KR102610876B1 - Crystal form I of Ticagrelor Fumarateand its preparing method - Google Patents

Abstract

The present invention relates to Form I crystals, a new crystalline form of ticagrelor fumaric acid, and a method for producing the same. The type I crystal according to the present invention is not hygroscopic, so it is very advantageous for storage and distribution, and therefore has a very advantageous advantage for the storage and distribution of preparations made using it. In addition, the type I crystal according to the present invention has a spherical shape and the crystal forms have similar sizes, so the sticking phenomenon is reduced during tableting, mixing with other additives is easy, and content uniformity can be ensured. It shows very good physical properties for making preparations such as: Meanwhile, the production method according to the present invention has a very high yield and can produce type I crystals with good purity through a simple process.

Description

Ticagrelor fumarate form I crystal and its manufacturing method {Crystal form I of Ticagrelor Fumarateand its method preparing}

The present invention relates to a new crystalline form of ticagrelor fumaric acid (Form I) and a method for producing the same.

Ticagrelor of the following formula 1, sold under the trade name Brilinta, namely (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4 -difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2 -Hydroxyethoxy)cyclopentane-1,2-diol is a new chemical class of oral antithrombotic agent that binds directly to the adenosine diphosphate (ADP) receptor, P2Y ₁₂ , without metabolism, showing faster activity than clopidogrel. Additionally, unlike clopidogrel, it has the characteristic of lowering the frequency of cardiovascular death, myocardial infarction, and stroke regardless of CYP2C19 or ABCB1 genotype.

[Formula 1]

U.S. Patent No. 9,233,966 describes various salts of ticagrelor and introduces fumaric acid as a type of acid that can form a pharmaceutically acceptable salt of ticagrelor. However, the method for producing ticagrelor fumaric acid in U.S. Patent No. 9,233,966 has a very low yield and is undesirable because it uses n-hexane, which is currently prohibited from being used in pharmaceutical manufacturing.

Republic of Korea Patent Publication No. 10-2014-0028011 and the corresponding U.S. Patent No. 9,101,642 disclose a pharmaceutical composition containing a ticagrelor co-crystal using acetylsalicylic acid, and these co-crystals are used in coronary arteries, cerebrovascular or It is disclosed that the present invention can be used in the manufacture of a medicament for use in preventing arterial thrombotic complications in patients with peripheral vascular disease.

In addition, various cocrystals of ticagrelor are introduced in Korean Patent Publication No. 10-2012-0123659 and the corresponding U.S. Patent No. 8,883,802. In the above patent, co-crystals were manufactured using malonic acid, succinic acid, decanoic acid, salicylic acid, genticic acid, glutaric acid, vanillic acid, maltol, or glycolic acid, but it requires a manufacturing period of more than a week and the manufacturing method is difficult, so mass production is not possible. This has a difficult drawback.

However, there are still no reports or literature on crystalline forms of ticagrelor fumaric acid that are not hygroscopic and have useful physical properties in terms of drug production, and these useful new crystalline forms and useful new crystalline forms can be easily produced in high yield. The demand for methods continues.

US Patent No. 9,233,966 US Patent No. 9,101,642 US Patent No. 8,883,802

Therefore, the problem to be solved by the present invention is to provide a new crystalline form of ticagrelor fumaric acid that is not hygroscopic and has a useful form and physical properties in terms of drug production.

Another problem to be solved by the present invention is to provide a production method that can easily produce a new crystalline form that is desirable in many aspects with high yield.

In order to solve the above problem, the present invention has a 2θ diffraction angle of 5.5±0.2°, 9.8±0.2°, 14.1±0.2°, 15.5±0.2°, 20.3±0.2°, and 21.4° during powder X-ray diffraction (XRD) analysis. Provides a novel ticagrelor fumaric acid crystalline form (hereinafter referred to as “Form I crystal”), characterized by ±0.2°, 26.5±0.2°, and 29.0±0.2°.

More specifically, the type I crystal according to the present invention further has peaks of 18.5 ± 0.2°, 19.0 ± 0.2°, 28.3 ± 0.2°, and 31.9 ± 0.2° in addition to the above peaks.

More specifically, the type I crystal according to the present invention has the XRD pattern in Figure 1.

In addition, according to the present invention, ticagrelor fumaric acid form I crystals have an onset temperature (onset) of 141 ± 1 ° C and an endothermic peak of 145 ± 1 ° C in differential scanning calorimetry (DSC) analysis.

