CN108530382A - A kind of Febuxostat ligustrazine eutectic and its preparation method and application - Google Patents

Abstract

The present invention provides a kind of Febuxostat ligustrazine eutectics and its preparation method and application, belong to field of medicaments.Febuxostat ligustrazine eutectic includes characteristic peak shown in the angles following 2 θ：4.18±0.2°、8.41±0.2°、11.75±0.2°、12.96±0.2°、14.25±0.2°、24.61±0.2°、25.86±0.2°、26.95°±0.2°.This eutectiferous stable crystal form of Febuxostat ligustrazine is good, and crystallinity is high, and its solubility is big, can prepare the drug for treating or preventing gout.

Description

A kind of febuxostat ligustrazine co-crystal and its preparation method and application

technical field

The invention relates to the field of medicine, in particular to a febuxostat and ligustrazine co-crystal and a preparation method and application thereof.

Background technique

Gout is a group of heterogeneous diseases, which are hereditary and (or) acquired uric acid excretion reduction and (or) purine metabolism disorder. Its occurrence is due to the excessive production of uric acid in the body and the decline of renal clearance, and the accumulation of uric acid in the body This leads to the deposition of urate crystals in joints and various organs. Febuxostat (also known as: febuxostat, structure shown below), is a new and highly efficient non-purine xanthine oxidoreductase (XOR, a key enzyme that promotes uric acid production) selective inhibitor, It acts highly selectively on the oxidoreductase to reduce the level of uric acid in the patient's blood to improve the symptoms of gout patients and achieve the purpose of treating gout.

There are many crystal forms of febuxostat, and there are many articles and patent reports. The crystal form of febuxostat can be transformed into each other under different conditions (such as temperature, solvent, cooling rate, etc.), and the stability of the crystal form is poor, which makes it difficult to control the preparation and quality of the crystal form. The technical difficulty of product development.

Contents of the invention

The object of the present invention is to provide a febuxostat ligustrazine co-crystal and its preparation method and application, aiming at improving the stability of the crystal form of febuxostat, thereby solving the technical problem that the crystal form is difficult to control in the prior art .

In order to realize the above-mentioned purpose of the present invention, special adopt following technical scheme:

A febuxostat ligustrazine co-crystal shown in formula I:

Further, the febuxostat ligustrazine cocrystal includes the following characteristic peaks shown by the 2θ angles: 4.18±0.2°, 8.41±0.2°, 11.75±0.2°, 12.96±0.2°, 14.25±0.2°, 24.61±0.2° , 25.86±0.2°, 26.95°±0.2°.

Further, the febuxostat ligustrazine co-crystal includes the following characteristic peaks at 2θ angles: 12.68±0.2°, 16.27±0.2°, 17.87±0.2°, 22.53±0.2°, 24.22±0.2°.

Further, the space group of the febuxostat ligustrazine cocrystal is monoclinic, and the axis length α=90°, β=103.7±0.2°, γ=90°.

Further, the decomposition temperature of febuxostat ligustrazine co-crystal is 166-171°C.

A preparation method of the above-mentioned febuxostat ligustrazine co-crystal, which comprises:

The febuxostat solution and the ligustrazine solution respectively dissolved in the organic solvent are mixed, concentrated and then crystallized.

Further, the molar ratio of febuxostat in the febuxostat solution to ligustrazine in the ligustrazine solution is 0.8-1.2:1.

Further, the volume-mass ratio of the organic solvent to febuxostat or ligustrazine is (3-30):1.

Further, the organic solvent includes at least one of C1-C4 alcohols, ethers, esters, ketones or nitriles and combinations thereof;

Preferably, the C1-C4 alcohols include at least one of methanol, ethanol, propanol, isopropanol or butanol;

Preferably, the ethers include at least one of diethyl ether, methyl ethyl ether or petroleum ether;

Preferably, the esters include at least one of ethyl acetate, methyl acetate, propyl acetate or propyl formate;

Preferably, the ketones are acetone or butanone and combinations thereof;

Preferably, the nitriles are acetonitrile or propionitrile and combinations thereof.

A pharmaceutical composition, which comprises the above-mentioned febuxostat and ligustrazine co-crystal, and a pharmaceutically acceptable carrier.

A use of the above-mentioned febuxostat ligustrazine co-crystal in the preparation of medicines for treating or preventing gout.

