KR20210017070A - A New Crystal form of Ticagrelor, Method for Preparing or Use Thereof - Google Patents

Abstract

The present invention relates to a novel crystal form of ticagrelor, and a manufacturing method thereof. An aqueous solubility of ticagrelor is only 10 μg/mL, and thus ticagrelor is a poorly soluble drug. Therefore, the present inventors have continuously conducted researches on novel crystal forms to overcome said problems, and have developed novel crystal forms with excellent stability and water solubility increased by more than 20 times while maintaining the activity of ticagrelor.

Description

[A New Crystal form of Ticagrelor, Method for Preparing or Use Thereof}

The present invention relates to a novel ticagrelor crystalline form and a method for producing the same. Ticagrelor is a poorly soluble drug that only dissolves in water solubility of 10 μg/mL. Accordingly, the present inventors have continuously conducted research on a new crystal form to overcome this problem, and developed a novel crystal form having excellent stability and water solubility increased by 20 times or more while maintaining the activity of ticagrelor.

Polymorphs refer to crystalline solids that have the same molecular structure, but whose crystal structure changes due to changes in the molecular packing and molecular conformation. Therefore, polymorphs include polymorphs, pesudo-polymorphs aka: hydrate or solvate, salt-form, co-crystal, etc. (Crystal Growth & Design (2011) 11, 887-895, Polymorphism in the Pharmaceutical Industry: Wiley-Vch, 2006; pp. 1-19). Polymorphs are generally characterized to maintain thermodynamic stability by preferentially precipitating metastable polymorphs with higher thermodynamic energy during the crystallization process and then transferring them from solvent mediated and solid state to more stable polymorphs. Since it has, in general, molecules are rearranged through a phase transformation in a solvent to form a more stable crystal structure. This creates polymorphism, which is called Ostwald's rule of stage. This is called polymorphic transformation. Since the polymorphs generated through crystallization have different thermodynamic energies, the physicochemical properties of the metastable polymorph and the stable polymorph are changed. Therefore, it causes a change in solubility, which represents the thermodynamic energy of the crystal, which is most important as a drug (Crystal Growth & Design (2011) 11, 887-895, Polymorphism in the Pharmaceutical Industry: Wiley-Vch, 2006; pp.1-19). .

The search for polymorphism can be searched through a commonly performed crystallization method. However, it is very unusual to control the transition of these polymorphs. If the metastable polymorph is preferred by the higher solubility and dissolution rate than the stable polymorph, a high degree of crystal that allows only the metastable polymorph to be obtained by controlling the transfer rate of the metastable polymorph to the stable polymorph. Engineering skills are needed (Crystal Growth & Design (2011) 11, 887-895, Polymorphism in the Pharmaceutical Industry: Wiley-Vch, 2006; pp.1-19). For example, in the case of clopidogrel bisulphate, according to Korean Patent Registration No. 10-1567438 and Crystal Growth & Design 2016, 16, 1829-1836, Crystal Type 1 has a high solubility, so Crystal Type 1 is pharmaceutically preferred. There are studies that can be obtained by controlling the polymorphic transition rate of Form 1 through crystallographic studies to control the polymorphism transition rate to Form 2, as it does not exceed 5 minutes. To obtain and control such metastable polymorphs, many crystal engineering studies are required. Therefore, in the case of designing a new polymorphism of active pharmaceutical ingredients released on the market after the search for polymorphism has been completed, the metastable polymorphism is designed first because it exists as a final stable polymorphism. Since all metastable polymorphisms are transferred to stable polymorphisms, such polymorphic design studies require advanced crystal engineering studies.

In addition, in order to increase the reproducibility of a novel polymorphism, it is possible to establish a reproducible crystallization process only when the design of an advanced crystal engineer is required, and it is executed based on knowledge of chemical engineering.

Ticagrelor represented by the following formula [1] is used as a therapeutic agent for thrombosis. It is known that adenosine 5′-diphosphate acts as a main medium for thrombosis, and platelet aggregation induced by adenosine 5′-diphosphate is expressed by the P _2T receptor located on the platelet surface.

