WO2008067773A1

WO2008067773A1 - New crystal types of febuxostat and their preparation methods

Info

Publication number: WO2008067773A1
Application number: PCT/CN2007/071194
Authority: WO
Inventors: Xingguo Zhou; Xuemin Tang; Jie Deng; Wenrun Ye; Jie Luo; Daolin Zhang; Bin Fan
Original assignee: Chongqing Pharmaceutical Research Institute Co., Ltd.
Priority date: 2006-12-07
Filing date: 2007-12-06
Publication date: 2008-06-12
Also published as: CN1970547B; CN1970547A

Abstract

The present application belongs to pharmaceutical technology field. Three new crystal types of 2-(3-cyano-4-isobutyloxy) phenyl-4-methyl-5-thiazolecarboxylic acid (febuxostat) i.e. crystal types H, I and J and their preparation methods. Pharmaceutical compositions containing the new crystal types and the uses of crystal types as pharmaceutical medicaments for treatment diseases relating to excessive uric acid. Furthermore, the present application discloses X-ray diffraction characteristic absorption peak and IR absorption peak.

Description

New crystalline form of febuxostat and preparation method thereof

The invention belongs to the technical field of medicinal chemistry, and specifically relates to three novel crystal forms H, I and J of febuxostat and a preparation method thereof, a pharmaceutical composition containing the three new crystal forms, and the same thereof. The use of a medicament for the treatment of a disease associated with hyperuricemia. Background technique

Febuxostat, its chemical name is: 2-(3-cyano-4-isobutoxy)phenyl _4-mercapto-5-thiazolyl acid.

Chemical Structure:

Febuxostat has been registered with the US FDA for the treatment of diseases associated with high levels of uric acid, such as gout, to lower uric acid in the blood. There are a variety of crystal forms of febuxostat. Chinese patent CN1275126 describes polymorphs A, B, C, D, G, and amorphous forms thereof, which are invented by Teijin Corporation, and which are invented by the Japanese Teijin Corporation. Wherein, crystal A exists in a metastable crystal form; crystal B is obtained by hydrated G by drying under reduced pressure; crystal C is prepared by solvent-mediated polymorphic conversion; crystal D is a decyl alcoholate, which is at a low temperature. Under reduced pressure, it is obtained by recrystallization from a decyl alcohol solvent or a mixed solvent of decyl alcohol and water; and crystal G is a hydrate. According to infrared spectroscopy, crystal A has a characteristic absorption at about 1678 cm- ¹ which distinguishes it from other crystal forms; crystal B has a difference between 1715, 1701 and 1682 cm- ¹ to distinguish it from other crystal forms. Characteristic absorption; crystal C has characteristic absorption at about 1703 and 1705 cm which can distinguish it from other crystal forms; crystal D has a characteristic absorption at about 1705 cm- ¹ which can distinguish it from other crystal forms. And crystal G has characteristic absorption at about 1703 and 1684 cm- ¹ that distinguishes it from other crystal forms. In the process of studying febuxostat, the present inventors unexpectedly discovered that there are three other crystal forms of febuxostat, which are different from any of the six crystal forms disclosed in CN1275126, the three new crystal forms. In the absence of water and other crystalline forms of the solvent, the crystal form has good stability and can be used for the manufacture of a medicament for treating diseases associated with hyperuricemia, and is suitable for the formulation process and long-term storage. Summary of the invention

The object of the present invention provides three crystal forms of febuxostat.

The first non-busvastatin crystal form of the present invention, the crystal form is named H type, and the x-ray ray powder diffraction (XRPD) characteristic absorption peak (2 Θ ) 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 crystals have characteristic absorption peaks at about 2238, 1701, 1678, and 1116 cm ¹ that can be distinguished from other crystal forms by infrared analysis, as shown in FIG.

The second non-bustaster new crystal form disclosed by the present invention, the crystal form is named I type, and the X-ray ray powder diffraction (XRPD) characteristic absorption peak (2 Θ ) value of the crystal form is about 3.28, 6.58, 12.70, 13.34, 19.97, 24.26 and 25.43°, see Figure 3. The crystal was analyzed by infrared, and its infrared spectrum has characteristic absorption peaks at about 1730, 1253 and 1097 cu ¹ which can distinguish it from other crystal forms, as shown in Fig. 4.

The third novel form of febuxostat disclosed in the present invention, the crystal form is named J type, and the X-ray ray powder diffraction (XRPD) characteristic absorption peak (2 Θ ) value of the crystal form is about 3.07, 12.25, 13.16, 25.21 and 26.86°, see Figure 5. The crystal was analyzed by infrared, and its infrared spectrum has characteristic absorption at about 1686 and 1655 cm" which distinguishes it from other crystal forms, as shown in Fig. 6.