The ticagrelor fumaric acid form I crystal according to the present invention has higher chemical stability and lower hygroscopicity than the known ticagrelor free base and other crystal forms, making it possible to prepare a pharmaceutically very stable preparation, and the shape of the crystal is spherical. It has a certain crystal size, so it has good crystal flow, making it easy to ensure content uniformity, and has better properties in dealing with various problems during the manufacturing process, such as sticking.

The present invention also includes the steps of (S1) dissolving ticagrelor free base and fumaric acid in an organic solvent and crystallizing them by dropping a crystallization solvent, and (S2) maturing the crystals obtained in the above step at a temperature of 0 to 5 ° C. A method for producing ticagrelor fumaric acid form I crystals is provided, comprising the step:

More preferably, the organic solvent is acetone, methyl ethyl ketone, methyl isobutyl ketone, or a mixture thereof, and the crystallization solvent is n-heptane, n-octane, n-nonane, n-decane, or a mixture thereof.

According to the present invention, the method for producing ticagrelor fumaric acid type I crystals has an easy overall process, has high purity and yield, and can significantly reduce the production cost of ticagrelor fumaric acid type I crystals.

Specifically, oil-phase ticagrelor free base and fumaric acid are dissolved in an organic solvent at approximately 30 to 40°C, and then the crystallization solvent is added dropwise. The amount of the organic solvent used is preferably 5 to 20 mL/g based on ticagrelor free base.

At this time, the amount of fumaric acid is 0.9 to 2 equivalents, preferably 1 to 1.05 equivalents, based on ticagrelor free base. If the amount of fumaric acid is less than 0.9 equivalents, the yield of ticagrelor fumaric acid type I crystals decreases, and if it is more than 2 equivalents, the use of excess fumaric acid may result in a decrease in content and an increase in cost.

Preferably, the amount of the crystallization solvent used is 10 to 100 v/w (mL/g), preferably 90 to 100 v/w, relative to the free base of ticagrelor. At this time, if the amount of the crystallization solvent used is less than 90 v/w, the yield and content in the crystallization step decrease and homogeneous crystallization does not occur. If it exceeds 100 v/w, it does not affect the yield and content, but may result in an increase in cost. .

The ticagrelor fumaric acid type I crystal solution obtained through the above process (S1) is cooled to a temperature of 0 to 5°C, aged for approximately 1 to 2 hours, and then the precipitated crystals are filtered to obtain ticagrelor fumaric acid type I crystals. do.

Preferably, the oil-phase ticagrelor free base used in the production method of the present invention can be prepared as follows. First, 2-(((3aR,4S,6R,6aS)-6-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclo, which is a ticagrelor precursor of the following formula (2) propyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-cyclo After deprotecting penta[d][1,3]dioxo-4-yl)oxy)ethanol with hydrochloric acid and methanol, ethyl acetate was added and neutralized with aqueous sodium bicarbonate solution, and then the organic layer was separated and washed with brine. , and then it can be obtained by concentrating the organic layer to recover the oil-like ticagrelor free base.

[Formula 2]

At this time, concentrated hydrochloric acid is used as the hydrochloric acid, and the amount of concentrated hydrochloric acid is 1.1 to 5 equivalents, preferably 3.5 to 5 equivalents. If the amount of concentrated hydrochloric acid is less than 1.1 equivalents, the deprotection reaction may not be completed, and if more than 5 equivalents are used, the use of excessive concentrated hydrochloric acid causes decomposition of ticagrelor, lowering the purity.

The type I crystal according to the present invention is not hygroscopic, so it is very advantageous for storage and distribution, and therefore has a very advantageous advantage for the storage and distribution of preparations made using it. In addition, the type I crystal according to the present invention has a spherical shape and the crystal forms have similar sizes, so the sticking phenomenon is reduced during tableting, mixing with other additives is easy, and content uniformity can be ensured. It shows very good physical properties for making preparations such as:

Meanwhile, the production method according to the present invention has a very high yield and can produce type I crystals with good purity through a simple process.

Figure 1 is an X-ray diffraction spectrum for the ticagrelor fumaric acid form I crystal of the present invention.
Figure 2 is an X-ray diffraction spectrum for ticagrelor free base form II crystals.
Figure 3 is a differential scanning calorimetry spectrum for ticagrelor fumaric acid form I crystals of the present invention.
Figure 4 is a hydrogen nuclear magnetic resonance spectrum for the ticagrelor fumaric acid form I crystal of the present invention.
Figures 5 and 6 are microscopic photographs of ticagrelor fumaric acid type I crystals and ticagrelor free base type II crystals of the present invention, respectively.