[Formula 1]

Ticagrelor is sold in 60mg and 90mg doses under the name of Brilinta, and is used as a cardiovascular treatment for myocardial infarction or nozolosis.

International patent application WO 1999/05143 describes a compound having an activity as a P2T antagonist, and international patent application WO 2000/034283 specifically specifies ticagrelor represented by Formula 1, which is used as a thrombosis treatment.

In addition, international patent application WO 2001/092262 describes ticagrelor crystalline forms 1, 2, 3 and 4 and amorphous forms, and international patent application WO 2011/06751 describes glycolic acid, salicylic acid, decanoic acid, gentisic acid, and Ticagrelor co-crystal with glutaric acid, vanillic acid, succinic acid, malonic acid, and maltol copolymer is described, and international patent application WO 2012/164286 describes ticagrelor co-crystal with an aspirin copolymer. In addition, Korean Patent No. 10-1781449 describes ticagrelor in the form of heminapadicylate.

However, although crystalline solids of ticagrelor such as such crystalline form, co-crystalline form, and salt form are described, the increase in water solubility, which is a problem of ticagrelor, has not been properly achieved. Also, there are no exact results for stability.

In addition, ticagrelor is manufactured and sold using crystalline form 2 known in international patent application WO 2001/092262. However, crystalline form 2 has only 10 µg/mL of water solubility and is sold as an oral drug using a special formulation method, so it is necessary to improve its solubility at the raw material stage.

The criterion for selecting an excellent crystal form is due to the most important physicochemical properties required by the drug. Choose the one that is thermodynamically most stable, choose the one optimized for the manufacture of pharmaceutical raw materials and final products, or improve the solubility and dissolution rate of the drug. The selection of the optimized crystalline form may vary depending on the purpose, such as to change the pharmacokinetic properties.

The present inventors aimed at increasing the water solubility of ticagrelor, a poorly soluble drug, as a result of which, as a result of increasing the water solubility of ticagrelor more than 10 times compared to the currently commercially available pharmaceutical ingredients, a novel ticagrelor with excellent stability against it The anhydrous crystalline form of was developed.

Accordingly, the present inventors intend to disclose a novel ticagrelor anhydrous crystalline form, a preparation method therefor, and the physicochemical properties of the novel anhydrous crystalline form.

The present invention aims to increase the water solubility of ticagrelor, a poorly soluble drug, as a result of which it is a novel ticagrelor with excellent stability while increasing the water solubility of ticagrelor more than 10 times compared to the currently commercially available pharmaceutical ingredients. The anhydrous crystalline form of was developed.

Powder X-ray diffraction (PXRD) data, thermogravimetric analysis (TGA) data, and temperature differential scanning calorimetry (DSC) data were analyzed to confirm a novel ticagrelor anhydrous crystalline form, thereby completing the present invention. In the present invention, this will be referred to as an anhydrous crystalline form.

Accordingly, an object of the present invention is to provide a crystalline solid of ticagrelor characterized in that it is an anhydrous crystalline form.

Another object of the present invention is to provide an anhydrous crystalline manufacturing method of the novel ticagrelor of the present invention described above.

Another object of the present invention is to provide the physicochemical properties of the ticagrelor anhydrous crystalline form.

Other objects and advantages of the present invention will become more apparent by the following description, claims, and drawings.

According to the above object, the present invention provides a novel ticagrelor anhydrous crystalline form of the following formula 1, which is pharmaceutically acceptable and has improved solubility, and thus can be very usefully used as a pharmaceutical composition for treating urination disorders.