In the present invention, the measurement of the 2 Θ value is performed using a CuKa light source with an accuracy of ± 0.2°. Therefore, the above-mentioned "X-ray ray powder diffraction (XRPD) characteristic absorption peak (2 Θ ) value of the crystal form is approximately "about" "It should be defined as 2 Θ ± 0.2°, which means that the 2 Θ value taken above allows a reasonable margin of error with an error range of ± 0.2°.

Another object of the invention is to disclose a process for the preparation of a new form of febuxostat.

In one aspect, the preparation method of the febuxostat form H of the present invention comprises: tempering a solution of febuxostat in a solvent of CN at a temperature of about 15 to 50 C, wherein the alkyl group or the alkyl group is represented by an alkyl group or an alkyl group. . In a more specific technical solution, the mass to volume ratio (g/ml) of the febuxostat to the RN solvent in the solution is about 1:30 to 1:100, preferably about 1:35 to 1:50. More preferably, it is 1:40; if it needs to be dissolved by heating; it is subjected to thermal crystallization by, for example, a water bath, and the crystallization tempering temperature is preferably about crystallization and can be filtered if necessary; optionally at about 80-120 C under normal pressure. Drying for a suitable period of time, for example, about 8-24 hours, preferably about 12 hours (both under reduced pressure and atmospheric pressure) to obtain substantially dry H-type crystals; preferably fluorenyl, ethyl, propyl, chloro-substituted ethyl, Specific examples of the CN solvent may be acetonitrile, propionitrile, butyronitrile, chloropropionitrile or the like, preferably acetonitrile, propionitrile or a mixture thereof.

In yet another aspect, the method of the febuxostat Form I of the present invention comprises: optionally at rest In the state, a solution of febuxostat in a solvent of CN is decompressed to a crystal at a temperature of 20 to 60, wherein an alkyl group or an alkyl group is represented. In a more specific embodiment, the mass to volume ratio (g/ml) of the febuxostat to the CN solvent in the solution is preferably from about 1:30 to 1:100, preferably about 1:50; if heating is required Dissolving; at a standstill, the temperature at which the solvent is withdrawn under reduced pressure is preferably about to be filtered if necessary after crystallization; optionally drying under reduced pressure, preferably under reduced pressure for a suitable period of time, for example 24 hours, to obtain substantially dry Form I; preferably fluorenyl, ethyl, propyl, chloro-substituted ethyl, preferred solvents are acetonitrile, propionitrile or mixtures thereof.

In still another aspect, the method of the non-buxostat form J of the present invention comprises: heating and melting febuxostat, followed by crystallization by cooling, for example, by natural cooling or forced cooling, especially rapid cooling to room temperature. In a more specific embodiment, the febuxostat is dissolved in the RN solvent, and the mass to volume ratio (g/ml) of the febuxostat to the RN solvent is preferably 1:30 to 1:100, more preferably 1 : 30; if necessary, can be dissolved by heating, and then decrystallized, for example, static crystallization; optionally, suction filtration, and then the product obtained by suction filtration, for example, is heated and melted under normal pressure, and then cooled and crystallized to obtain a crystal form J; Alkyl or haloalkyl, preferably decyl, ethyl, propyl, chloro substituted ethyl, preferred solvents are acetonitrile, propionitrile or mixtures thereof.

A further object of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of febuxostat Form H, Form I or Form J of the present invention and a pharmaceutically acceptable adjuvant or carrier, wherein The bucystat form preferably has an average particle size suitable for the process, for example, 1 μm or more and 50 μm or less. Examples of the preparation form of the pharmaceutical composition may be an oral preparation, an injection and an external preparation; and the oral preparation may be, for example, a tablet, capsule, granule, controlled release tablet or capsule, orally disintegrated, dissolved and dispersed. Tablets. The various preparations can be prepared by the corresponding known pharmaceutical preparation techniques using corresponding excipients known to those of ordinary skill in the art. The effective therapeutic amount may be, for example, 10 to 200 mg, preferably 40 to 120 mg.

More specifically, the above-mentioned oral solid dosage form contains 20 mg, 40 mg, 80 mg, or 120 mg of the febuxostat crystal form of the present invention per dose, and the "per dose" means each tablet. , each capsule (gelatin), etc., use 1 ~ 2 times a day, 1 ~ 4 doses each time.