Compared with the prior art, the beneficial effects of the present invention include, for example:

The present invention provides a new pharmaceutical co-crystal form of febuxostat, the crystal form of the febuxostat ligustrazine co-crystal is good, the crystallinity is high, and its solubility is large, and it can be used to develop into various preparations , for the preparation of medicines for treating or preventing gout.

The preparation method of the febuxostat ligustrazine co-crystal provided by the invention is simple in operation and difficult to form hydrates and solvates.

Description of drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following will briefly introduce the drawings that need to be used in the description of the embodiments or the prior art.

Fig. 1 is a schematic diagram of the crystal structure unit of febuxostat and ligustrazine according to the present invention.

Fig. 2 is the powder XRD pattern of the co-crystal of febuxostat and ligustrazine in Example 1.

Fig. 3 is the DSC graph of the co-crystal of febuxostat and ligustrazine in Example 1.

Fig. 4 is the powder XRD pattern of the febuxostat ligustrazine co-crystal after the stability test of Experimental Example 2.

Detailed ways

Embodiments of the present invention will be described in detail below in conjunction with examples, but those skilled in the art will understand that the following examples are only for illustrating the present invention, and should not be considered as limiting the scope of the present invention. Those who do not indicate the specific conditions in the examples are carried out according to the conventional conditions or the conditions suggested by the manufacturer. The reagents or instruments used were not indicated by the manufacturer, and they were all conventional products that could be purchased from the market.

At present, the crystal form of febuxostat can be transformed into each other under different conditions (such as temperature, solvent, cooling rate, etc.), and the stability of the crystal form is poor; at the same time, its solubility in water is very low, making it difficult to develop into corresponding Medicinal products.

In order to overcome the above defects, the inventor provided a febuxostat ligustrazine co-crystal through research and development, the structural formula of which is as follows:

In the present invention, the term "co-crystal" refers to "a crystalline material composed of two or more different molecules, usually pharmaceutical ingredients and co-crystal formers, in the same crystal lattice". According to this definition, pharmaceutical co-crystals can provide a new solid-state form of conventional pharmaceutical active ingredients. Therefore, the inventor utilizes drug co-crystal technology to solve the low solubility and crystal stability problems of febuxostat, in order to improve the bioavailability and stability of febuxostat, making febuxostat more efficient in the production process. Easy to process.

At the same time, ligustrazine, a pyrazine organic base, is often used as a food additive or food stabilizer, and its acute toxicity (LD ₅₀ ) is 1,400 mg/kg (oral administration to mice), 1,910 mg/kg (oral administration to rats) , 239 mg/kg (mouse injection), good safety, among which Ligustrazine Phosphate Sodium Chloride Injection has been used as a clinical drug. In this embodiment, the co-crystal of tetramethylpyrazine and febuxostat is used, which is safe and reliable, and can solve the problems of easy mutual conversion of febuxostat crystal forms and low solubility.

In febuxostat and ligustrazine co-crystal, the molar ratio of febuxostat to ligustrazine is 1:1. In its crystal structure unit, a carboxyl group on febuxostat and a nitrogen atom on ligustrazine form an O=C-OH...N hydrogen bond structure, and the crystal structure does not contain solvent molecules.

Febuxostat ligustrazine co-crystal has good stability and solubility, and is not easy to form hydrates or solvates, which can further promote the promotion and promotion of febuxostat ligustrazine co-crystal in medicine and product development. application.

Further, the febuxostat ligustrazine cocrystal includes the following characteristic peaks shown by the 2θ angles: 4.18±0.2°, 8.41±0.2°, 11.75±0.2°, 12.96±0.2°, 14.25±0.2°, 24.61±0.2° , 25.86±0.2°, 26.95°±0.2°; the radiation source is Cu-Kα.

Further, the febuxostat ligustrazine co-crystal includes the following characteristic peaks at 2θ angles: 12.68±0.2°, 16.27±0.2°, 17.87±0.2°, 22.53±0.2°, 24.22±0.2°; the radiation source is Cu -Kα.

Further, the space group of febuxostat ligustrazine eutectic is monoclinic system, and the axial length a= α=90°, β=103.7±0.2°, γ=90°.

