Flutamide trihydrate, preparation method thereof and composition preparation containing the flutamide trihydrate

Abstract

The present invention relates to flutamide trihydrate, a preparation method thereof and a composition preparation containing the flutamide trihydrate. A mixture of methanol, ethanol and chloroform is used as a solvent, and flutamide is dissolved in the solvent, wherein the weight ratio of the solvent to flutamide is 20:(1-5). The obtained mixed solution is filtered, diluted, low-temperature crystallized, washed and dried to obtain flutamide trihydrate. The flutamide trihydrate prepared by the present invention has extremely high quality stability and significantly improves solubility and reduces hygroscopicity. The prepared flutamide is prepared into a preparation, which increases the convenience of medication and preparation, and is significantly better than the prior art.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to flutamide trihydrate, a preparation method thereof and a composition preparation containing the flutamide trihydrate. Background Art

[0002] Flutamide: Chemical name: 2-dimethyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propionamide, a non-steroidal androgen antagonist, competes with androgens for androgen receptors in tumor sites, blocks cell uptake of androgens, and inhibits the binding of androgens to target organs. After binding to androgen receptors, it forms a receptor complex, enters the cell nucleus, and binds to nuclear proteins, thereby inhibiting tumor cell growth. It is suitable for prostate cancer and is effective for both first-time and second-time patients.

[0003] Prostate cancer is an epithelial malignant tumor that occurs in the prostate gland and is the most common malignant tumor in the male urogenital system. The prevalence rate in countries around the world is as high as 10% to 20%. Flutamide is a drug used to treat prostate cancer in my country, with outstanding efficacy and low price.

[0004] Although flutamide has a positive effect on prostate cancer, it is almost insoluble in water, which limits its clinical use. To solve this problem, the prior art often adopts a complex preparation process, such as Chinese application: 200910199308.2. Research on a flutamide compound with better solubility and more stability has a positive effect on the application of flutamide. Summary of the invention

[0005] The object of the present invention is to provide a method for preparing a flutamide compound. The obtained compound has good stability and solubility, low hygroscopicity, and is convenient for the preparation of pharmaceutical preparations.

[0006] The solution adopted by the present invention to solve the above technical problems is:

[0007] A method for preparing flutamide trihydrate comprises the following steps:

[0008] (1) using a mixture of methanol, ethanol and chloroform as a solvent, and dissolving flutamide in the solvent;

[0009] (2) filtering, diluting, low-temperature crystallizing, washing, and drying the mixed solution obtained in step (1) to obtain flutamide trihydrate.

[0010] Furthermore, in step (1), the weight ratio of the solvent to flutamide is 20:(1-5), and more preferably 20:3.

[0011] Furthermore, the weight ratio of methanol, ethanol and chloroform in the solvent used in step (1) is 10:7:3.

[0012] Furthermore, the flutamide raw material used is an anhydrous substance, which can be synthesized according to known techniques or purchased commercially.

[0013] Furthermore, step (2) is diluted with purified water, and the mixture is stirred while adding the purified water, with a stirring speed of 120 to 140 rpm; the temperature of the mixed solution is maintained at 34° C. to 36° C. during the dilution process; the purified water is added at a speed of 100 ml to 120 ml / min, and the amount added is 8 to 15 times the total volume of the solvent used in step (1), for example, the amount of purified water added is 10 times, 11 times, or 12 times the total volume of the solvent used in step (1).

[0014] Furthermore, the process of low temperature crystallization in step (2) is as follows: the diluted mixed solution is cooled to 3-5°C at a rate of 2°C / min-2.4°C / min, and allowed to stand for 5-10 hours to grow crystals.

[0015] Further, the drying process in step (2) comprises the following steps:

[0016] a. Dry the washed material at a temperature of 60 to 70°C for 2 to 6 hours;

[0017] b. The dried material is crushed and passed through a 60-80 mesh sieve;

[0018] c. The material obtained in step b is placed in a constant temperature and humidity chamber at 25-30°C and 70-80% humidity for 24-48 hours;

[0019] d. The material obtained in step c is heated to 40-50° C. under vacuum conditions and dried to constant weight.

[0020] Furthermore, in step c, the material is flattened to a thickness not exceeding 5 mm and subjected to constant temperature and humidity treatment.

[0021] Furthermore, in step d, the temperature is increased at a rate of 3 to 10°C / h (e.g., 3°C / h, 5°C / h, 8°C / h, 10°C / h), and the temperature is stopped when the final temperature reaches 40 to 50°C, more preferably 45°C.

