CN102093309B - Novel crystal forms of Febuxostat and preparation method of novel crystal forms - Google Patents

Abstract

The invention belongs to the technical field of pharmaceutical chemistry, particularly relates to three crystal forms comprising H, I and J of 2-(3-cyan-4-isobutoxy)phenyl-4-methyl-5-thiazole formic acid (Febuxostat) and a preparation method of the three crystal forms. The invention also provides X-ray powder diffraction characteristic absorption peaks and infrared absorption peaks of the three crystal forms. The characteristic absorption peaks occur at the reflected angles 2 theta of about 6.71, 7.19, 10.03, 11.10, 12.96, 13.48, 15.78, 17.60 and 22.15 degrees in an X-ray powder diffraction pattern of the crystal forms. The invention further relates to a pharmaceutical composite containing the novel crystal forms and application of the novel crystal forms in preparation of medicaments for treating over-high uric acid-related diseases.

Description

Crystal form of febuxostat and preparation method thereof

This application is a divisional application of the invention patent application with the Chinese application number 200610095263.0, the application date is December 7, 2006, and the invention name is "the crystal form of febuxostat and its preparation method". the

technical field

The invention belongs to the technical field of medicinal chemistry, and in particular relates to three new febuxostat (febuxostat) new crystal forms H, I and J and a preparation method thereof, a pharmaceutical composition containing these three new crystal forms, and a method for manufacturing febuxostat Use in medicine for diseases related to hyperuricemia. the

technical background

Febuxostat, its chemical name is: 2-(3-cyano-4-isobutoxy)phenyl-4-methyl-5-thiazolecarboxylic acid. the

Chemical Structure:

Febuxostat has been submitted for new drug registration in the US FDA for the treatment of diseases related to hyperuricemia, such as gout, for reducing uric acid in the blood. Febuxostat has various crystal forms. Chinese patent CN1275126 records A, B, C, D, G and amorphous forms and preparation methods of this compound invented by Teijin Corporation. Among them, crystal A exists in a metastable crystal form; crystal B is obtained from hydrate G by drying under reduced pressure; crystal C is prepared by solvent-mediated polymorph conversion; crystal D is a methanolate, which is decompressed at low temperature Under high pressure, it can be obtained by recrystallization from methanol solvent or a mixed solvent of methanol and water; crystal G is a hydrate. According to infrared spectrum analysis, crystal A has characteristic absorption at about 1678cm-1 that can distinguish it from other crystal forms; crystal B has characteristic absorption at about 1715, 1701 and 1682cm-1 that can distinguish it from other crystal forms Crystal C has characteristic absorptions at about 1703 and 1705 cm-1 that can distinguish it from other crystal forms; crystal D has a characteristic absorption at about 1705 cm-1 that can distinguish it from other crystal forms characteristic absorption; and Crystal G has characteristic absorptions at about 1703 and 1684 cm-1 that distinguish it from other crystalline forms. In the process of researching febuxostat, the inventor unexpectedly found that there are three other crystal forms of febuxostat, which are different from any of the six crystal forms disclosed in CN1275126. These three new crystal forms are The crystal form does not contain water and other solvents, and its crystal form has good stability, which is suitable for the preparation process and long-term storage. the

Contents of the invention

The purpose of the present invention provides three new febuxostat crystal forms. the

The first crystalline form of febuxostat of the present invention, the crystalline form is named H-form, and its x-ray powder diffraction (XRPD) characteristic absorption peak (2θ) value is about 6.71, 7.19, 10.03, 11.10, 12.96 , 13.48, 15.78, 17.60 and 22.15°; see Figure 1. The crystal has characteristic absorption peaks at about 2238, 1701, 1678 and 1116 cm ^-1 through infrared analysis, which can distinguish it from other crystal forms, see Figure 2.

The second novel crystalline form of febuxostat disclosed by the present invention is named as type I, and the x-ray powder diffraction (XRPD) characteristic absorption peak (2θ) value of this crystalline form is about: 3.28, 6.58 , 12.70, 13.34, 19.97, 24.26 and 25.43°, see Fig. 3. The crystal is analyzed by infrared, and its infrared spectrum has characteristic absorption peaks at about 1730, 1253 and 1097 cm ^-1 that can distinguish it from other crystal forms, as shown in Figure 4 .

