CN111320589A

CN111320589A - Febuxostat sodium salt crystal form A and preparation method and application thereof

Info

Publication number: CN111320589A
Application number: CN202010016276.4A
Authority: CN
Inventors: 姚世伦; 刘迁; 肖文升; 王胜志
Original assignee: Wuhan Berek Pharmaceutical Technology Co Ltd
Current assignee: Wuhan Berek Pharmaceutical Technology Co Ltd
Priority date: 2020-01-08
Filing date: 2020-01-08
Publication date: 2020-06-23

Abstract

The invention relates to the field of drug crystal forms, and discloses a febuxostat sodium salt crystal form A, a preparation method and application thereof. The preparation process is simple, and the obtained crystal form has high solubility, good process reproducibility and high purity, and has high application value in developing febuxostat sodium salt and a pharmaceutical composition thereof in preparation of anti-ventilation symptom hyperuricemia drugs.

Description

Febuxostat sodium salt crystal form A and preparation method and application thereof

[ technical field ] A method for producing a semiconductor device

The application relates to the field of drug crystal forms, in particular to a febuxostat sodium salt crystal form and a preparation method and application thereof.

[ background of the invention ]

Febuxostat (Febuxostat), chemical name: 2- [ 3-cyano-4-isobutoxyphenyl ] -4-methylthiazole-5-carboxylic acid, structural formula as follows:

febuxostat (TMX-67, TEI-6720) is a new generation anti-gout drug synthesized by Teijin, shows excellent activity, is a selective xanthine oxidase/xanthine dehydrogenase inhibitor and has good development prospect. Compared with the medicine for treating gout by allopurin, febuxostat has the following obvious advantages: has obvious inhibition effect on xanthine oxidase, stronger and more durable capability of reducing uric acid, does not influence the activity of various enzymes in purine and pyridine metabolism, and is safer.

Febuxostat is currently used in oral solid preparations, and because the febuxostat water solubility is poor, micronization is adopted in the current preparation process to reduce the particle size of febuxostat particles so as to improve the absorption of febuxostat in vivo.

At present, patent CN103288773A discloses febuxostat sodium salt, but the crystal form of febuxostat sodium salt is not studied. It is well known that crystals are more pure relative to salts and less impurities; in addition, for polymorphic forms of a drug, different crystalline forms may have different chemical and physical properties, including chemical stability, solubility, optical and mechanical properties, etc., which may directly affect the handling and manufacturing processes of the drug substance and formulation, and may affect the stability, solubility and bioavailability of the formulation. The crystal form of a drug directly affects the quality of a pharmaceutical formulation of the drug, the absorption behavior in the human body, and ultimately the therapeutic effect and the benefit ratio of side effects produced by the formulation in the human body. Therefore, the research on polymorphism of the drug and the preparation method of different crystal forms have important significance.

Therefore, the invention provides a preparation method and application of febuxostat sodium salt crystal form A, and has high application value in the development of preparing anti-aeration hyperuricemia drugs.

[ summary of the invention ]

One object of the present invention is to provide febuxostat sodium salt crystal form a.

The invention also aims to provide a preparation method of the febuxostat sodium salt crystal form A.

The invention also aims to provide a febuxostat sodium salt crystal form A as an effective component, a pharmaceutical composition containing one or more pharmaceutically acceptable carriers, excipients or diluents, and application of the febuxostat sodium salt crystal form A in preparing medicaments for resisting ventilation symptom hyperuricemia.

The febuxostat sodium salt has the following structural formula:

the febuxostat sodium salt A crystal form disclosed by the invention has the following characteristics:

measured by an X-ray diffractometer, and the measurement conditions are as follows: CuKa, 40mA, 40kV, having diffraction angles (2 θ angles, error 0.5), interplanar spacings (D values) and relative intensities as shown in table 1:

table 1:

further, the crystalline form has an X-ray diffraction pattern substantially as shown in figure 1.

Furthermore, the substantially pure febuxostat sodium salt crystal form a provided by the invention has a differential scanning calorimetry analysis curve shown in fig. 2, and has the following characteristics: the Differential Scanning Calorimetry (DSC) has an endothermic peak at 133.89 ℃.