[0022] The present invention also provides a flutamide trihydrate, which is prepared by the above method. The flutamide trihydrate is a crystal with a molecular formula of C 11 H 11 F3N2 O3·3H2O. The flutamide trihydrate prepared by the above method has extremely high quality stability and significantly improves solubility and reduces hygroscopicity. The prepared flutamide is prepared into a preparation, which increases the convenience of medication and preparation, and is significantly better than the prior art.

[0023] The present invention also provides a pharmaceutical composition preparation with good stability, high solubility and simple preparation process, comprising flutamide trihydrate and pharmaceutically acceptable excipients.

[0024] Furthermore, the auxiliary materials include sodium carboxymethyl starch and calcium chloride. The combined use of these two auxiliary materials can further increase the solubility of flutamide trihydrate.

[0025] Furthermore, based on the weight of the anhydrous substance in flutamide trihydrate, the mass ratio of flutamide trihydrate, sodium carboxymethyl starch and calcium chloride in the pharmaceutical composition preparation is 250:(100-110):(10-20), and more preferably 250:105:15.

[0026] Furthermore, the pharmaceutical combination preparation is a tablet or a capsule. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is the X-ray powder diffraction pattern of the flutamide compound prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0028] For a better understanding of the present invention, the following examples are provided to further illustrate the present invention, but the present invention is not limited to the following examples.

[0029] The flutamide raw material (anhydrous substance) used in the following examples is a commercially available product produced by Jiangsu Tasly Diyi Pharmaceutical Co., Ltd.

[0030] Example 1 Preparation of Flutamide Trihydrate

[0031] (1) adding methanol, ethanol, chloroform and flutamide into a reaction pot in sequence at a stirring speed of 80 rpm, and stirring to dissolve; wherein the weight ratio of methanol, ethanol, chloroform and flutamide is 10:7:3:3;

[0032] (2) filtering the mixed solution obtained by stirring and dissolving in step (1) into a crystallization kettle, maintaining the solution temperature at 34° C., adding purified water at a weight of 11 times the total weight of methanol, ethanol and chloroform used in step (1) at a rate of 100 ml / min while stirring at a stirring speed of 120 rpm, stopping stirring after the addition, cooling to 3° C. at a rate of 2° C. / min, standing for crystal growth for 7 hours, filtering to obtain a filter cake, and washing the filter cake three times with 3 times the weight of purified water;

[0033] (3) The filter cake obtained in step (2) is placed in a drying oven, dried at 60°C for 4 hours, then crushed, passed through a 60-mesh sieve, and flattened to a thickness of no more than 5 mm. The filter cake is placed in a constant temperature and humidity chamber at 25°C and 70% humidity for 40 hours, taken out, and dried under vacuum conditions. The drying starting temperature is 20°C, and the temperature is increased by 5°C every hour to 45°C. The filter cake is dried at 45°C to constant weight to obtain a flutamide compound. The X-ray powder diffraction pattern of the obtained ammonium fluoride compound is shown in the attached figure. Figure 1 .

[0034] Test Example 1 Element Analysis

[0035] The flutamide trihydrate prepared in Example 1 of the present invention was subjected to elemental analysis, and the results were: C: 40.03%, H: 5.13%, N: 8.46% (accurate to two decimal places), which is consistent with the theoretical value of flutamide trihydrate. The theoretical value of flutamide trihydrate is: C: 40.00%, H: 5.15%, N: 8.48% (accurate to two decimal places).

[0036] Test Example 2 Differential Thermal Analysis

[0037] The flutamide trihydrate prepared in Example 1 of the present invention was subjected to differential thermal analysis, and compared with the flutamide (anhydrous) used in the example. The results showed that flutamide trihydrate had an absorption peak between 102 and 105°C, indicating that there was crystal water or crystallization solvent in the sample, while the raw material flutamide (anhydrous) had no absorption peak, indicating that there was no crystal water or crystallization solvent in the raw material flutamide.

[0038] Test Example 3: Moisture Analysis

[0039] The water content of the flutamide trihydrate prepared in Example 1 of the present invention was measured by Karl Fischer water determination method, and the result was between 16.32% and 16.40%, which was consistent with the theoretical water content of flutamide trihydrate of 16.36%, and the two results were consistent. This shows that the sample only contains water and no other solvents.

[0040] Comprehensive elemental analysis, differential thermal analysis, and water analysis results show that the flutamide trihydrate prepared in Example 1 contains 3 molecules of crystal water.

