, 27.10, 28.95, 31.34+0.2oHas characteristic absorption peaks.
The method comprises the steps of adding etoricoxib into 5-10 times of organic solvent by volume, heating to dissolve, keeping the temperature at 50-70 ℃, adding acid, stirring for 0.4-0.6h, preferably about 0.5h, then slowly cooling to crystallize, filtering, and drying to obtain the etoricoxib specific seed crystal, wherein the acid is selected from lower fatty acid, inorganic acid and sulfonic acid.
In the above method of the present invention, the inorganic acid is hydrochloric acid, sulfuric acid or phosphoric acid, the lower fatty acid is formic acid, acetic acid, propionic acid, butyric acid or isobutyric acid, and the sulfonic acid is methanesulfonic acid or p-toluenesulfonic acid. Preferably, the acid is selected from the group consisting of hydrochloric acid, acetic acid, propionic acid and p-toluenesulfonic acid.
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 the method of the invention, the molar mass ratio of the acid to the etoricoxib is (0.01-0.9): 1, preferably (0.01 to 0.5): 1, more preferably (0.01 to 0.1): 1.
according to the method, the heating and dissolving temperature is 55-70 ℃, the temperature for adding the seed crystal is kept at 60-70 ℃, and the lower fatty acid is acetic acid or propionic acid.
In a specific embodiment, the specific etoricoxib seed crystal is prepared by the following method, wherein the method comprises the steps of adding etoricoxib into 5-10 times of organic solvent by volume, heating to 55-70 ℃ for dissolution, adding a little acid at 50-70 ℃, stirring for about 0.4-0.6h, preferably about 0.5h, slowly cooling for crystallization, filtering, and drying, so as to obtain the specific etoricoxib seed crystal, wherein the organic solvent is toluene, ethyl acetate, isopropyl acetate or acetone, the acid is selected from hydrochloric acid, acetic acid, propionic acid and p-toluenesulfonic acid, the molar mass ratio of the acid to the etoricoxib is (0.01-0.5): 1, preferably (0.01 to 0.1): 1.
the invention also provides a pharmaceutical composition containing the etoricoxib crystal form V obtained by the method and a pharmaceutically acceptable carrier.
The etoricoxib crystal form obtained by the method is used for preparing medicines for treating inflammation and pain.
A process of the present invention for preparing an etoricoxib polymorph comprising: adding the etoricoxib crude product into 5-10 times of the volume of the organic solvent, heating until the etoricoxib is dissolved, keeping the temperature at 55-70 ℃, adding the specific etoricoxib seed crystal, stirring for about 0.4-0.6h, then slowly cooling for crystallization, filtering, and drying to obtain the etoricoxib crystal form V.
The term "volume amount" refers to the volume amount of a solvent which is a multiple of the mass of a solute, such as 5 to 20 volume amounts, and refers to the volume amount (L or ml) of a solvent which is 5 to 20 times the mass (KG or g) of the solute etoricoxib, such as 5 to 20L/KG.
In the above embodiment, the amount of the solvent is preferably 5 times the volume amount.
In the above embodiments, 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, methyl ethyl ketone. Preferably the solvent is toluene, ethyl acetate, isopropyl acetate or acetone.
In the above embodiment, the heating temperature is preferably 50 to 75 ℃.
In the above embodiment, the temperature for adding the seed crystal is 50 to 70 ℃, preferably 60 to 70 ℃.
In the above embodiment, the added acid is selected from inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid or the like, sulfonic acids such as methanesulfonic acid or p-toluenesulfonic acid, and organic acids such as formic acid, acetic acid, propionic acid, butyric acid, or isobutyric acid, preferably hydrochloric acid and acetic acid, more preferably acetic acid.
In the above embodiment, the acid is added at a temperature of 50 to 70 ℃ for dissolution, preferably 50 to 65 ℃.
The invention also provides a pharmaceutical composition, which comprises the etoricoxib polymorph prepared by the method and pharmaceutic adjuvants.
After the polymorphic form 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 XRCOXIA tablet are measured, and XRD of the tablet and the marketed products (ARCOXIA tablet) are compared, and the XRD pattern data of the tablet and the ARCOXIA tablet are basically consistent, which shows that the polymorphic form etoricoxib prepared by the preparation method of the invention is basically the same as the crystal form of the raw material medicine of the marketed products. Accordingly, the polymorphic form of etoricoxib prepared by the present invention can be used for the manufacture of formulations, suitable pharmaceutical formulations include tablets, capsules, orally disintegrating tablets, dispersible tablets and the like.