The third new crystalline form of febuxostat disclosed by the present invention is named J-type, and the x-ray powder diffraction (XRPD) characteristic absorption peak (2θ) value of this crystalline form is about: 3.07, 12.25 , 13.16, 25.21 and 26.86°, see Fig. 5. The crystal has been analyzed by infrared, and its infrared spectrum has characteristic absorptions at about 1686 and 1655 cm ^-1 that can distinguish it from other crystal forms, see Figure 6.

In the present invention, the measurement of the 2θ value uses a CuKα light source with an accuracy of ±0.2°. Therefore, the "about" in the above-mentioned "x-ray powder diffraction (XRPD) characteristic absorption peak (2θ) value of the crystal form is about" should be It is defined as 2θ±0.2°, which means that the above-mentioned 2θ value allows a certain reasonable error range, and the error range is ±0.2°. the

Another object of the present invention is to disclose a preparation method of a new crystal form of febuxostat. the

The preparation method of febuxostat crystal form H of the present invention comprises: dissolving febuxostat in a R ₁ CN solvent with a mass volume ratio (g/ml) of 1:30 to 1:100, heating and dissolving, Heat preservation and crystallization in a water bath at a heat preservation temperature of 15-50°C, filter, and dry at 100°C under normal pressure for 12 hours to obtain crystal form H, wherein R ₁ represents an alkyl or haloalkyl group, such as methyl, ethyl, propyl, Chlorine replaces ethyl, and the specific compound can be acetonitrile, propionitrile, butyronitrile and chloropropionitrile, etc., and the preferred solvent is acetonitrile, propionitrile or a mixture thereof. The definition of R ₁ below is the same as this.

The mass volume ratio of the above-mentioned febuxostat to the R ₁ CN solvent is preferably 1:40, and the temperature of the water bath during crystallization is preferably 25°C. The preparation method of febuxostat crystal form I of the present invention comprises: dissolving febuxostat in a R ₁ CN solvent with a mass volume ratio (g/ml) of 1:30 to 1:100, heating and dissolving, In a static state, extract the solvent under reduced pressure at 20-60°C until crystallization, preferably at 50°C, filter, and dry at 80°C under reduced pressure for 24 hours to obtain crystal form I; wherein, _R1 is as defined above; preferred solvents are acetonitrile and propionitrile Or their mixture; the mass volume ratio of febuxostat and R ₁ CN solvent is 1:50, wherein R ₁ is defined. The method for the febuxostat crystal form J of the present invention comprises: dissolving febuxostat in a R ₁ CN solvent with a mass-volume ratio (g/ml) of 1:30 to 1:100, heating and dissolving, Static crystallization, after suction filtration, under normal pressure, heating and melting, precipitation at room temperature, to obtain crystal form J, wherein, _R In the definition, the preferred solvent is acetonitrile, propionitrile or their mixture, wherein febuxostat and The mass volume ratio of R ₁ CN solvent is 1:30.

Another object of the present invention is to provide a pharmaceutical composition, comprising the crystalline form H, crystalline form I or crystalline form J of febuxostat of the present invention and a pharmaceutically acceptable adjuvant or carrier, wherein non- The average particle size of the crystalline form of Buxostat is more than 1 μm and less than 50 μm. The preparation forms of the pharmaceutical composition can be oral preparations, injections and external preparations; the oral preparations can be tablets, capsules, granules, controlled-sustained-release tablets or capsules, orally disintegrating, dissolving and dispersing tablets. Various preparations can be prepared by using corresponding excipients known to those skilled in the art and using corresponding well-known preparation techniques for pharmaceutical preparations. The effective therapeutic dose is 10-200 mg, preferably 40-120 mg. the

Specifically, the febuxostat new crystal form of the present invention contained in each dose in the above-mentioned oral solid dosage form is 20mg, 40mg, 80mg, 120mg, and said "every dose" means that each tablet, each (capsule) ), etc., use 1-2 times a day, 1-4 doses each time. the

When the pharmaceutical composition of the present invention is a solid oral preparation, it may contain commonly used excipients, such as binders, fillers, diluents, tableting agents, lubricants, disintegrating agents, coloring agents, flavoring agents and lubricants, Tablets may be coated if necessary. the

The filler (excipient) includes lactose, mannitol, xylitol, starch, pregelatinized starch, cornstarch, microcrystalline cellulose, sorbitol, and they can be used alone or in combination. The aforementioned fillers are preferably lactose, mannitol, and microcrystalline cellulose. the

The disintegrants include low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, polyvinylpyrrolidone, starch, microcrystalline cellulose, and sodium carboxymethylcellulose, which can be used alone or in combination. The aforementioned disintegrants are preferably low-substituted hydroxypropyl cellulose, starch, and polyvinylpyrrolidone. the