[0041] Example 2 Preparation of Flutamide Trihydrate

[0042] (1) adding methanol, ethanol, chloroform and flutamide into a reaction pot in sequence at a stirring speed of 100 rpm, and stirring to dissolve; wherein the weight ratio of methanol, ethanol, chloroform and flutamide is 10:7:3:3;

[0043] (2) filtering the mixed solution obtained by stirring and dissolving in step (1) into a crystallization kettle, maintaining the solution temperature at 36° C., adding purified water at a weight of 11 times the total weight of methanol, ethanol and chloroform used in step (1) at a rate of 120 ml / min while stirring at a stirring speed of 140 rpm, stopping stirring after the addition, cooling to 5° C. at a rate of 2.4° C. / min, standing for crystal growth for 7 hours, filtering to obtain a filter cake, and washing the filter cake three times with 3 times the weight of purified water;

[0044] (3) The filter cake obtained in step (2) was placed in a drying oven, dried at 70° C. for 4 hours, then crushed, passed through an 80-mesh sieve, and flattened to a thickness of no more than 5 mm. The filter cake was placed in a constant temperature and humidity chamber at 30° C. and 80% humidity for 44 hours, then taken out and dried under vacuum conditions, with the drying starting temperature being 20° C., and then increased by 5° C. every hour to 45° C., and then dried at 45° C. to constant weight to obtain a flutamide compound. The X-ray powder diffraction pattern of the obtained ammonium fluoride compound was consistent with that of Example 1.

[0045] Example 3 Preparation of Flutamide Trihydrate

[0046] (1) adding methanol, ethanol, chloroform and flutamide into a reaction pot in sequence at a stirring speed of 90 rpm, and stirring to dissolve; wherein the weight ratio of methanol, ethanol, chloroform and flutamide is 10:7:3:3;

[0047] (2) filtering the mixed solution obtained by stirring and dissolving in step (1) into a crystallization kettle, maintaining the solution temperature at 35° C., adding purified water at a weight of 11 times the total weight of methanol, ethanol and chloroform used in step (1) at a rate of 110 ml / min while stirring at a stirring speed of 130 rpm, stopping stirring after the addition, cooling to 4° C. at a rate of 2.2° C. / min, standing for crystal growth for 7 hours, filtering to obtain a filter cake, and washing the filter cake three times with 3 times the weight of purified water;

[0048] (3) The filter cake obtained in step (2) was placed in a drying oven, dried at 65° C. for 4 hours, then crushed, passed through a 70-mesh sieve, and flattened to a thickness of no more than 5 mm. The filter cake was placed in a constant temperature and humidity chamber at 27° C. and 75% humidity for 42 hours, then taken out and dried under vacuum conditions, with the drying starting temperature being 20° C., and then increased by 5° C. every hour to 45° C., and then dried at 45° C. to constant weight to obtain a flutamide compound. The X-ray powder diffraction pattern of the obtained ammonium fluoride compound was consistent with that of Example 1.

[0049] Test Example 4 Experimental Comparative Analysis

[0050] Sample 1: Flutamide trihydrate prepared in Example 1 of the present invention;

[0051] Sample 2: Flutamide raw material (anhydrous) used in the embodiment of the present invention

[0052] 4.1 Stability and high humidity test

[0053] Samples 1-2 were tested for influencing factors and placed under high temperature (60°C), high humidity (RH92.5%±5%) and light (4500lx) conditions for 10 days. Samples were taken on the 10th day to examine the content and moisture content. The results were compared with those on day 0, see Table 1.

[0054] Table 1 Test results of factors affecting flutamide trihydrate

[0055]

[0056] The test results in Table 1 show that flutamide trihydrate has good stability and low hygroscopicity. The flutamide trihydrate obtained in other embodiments of the present invention was also subjected to the same test and obtained similar results.

[0057] 42 Solubility Analysis

[0058] Comparison of the solubility of samples 1-2 in water (25°C ± 2°C), the results are shown in Table 2:

[0059] Table 2 Solubility comparison

[0060] sample Solubility (μg / ml) Sample 1 90.2 Sample 2 42.5

[0061] The test results in Table 2 show that the solubility of the flutamide trihydrate prepared by the present invention is significantly improved.

[0062] 4.3 Accelerated stability analysis

[0063] Samples 1 and 2 were subjected to accelerated tests in the following manner: the samples were placed in a stability test chamber (40°C ± 2°C, RH 75% ± 5%), and samples were taken at 1, 2, 3, and 6 months for inspection. The results are shown in Table 3.

[0064] Table 3 Flutamide accelerated test results

[0065]

[0066] It can be seen from the results in Table 3 that the flutamide trihydrate prepared in the present invention has good stability under accelerated conditions and has obvious advantages over the marketed product (anhydrous substance). The same test was also carried out in other embodiments of the present invention, and similar results were obtained.

[0067] Example 4 Preparation of Flutamide Tablets (0.25 g)

[0068] prescription:

[0069] Flutamide trihydrate prepared in Example 1: 250 g (in terms of anhydrous form),

[0070] Sodium carboxymethyl starch: 105g,

[0071] Calcium chloride: 15g.