The pharmaceutical composition of the present invention may contain a usual excipient such as a binder, a filler, a diluent, a tablet, a lubricant, a disintegrant, a coloring agent, a flavoring agent, and a lubricant when it is a solid oral preparation. The tablets can be coated if necessary.

Examples of the filler (excipient) include lactose, mannitol, xylitol, starch, pregelatinized starch, corn starch, microcrystalline cellulose, sorbitol, which can be used alone It can also be used in combination. The aforementioned filler is preferably lactose, mannitol or microcrystalline cellulose. Examples of the disintegrant include low-substituted hydroxypropylcellulose, crosslinked polyvinylpyrrolidone, polyvinylpyrrolidone, starch, microcrystalline cellulose, and sodium carboxymethylcellulose, which may be used singly or in combination. The above disintegrant is preferably a low-substituted hydroxypropylcellulose, a starch, or a polyvinylpyrrolidone.

Examples of the binder include hydroxypropyl decyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, starch syrup, polyvinyl alcohol, microcrystalline cellulose, water, various concentrations of ethanol solution, which can It can also be used alone or in combination. The aforementioned binder is preferably microcrystalline cellulose, hydroxypropyl decyl cellulose, various concentrations of ethanol solution.

Examples of the lubricant include stearic acid, magnesium stearate, stearic acid 5, palmitic acid, aluminum silicate, stearic acid amide, talc, and silica, which may be used singly or in combination. The aforementioned lubricant is preferably magnesium stearate or aluminum silicate.

If desired, other excipients such as sweeteners, colorants, taste masking agents, stabilizers may also be added to the pharmaceutical compositions of the present invention.

The pharmaceutical composition of the present invention can be prepared according to any of the conventional methods for preparing an oral solid preparation, such as: wet granulation tablet, direct tablet compression, and granulation. The pharmaceutical composition can be coated into a film-coated tablet or a sugar-coated tablet using a conventional coating device. The coating base includes celluloses, acrylics, saccharides such as hydroxypropyl thioglycolate, Eudragit L, sucrose. A plasticizer, an anti-adhesive agent, and an opacifier may also be added to the coating base.

In the preparation of the pharmaceutical composition of the present invention, wetting agents which may be added include ethylene glycol, propylene glycol, sorbitol and glycerin and fatty acid esters thereof, and these wetting agents may be used singly or in the form of two or more of them. Use in any combination.

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 a surface coated tablet, a powder. , granules, surface coated granules or capsule dosage forms. The tablets include conventional tablets, sustained release tablets, buccal tablets, orally disintegrating tablets, chewable tablets, effervescent tablets and the like.

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

The present invention also provides the use of the crystalline forms of febuxostat of H, I, and J in the manufacture of a medicament for treating diseases associated with hyperuricemia, said hyperacic acid-related diseases mainly referring to hyperuricemia. Caused by gout, high blood uric acid caused by radiotherapy and chemotherapy in cancer patients, and a condition of hyperuricemia.

According to the animal dog test, the form of H, Form I or Form J of febuxostat of the present invention It has strong uric acid activity in the blood, and it also has good stability. DRAWINGS

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is an X-ray diffraction pattern of the H-form of febuxostat according to Example 1 of the present invention.

Fig. 2 is a chart showing the infrared absorption spectrum of H-form of febuxostat according to Example 1 of the present invention. Figure 3 is a X-ray diffraction pattern of Form I of febuxostat according to Example 2 of the present invention.

Fig. 4 is a chart showing the infrared absorption spectrum of Form I of febuxostat according to Example 2 of the present invention. Fig. 5 is a J-type X-ray diffraction pattern of the non-busestat of Example 3 of the present invention.

Fig. 6 is a chart showing the infrared absorption spectrum of J crystal form of febuxostat according to Example 3 of the present invention. detailed description

The present invention will be further understood by those skilled in the art, and the scope of the invention is not limited in any way. Example 1

20 g of febuxostat was placed in a 1000 ml two-necked flask, 800 ml of acetonitrile was added, and the mixture was heated and stirred in an oil bath until dissolved. The raw material was completely dissolved, and the heating was stopped. The mixture was allowed to stand at room temperature for 20 hours in an oil bath, allowed to stand for 2 hours, and filtered. After drying in a vacuum for 12 hours, a crystalline powder was obtained. The X powder diffraction pattern and the infrared spectrum were measured. According to the powder diffraction pattern and the infrared absorption spectrum, it was apparent that the crystal form H was formed, as shown in Fig. 1 and Fig. 2.

