KR20190105389A - Crystal form I of Ticagrelor Fumarateand its preparing method - Google Patents

Abstract

The present invention relates to: a type I crystal which is a novel crystalline form of ticagrelor fumarate; and a method for manufacturing the same. The type I crystal according to the present invention is very hygroscopic and is very advantageous for storage and distribution, thereby having an advantage that it is also very advantageous for storage and distribution of formulations made by using the same. In addition, the type I crystal according to the present invention exhibits a spherical shape and has a similar size of crystalline, thereby exhibiting very good physical properties to make formulations such as reducing sticking phenomenon during tableting, being easily mixed with other additives, and ensuring a content uniformity. On the other hand, a manufacturing method according to the present invention can manufacture the type I crystal having a high yield and purity with a simple process.

Description

Ticagrelor fumaric acid type I crystal and its preparation method {Crystal form I of Ticagrelor Fumarateand its preparing method}

The present invention relates to a ticagrelor fumaric acid novel crystalline form (form I) and a preparation method thereof.

Ticagrelor of the formula (1), ie, (1S, 2S, 3R, 5S) -3- [7-{[(1R, 2S) -2- (3,4), sold under the trade name Brilinta -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 oral antithrombotic agent that binds directly to adenosine diphosphate (ADP) receptor P2Y ₁₂ without metabolism and exhibits faster activity than clopidogrel. In addition, unlike clopidogrel, regardless of the CYP2C19 or ABCB1 genotype, cardiovascular death, myocardial infarction, and stroke are lowered.

[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 the pharmaceutically acceptable salt of ticagrelor. However, the method for preparing ticagrelor fumaric acid of US Pat. No. 9,233,966 is very low in yield and is not preferable using n-hexane, which is currently prohibited for use in the manufacture of pharmaceuticals.

Korean Patent Publication No. 10-2014-0028011 and the corresponding US Patent No. 9,101,642 disclose pharmaceutical compositions containing ticagrelor cocrystals using acetylsalicylic acid, which cocrystals are coronary, cerebrovascular or It is disclosed that it can be used in the manufacture of a medicament for use in preventing arterial thrombotic complications in patients with peripheral vascular disease.

In addition, Korean Unexamined Patent Publication No. 10-2012-0123659 and corresponding US Patent No. 8,883,802 disclose various co-crystals of ticagrelor. The patent uses the malonic acid, succinic acid, decanoic acid, salicylic acid, gentic acid, glutaric acid, vanylic acid, maltol, or glycolic acid to produce co-crystals, but it requires more than one week and the manufacturing method is difficult and mass production. This is a difficult drawback.

However, there are no reports and literature on the crystal form of ticagrelor fumaric acid, which is yet hygroscopic and has useful properties in terms of preparation of a medicament, and it is possible to easily prepare such useful new crystalline forms and useful new crystalline forms in high yield. The demand for the method is steady.

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

Accordingly, the problem to be solved by the present invention is to provide a novel crystalline form of ticagrelor fumaric acid, which has no hygroscopicity and has useful forms and properties in terms of preparation of a medicament.

Another problem to be solved by the present invention is to provide a production method which can easily prepare a novel crystalline form desirable in many aspects in high yield.

In order to solve the above problems, the present invention, when the powder X-ray diffraction (XRD) analysis, 2θ diffraction angle is 5.5 ± 0.2 °, 9.8 ± 0.2 °, 14.1 ± 0.2 °, 15.5 ± 0.2 °, 20.3 ± 0.2 °, 21.4 A novel ticagrelor fumaric acid crystalline form (hereinafter referred to as "form I crystal") is characterized by being ± 0.2 °, 26.5 ± 0.2 °, and 29.0 ± 0.2 °.

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

More specifically, the Form I crystal according to the present invention has the XRD pattern of FIG.

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

The ticagrelor fumaric acid type I crystal according to the present invention has a high chemical stability and low hygroscopicity compared to known ticagrelor free bases and other crystalline forms to prepare a very pharmaceutically stable formulation, and the crystal shape is spherical. It has a constant crystal size, good flow of crystals, easy to secure content uniformity, and has better properties in various problems during the manufacturing process, such as sticking.

The present invention also provides a step of dissolving (S1) ticagrelor free base and fumaric acid in an organic solvent, dropping a crystallization solvent to crystallize, and (S2) aging the crystal obtained in the above step at a temperature of 0 to 5 ° C. It provides a method for producing ticagrelor fumaric acid type I crystals 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 manufacturing method of the ticagrelor fumaric acid type I crystal can be greatly reduced and the production cost of the ticagrelar fumaric acid type I crystal can be greatly reduced.