The binder includes hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, starch slurry, polyvinyl alcohol, microcrystalline cellulose, water, ethanol solutions of various concentrations, and they can be used alone Mixtures are also possible. The aforementioned binder is preferably microcrystalline cellulose, hydroxypropyl methylcellulose, and ethanol solutions of various concentrations. the

Described lubricant comprises stearic acid, magnesium stearate, calcium stearate, palmitic acid, aluminum silicate, stearamide, talc, silicon dioxide, and they can be used alone or in combination. The aforementioned lubricants are preferably magnesium stearate and aluminum silicate. the

If necessary, other excipients, such as sweeteners, colorants, taste-masking agents, and stabilizers, can also be added to the pharmaceutical composition of the present invention. the

The pharmaceutical composition of the present invention can be prepared according to any conventional method used in the preparation of oral solid preparations, such as: wet granulation and compression, direct compression of powder, and capsules after granulation. Using conventional coating equipment, the pharmaceutical composition can be film-coated to make film-coated tablets or sugar-coated tablets. Coating bases include celluloses, acrylic resins, sugars such as hydroxypropyl methylcellulose, Eudragit L, and sucrose. Plasticizers, anti-sticking agents, and opacifying agents can also be added to the coating matrix. the

In the process of preparing the pharmaceutical composition of the present invention, the wetting agents that can be added include ethylene glycol, propylene glycol, sorbitol, glycerin and fatty acid esters thereof, these wetting agents can be used alone or in combination of two or more Use in any combination. the

The solid pharmaceutical composition of the present invention can be obtained in a conventional dosage form by sequentially performing a granulation step, an encapsulation step or a tableting step, and a coating step (if necessary), usually a tablet or surface-coated tablet, powder , granules, top-coated granules or capsule dosage forms. Said tablets include conventional tablets, sustained-release tablets, buccal tablets, orally disintegrating tablets, chewable tablets, effervescent tablets and the like. the

The pharmaceutical composition of the present invention can be prepared by conventional techniques of pharmacy. For example, wet granulation and direct compression of dry powder can be used for tablets. the

The present invention also provides the use of H, I, and J crystal forms of febuxostat in the manufacture of medicines for treating diseases related to hyperuricemia, and said diseases related to hyperuricemia mainly refer to hyperuricemia Gout caused by cancer patients, high blood uric acid caused by radiotherapy and chemotherapy, and the disease of high blood uric acid. the

According to animal dog experiments, the febuxostat crystal form H, crystal form I or crystal form J of the present invention all have strong activity of reducing uric acid in blood in the body. the

Description of drawings

Fig. 1 is the X-ray diffraction pattern of H crystal form of febuxostat in Example 1 of the present invention. the

Fig. 2 is the infrared absorption spectrum diagram of the H crystal form of febuxostat in Example 1 of the present invention. the

Fig. 3 is the X-ray diffraction diagram of the I crystal form of febuxostat in Example 2 of the present invention. the

Fig. 4 is the IR absorption spectrum of febuxostat in Example 2 of the present invention. the

Fig. 5 is an X-ray diffraction diagram of the J crystal form of febuxostat in Example 3 of the present invention. the

Fig. 6 is an infrared absorption spectrum diagram of the J crystal form of febuxostat in Example 3 of the present invention. the

Detailed ways

The present invention will be further described in conjunction with the examples, which can enable those skilled in the art to better understand the present invention, but does not limit the scope of the present invention in any way. the

Example 1

Put 20g of febuxostat in a 1000ml two-necked flask, add 800ml of acetonitrile, heat and stir in an oil bath at 80°C until dissolved, stop heating until the raw material is completely dissolved, keep warm and crystallize in an oil bath at room temperature (20°C), and let stand After 2 hours, filter, and vacuum-dry at 100°C for 12 hours to obtain crystalline powder. Measure its X powder diffraction pattern and infrared spectrum pattern, according to powder diffraction pattern and infrared absorption spectrum, what obviously produces is crystal form H, see Fig. 1 and Fig. 2. the

Example 2

Put 20g of febuxostat in a 2000ml two-neck flask, add 1000ml of acetonitrile, heat and stir until dissolved, stop heating until the raw material is completely dissolved, pump under reduced pressure at 50°C until crystals precipitate, dry at 80°C for 24 hours under reduced pressure, and obtain crystals powder. Measure its X powder diffractogram and infrared spectrogram, according to powder diffractogram and infrared absorption spectrum, what obviously produces is crystal form I, see Fig. 3 and Fig. 4. the