The preparation method of the febuxostat and ligustrazine co-crystal of the present invention is relatively convenient, and is prepared by reacting febuxostat and ligustrazine in a suitable organic solvent to form a co-crystal, specifically comprising the following steps:

(1) Dissolving febuxostat and ligustrazine in an organic solvent respectively to obtain febuxostat solution and ligustrazine solution.

In step (1), preferably, the molar ratio of febuxostat to ligustrazine is 0.8-1.2:1; more preferably, the molar ratio of febuxostat to ligustrazine is 1:1.

Simultaneously, in step (1), preferably, the volume mass ratio of organic solvent and febuxostat or ligustrazine is (3～30): 1; Or is (10～20): 1; More preferably, organic solvent The volume-mass ratio with febuxostat or ligustrazine is (5-15):1;

Meanwhile, the organic solvent is one of C1-C4 low-carbon alcohols, ethers, esters, ketones or nitriles, or a mixed organic solvent of several kinds;

Preferably, the alcohol solvent is methanol, ethanol, propanol, isopropanol, butanol; ethers include ether, methyl ethyl ether, petroleum ether; esters include ethyl acetate, methyl acetate, propyl acetate, formic acid Propyl esters; ketones have acetone, butanone; nitriles have acetonitrile, propionitrile; thus, further, the solvent used in the present invention is one of the above-mentioned specific solvents, or two, three or even more solvents mixed organic solvents;

(2) Mix febuxostat solution and ligustrazine solution, concentrate and crystallize.

Preferably, in step (2), the crystallization temperature is 0-50°C, more preferably, the crystallization temperature is 10-25°C.

This embodiment also provides a pharmaceutical composition, which includes febuxostat and ligustrazine co-crystal, and a pharmaceutically acceptable carrier.

In order to release the active ingredient quickly, continuously and over a long period of time, the pharmaceutical composition of the present invention can be manufactured according to conventional methods disclosed in those skilled in the art. The administration route of the pharmaceutical composition of the present invention is oral administration, nasal inhalation, or parenteral administration. The formulation of the pharmaceutical composition can be powder, granule, tablet, emulsion, syrup, aerosol, soft capsule, hard capsule, sterile injection, sterile powder and the like.

Here, the term "pharmaceutically acceptable" means that the compound is physiologically acceptable when the compound is administered to humans, and does not cause allergic reactions such as gastrointestinal disturbances, dizziness, or systemic allergic reactions similar to these allergic reactions .

In the present invention, "pharmaceutically acceptable carrier" includes, but is not limited to: binders (such as microcrystalline cellulose, alginate, gelatin and polyvinylpyrrolidone), fillers (such as starch, sucrose, glucose and Anhydrous lactic acid), disintegrants (such as cross-linked PVP, cross-linked sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose), lubricants (magnesium stearate, hard Aluminum fatty acid, talc, polyethylene glycol, sodium benzoate), wetting agents (such as glycerin), surfactants (such as cetyl alcohol) and absorption enhancers, flavoring agents, sweeteners, diluents, packaging Coating agents, etc.

The test instrument used in the present invention can specifically refer to as follows:

The crystal structure was determined by X-ray single crystal diffractometer, full name: Agilent Gemini E single crystal diffractometer;

The powder XRD spectrum adopts the model X'Pert ³ Powder diffractometer produced by Holland PANalytical Company to measure;

Thermogravimetric analysis was measured by STA4 49C synchronous thermal analyzer from NETZSCH, Germany, using nitrogen atmosphere, and the heating rate was 10°C/min;

Infrared spectrum was measured by Spectrum Two infrared spectrometer from PerkinElmer, USA;

The NMR spectra were collected by a 400 MHz red NMR spectrometer produced by Bruker, Germany.

Example 1

This embodiment provides a febuxostat ligustrazine co-crystal, the preparation method of which is:

Dissolve 1.01 g of febuxostat in 15 mL of methanol; dissolve 0.43 g of ligustrazine in 5 mL of methanol, mix and stir the resulting two solutions, concentrate, cool to room temperature for crystallization, and filter to obtain 0.88 g of colorless crystals.