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

At this time, the amount of fumaric acid is used in the amount of 0.9 to 2 equivalents, preferably 1 to 1.05 equivalents relative to the ticagrelor free base. If the amount of fumaric acid is less than 0.9 equivalent, the yield of ticagrelar fumaric acid type I crystal is reduced, and if it is more than 2 equivalents, it can lead to a decrease in content and an increase in cost due to the use of excess fumaric acid.

Preferably, the amount of the crystallization solvent used is 10-100 v / w (mL / g), preferably 90-100 v / w, based on the ticagrelor free base. In this case, when the amount of the crystallization solvent is less than 90 v / w, the yield and content in the crystallization step do not fall, so that homogeneous crystallization does not occur, and when the amount of the crystallization solvent exceeds 100 v / w, the yield and content do not affect the yield, but may cause an increase in cost. .

The ticagrelor fumaric acid type I crystal was obtained through the step (S1), cooled to a temperature of 0-5 ° C., aged for about 1 to 2 hours, and the precipitated crystals were filtered to obtain a ticagrelar fumaric acid type I crystal. do.

Preferably, the oily ticagrelor free base used in the production method of the present invention may be prepared as follows. First, 2-(((3aR, 4S, 6R, 6aS) -6- (7-(((1R, 2S) -2- (3,4-difluorophenyl) cyclo) Propyl) amino) -5- (propylthio) -3H- [1,2,3] triazolo [4,5-d] pyrimidin-3-yl) -2,2-dimethyltetrahydro-3aH-cyclo Hydrochloric acid and methanol were added to penta [d] [1,3] dioxo-4-yl) oxy) ethanol and deprotected. Then, ethyl acetate was added and neutralized with an aqueous sodium bicarbonate solution. The organic layer was separated and washed with brine. The organic layer can then be concentrated to recover the oily ticagrelor freebase.

[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 gasification reaction may not be terminated. If it is used in excess of 5 equivalents, the use of excess concentrated hydrochloric acid may cause decomposition of ticagrelor and thus reduce the purity.

Form I crystal according to the present invention is very hygroscopic and is very advantageous for storage and distribution, and thus has an advantageous advantage for storage and distribution of the preparation made using the same. In addition, Form I crystals according to the present invention have a spherical shape and have a similar size to the crystal forms, reducing sticking phenomenon during tableting, easy mixing with other additives, and ensuring content uniformity. It has very good physical properties to make the formulation.

On the other hand, the production method according to the present invention is very high in yield, it is possible to make a good type I crystal with a simple process.

1 is an X-ray diffraction spectrum of a ticagrelor fumaric acid type I crystal of the present invention.
2 is an X-ray diffraction spectrum of a ticagrelor free base Form II crystal.
Figure 3 is a differential scanning calorie spectrum of the ticagrelor fumaric acid type I crystal of the present invention.
4 is a hydrogen nuclear magnetic resonance spectrum of the ticagrelor fumaric acid type I crystal of the present invention.
5 and 6 are micrographs of the ticagrelor fumaric acid type I crystal and the ticagrelor free base type II crystal of the present invention, respectively.

Hereinafter, examples and the like will be described in detail to help understand the present invention. However, embodiments according to the present invention can be modified in many different forms, the scope of the invention should not be construed as limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.

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] diox-4-yl) oxy) ethanol was added to a mixture of 9.5 g of concentrated hydrochloric acid and 100 mL of methanol. After the reaction was completed, 150 mL of ethyl acetate was added and neutralized with an aqueous sodium bicarbonate solution. The organic layer was separated and washed with brine. The organic layer was concentrated to obtain a ticagrelor free base that is an oil phase.

2.4 g of fumaric acid and 260 mL of acetone were added thereto and completely dissolved at 35 ° C. 1 L of n-heptane was dripped gradually, the reaction solution was cooled to 0-5 degreeC, and it stirred for 1 hour. The resulting white crystalline solid was filtered off. Thereafter, the mixture 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 crystal. (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 dripped slowly here. The temperature of the reaction solution was cooled to 0-5 ° C. 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 ticagrelar fumaric acid Form I crystals. (Yield 93.1%, Purity: 99.87%).

Comparative Example 1

Ticagrelor fumaric acid salt was prepared according to the method of Example 24 described in US Pat. No. 9,233,966. (Yield 65.0%, Purity: 99.81%).