20 g of febuxostat was placed in a 2000 ml two-necked flask, and 1000 ml of acetonitrile was added thereto, and the mixture was stirred while heating until dissolved. The raw material was completely dissolved, heating was stopped, and the crystal was precipitated under reduced pressure, and dried under reduced pressure for 24 hours to obtain a crystalline powder. The X powder diffraction pattern and the infrared spectrum were measured. According to the powder diffraction pattern and the infrared absorption spectrum, it was apparent that the crystal form I was formed, as shown in Figs. 3 and 4. Example 3

20 g of febuxostat was placed in a 1000 ml two-necked flask, 600 ml of acetonitrile was added, and the mixture was heated and stirred until dissolved. The raw material was completely dissolved, the heating was stopped, and the crystal was allowed to stand for standing. After suction filtration, it is condensed at room temperature after atmospheric pressure melting. The X-powder diffraction pattern and infrared absorption spectrum are determined by X powder diffraction measurement and infrared spectroscopy, and the resulting crystal form is crystal form J, as shown in Fig. 5. Example 4

20 g of febuxostat was placed in a 2000 ml two-necked flask, and 1200 ml of propionitrile was added thereto, and the mixture was heated and stirred until dissolved. The raw material was completely dissolved, the heating was stopped, and the crystal was precipitated under reduced pressure, and dried under reduced pressure for 24 hours, and the obtained powder was analyzed. Confirmed to be Form I powder "· Example 5

Non-Butstatin Form I Capsule (Specification: 120mg)

The 120 mg febuxostat gum granules were prepared as follows:

Prescription: 120 g of febuxostat I crystal form, 1.2 ml of butanediol, 25 g of starch, and made into 1000 tablets.

Method: 120 g of febuxostat H crystal form, 25 g of starch, wetted with 1.2 ml of 10% aqueous solution of butanediol, uniformly mixed, sieved, granulated, dried, whole, filled with a plastic filling machine under pressure. . Example 6

Non-buxostat crystal form H piece

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

Preparation Process: The form of febuxostat H, pregelatinized starch, low-substituted hydroxypropyl thiol cellulose and magnesium stearate were respectively passed through 100 mesh, uniformly mixed, and tableted. Example 7

Non-buxostat crystal form J piece

Prescription: 20 mg of febuxostat J crystal form, 35 g of starch, 5.5 g of polyvinylpyrrolidone, and 0.5 g of magnesium stearate.

Preparation process: The form of febuxostat J, starch, polyvinylpyrrolidone and magnesium stearate were respectively passed through 100 mesh, uniformly mixed, and tableted. Stability test

Take the H, I and J crystals of febuxostat, each of which is placed in a plate numbered H1, I1, J1; H2, I2, J2; H3, I3, J3. Stability test under conditions (storage condition 1: 45001ux ± 5001ux illumination; storage condition 2: high temperature; storage condition 3: relative humidity 92.5 high humidity). HPLC detection, Anjielun-1100, C18 column, detection wavelength 220nm, mobile phase acetonitrile: 0.001 phosphoric acid = 65: 35, the results are shown in Tables 1-3, where "content" means the content of febuxostat, and "relevant substance content" means the amount measured under the above experimental conditions, except for the cloth itself. The sum of all organic substances that can be detected.

Table 1. Investigation of the stability of strong light irradiation (45001ux ± 5001ux) Sample No. The content of the substance in the test X-powder derived infrared absorption spectrum (days) (%) Content (%) Shot

HI 0 99.42 0.58 No change No change

5 99.43 0.57 No change No change

10 99.42 0.58 No change No change

11 0 99.37 0.63 No change No change

5 99.36 0.64 No change No change

10 99.39 0.61 No change No change

J1 0 99.44 0.56 No change No change

5 99.45 0.55 No change No change

10 99.43 0.57 No change has not changed Table 2, high temperature «Qualitative investigation (60 ± 2) Samples related to the content of the substance X - powder derivative X - powder derivative number (days) (%) Content (%) Shooting

H2 0 99.44 0.56 No change No change

5 99.46 0.54 No change No change

10 99.46 0.54 No change No change

12 0 99.36 0.64 No change No change

5 99.37 0.63 No change No change

10 99.34 0.66 No change No change

J2 0 99.44 0.56 No change No change

5 99.47 0.53 No change has not changed

10 99.50 0.50 No change has not changed Table 3, high humidity « qualitative investigation (RH90 ± 5o / _o )

Results The infrared spectrum and X-ray powder diffraction analysis confirmed that the infrared spectra and X-ray powder diffraction of crystal forms H, I and J did not change, which proved that they remained in the original crystal form.

The total amount of impurities in each polymorph did not change during the entire test period as compared to before the start of the test. It is demonstrated that the crystalline form of the present invention is relatively stable and is suitable for the manufacture of pharmaceutical agents and for long term storage.