[0072] Made into 1000 pieces.

[0073] Process:

[0074] (1) Flutamide trihydrate, sodium carboxymethyl starch and calcium chloride, which have been dried at 60° C. in advance, are sequentially passed through an 80-mesh sieve;

[0075] (2) After the raw materials and auxiliary materials are fully mixed, their contents are determined, and the tablet weight is determined according to the specifications. The tablets are pressed onto a tabletting machine, inspected, and packaged.

[0076] Test Example 5:

[0077] The flutamide tablets prepared in Example 4 of the present invention and the marketed flutamide tablets (produced by Jiangsu Tasly Diyi Pharmaceutical Co., Ltd.) were subjected to accelerated testing, and the method is as follows: the samples were placed in a stability test box (40°C ± 2°C, RH 75% ± 5%), and samples were taken at 1, 2, 3, and 6 months, respectively, and the results are shown in Table 4.

[0078] Table 4 Flutamide tablets accelerated test results

[0079]

[0080] It can be seen from the results in Table 4 that the flutamide tablets prepared by the present invention have good stability and dissolution under accelerated conditions without the need for complex formulation processes, and have obvious advantages over marketed products.

[0081] Test Example 6

[0082] In order to make the technical effect of the combined use of sodium carboxymethyl starch and calcium chloride easier to understand, the following test illustrates the effect of the combined use of sodium carboxymethyl starch and calcium chloride on the dissolution effect of flutamide tablets. The dissolution test was carried out according to the standard method of flutamide tablets in the 2020 edition of the Chinese Pharmacopoeia. The test results are shown in Table 5:

[0083] Table 5 Comparative test results of different prescription amounts of sodium carboxymethyl starch and calcium chloride

[0084]

[0085] From the results in Table 3, it can be seen that the combined use of calcium chloride and sodium carboxymethyl starch has a significant effect on improving the solubility of flutamide compounds, especially the best effect is achieved by adding 105g sodium carboxymethyl starch and 15g calcium chloride per 250g flutamide.

[0086] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing flutamide trihydrate, characterized in that: The steps include: (1) using a mixture of methanol, ethanol and chloroform as a solvent, dissolving flutamide in the solvent, wherein the weight ratio of the solvent to flutamide is 20:(1-5); (2) The mixed solution obtained in step (1) is filtered, diluted with purified water, low-temperature crystallized, washed, and dried to obtain flutamide trihydrate.

2. The preparation method according to claim 1, characterized in that: In step (2), the mixture is stirred while adding purified water for dilution at a speed of 120 to 140 rpm; the temperature of the mixed solution is maintained at 34° C. to 36° C. during the dilution process; the purified water is added at a speed of 100 ml to 120 ml / min, and the amount added is 8 to 15 times the total volume of the solvent used in step (1).

3. The preparation method according to claim 1, characterized in that: The process of low temperature crystallization in step (2) comprises: cooling the diluted mixed solution to 3-5°C at a rate of 2°C / min-2.4°C / min, and standing for crystal growth for 5-10 hours.

4. The preparation method according to claim 1, characterized in that: Step (2) The drying process includes the following steps: a. Dry the washed material at a temperature of 60-70°C; b. The dried material is crushed and passed through a 60-80 mesh sieve; c. The material obtained in step b is placed in a constant temperature and humidity chamber at 25-30°C and 70-80% humidity for 24-48 hours; d. The material obtained in step c is heated to 40-50° C. under vacuum conditions and dried to constant weight.

5. The preparation method according to claim 4, characterized in that: Step c: Flatten the material to a thickness not exceeding 5 mm and subject it to constant temperature and humidity treatment.

6. A flutamide trihydrate, characterized in that: The flutamide trihydrate is prepared by the method according to any one of claims 1 to 5, wherein the flutamide trihydrate is a crystal with a molecular formula of C 11 H 11 F3N2O3·3H2O.

7. A pharmaceutical composition preparation, characterized in that: The invention comprises the flutamide trihydrate as claimed in claim 6 and pharmaceutically acceptable excipients.

8. The pharmaceutical composition preparation according to claim 7, characterized in that The auxiliary materials include sodium carboxymethyl starch and calcium chloride.

9. The pharmaceutical composition preparation according to claim 7, characterized in that: The mass ratio of flutamide trihydrate, sodium carboxymethyl starch and calcium chloride in the pharmaceutical composition preparation is 250: (100-110): (10-20) based on the weight of the anhydrous substance in flutamide trihydrate.

10. The pharmaceutical composition preparation according to claim 7, characterized in that: The pharmaceutical combination preparation is a tablet or a capsule.

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