Further, through the study on the stability of the febuxostat sodium salt crystal form a, the characteristics shown in table 2 are obtained:

table 2:

therefore, the febuxostat sodium salt A crystal form has better stability, and the crystal form can not be changed after long-term storage, so that the febuxostat sodium salt A crystal form has good practical value for preparing the pharmaceutical composition.

It is noted that for the X-ray powder diffraction pattern of the above-described crystalline form, the characteristic peaks of the X-ray powder diffraction pattern may vary slightly, with values that may differ by about 1 unit, or by about 0.8 unit, or by about 0.5 unit, or by about 0.3 unit, or by about 0.1 unit, between different models of machines and between different samples, and thus the values given cannot be considered absolute. Also the numerical values given in the differential scanning calorimetry diagrams of the above described forms cannot be considered absolute.

According to another aspect of the invention, the application of the invention also discloses a preparation method of the febuxostat sodium salt crystal form A, which specifically comprises the following steps:

(1) dissolving febuxostat sodium salt in a mixed solvent of ethanol and water, wherein the volume of the ethanol accounts for 16-100% of the total volume of the mixed solvent, and the dosage ratio of the mixed solvent to the febuxostat sodium salt is (1-50) g: 1g, the dissolving temperature is 30-100 ℃;

wherein, the mixed solution of hot ethanol and water is preferably 50-80%; the dissolution temperature is preferably 70-90 ℃.

(2) Cooling the solution in the step (1) to 0-30 ℃, wherein the crystallization time is 3-24 h;

wherein the temperature reduction is preferably 10-20 ℃, and the crystallization time is preferably 3-6 h.

(3) Filtering and drying the crystals generated in the step (2);

wherein the drying process is vacuum drying at 50 ℃ for 6 hours.

The above preparation process gives a white solid crystalline powder.

Furthermore, the comparison data of the febuxostat sodium salt crystal form a and the solubility of non-bustat in water obtained by the preparation method are shown in table 3:

table 3:

the result shows that the solubility of the febuxostat sodium salt crystal form A is more than 500 times that of febuxostat, and the solubility of febuxostat is greatly improved.

According to another aspect of the invention, the invention also provides an application of the febuxostat sodium salt crystal form A in preparation of a pharmaceutical composition.

The amount of active ingredient contained in the pharmaceutical composition and unit dosage form may be adjusted according to the prescribed design, the pharmaceutical dosage, and the amount or concentration of the compound used may be adjusted over a wide range, typically, the amount of active compound ranges from 0.5% to 90% by weight of the composition. For human patients, the dosage of form a may be at a level of from about 0.001mg/kg body weight to about 100mg/kg body weight. Generally, the unit dose of the active agent is from about 0.01mg to about 10000mg, preferably from about 0.1mg to about 1000mg, depending on the particular indication, route of administration, etc. Depending on the route of administration, the appropriate dosage can be calculated according to body weight, body surface area or organ size. The ultimate dosage regimen will be determined by the clinician in accordance with good medical practice, taking into account a number of factors that improve the action of the drug, such as the specific activity of the active agent, the nature and severity of the disease state, the patient's response, the patient's age, physical condition, body weight, sex and diet, the severity of any infection, etc. Other factors that may be considered include the time and frequency of administration, the combination of drugs, the sensitivity of the response, and the tolerability/response of the therapy. The skilled artisan can further precisely determine dosages suitable for treatment with any of the formulations mentioned herein, especially in light of the disclosed dosage information and trials, as well as pharmacokinetic data observed in human clinical trials.

Depending on the route of administration and the desired dosage, the optimal pharmaceutical formulation can be determined by one skilled in the art. Such formulations may affect the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the administered active agent. These pharmaceutical compositions may be formulated for the condition to be treated and may be administered systemically or locally.

For example, the compounds of the present invention are combined with pharmaceutically acceptable solid or liquid carriers and optionally with pharmaceutically acceptable adjuvants and excipients and prepared in dosage forms using standard and conventional techniques. Solid dosage forms include tablets, dispersible granules, capsules, sustained release tablets, sustained release pellets and the like, and the solid carrier may be at least one substance which may act as a diluent, lubricant, filler, disintegrant, flavoring agent, suspending agent, or the like. Solid carriers include magnesium stearate, lactose, microcrystalline cellulose, methylcellulose, hydroxypropylcellulose, croscarmellose sodium, carboxymethyl starch sodium, pectin, polysorbate, dextrin, starch, gelatin, polyethylene glycol, and the like. Liquid preparations include injections, powders, and the like.