According to another embodiment of the present invention, 2θ diffraction angles 5.482±0.2, 5.785±0.2, 6.668±0.2, 6.904±0.2, 10.552±0.2, in powder X-ray diffraction (PXRD) analysis of the anhydrous crystalline form of Ticagrelor of Formula 1 above, 11.072±0.2, 11.518±0.2, 12.104±0.2, 12.452±0.2, 13.367±0.2, 13.904±0.2, 14.571±0.2, 15.715±0.2, 16.183±0.2, 16.571±0.2, 16.885±0.2, 17.364±0.2, 17.846±0.2 0.2, 18.199±0.2, 18.891±0.2, 19.438±0.2, 20.05±0.2, 21.336±0.2, 22.104±0.2, 22.733±0.2, 23.137±0.2, 24.134±0.2, 24.416±0.2, 24.664±0.2, 25.5±0.2, 26.229±0.2, 26.704±0.2, 26.984±0.2, 27.53±0.2, 28.729±0.2, 28.925±0.2, 29.135±0.2, 29.837±0.2, 31.054±0.2, 32.274±0.2, 32.718±0.2, 33.61±0.2, 33.996±0.2 It provides a Ticagrelor anhydrous crystalline form, characterized in that it has a powder X-ray diffraction pattern having characteristic peaks at 0.2 and 34.533±0.2. If necessary, the present invention may be specified from 5 to 10 2θ diffraction angles sequentially from the one having a large relative peak intensity among the above 2θ diffraction angles. For example, the present invention is characterized by including 2θ diffraction angles of 5.482±0.2, 12.452±0.2, 13.367±0.2, 13.904±0.2, 17.364±0.2, 18.199±0.2 and 21.336±0.2. For example, the intensity and peak position of the powder X-ray diffraction of one embodiment of the ticagrelor anhydrous crystalline form according to the present invention may be as shown in Table 1 below.

[Table 1]

Intensity and peak position of ticagrelor anhydrous PXRD

Comparison of the intensity and peak position of the powder X-ray diffraction of the ticagrelor crystalline forms 1, 2, 3, and 4 described in the international patent application WO 2001/092262 and the novel anhydrous crystalline form of ticagrelor developed by the present inventors As a result, it was confirmed that the location was different. The position of the peak is disclosed in [Table 2].

[Table 2]

Intensity and peak position of PXRD of ticagrelor crystalline form and ticagrelor novel anhydrous crystalline form described in international patent application WO 2001/092262

Thermogravimetric (TGA) analysis provides a Ticagrelor anhydrous crystalline solid, characterized in that there is no decrease in thermogravimetric weight before 100°C.

In the differential scanning calorimetry (DSC) analysis using a sealed fan, Ticagrelor anhydrous crystalline solids showing endothermic peaks of 130.48°C±3°C and 135.03°C±3°C are provided.

The reported value in relation to the DSC thermogram may show a difference of ±3℃, which means that the temperature observed through DSC may have a deviation of ±3℃ depending on the heating rate, sample preparation method, and type of equipment used. Because it can.

The most rational method for identifying and determining the ticagrelor anhydrous crystalline solid of the present invention is based on the characteristic 2θ diffraction angle of the powder X-ray diffraction (PXRD) analysis, and thermogravimetric (TGA) and temperature differential scanning calorimeter (DSC). ) It is specified by the measurement result.

In some embodiments, the crystalline form of the ticagrelor drug substance according to the present invention comprises at least 50% anhydrous crystalline form.

In addition, the endothermic temperature in the differential scanning calorimetry (DSC) analysis of the ticagrelor crystalline forms 1, 2, 3, and 4 described in the international patent application WO 2001/092262 and the novel anhydrous crystalline ticagrelor developed by the present inventors. As a result of comparison, the Ticagrelor crystalline form 1 described in International Patent Application WO 2001/092262 has an endothermic temperature of 152°C, crystalline form 2 is 139°C, crystalline form 3 is 132°C, and crystalline form 4 is 140°C. However, the ticagrelor anhydrous crystalline form developed by the present inventors exhibits an endothermic peak at 135°C.

Therefore, the ticagrelor anhydrous crystalline form developed by the present inventors is a novel ticagrelor anhydrous crystalline form having a different crystal structure from the currently described crystalline forms. Powder powder X-ray diffraction (PXRD) analysis, thermogravimetric (TGA) analysis and parallax It was confirmed by comparing the scanning calorimetry (DSC) analysis results.

In the present invention, ticagrelor anhydrous crystalline solids can be used as therapeutically active substances.

The novel ticagrelor anhydrous crystalline form is used as a therapeutic agent for thrombosis. Each dosage may vary according to symptoms, age, sex, weight and sensitivity of the patient, administration method, administration time and interval, and pharmaceutical formulation. Therefore, there is no specific limitation on the dosage.

The effects of the present invention are as follows.