According to the animal dog test, the form of H, Form I or Form J of febuxostat of the present invention has a strong activity of lowering uric acid in the blood.

Claims

Rights request

1. A crystalline form H of febuxostat, characterized in that: the reflection angle of the X-ray powder diffraction pattern of the crystal is about 6.71, 7.19, 10.03, 11.10, 12.96, 13.48,

15.78, 17.60 and 22.15. There are characteristic absorption peaks.

2. The Form H of claim 1 wherein: the infrared spectrum is approximately

Characteristic absorption peaks at 2238, 1701, 1678 and 1116 cm".

3. A crystalline form I of febuxostat, characterized in that: the X-ray powder diffraction pattern of the crystal has a reflection angle of 2 Θ at about 3.28, 6.58, 12.70, 13.34, 19.97, 24.26 and 25.43°. Absorption peak.

4. Form I according to claim 3, characterized in that the infrared spectrum is approximately

Characteristic absorption peaks at 1730, 1253 and 1097 cm ¹ .

5. A crystalline form of febuxostat J, the angle of reflection of the X-ray powder diffraction pattern of the crystal

2 There are characteristic absorption peaks at about 3.07, 12.25, 13.16, 25.21 and 26.86°.

6. The crystal form J according to claim 5, wherein: the infrared spectrum is about

Characteristic absorption peaks at 1686 and 1655 cm ¹ .

7. A method of preparing the febuxostat form H of claim 1, comprising: subjecting a solution of febuxostat in a RiCN solvent to a crystallization, the incubation temperature being about 15 to 50 C, wherein Alkyl or haloalkyl.

8. The method according to claim 7, wherein: the mass-to-volume ratio (g/ml) of the febuxostat to the RN solvent in the solution is about 1:30 to 1:100, preferably about 1: 35-1: 50, more preferably 1:40, the crystallization tempering temperature is preferably about, and can be filtered if necessary after crystallization, optionally at a pressure of about 80-120 at normal pressure. V, preferably about 8 to 24 hours, preferably about 12 hours to obtain a substantially dry H-type crystal, preferably a mercapto group, an ethyl group, a propyl group, a chlorine-substituted ethyl group, and a specific example of the RN solvent may be acetonitrile or propylene. Nitrile, nitrile and chloropropionitrile, etc., preferably acetonitrile, propionitrile or a mixture thereof.

9. A method of preparing the febuxostat crystal form I according to claim 3, comprising: at 20~

At a temperature, a solution of febuxostat in a CN solvent is subjected to a solvent extraction to decrystallization, wherein it represents an alkyl group or a halogenated alkyl group.

10. The method according to claim 9, wherein: the mass to volume ratio (g/ml) of the febuxostat to the αν solvent in the solution is preferably about 1:30 - 1: loo is preferably about 1: 35-1: 50, the temperature at which the solvent is extracted under reduced pressure is preferably about 50 C. After the crystallization, filtration may be carried out if necessary, optionally under reduced pressure, preferably under reduced pressure for a suitable period of time, for example 24 hours, to obtain a basic The dried Form I is preferably a mercapto group, an ethyl group, a propyl group or a chlorine-substituted ethyl group. A preferred solvent is acetonitrile, propionitrile or a mixture thereof.

A method of preparing the febuxostat form J according to claim 5, which comprises: heating and melting the febuxostat, followed by crystallization by cooling.

12. The method according to claim 11, wherein: the solution of febuxostat in a solvent of CN is crystallized, for example, by static crystallization, and after removing the solvent, the obtained product is heated and melted, and then crystallized, for example, by nature. Cooling or forced cooling, especially cooling to room temperature, wherein alkyl or haloalkyl, preferably decyl, ethyl, propyl, chloro-substituted ethyl, preferred solvents are acetonitrile, propionitrile or mixtures thereof, The mass-to-volume ratio (g/ml) of the febuxostat to the RN solvent in the solution is 1:30 to 1:100, preferably about 1:30, and the solvent is preferably subjected to suction filtration, hot melting and room temperature precipitation. It is carried out under normal pressure. The febuxostat crystal form according to any one of claims 1 to 6, which is in the form of particles having an average particle diameter of not more than 50 μmη.

A pharmaceutical composition comprising the febuxostat crystalline form of any one of claims 1 to 6 and a pharmaceutically acceptable adjuvant or carrier.

Use of the febuxostat crystal form according to any one of claims 1 to 6 for the manufacture of a medicament for treating a disease associated with hyperuricemia.