Example 3

Put 20g of febuxostat in a 1000ml two-necked flask, add 600ml of acetonitrile, heat and stir until dissolved, stop heating until the raw material is completely dissolved, and let stand for crystallization. After suction filtration, after melting at 210°C under normal pressure, crystallization at room temperature. The X-powder diffraction pattern and infrared absorption spectrum obtained by X powder diffraction measurement and infrared spectrum measurement show that the generated crystal form is crystal form J, see Figure 5 and Figure 6. the

Example 4

Put 20g of febuxostat in a 2000ml two-necked flask, add 1200ml of propionitrile, heat and stir until dissolved, stop heating until the raw material is completely dissolved, pump under reduced pressure at 50°C until crystals are precipitated, and dry at 80°C for 24 hours under reduced pressure to obtain Form I powder. the

Example 5

Febuxostat Form I Capsules (Specification: 120mg)

Prepare each capsule containing 120mg febuxostat as follows:

Prescription: febuxostat I crystal form 120g, butanediol 1.2ml, starch 25g, made into 1000 capsules. the

Method: Wet 120g febuxostat H crystal form and 25g starch with 1.2ml 10% butanediol aqueous solution, mix well, sieve and granulate, dry at 60°C, granulate, and use a capsule filling machine under pressure filling. the

Example 6

Febuxostat Form H Tablets

Prescription: febuxostat H crystal form 80g, pregelatinized starch 110.5g, low-substituted hydroxypropyl methylcellulose 10.5g, magnesium stearate 0.8g, made into 1000 tablets

Preparation process: Febuxostat H crystal form, pregelatinized starch, low-substituted hydroxypropyl methylcellulose and magnesium stearate are respectively passed through 100 mesh, mixed evenly, and compressed into tablets. the

Example 7

Febuxostat Form J Tablets

Prescription: febuxostat J crystal form 20g, starch 35g, polyvinylpyrrolidone 5.5g, magnesium stearate 0.5g, made into 1000 tablets. the

Preparation process: Febuxostat J crystal form, starch, polyvinylpyrrolidone and magnesium stearate are respectively passed through 100 mesh, mixed evenly, and compressed into tablets. the

Stability test

Take the H, I, and J crystals of febuxostat respectively, and put an appropriate amount of each crystal into the plates numbered H1, I1, J1; H2, 12, J2; H3, I3, J3, and place them as follows: Stability test under different conditions (storage condition 1: 4500lx±500lx light, storage condition 2: high temperature of 60°C, storage condition 3: relative humidity of 92.5 high humidity). The measurement results are shown in Tables 1-3. the

Table 1 Stability investigation under strong light irradiation (4500lx±500lx)

Table 2 High temperature experiment stability investigation (60±2℃)

Table 3 High humidity experiment stability investigation (RH90±5%)

Results It was confirmed by infrared spectrum and X-ray powder diffraction analysis that the infrared spectrum and X-ray powder diffraction of crystal forms H, I and J did not change, which proved that they still kept the original crystal form. the

The total amount of impurities in each polymorph did not change throughout the trial period compared to before the trial started. It is proved that the crystal form of the present invention is quite stable and suitable for the manufacture and long-term storage of medicaments. the

Claims (6)

1. the crystal formation J of a TMX-67, it is characterized in that: reflection angle 2 θ of the X-ray powder diffraction figure of this crystal formation have the charateristic avsorption band like Figure of description 5.

2. method for preparing Febuxostat crystal form J as claimed in claim 1; Its process comprises: TMX-67 is dissolved in the acetonitrile solvent that mass volume ratio is 1: 30～1: 100 grams per milliliter, after the heating for dissolving, leaves standstill crystallization; Behind the suction filtration; Under the normal pressure, room temperature is separated out behind the heating and melting, obtains crystal formation J.

3. method as claimed in claim 2 is characterized in that: the mass volume ratio of TMX-67 and acetonitrile is 1: 30 grams per milliliter.

4. a pharmaceutical composition comprises described Febuxostat crystal form J of claim 1 and pharmaceutically acceptable auxiliary material.

5. pharmaceutical composition as claimed in claim 4, the median size of Febuxostat crystal form J is below 50 μ m more than the 1 μ m.

6. the utilization of the described Febuxostat crystal form J of claim 1 in the medicine of making treatment and the too high diseases associated of blood uric acid.

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