(a) The present invention provides a method for producing ticagrelor anhydrous crystals and uses thereof.

(b) As a new anhydrous crystalline form of ticagrelor, it has excellent stability in long-term storage because it is not moisture-absorbed, and its solubility is improved than that of crystalline form 2 known in WO 2001/092262, making it suitable for oral preparation.

(c) The novel ticagrelor anhydrous crystalline form of the present invention can be used for pharmaceutical use for the treatment of thrombosis.

1 shows a powder X-ray diffraction pattern of a crystalline solid of ticagrelor anhydrous crystalline prepared according to an embodiment of the present invention.
FIG. 2 shows an X-ray diffraction pattern of a crystalline solid of ticagrelor anhydrous crystalline form prepared according to an embodiment of the present invention and a powder of crystalline form 2 known in WO 2001/092262.
3 is a thermogravimetric analysis-temperature differential scanning calorimeter (TGA-DSC) result of a crystalline solid of Ticagrelor anhydrous crystalline prepared according to an embodiment of the present invention.
Figure 4 shows the temperature differential scanning calorimetry (DSC) analysis of ticagrelor crystalline forms 1, 2, 3, 4 and amorphous forms known in WO 2001/09226.

The present invention will be described in more detail through the following examples. These examples are only for describing the present invention in more detail, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .

[Example 1] Preparation of new anhydrous crystalline form of ticagrelor using crystallization of mollusk

10 g of ticagrelor is dissolved in 100 ml of acetone. After adding 200 ml of distilled water to the dissolved ticagrelor solution, the mixture is stirred for 30 minutes. After that, it was filtered under reduced pressure and vacuum-dried at 40° C. for 16 hours to obtain 9 g (90%) of ticagrelor anhydrous crystalline form.

[Example 2] Preparation of a novel anhydrous crystalline form of ticagrelor using crystallization of mollusk

10 g of ticagrelor is dissolved in 150 ml of methanol. After adding 300 ml of distilled water to the dissolved ticagrelor solution, it is stirred for 30 minutes. After that, it was filtered under reduced pressure and vacuum-dried at 40 degrees for 16 hours to obtain 7.8 g (78%) of anhydrous crystalline Ticagrelor.

[Example 3] Preparation of new anhydrous crystalline form of ticagrelor using crystallization of mollusk

10 g of ticagrelor is dissolved in 200 ml of ethanol. After adding 400 ml of distilled water to the dissolved ticagrelor solution, the mixture is stirred for 30 minutes. After that, it was filtered under reduced pressure and vacuum-dried at 40° C. for 16 hours to obtain 6.5 g (65%) of anhydrous crystalline Ticagrelor.

[Experimental Example 1] Powder X-ray diffraction (PXRD)

PXRD analysis (see Fig. 1) was performed on an X-ray powder diffractometer (D8 Advance) using Cu Kα radiation. The instrument was equipped with tube power, and the amount of current was set at 45 kV and 40 mA. The divergence and scattering slits were set to 1°, and the light receiving slits were set to 0.2 mm. A θ-2θ continuous scan of 3° minutes (0.4 sec/0.02° interval) from 5 to 35°2θ was used.

[Experimental Example 2] Thermogravimetric Analysis (TGA)

Using a TGA Q50 obtained from TA company, measurement (see Fig. 3) was performed using a TGA fan at a scan rate of 10°C/min from 30°C to 400°C under nitrogen purification.

[Experimental Example 3] Temperature Differential Scanning Calorimetry (DSC)

Using DSC Q20 obtained from TA company, DSC measurement (see Fig. 3) was performed in a sealed pan from 30°C to 200°C under nitrogen purification at a scan rate of 10°C/min.