Hereinafter, to aid understanding of the present invention, it will be described in detail through examples. However, the embodiments according to the present invention may be modified into various other forms, and the scope of the present invention should not be construed as being limited to the following embodiments. Embodiments of the present invention are provided to more completely explain the present invention to those with average knowledge in the field to which the present invention pertains.

Example 1

Ticagrelor precursor 2-(((3aR,4S,6R,6aS)-6-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5 -(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1 ,3] A mixture of 9.5 g of concentrated hydrochloric acid and 100 mL of methanol was added to 10.76 g of dioxo-4-yl)oxy)ethanol. When the reaction is complete, 150 mL of ethyl acetate is added and neutralized with aqueous sodium bicarbonate solution. The organic layer was separated and washed with brine. The organic layer was concentrated to obtain oil-like ticagrelor free base.

To this, 2.4 g of fumaric acid and 260 mL of acetone were added and completely dissolved at 35°C. 1 L of n-heptane was slowly added dropwise, the temperature of the reaction solution was cooled to 0-5°C, and the mixture was stirred for 1 hour. The resulting white crystalline solid was filtered. Afterwards, it was washed with 100 mL of n-heptane and dried under vacuum at 40°C for 12 hours to obtain 11.7 g of ticagrelor fumaric acid form I crystals. (Yield: 94.4%, Purity: 99.88%).

Example 2

10.0 g of ticagrelor free base and 2.2 g of fumaric acid were added to 200 mL of methyl ethyl ketone and completely dissolved at 40°C. 950 mL of n-heptane was slowly added dropwise here. The temperature of the reaction solution was cooled to 0~5℃ and stirred for 1 hour. The resulting white crystalline solid was filtered, washed with 100 mL of n-heptane, and dried under vacuum at 40°C for 12 hours to obtain 11.5 g of ticagrelor fumaric acid form I crystals. (Yield: 93.1%, Purity: 99.87%).

Comparative Example 1

Ticagrelor fumarate salt was prepared according to the method of Example 24 described in U.S. Patent No. 9,233,966. (Yield: 65.0%, Purity: 99.81%).

Crystal analysis and physical property testing

go. Powder X-ray diffraction (XRD) analysis

Powder X-ray diffraction (XRD) analysis was performed on the ticagrelor fumaric acid form I crystals obtained in Example 1, and the results are attached to FIG. 1. As shown in Figure 1, 5.5±0.2°, 9.8±0.2°, 14.1±0.2°, 15.5±0.2°, 18.5±0.2°, 19.0±0.2°, 20.3±0.2°, 21.4±0.2°, 26.5±0.2 Peaks were seen at °, 28.3±0.2°, 29.0±0.2°, and 31.9±0.2°, respectively.

The measurement conditions for the powder X-ray diffraction (XRD) spectrum were as follows.

1) Device: RIGAKU's MiniFlex 600 / X-ray source: Cu

2) Tube voltage: 40 kV / Tube current: 15 mA

3) Divergent slit: 1° / Scattering slit: 1° / Light receiving slit: 0.15 mm

4) Scanning range: 3 to 40° 2θ / Sampling interval: 0.04℃

5) Scan speed: 10°/min

The results of powder X-ray diffraction analysis of ticagrelor free base form II crystals measured by the same method are shown in Figure 2.

me. Differential scanning calorimetry (DSC) analysis

Differential scanning calorimetry (DSC) analysis was performed on the ticagrelor fumarate form I crystals obtained in Example 1, and the results are attached to FIG. 3. As shown in Figure 3, the type I crystal showed an onset temperature of 141°C and an endothermic peak of 145°C. The measurement conditions for the differential scanning calorimeter spectrum are as follows.

1) Device: Q20 (TA instrument)

2) Measurement range: 10 to 200 ℃ / Temperature increase interval: 10℃/min

all. Hydrogen nuclear magnetic resonance spectrum analysis

Hydrogen nuclear magnetic resonance spectrum analysis was performed on the ticagrelor fumarate form I crystals obtained in Example 1, and the results are attached to FIG. 4. As shown in Figure 4, the type I crystal has d 9.36 (d, 1H), 7.33 (m, 2H), 7.07 (m, 1H), 6.62 (s, 1H), 5.10 (m, 2H), 4.95 (q, 1H), 4.60(m, 2H), 3.93(b, 1H), 3.74(m, 1H), 3.47(m, 4H), 3.25(m, 1H), 2.93(m, 1H), 2.84( Peaks at m, 1H), 2.63(m, 1H), 2.12(m, 1H), 2.02(m, 1H), 1.54(m, 1H), 1.37(m, 1H), and 0.81(t, 3H), respectively. It seemed.