The ¹ H NMR of the crystal shows: δ: 13.43(s, 1H), 8.30(d, J=2.2Hz, 1H), 8.23(dd, J=8.9, 2.2Hz, 1H), 7.38(d, J=9.0 Hz, 1H), 4.01(d, J=6.5Hz, 2H), 2.66(s, 3H), 2.38(s, 12H), 2.05-2.14(m, 1H), 1.02(d, J=6.7Hz, 6H ).

The infrared spectrum of the crystal is at 2231±2cm ^-1 , 1683±2cm ^-1 , 1606±2cm ^-1 , 1434±2cm ^-1 , 1377±2cm ^-1 , 1294±2cm ^-1 , 1254±2cm ^-1 , 1010±2cm There are absorption peaks at ^-1 , 1175±2cm ^-1 , and 825±2cm ^-1 .

The powder XRD pattern of the crystal is shown in Figure 2. It can be seen from Figure 2 that the obtained crystals have 2θ angles of 4.18°, 8.41°, 11.75°, 12.96°, 14.25°, 24.22°, 24.61°, 25.86°, and 26.95° There are obvious diffraction peaks;

The DSC of the crystal is shown in Figure 3; it can be seen from Figure 3 that the decomposition temperature of the eutectic is 168.7±2°C.

The filtered solution was slowly evaporated at room temperature to obtain a single crystal of febuxostat ligustrazine. The schematic diagram of the structural unit of the crystal is shown in FIG. 1 .

Example 2

This embodiment provides a febuxostat ligustrazine co-crystal, the preparation method of which is:

Dissolve 35.0 g of febuxostat in 400 mL of acetonitrile, and dissolve 15.1 g of ligustrazine in 150 mL of acetonitrile, mix and stir the resulting two solutions, concentrate, cool to 5°C for crystallization, and obtain 38.2 g of colorless crystals after filtration.

The NMR, powder XRD diffraction and infrared spectrum tests of the crystal obtained in this example are all consistent with the results in Example 1, and the decomposition temperature is 169.3°C.

Example 3

This embodiment provides a febuxostat ligustrazine co-crystal, the preparation method of which is:

Dissolve 5.0 g of febuxostat in 80 mL of acetone, dissolve 2.2 g of ligustrazine in 30 mL of acetone, mix and stir the resulting two solutions, concentrate, cool to 15°C and crystallize to obtain 4.4 g of colorless crystals.

The NMR, powder XRD diffraction, and infrared spectrum tests of the crystal obtained in Example 3 are consistent with the results in Example 1, and its decomposition temperature is 168.9°C.

Example 4

This embodiment provides a febuxostat ligustrazine co-crystal, the preparation method of which is:

Dissolve 10.0 g of febuxostat in 250 mL of ethyl acetate, and dissolve 4.3 g of ligustrazine in 100 mL of ethyl acetate, mix and stir the two solutions, concentrate, cool to 20°C and crystallize to obtain 9.1 g of colorless crystals.

The NMR, powder XRD diffraction, and infrared spectrum tests of the crystal obtained in Example 4 are consistent with the results in Example 1, and its decomposition temperature is 169.3°C.

Experimental example 1

Accelerated stability test of febuxostat ligustrazine cocrystal 1:

Get an appropriate amount (about 6g) of the febuxostat ligustrazine eutectic crystal prepared by the method of Example 2, divide it into 3 parts, and place it in flat dishes numbered 1, 2 and 3, and then place the three flat dishes The dishes were respectively placed under the following conditions (storage condition 1: 4500±500lx light; storage condition 2: high temperature of 60°C; storage condition 3: relative humidity of 92.5 high humidity) for stability test. The test results are shown in Table 1:

Table 1 Stability test of febuxostat ligustrazine co-crystal

As can be seen from the experimental results, compared with the sample at the beginning of the experiment, during the whole experiment, the crystal form of febuxostat ligustrazine co-crystal did not transform, thus it can be seen that the febuxostat ligustrazine co-crystal form of the present invention The structure is stable and suitable for long-term storage.

Experimental example 2

Accelerated stability test of febuxostat ligustrazine cocrystal 1:

Take 6.0 grams of the febuxostat ligustrazine co-crystal obtained in Example 2, add it to 25 mL of water, and filter at 37 ° C for 24 hours to obtain 2.6 grams of sample. The obtained sample is subjected to powder XRD diffraction analysis, and the test results are shown in Figure 4 Show.