The amount of active ingredient contained in the pharmaceutical composition and the unit dosage form can be adjusted according to the prescribed design, the pharmaceutical dosage, the amount or concentration of the compound used can be adjusted within a wide range, and generally, the amount of active compound to the weight of the composition is 0.5% to 90%.

The invention has the beneficial effects that:

1. solubility experiments show that compared with febuxostat, the febuxostat sodium salt crystal form A prepared by the method has better solubility; as is known, febuxostat is an insoluble drug, and the dissolution and final quality of a later-stage preparation product are greatly influenced by water solubility, so that the crystal form A has more preparation advantages compared with the existing crystal form.

2. The febuxostat sodium salt crystal form A preparation reaction condition is mild, the operation is simple, and the used solvents are only ethanol and water, so that the environment is protected, and the recycling is convenient.

3. By controlling each key parameter in the preparation process of the febuxostat sodium salt crystal form A, the preparation method has the advantages of high yield of the crystal form A, single crystal form, good process reproducibility, good stability and high purity, so that the industrial production condition is controllable, and the large-scale industrialization is facilitated.

[ description of the drawings ]

In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.

FIG. 1 is an X-powder diffraction pattern of febuxostat sodium salt A crystal form provided by the invention.

Fig. 2 is a DSC diagram of febuxostat sodium salt crystal form a provided by the invention.

[ detailed description ] embodiments

In order to make the objects, technical solutions and advantageous effects of the present invention more clearly apparent, the present invention is further described in detail below with reference to the accompanying drawings and the detailed description. It should be understood that the detailed description and specific examples, while indicating the preferred embodiment of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention.

Wherein the X-ray powder diffraction pattern of the invention is collected on a Panalytical Empyrean X-ray powder diffractometer. The parameters of the X-ray powder diffraction method are as follows:

x-ray parameters: Cu-Ka;

voltage: 40 Kilovolts (KV);

current: 40 milliamperes (mA);

divergent slit: 1/32 degrees;

anti-scattering slit: 1/16 degrees;

scanning range: from 4.0 to 60.0 degrees;

sampling step length: 0.02 degree;

measurement time per step: 40 seconds per step.

The differential scanning thermograms of the present invention were collected on a DSC 204F1 differential scanning calorimeter. The parameters of the differential scanning calorimetry analysis method are as follows:

temperature range/° c: 100 ℃ and 200 ℃;

scan rate/° c/: 10 ℃/minute;

protective gas: nitrogen, 20 ml/min.

Example 1:

weighing 10.0g of febuxostat sodium salt, adding 50ml of ethanol-water mixed solution (the volume ratio of ethanol to water is 1:1), heating to 75 ℃, stirring to dissolve, filtering while hot, cooling the filtrate to 25 ℃, crystallizing for 3 hours, filtering, and vacuum drying for 6 hours at 50 ℃ to obtain white solid crystalline powder.

The absorption peaks obtained by measuring the samples with an X-ray diffractometer are shown in FIG. 1, and the data of the absorption peaks are shown in Table 1.

Table 1:

the febuxostat sodium salt A crystal form standing stability study shows that the febuxostat sodium salt A crystal form has the characteristics shown in the table 2:

table 2:

in addition, the differential scanning calorimetry analysis curve of the febuxostat sodium salt crystal form a prepared in the embodiment is shown in fig. 2, and the febuxostat sodium salt crystal form a has the following characteristics: the Differential Scanning Calorimetry (DSC) has an endothermic peak at 133.89 ℃.

Example 2:

weighing 10.0g of febuxostat sodium salt, adding 10ml of ethanol-water mixed solution (the volume ratio of ethanol to water is 1:5), heating to 90 ℃, stirring for dissolving, filtering while hot, cooling the filtrate to 0 ℃, crystallizing for 15 hours, filtering, and vacuum drying at 50 ℃ for 6 hours to obtain white solid crystalline powder, wherein X-ray powder diffraction pattern and Differential Scanning Calorimetry (DSC) curve diagrams of the crystalline form are consistent with those of example 1.