The measurement conditions for the hydrogen nuclear magnetic resonance (NMR) are as follows.

1) Device: Bruker Avance I NMR 400

2) Measurement range: -1.0 ∼ 10 ppm

3) Number of scans: 4

la. microscopic photography

Figures 5 and 6 are micrographs of ticagrelor fumaric acid form I crystals and ticagrelor free base, respectively. The ticagrelor fumaric acid form I crystals of the present invention have a spherical shape as shown in Figure 5, and grow uniformly with a particle size of about 40㎛, while the conventional ticagrelor free base has a size as shown in Figure 6. Crystal particles measuring 25 to 75㎛ are formed in a needle shape. Like Ticagrelor free base, the needle-shaped form has poor fluidity and is not ideal for compression processes, so it is not suitable for pharmaceutical development. However, ticagrelor fumarate type I crystals have excellent fluidity and are spherical, making them advantageous for the compression process.

mind. Hygroscopicity test

The hygroscopicity of the ticagrelor fumaric acid form I crystals and ticagrelor free base crystals obtained in Example 1 was measured, and the results are compared and shown in Table 1 below. Specifically, the water content (K.F. moisture %) of each of the above compounds over time was measured under the conditions of a temperature of 25°C and a relative humidity of 30%.

Sample Early 2 weeks 4 weeks Example 1 (crystals of ticagrelor fumaric acid form I) 0.04% 0.04% 0.04% Comparative Example 1 (ticagrelor fumarate) 0.04% 0.05% 0.08% Ticagrelor free base (type II crystals) 0.04% 0.05% 0.07%

As shown in Table 1, the ticagrelor fumaric acid form I crystals of the present invention did not exhibit hygroscopicity. In other words, compared to the initial water content, the water content is maintained at a similar level even after 2 or 4 weeks. On the other hand, it can be seen that the water content of Comparative Example 1 and Ticagrelor free base type II crystals absorbs moisture in the air over time and increases.

bar. Specific rotation measurement

In the present invention, the specific rotation of the form I crystals and the ticagrelor free base form II crystals were measured and shown in Table 2 below.

The specific rotation measurement method was as follows.

1) Device: JASCO P-1020

2) Ray: D line of the sodium spectrum

3) Temperature: 20℃

4) Measuring pipe: 100mm

Specific rotation Ticagrelor free base type II crystals -51.3° Ticagrelor fumarate type I crystals -42.9°

Claims (7)

When analyzing powder Ticagrelor fumaric acid form I crystals, characterized by having peaks at ±0.2°, 26.5±0.2°, 28.3±0.2°, 29.0±0.2° and 31.9±0.2°. delete The type I crystal of ticagrelor fumarate according to claim 1, wherein the type I crystal has an onset temperature of 141 ± 1°C and an endothermic peak of 145 ± 1°C in differential scanning calorimetry (DSC) analysis. . Dissolving ticagrelor free base and fumaric acid in an organic solvent and crystallizing it by dropping a crystallization solvent, and
A method for producing ticagrelor fumaric acid form I crystals according to claim 1, comprising the step of maturing the crystals obtained in the above step at a temperature of 0 to 5°C. The method of claim 4, wherein the organic solvent is acetone, methyl ethyl ketone, methyl isobutyl ketone, or a mixture thereof, and the crystallization solvent is n-heptane, n-octane, n-nonane, n-decane, or a mixture thereof. Method for producing ticagrelor fumaric acid type I crystals. The method of claim 5, wherein the amount of the organic solvent used is 5 to 20 mL/g relative to the ticagrelor free base, and the amount of the crystallization solvent used is 90 to 100 mL/g relative to the ticagrelor free base. Method for producing ticagrelor fumaric acid type I crystals. The method of claim 4, wherein the ticagrelor free base is 2-(((3aR,4S,6R,6aS)-6-(7-(((1R,2S)-2-(3,4-difluoro phenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro- 3aH-cyclopenta[d][1,3]dioxo-4-yl)oxy)ethanol was deprotected by adding hydrochloric acid and methanol, then ethyl acetate was added and neutralized with aqueous sodium bicarbonate solution, the organic layer was separated, and brine was added. A method for producing ticagrelor fumaric acid type I crystals, which is obtained by washing with and then concentrating the organic layer to recover ticagrelor free base in the oil phase.