CN108069896B

CN108069896B - Preparation method of etoricoxib crystal form

Info

Publication number: CN108069896B
Application number: CN201610992825.5A
Authority: CN
Inventors: 王亮; 张朴永; 郭雷雷; 王立江; 张云
Original assignee: Kunming Jida Pharmaceutical Co ltd
Current assignee: Kunming Jida Pharmaceutical Co ltd
Priority date: 2016-11-11
Filing date: 2016-11-11
Publication date: 2022-08-12
Anticipated expiration: 2036-11-11
Also published as: CN108069896A

Abstract

The invention relates to a preparation method of etoricoxib form V crystal form, which comprises the following steps: adding etoricoxib into an organic solvent, heating to completely dissolve solids, adding V-crystal-form crystal seeds with the weight percentage of the etoricoxib being not higher than 10% into the solution, stirring at a constant temperature, slowly cooling to room temperature at a rate of not higher than 20 ℃ per hour, stirring, and filtering crystals to obtain the etoricoxib crystal. The method for preparing the etoricoxib V crystal has the advantages of high yield, stable process and good reproducibility, and simultaneously can remove the impurity ET-IMP-409 to the maximum extent in the crystallization process, the raw material purity is higher, and no additional purification step is needed.

Description

Preparation method of etoricoxib crystal form

Technical Field

The invention belongs to the field of medicines, and relates to a preparation method of etoricoxib V crystal.

Background

Etoricoxib (Etoricoxib), chemical name: 5-chloro-3- (4-methanesulfonylphenyl) -6-methyl- [2,3] bipyridine, having the following structural formula:

etoricoxib is a high-selectivity COX-2 inhibitor, and plays a role in relieving fever, easing pain and resisting inflammation by inhibiting COX and reducing the generation of Prostaglandin (PG) and thromboxane. Can be used for treating rheumatoid arthritis, OA chronic low back pain, postoperative toothache, pain relieving and antiinflammatory effects, and has no adverse reaction such as gastrointestinal reaction caused by non-selective COX-1.

Etoricoxib was first marketed in mexico, the united kingdom, brazil in 2002, and subsequently marketed countries and regions including the european union, asia, australia, and latin america, etc., and by the end of 2013, etoricoxib has been approved in 97 countries worldwide for the treatment of various diseases such as Osteoarthritis (OA), rheumatoid arthritis, ankylosing spondylitis, chronic lower back pain, acute gouty arthritis, primary dysmenorrhea, and postoperative pain.

The etoricoxib pharmaceutical preparation is in the form of a film-coated tablet, and belongs to a solid tablet. It is well known that the crystal form of the drug has a great influence on the solid formulation of the drug, and WO2001092230 discloses the existence of five polymorphic forms (forms I, II, III, IV, V), one amorphous and two hydrated forms of etoricoxib. Wherein form V is a pharmaceutically acceptable form of an etoricoxib drug, but in the process for preparing etoricoxib form V disclosed in this patent, etoricoxib is mixed with isopropyl acetate, heated to an elevated temperature of less than about 75 ℃, and then cooled to a lower temperature to produce form V polymorph, the process has the following disadvantages: the stability of the experimental result has a larger problem, and the V crystal form cannot be obtained or can be obtained only occasionally according to the method, so that the preparation process of the crystal form is very unstable; in addition, the crystallization yield is not high, the highest yield is about 80 percent after a plurality of batches of experiments are carried out, the production loss is extremely high, and the method is not suitable for industrial large-scale production; thirdly, the crystallization method has a problem that a specific impurity ET-IMP-409 cannot be effectively removed after crystallization, and since the physical and chemical properties of the impurity are similar to those of the raw material, the impurity cannot be removed at one time by the crystallization method, and a purification process is required later, the process is long, and is not suitable for mass production.

Disclosure of Invention

In order to overcome the defects of poor stability, low yield, low purity and the like of a preparation process for preparing the crystal form V of etoricoxib in the prior art, the invention aims to provide the preparation method of the crystal form V of etoricoxib, which has good and stable repeatability, high yield and high purity and is suitable for industrial scale-up production.

In order to achieve the purpose, a large number of experiments are carried out, a crystallization solvent is replaced, the heating temperature and the like are changed, the crystallization yield is not ideal, finally, seed crystals are introduced into the solvent of etoricoxib, so that V crystals are obtained, although the V crystals of etoricoxib can be obtained, ET-IMP-409 impurities exist in the crystals, the impurities are removed through a purification process, and the loss of main components of the etoricoxib and the etoricoxib is large and the impurities are difficult to remove due to the fact that the peak emergence time of the impurities is close to the peak emergence time of a finished liquid phase and the properties of the impurities are close, and meanwhile, the finished product yield is low due to multiple refining. The reaction principle of the ET-IMP-409 impurity is as follows:

the ET-IMP-409 impurity is similar to the finished product in a liquid phase map, which shows that the property is similar and is not easy to remove in the later purification process.