Before the experiment shown in Figure 1, the febuxostat ligustrazine co-crystal powder XRD diffraction pattern and the comparison of the febuxostat ligustrazine co-crystal powder XRD diffraction pattern after the experiment shown in Figure 4 show that after the experiment, the febuxostat ligustrazine co-crystal powder XRD diffraction pattern of the present invention The crystal form of the Sutent and Ligustrazine co-crystal has not changed, so it can be seen that the Febuxostat and Ligustrazine co-crystal of the present invention has good structural stability and does not form hydrates.

Experimental example 3

Solubility test of febuxostat ligustrazine cocrystal in pure water

The saturated solution of febuxostat at 37°C and the obtained febuxostat ligustrazine co-crystal solution obtained after filtration in Experimental Example 2 were respectively taken to measure their solubility in water;

The results showed that: the solubility of febuxostat was 0.012mg/mL; the solubility of febuxostat ligustrazine co-crystal was 0.150mg/mL. It shows that after febuxostat and Ligustrazine form a co-crystal, the solubility of febuxostat is greatly improved, which is about 13 times that of febuxostat.

The febuxostat ligustrazine co-crystal provided by the present invention has good stability, can be stored for a long time, and even after re-dissolving and crystallizing, its crystal structure will not change; Crystals also have good solubility, and these provide new ideas for the development of febuxostat products. Further, the preparation method of the febuxostat ligustrazine co-crystal of the present invention is simple and convenient, which also makes it suitable for large-scale industrial production and preparation.

While particular embodiments of the invention have been illustrated and described, it should be appreciated that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

Claims (10)

1. Febuxostat ligustrazine eutectic shown in a kind of Formulas I：

2. Febuxostat ligustrazine eutectic according to claim 1, which is characterized in that the Febuxostat ligustrazine is total Crystal includes characteristic peak shown in the angles following 2 θ：4.18±0.2°、8.41±0.2°、11.75±0.2°、12.96±0.2°、 14.25±0.2°、24.61±0.2°、25.86±0.2°、26.95°±0.2°。

3. Febuxostat ligustrazine eutectic according to claim 2, which is characterized in that the Febuxostat ligustrazine is total Crystal includes characteristic peak shown in the angles following 2 θ：12.68±0.2°、16.27±0.2°、17.87±0.2°、22.53±0.2°、 24.22±0.2°。

4. Febuxostat ligustrazine eutectic according to claim 1, which is characterized in that the Febuxostat ligustrazine is total The space group of crystal is monoclinic system, axial length α=90 °, β=103.7 ± 0.2 °, γ=90 °.

5. Febuxostat ligustrazine eutectic according to claim 1, which is characterized in that the Febuxostat ligustrazine is total The decomposition temperature of crystal is 166~171 DEG C.

6. a kind of eutectiferous preparation method of Febuxostat ligustrazine, feature as described in any one of Claims 1 to 5 exists In comprising：

Febuxostat solution and the mixing of ligustrazine solution in organic solvent, crystallization after concentration will be dissolved respectively.

7. the eutectiferous preparation method of Febuxostat ligustrazine according to claim 6, which is characterized in that the Fei Busuo The molar ratio of Febuxostat in smooth solution and the ligustrazine in the ligustrazine solution is 0.8~1.2：1.

8. the eutectiferous preparation method of Febuxostat ligustrazine according to claim 6, which is characterized in that described organic molten Agent includes at least one of alcohols, ethers, esters, ketone or nitrile of C1-C4 and combinations thereof；

Preferably, the alcohols of the C1-C4 includes at least one of methanol, ethyl alcohol, propyl alcohol, isopropanol or butanol；

Preferably, the ethers includes at least one of ether, ethyl methyl ether or petroleum ether；

Preferably, the esters include at least one of ethyl acetate, methyl acetate, propyl acetate or propyl formate；

Preferably, the ketone is acetone or butanone and combinations thereof；

Preferably, the nitrile is acetonitrile or propionitrile and combinations thereof.

9. a kind of pharmaceutical composition, which is characterized in that it includes such as Claims 1 to 5 any one of them Febuxostat Rhizoma Chuanxiong Piperazine eutectic and pharmaceutically acceptable carrier.

10. a kind of as Claims 1 to 5 any one of them Febuxostat ligustrazine eutectic is being prepared for treating or preventing Purposes in the drug of gout.