Example 3:

weighing 10.0g of febuxostat sodium salt, adding 20ml of ethanol, heating to 80 ℃, stirring for dissolving, filtering while hot, cooling the filtrate to 5 ℃, crystallizing for 2 hours, filtering, and vacuum drying at 50 ℃ for 6 hours to obtain white solid crystalline powder, wherein X-ray powder diffraction pattern and Differential Scanning Calorimetry (DSC) curve diagrams of the crystalline form are consistent with those of example 1.

Example 4:

weighing 10.0g of febuxostat sodium salt, adding 200ml of ethanol-water mixed solution (the volume ratio of ethanol to water is 10:1), heating to 70 ℃, stirring for dissolving, filtering while hot, cooling the filtrate to 10 ℃, crystallizing for 5 hours, filtering, and vacuum drying for 6 hours at 50 ℃ to obtain white solid crystalline powder, wherein X-ray powder diffraction pattern and Differential Scanning Calorimetry (DSC) curve diagrams of the crystalline form are consistent with those of example 1.

Example 5:

weighing 10.0g of febuxostat sodium salt, adding 100ml of ethanol-water mixed solution (the volume ratio of ethanol to water is 5:1), heating to 80 ℃, stirring for dissolving, filtering while hot, cooling the filtrate to 15 ℃, crystallizing for 3 hours, filtering, and vacuum drying for 6 hours at 50 ℃ to obtain white solid crystalline powder, wherein X-ray powder diffraction pattern and Differential Scanning Calorimetry (DSC) curve diagrams of the crystalline form are consistent with those of example 1.

Example 6:

weighing 10.0g of febuxostat sodium salt, adding 500ml of ethanol-water mixed solution (the volume ratio of ethanol to water is 50:1), heating to 70 ℃, stirring for dissolving, filtering while hot, cooling the filtrate to 20 ℃, crystallizing for 24 hours, filtering, and vacuum drying for 6 hours at 50 ℃ to obtain white solid crystalline powder, wherein X-ray powder diffraction pattern and Differential Scanning Calorimetry (DSC) curve diagrams of the crystalline form are consistent with those of example 1.

Example 7:

weighing 10.0g of febuxostat sodium salt, adding 20ml of ethanol-water mixed solution (the volume ratio of ethanol to water is 1:2), heating to 75 ℃, stirring for dissolving, filtering while hot, cooling the filtrate to 25 ℃, crystallizing for 3 hours, filtering, and vacuum drying for 6 hours at 50 ℃ to obtain white solid crystalline powder, wherein X-ray powder diffraction pattern and Differential Scanning Calorimetry (DSC) curve diagrams of the crystalline form are consistent with those of example 1.

Example 8:

weighing 10.0g of febuxostat sodium salt, adding 300ml of ethanol-water mixed solution (the volume ratio of ethanol to water is 3:2), heating to 85 ℃, stirring for dissolving, filtering while hot, cooling the filtrate to 30 ℃, crystallizing for 6 hours, filtering, and vacuum drying for 6 hours at 50 ℃ to obtain white solid crystalline powder, wherein X-ray powder diffraction pattern and Differential Scanning Calorimetry (DSC) curve diagrams of the crystalline form are consistent with those of example 1.

Example 9:

tablets containing 20mg of active ingredient per tablet were prepared:

the process comprises the following steps: sieving active ingredients, lactose and microcrystalline cellulose with 100 mesh sieve respectively, weighing according to prescription amount, mixing well, adding 2% carboxymethyl starch sodium water solution into the mixture, granulating, sieving with 20 mesh sieve to obtain soft material, making into wet granule, drying at 50-60 deg.C for 2 hr, adding magnesium stearate into the above dry granule, and tabletting.

Example 10:

preparation of capsules containing 10mg of active ingredient per capsule:

the process comprises the following steps: sieving active ingredients, lactose and microcrystalline cellulose with 100 mesh sieve respectively, weighing according to prescription amount, mixing well, adding appropriate amount of hypromellose solution to make soft material, sieving with 20 mesh sieve, making into wet granule, drying at 50-60 deg.C for 2 hr, mixing magnesium stearate and pulvis Talci with the granule, grading, measuring content, and making into capsule.