In an accidental experiment, the crystal seed adding amount can obtain different levels of ET-IMP-409 impurities in a finished product, namely different crystal seed adding amounts can cause different levels of ET-IMP-409 impurities in the finished product.

The amount of seed crystals added was further screened and the temperature of crystallization was investigated.

The following is the investigation of the seed crystal addition, the cooling rate is uniformly 10 ℃/h, and the results are as follows:

therefore, the crystal seed adding amount has little influence on the yield, the yield is stable, the influence on the purity of a finished product and a specific impurity ET-IMP-409 is large, the finished product is lowered along with the crystal seed adding amount, the purity of the finished product is improved, the limit of less than 0.1 percent required by the state is reached, and the purification process is not needed in the later period.

Meanwhile, different cooling rates are considered, the adding amount of the crystal seeds is unified to be 5%, and the results are as follows:

after the seed crystal is added, the finished product with stable yield can be obtained at different cooling rates, but the purity of the finished product and the content of the impurity ET-IMP-409 are greatly influenced. When the temperature reduction rate is 25 ℃/h, the impurity level exceeds the standard, and when the temperature reduction rate is reduced to 20 ℃/h, the content of the impurity ET-IMP-409 is greatly reduced, and the purity of the sample is further higher along with the reduction of the temperature reduction rate.

On the basis of a large number of experiments, the preparation method of the etoricoxib V crystal form comprises the steps of adding etoricoxib into an organic solvent, heating to completely dissolve solids, adding V crystal form crystal seeds with the weight percentage of the etoricoxib being not higher than 10% into the solution, keeping the temperature and stirring, slowly cooling to room temperature at the rate of cooling to 20 ℃ per hour, stirring and filtering crystals to obtain the etoricoxib V crystal form. The process can obtain the V crystal form in one step, the yield reaches more than 90 percent, and ET-IMP-409 is reduced to be less than 0.1 percent, thereby avoiding the subsequent purification process.

The method of the application is a significant improvement over the methods disclosed in the prior art:

(1) in the aspect of process stability, the crystal form preparation method reported in patent WO2001092230 is difficult to repeat or poor in repeatability, and has a larger problem in stability, and the crystal form V etoricoxib can be stably obtained.

(2) In terms of yield, the method reported in patent WO2001092230 only has 80 percent of yield, and the yield of the method can reach 93 percent, thereby greatly reducing the unit price of raw materials.

(3) In terms of the quality of etoricoxib products, the method can achieve the aim of detecting high-purity products with the purity of more than 99.8% by HPLC, and brings great convenience to industrialization as the specific impurity ET-IMP-409 is reduced to be below the limit.

The crystallization process can solve two problems in one step, has good process reproducibility and high yield, and removes the specific impurity ET-IMP-409 in one step through the crystallization process without a subsequent purification process.

Drawings

FIG. 1 shows the results of the impurity measurement of the final product of example 1;

FIG. 2 is the results of the impurity determination of example 2;

FIG. 3 is a diffraction pattern of the crystalline form of the finished product of example 2.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, embodiments of the present invention will be described in detail below. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention.

Example 1: comparative example, case of crystallization without addition of seed Crystal

Adding 5g of etoricoxib and 15ml of isopropyl acetate into a three-mouth bottle, heating to 75 ℃ to fully dissolve the solid, stirring at the temperature (75 ℃) for 1h, slowly cooling to room temperature, stirring for 2h, filtering, and performing forced air drying on the obtained solid for 12h at 60 ℃ to obtain 4.04g of V-crystal form etoricoxib, wherein the purity is as follows: 99.0%, yield 80.8%, specific impurity ET-IMP-409 is 0.199%. The liquid phase measurement spectrum of the final product is shown in figure 1.