Crystal analysis and property test

end. Powder X-ray Diffraction (XRD) Analysis

Powder X-ray diffraction (XRD) analysis was performed on the ticagrelor fumaric acid type I crystal obtained in Example 1, and the results are attached to FIG. 1. As shown in FIG. 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 The peaks were shown at °, 28.3 ± 0.2 °, 29.0 ± 0.2 °, and 31.9 ± 0.2 °.

The measurement conditions of 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) Divergence Slit: 1 ° / Scattering Slit: 1 ° / Light Slit: 0.15 mm

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

5) Scan Speed: 10 ° / min

Powder X-ray diffraction analysis of the ticagrelor free base type II crystals measured in the same manner is shown in FIG.

I. Differential Scanning Calorimetry (DSC) Analysis

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

1) Device: Q20 (TA instrument)

2) Measuring 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 fumaric acid type I crystal obtained in Example 1, and the results are attached to FIG. 4. As shown in FIG. 4, the Type I crystals are d 9.36 (d, 1H), 7.33 (m, 2H), 7.07 (m, 1H), 6.62 (s, 1H), 5.10 (m, 2H), and 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. Seemed.

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

1) Device: Bruker Avance I NMR 400

2) Measuring range: -1.0 to 10 ppm

3) Scan count: 4

la. Photomicrograph

5 and 6 are micrographs of ticagrelor fumaric acid type I crystal and ticagrelor free base, respectively. The ticagrelor fumaric acid type I crystal of the present invention has a spherical shape as shown in FIG. 5, and the grain size is uniformly grown to about 40 μm, while the conventional ticagrelor free base has a size as shown in FIG. 6. 25-75 micrometers crystal grains are formed in the acicular form. Needle-like shapes, such as ticagrelor freebases, are not suitable for pharmaceutical development because they have poor fluidity and are not ideal for compression processes. However, Ticagrelar fumaric acid type I crystals are advantageous for the compression process because they have excellent flowability and spherical shape.

hemp. Hygroscopic test

The hygroscopicity of the ticagrelor fumaric acid type I crystal and the ticagrelor free base crystal obtained in Example 1 was measured, and the results are shown in Table 1 below. Specifically, the water content (K.F. moisture%) with time of each compound was measured under the condition of a temperature of 25 ° C. and a relative humidity of 30%.

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

As shown in Table 1, the ticagrelor fumaric acid type I crystal of the present invention did not exhibit hygroscopicity. That is, the water content is maintained at a similar level even after two or four weeks as compared to the initial water content. On the other hand, Comparative Example 1 and ticagrelor free base type II crystals can be seen that the moisture content increases by the moisture in the air as time passes.

bar. Non-photometric measurement

The specific light intensity of Form I crystals and Ticagrelor free base Form II crystals was measured in the present invention and is shown in Table 2 below.

The specific light measurement method was as follows.

1) Device: JASCO P-1020

2) Rays: D line of sodium spectrum

3) Temperature: 20 ℃

4) Measuring tube: 100mm

Non-luminescence Ticagrelor Free Base Form II Crystals -51.3 ° Ticagrelor fumaric acid type I crystal -42.9 °

Claims (7)

In powder X-ray diffraction (XRD) analysis, the 2θ diffraction angles are 5.5 ± 0.2 °, 9.8 ± 0.2 °, 14.1 ± 0.2 °, 15.5 ± 0.2 °, 20.3 ± 0.2 °, 21.4 ± 0.2 °, 26.5 ± 0.2 °, and Ticagrelor fumaric acid Form I crystal, characterized in that 29.0 ± 0.2 °. The Ticagrelor fumaric acid type I crystal according to claim 1, wherein the crystal of Form I 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 peaks. . The ticagrelor according to claim 1 or 2, 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. Fumaric acid type I crystal. Dissolving ticagrelor free base and fumaric acid in an organic solvent, and dropping the crystallization solvent to crystallize, and
A method for producing ticagrelor fumaric acid type I crystal comprising the step of aging the crystal obtained in the step at a temperature of 0 ~ 5 ℃. 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. A method for producing ticagrelor fumaric acid type I crystals. The amount of the organic solvent is 5 to 20 mL / g based on the ticagrelor free base, the amount of the crystallization solvent is 90 to 100 mL / g relative to the ticagrelor free base. A 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- Hydrochloric acid and methanol were added to 3aH-cyclopenta [d] [1,3] dioxo-4-yl) oxy) ethanol and deprotected. Then, ethyl acetate was added and neutralized with an aqueous sodium bicarbonate solution. Washing with water and then concentrating the organic layer to obtain a process for recovering ticagrelor free base which is an oil phase.

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