Drawings
Figure 1 XRD pattern of the polymorphic form of etoricoxib obtained in example 1.
Figure 2 DSC and TGA profiles of the etoricoxib polymorph obtained in example 1.
Detailed Description
The following examples are intended to further illustrate the spirit of the invention, but not to limit the scope of the invention.
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 68 ℃, adding a little acetic acid (the molar mass ratio of the acetic acid to the etoricoxib is 0.01: 1), stirring for about 0.5h, slowly cooling for crystallization, filtering and drying to obtain 46.4g of etoricoxib specific crystal seed.
Adding 500g of etoricoxib crude product into 2500mL of isopropyl acetate with 5 times volume of the crude product, heating to 70 ℃ for dissolving, keeping the temperature between 65 and 70 ℃, adding 0.5g of etoricoxib specific crystal seed, stirring for about 0.5h, slowly cooling for crystallization, filtering, and drying to obtain 44.8g of polymorphic etoricoxib. The melting point is measured: 134.8-138.4 ℃.
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 XRD determination of 2 theta values and relative intensities I% of etoricoxib polymorphic absorption peaks
Differential Scanning Calorimetry (DSC) and thermogravimetric analysis (TGASDSC 40-350 deg.C. 10 deg.C/min) of the obtained crystalline forms were performed using TGA and DSC 2LF1100/155 test instruments, and the results are shown in FIG. 2.
Example 2
Adding 45g of the etoricoxib crude product into 420mL of ethyl acetate with volume of 7 times, heating to 65 ℃ for dissolving, keeping the temperature at 60 ℃, adding a little propionic acid (the molar mass ratio of the propionic acid to the etoricoxib is 0.1: 1), stirring for about 0.4-0.6h, slowly cooling for crystallization, filtering, and drying to obtain 41.3g of the etoricoxib specific crystal seed.
530g of etoricoxib crude product is added into 3180mL of ethyl acetate with 6 times volume, the mixture is heated to 70 ℃ for dissolution, 0.5g of etoricoxib specific crystal seed is added at the temperature of 67-69 ℃, the mixture is stirred for about 0.5h, the temperature is slowly reduced, the crystal is crystallized, filtered and dried, and 468.0g of polymorphic etoricoxib is obtained. The melting point is measured: 135.3 to 137.2 ℃.
Example 3
Adding 40g of the etoricoxib crude product into 400mL of acetone with the volume of 10 times, heating to 55 ℃ for dissolving, keeping the temperature at 50 ℃, adding hydrochloric acid (the molar mass ratio of the hydrochloric acid to the etoricoxib is 0.03: 1), stirring for about 0.5h, slowly cooling for crystallization, filtering and drying to obtain 33.2g of etoricoxib specific crystal seed.
550g of etoricoxib crude product is added into 8 times volume of isopropyl acetate 4400mL, the mixture is heated to 70 ℃ for dissolution, 0.5g of etoricoxib specific crystal seed is added at the temperature of 65-70 ℃, the mixture is stirred for 0.4-0.6h, the mixture is slowly cooled for crystallization, filtered and dried, and 44.8g of polymorphic etoricoxib is obtained. The melting point is measured: 134.9-136.8 ℃.
Example 4
Adding 45g of the etoricoxib crude product into 360mL of isopropyl acetate with volume of 8 times, heating to 70 ℃ for dissolving, keeping the temperature between 65 and 70 ℃, adding propionic acid (the molar mass ratio of the propionic acid to the etoricoxib is 0.5: 1), stirring for about 0.5h, slowly cooling for crystallization, filtering, and drying to obtain 40.7g of the specific etoricoxib seed crystal.
480g of etoricoxib crude product is added into toluene with 10 times volume of the etoricoxib crude product, the mixture is heated to 70 ℃ to be dissolved, 0.1g of etoricoxib specific crystal seed is added at the temperature of about 68 ℃, the mixture is stirred for about 0.5h, the mixture is slowly cooled and crystallized, filtered and dried, and 425.8g of polymorphic etoricoxib is obtained. The melting point is measured: 135.2 to 137.7 ℃.