Example 2: preparation of crystal form V etoricoxib

Adding 5g of etoricoxib and 15ml of isopropyl acetate into a three-mouth bottle, heating to 75 ℃ to fully dissolve the solid, adding 0.25g (5%) of etoricoxib V crystal form seed crystal at the temperature (75 ℃), stirring for 1h at the constant temperature, cooling to room temperature at the cooling rate of 10 ℃/h, stirring for 2h, filtering, and carrying out forced air drying on the obtained solid for 12h at the temperature of 60 ℃ to obtain 4.64g of the V crystal form etoricoxib, wherein the purity is as follows: 99.86 percent, the yield is 92.8 percent, the specific impurity ET-IMP-409 is 0.063 percent, the purity liquid phase determination pattern of the finished product is shown in figure 2, and the crystal form diffraction pattern of the finished product is shown in figure 3.

Example 3: preparation of crystal form V etoricoxib

Adding 5g of etoricoxib and 15ml of isopropyl acetate into a three-mouth bottle, heating to 75 ℃ to fully dissolve the solid, adding 0.15g (3%) of etoricoxib V crystal form seed crystal at the temperature (75 ℃), stirring for 1h at the constant temperature, cooling to room temperature at the cooling rate of 20 ℃/h, stirring for 2h, filtering, and carrying out forced air drying on the obtained solid for 12h at the temperature of 60 ℃ to obtain 4.61g of the V crystal form etoricoxib, wherein the purity is as follows: 99.95% and a yield of 92.2%.

Example 4: preparation of crystal form V etoricoxib

Adding 5g of etoricoxib and 15ml of isopropyl acetate into a three-mouth bottle, heating to 75 ℃ to fully dissolve the solid, adding 0.15g (3%) of etoricoxib V crystal form seed crystal at 72 ℃, stirring for 1h while keeping the temperature, then cooling to room temperature at a cooling rate of 5 ℃/h, stirring for 2h, filtering, and carrying out forced air drying on the obtained solid for 12h at 60 ℃ to obtain 4.73g of the V crystal form etoricoxib, wherein the purity is as follows: 99.94 percent, the yield is 91.8 percent, and the specific impurity ET-IMP-409 is 0.053 percent.

Example 5: preparation of crystal form V etoricoxib

Adding 5g of etoricoxib and 10ml of ethyl acetate into a three-mouth bottle, heating to 75 ℃ to fully dissolve the solid, adding 0.5g (10%) of etoricoxib V crystal form seed crystal at 61 ℃, stirring for 1h while keeping the temperature, then cooling to room temperature at a cooling rate of 5 ℃/h, stirring for 2h, filtering, and carrying out forced air drying on the obtained solid for 12h at 60 ℃ to obtain 4.63g of V crystal form etoricoxib with purity: 99.90 percent, the yield is 92.6 percent, and the specific impurity ET-IMP-409 is 0.066 percent.

Example 6: preparation of crystal form V etoricoxib

Adding 5g of etoricoxib and 10ml of acetone into a three-mouth bottle, heating to reflux to completely dissolve the solid, adding 0.15g (3%) of etoricoxib V crystal form seed crystal at 50 ℃, stirring for 1h while keeping the temperature, then cooling to room temperature at a cooling rate of 5 ℃/h, stirring for 2h, filtering, and carrying out forced air drying on the obtained solid for 12h at 60 ℃ to obtain 4.56g of the V crystal form etoricoxib, wherein the purity is as follows: 99.84 percent, the yield is 91.2 percent, and the specific impurity ET-IMP-409 is 0.071 percent.

The method comprises the steps of dissolving etoricoxib in a solvent, heating to completely dissolve solids, adding V-shaped crystal seeds of etoricoxib in the solution, keeping the temperature and stirring, slowly cooling to room temperature at the rate of not higher than 20 ℃ per hour, stirring and filtering crystals.

Claims

1. A preparation method of V-type etoricoxib comprises the steps of adding etoricoxib into an organic solvent, heating to completely dissolve solids, adding V-type crystal seeds with the weight percentage of the etoricoxib being not higher than 10% into the solution, stirring at a constant temperature, slowly cooling to room temperature at a cooling rate of not higher than 20 ℃ per hour, stirring and filtering crystals to obtain the V-type etoricoxib; wherein the organic solvent is any one of isopropyl acetate, ethyl acetate and acetone.

2. The preparation method according to claim 1, wherein the crystal seeds of form V are added to the solution in an amount of not more than 5% by weight of etoricoxib.

3. The preparation method according to claim 2, wherein the crystal form V seed is added to the solution in an amount of not more than 3% by weight of etoricoxib.

4. The method according to claim 1, wherein the temperature is slowly lowered to room temperature at a rate of not more than 10 ℃ per hour after the seed crystal is added.

5. The method according to claim 4, wherein the temperature is slowly lowered to room temperature at a rate of not more than 5 ℃ per hour after the seed crystal is added.