Example 11:

preparation of sustained release tablets containing 20mg of active ingredient per tablet:

the process comprises the following steps: adding croscarmellose sodium, microcrystalline cellulose, magnesium stearate, silicon dioxide and hydroxypropyl cellulose into the active ingredients, respectively sieving with a 100-mesh sieve, weighing according to the prescription amount, fully mixing, adding an appropriate amount of hydroxypropyl methylcellulose solution to prepare a soft material, sieving with a 20-mesh sieve, preparing wet granules, drying at 50-60 ℃ for 2 hours, adding magnesium stearate into the dry granules, and tabletting.

Example 12:

preparation of dispersible tablets containing 20mg of active ingredient per tablet:

the process comprises the following steps: respectively sieving active ingredients, lactose, microcrystalline cellulose, polyvidone K30, sodium hydroxymethyl starch and aspartame with 100 mesh sieve, weighing according to the prescription amount, mixing well, sieving with 20 mesh sieve, making into wet granule, drying at 50-60 deg.C for 2 hr, adding magnesium stearate into the above dry granule, and tabletting.

Comparative ratio 1:

Experiment 1: examples 9-13 comparison of dissolution data for active substances for formulations

The results show that the comparative example 1 has a dissolution rate lower than that of the febuxostat sodium salt crystal form A in the same formula in the examples 9-12, namely, the febuxostat sodium salt crystal form A in the same formula has a dissolution rate higher than that of the febuxostat, particularly, the dissolution rate is remarkably higher than that of the febuxostat in 5-20min, thereby showing that the febuxostat sodium salt crystal form A serving as a medicinal formula active substance has a remarkable advantage in solubility compared with the febuxostat.

The invention is not limited solely to that described in the specification and embodiments, and additional advantages and modifications will readily occur to those skilled in the art, so that the invention is not limited to the specific details, representative apparatus, and illustrative examples shown and described herein, without departing from the spirit and scope of the general concept as defined by the appended claims and their equivalents.

Claims

1. The febuxostat sodium salt crystal form A is characterized in that an X-ray powder diffraction pattern of the crystal form A has diffraction angle spectrum peaks shown as follows:

the differential scanning calorimetry analysis curve has an endothermic peak at 133.89 ℃.

2. The febuxostat sodium salt crystal form A according to claim 1, wherein an X-ray powder diffraction spectrum of the crystal form A is shown in figure 1, and a differential scanning calorimetry analysis curve of the crystal form A is shown in figure 2.

3. The preparation method of the febuxostat sodium salt crystal form A in claim 1 or 2, characterized by dissolving febuxostat sodium salt in a mixed solvent, cooling, crystallizing, collecting the solid and drying.

4. The preparation method of the febuxostat sodium salt crystal form A according to claim 3, wherein the mixed solvent is ethanol and water, and the volume of the ethanol accounts for 16-100% of the total volume of the mixed solvent; the volume mass ratio of the mixed solvent to the febuxostat sodium salt is (1-50) ml: 1g of the total weight of the composition.

5. The preparation method of the febuxostat sodium salt crystal form A according to claim 2, wherein the dissolving temperature is 30-100 ℃; the temperature is reduced to 0-30 ℃, and the crystallization time is 3-24 h.

6. The preparation method of the febuxostat sodium salt crystal form A according to claim 2, wherein the volume of ethanol in the mixed solvent accounts for 50-80% of the total volume, and the dissolving temperature is 70-90 ℃.

7. The preparation method of the febuxostat sodium salt crystal form A according to claim 2, wherein the temperature in the step (2) is reduced to 10-20 ℃; the crystallization time is 3-6 h; the drying is carried out for 6h under vacuum at 50 ℃.

8. A pharmaceutical composition characterized by: comprises the febuxostat sodium salt crystal form A in the claim 1 or 2 and a medicinal auxiliary material carrier.

9. The pharmaceutical composition of claim 8, wherein the febuxostat sodium salt crystal form A is 0.5-90% by weight of the composition.

10. Use of the febuxostat sodium salt in the crystal form A according to any one of claims 1-2 or the pharmaceutical composition according to claim 8 in preparation of a medicine for resisting hyperuricemia with ventilation symptoms.