Example 5
Adding 50g of etoricoxib crude product into 100mL of isopropyl acetate with volume of 8 times, heating to 70 ℃ for dissolving, keeping the temperature at 68 ℃, adding p-toluenesulfonic acid (the molar mass ratio of the p-toluenesulfonic acid to the etoricoxib is 0.05: 1), stirring for about 0.5h, slowly cooling for crystallization, filtering, and drying to obtain 46.4g of etoricoxib specific seed crystal.
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 0.5g of etoricoxib specific crystal seed, stirring for about 0.5h, slowly cooling for crystallization, filtering, and drying to obtain 44.8g of polymorphic etoricoxib. The melting point is measured: 134.8-138.2 ℃.
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 (8)
1. A method for preparing etoricoxib polymorph comprises the steps of adding etoricoxib into a toluene or ethyl acetate solvent, heating until etoricoxib is dissolved, keeping the temperature at 55-70 ℃, adding specific etoricoxib seed crystals, stirring, slowly cooling for crystallization, filtering and drying to obtain etoricoxib crystal form, wherein the X-diffraction powder pattern of the obtained crystal form has characteristic absorption peaks at 2 theta values of 6.49, 12.37, 12.98, 17.85, 19.74, 19.98, 21.00, 21.86, 22.96, 23.54, 24.11, 26.39, 27.10, 28.95 and 31.34 +/-0.2 degrees, wherein the specific seed crystals are prepared by the following method comprising the steps of adding etoricoxib into an organic solvent, heating until the mixture is dissolved, keeping the temperature at 50-70 ℃, adding acid, stirring for 0.4-0.6h, slowly cooling for crystallization, filtering and drying to obtain the specific etoricoxib seed crystals, wherein the etoricoxib acid is selected from low-grade fatty acid, Inorganic acid and sulfonic acid, wherein the molar ratio of the acid to the etoricoxib is (0.01-0.5): 1, the organic 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.
2. The method of claim 1: the dosage of the organic solvent is 5-10 times of the volume of etoricoxib.
3. The method of claim 1, wherein: in the seed crystal preparation method, the organic solvent is toluene, ethyl acetate, isopropyl acetate or acetone.
4. The method according to claim 1, wherein in the specific seed crystal production method, the heating is carried out until dissolution is carried out, and the heating dissolution temperature is 55-70 ℃.
5. The method according to claim 1, wherein the temperature of the seed crystal is 60 to 70 ℃.
6. The process of claim 1, the mineral acid is hydrochloric acid, sulfuric acid, or phosphoric acid, and the sulfonic acid is methanesulfonic acid or p-toluenesulfonic acid.
7. The method of claim 1, wherein the lower fatty acid is formic acid, acetic acid, propionic acid, butyric acid, or isobutyric acid.
8. A process according to claim 1, wherein the specific seed crystals are prepared by a process wherein the molar ratio of acid to etoricoxib is (0.01-0.1): 1.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002096877A1 (en) * | 2001-05-25 | 2002-12-05 | Merck & Co., Inc. | 5-chloro-3-(4-methanesulfonylphenyl)-6'-methyl-[2,3']bipyridinyl in pure crystalline form and process for synthesis |
| CN1443168A (en) * | 2000-05-26 | 2003-09-17 | 麦克公司 | 5-chloro-3-(4-methane sulfonylphenyl)-6-methyl-[2,3'] bipyridine and process for synthesis |
| CN108069896A (en) * | 2016-11-11 | 2018-05-25 | 昆明积大制药股份有限公司 | A kind of preparation method of Etoricoxib crystal form |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1443168A (en) * | 2000-05-26 | 2003-09-17 | 麦克公司 | 5-chloro-3-(4-methane sulfonylphenyl)-6-methyl-[2,3'] bipyridine and process for synthesis |
| WO2002096877A1 (en) * | 2001-05-25 | 2002-12-05 | Merck & Co., Inc. | 5-chloro-3-(4-methanesulfonylphenyl)-6'-methyl-[2,3']bipyridinyl in pure crystalline form and process for synthesis |
| CN108069896A (en) * | 2016-11-11 | 2018-05-25 | 昆明积大制药股份有限公司 | A kind of preparation method of Etoricoxib crystal form |
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