[Experimental Example 4] Evaluation of the solubility of the new crystal form of ticagrelor

Ticagrelor crystalline form 2 of WO 2001/092262, which is currently commercially available, is an extremely poorly soluble solid with low solubility in water or pH 6.8, and measures the water solubility of the anhydrous crystalline form of ticagrelor prepared in the above example and the solubility at pH 6.8. Thus, in order to compare with Ticagrelor type 2, the concentration was first set from 2µg/mL to 10µg/mL of Ticagrelor, diluted 10-fold, and then showed linearity. A reliable value was obtained with R ² =0.992 at the indicated linearity. Using this linearity, Ticagrelor type 2 and Ticagrelor new anhydrous crystalline form were added until solids precipitated in 5ml of water and pH 6.8 aqueous solution. After stirring for 1 hour, the mixture was allowed to stand for 1 hour. After sampling 1 ml of the supernatant of the still solution, it was diluted 10 times with methanol, and the diluted solvent was analyzed by HPLC, and the solubility was measured using the area of the ticagrelor peak. The results are summarized in [Table 3] below.

H ₂ O pH6.8 250 mL water Ticagrelor type 2 0.014 mg/mL 0.011 mg/mL 3.5 mg/mL Ticagrelor anhydrous crystalline 0.258 mg/mL 0.251 mg/mL 64.5 mg/mL

Solubility of ticagrelor anhydrous crystalline form and crystalline form 2

As shown in Table 3, it was confirmed that the water solubility and solubility at pH 6.8 of the anhydrous crystalline form of ticagrelor were significantly improved than the ticagrelor type 2. And the product name Brillinta Tablet contains 60 mg of ticagrelor. Therefore, 60mg should be well dissolved in 250ml of water, so that it is absorbed in the small intestine to show medicinal effects. However, as shown in Table 3, Ticagrelor α-type can only dissolve 3.5 mg in 250 ml of water, so 50 mg of it is absorbed into the body using polyethylene glycol 8000, a hydrophilic base. However, polyethylene glycol, which is a hydrophilic base, has a problem of causing damage to mucous membranes in the body. However, it was confirmed that the anhydrous crystalline form of ticagrelor of the present invention can dissolve 64.5 mg in 250 ml of water.

Therefore, it was predicted that the use of the ticagrelor anhydrous crystalline form of the present invention could enhance oral absorption even without the use of polyethylene glyphol 8000, which is a hydrophilic base that damages the mucous membrane of the body.

[Experimental Example 5] Evaluation of hygroscopicity of ticagrelor anhydrous crystalline form

Moisture Karl Fischer analysis after placing 40 mg of anhydrous crystalline form of Ticagrelor according to the present invention prepared by the examples in a desiccator having a relative humidity of 33%, 57%, 64%, 75% and 93% for more than two days, respectively, to absorb moisture. I tried. The results are shown in the following [Table 4].

Early 33% 57% 64% 75% 93% Ticagrelor
Anhydrous crystalline 0.3% 0.28% 0.41% 0.39% 0.43% 0.41

Evaluation of hygroscopicity of ticagrelor anhydrous crystalline form (% by weight)

This hygroscopicity test is to evaluate the hygroscopicity in the process of refrigerated storage. Therefore, as shown in [Table 4], it was confirmed that the anhydrous crystalline form of ticagrelor according to the present invention has stable hygroscopicity.

As the specific parts of the present invention have been described in detail above, it is clear that these specific techniques are only preferred embodiments for those of ordinary skill in the art, and the scope of the present invention is not limited thereto. Therefore, it will be said that the substantial scope of the present invention is defined by the appended claims and their equivalents.

Claims (3)

Powder X with characteristic peaks including 2θ diffraction angles 5.482±.02, 12.452±0.2, 13.367±0.2, 13.904±0.2, 17.364±0.2, 18.199±0.2 and 21.336±0.2 in powder X-ray diffraction (PXRD) analysis It has a line diffraction pattern and is characterized in that there is no decrease in thermoweight before 100°C in thermogravimetric (TGA) analysis, and endothermic initiation temperature 130.48°C±3°C and endothermic temperature 135.03°C±3 in differential scanning calorimetry (DSC) analysis. Ticagrelor anhydrous crystalline form showing an endothermic peak at °C. A method for producing an anhydrous crystalline ticagrelor according to claim 1, wherein the method is obtained by stirring, filtering, and drying after adding to at least one solvent selected from an alcohol group consisting of acetone, methanol, and ethanol, and water. A pharmaceutical composition for the treatment or prevention of cardiovascular diseases such as myocardial infarction and stroke, based on the anhydrous crystalline form of ticagrelor according to claim 1.

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