Spherical crystal of pharmaceutical crystal form B of nilotinib hydrochloride and preparation method of spherical crystal

Abstract

The invention relates to a spherical crystal of a medicinal crystal form B of nilotinib hydrochloride and a preparation method of the spherical crystal. According to the method, nilotinib hydrochloride is used as a substrate, and a methanol-water binary solvent is used as a solvent system; the crystal form prepared by the method is uniform in particle size distribution and controllable in size, genotoxic impurities can be stably controlled below 3ppm, the inherent dissolution is obviously improved, and the bioavailability is favorably improved.

Description

Technical Field

[0001] The invention relates to a spherical crystal of a medicinal crystal form B of nilotinib hydrochloride and a preparation method thereof, and belongs to the field of chemical pharmacy. Background Art

[0002] Nilotinib Hydrochloride Monohydrate is a BCR-ABL kinase inhibitor. It is indicated for adult patients with chronic or accelerated phase Philadelphia chromosome-positive chronic myeloid leukemia (Ph+CML) who are resistant or intolerant to previous treatments (including imatinib). The product was developed by Novartis and launched in the United States on October 29, 2007 and in China in July 2009. Its pharmaceutical crystalline form is hydrochloride monohydrate crystalline form B, with the trade name TASIGNA, and its chemical structure is shown in Formula I:

[0003]

[0004] According to the biopharmaceutical classification system, this product belongs to BCS IV class drugs, which have the characteristics of low solubility and low permeability, and low bioavailability. Ji Yanyan ("Methods for Improving the Bioavailability of Orally Insoluble Drugs", Chinese Journal of Pharmaceutics, 2012, 86-92) mentioned in the article: BCS IV drugs are the most difficult to absorb, and improving solubility and dissolution rate and prolonging the retention time at the absorption site are the primary methods to improve the bioavailability of such poorly soluble drugs.

[0005] The original patent WO200701587 discloses a method for preparing pharmaceutical crystal form B by reacting nilotinib free base with hydrochloric acid in methanol to form salt, and adding seed crystals for crystallization. The product obtained by this method has low bulk density, poor fluidity, and uneven particle size distribution, showing obvious polarization characteristics, with both a small amount of large particle agglomerates and a large amount of small particle size micropowders, and low dissolution. In large-scale production, it is often necessary to control the particle size of the raw material by adding a crushing process, which is easy to cause obvious material loss. At the same time, since this variety is an anti-tumor drug, the active dust pollution caused by crushing has a greater safety risk.

[0006] In addition, according to the synthesis route disclosed in the original patent CN201110258389.6, the 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (Examples 30 and 31, compound B6) used therein is a genotoxic impurity, and the EP standard requires that the content is less than 3 ppm, and the quality control limit is extremely low. Nilotinib free base is almost insoluble in various commonly used organic solvents. Therefore, it is difficult to control the genotoxic impurities of nilotinib free base by conventional solution crystallization methods, and it is difficult to directly obtain a product with qualified genotoxic impurities by one-step salt crystallization.

[0007] Therefore, due to the requirements of powder parameter optimization, particle size control, and genotoxic impurity control, it is still necessary to develop a pharmaceutical crystalline form B of nilotinib hydrochloride with better fluidity, higher solubility, uniform and controllable particle size without crushing, and fewer genotoxic impurities, and the preparation method is simple and easy to scale up, so as to provide more and better choices for API and solid preparation technicians in this field. Summary of the invention

[0008] The purpose of the present invention is to overcome the shortcomings of the prior art and provide a spherical crystal of nilotinib hydrochloride monohydrate medicinal crystal form B and a preparation method thereof. The method uses nilotinib hydrochloride as a substrate and a methanol-water binary solvent as a solvent system. After adding methanol to the substrate and heating it to dissolve it, water is added during the cooling and crystallization process, and the crystallization temperature and stirring rate are controlled to precipitate nilotinib hydrochloride from the solution in the form of spherical crystals, thereby obtaining spherical crystals. The method is simple and easy to operate, does not require the addition of crystal seeds, and can stably purify the base toxic impurity B6 to less than 3ppm. At the same time, the inventor unexpectedly found that the intrinsic dissolution of the obtained spherical crystals is significantly improved compared with the products of the prior art, which is of great significance for improving the bioavailability of BCS class IV drugs.

[0009] The specific plan is as follows:

[0010] The present invention provides a method for preparing spherical crystals of nilotinib hydrochloride pharmaceutical form B, the method comprising the following steps: 1) adding nilotinib hydrochloride raw material into a methanol solvent system;

[0011] 2) Add a certain amount of water and heat it up to dissolve it or dissolve it in methanol first and then cool it down to a certain temperature and add a certain amount of water;

[0012] 3) Continue to lower the temperature to the end point and stir to crystallize for a certain period of time;

[0013] 4) filtering, washing and drying the filter cake to obtain spherical crystals of Nilotinib hydrochloride Form B.

[0014] In step 1), the volume mass ratio of the amount of methanol added to the bulk drug is 5 ml / g to 30 ml / g, preferably 10 ml / g to 25 ml / g, and more preferably 12 ml / g to 18 ml / g.

[0015] The cooling temperature in step 2) is preferably 15°C to 60°C, more preferably 30°C to 50°C.

[0016] In step 2), the volume mass ratio of the amount of water added to the bulk drug is preferably 0.3 ml / g to 2 ml / g, more preferably 0.5 ml / g to 1 ml / g.

[0017] The cooling end point temperature in step 3) is preferably -5°C to 15°C, more preferably 0°C to 10°C.

[0018] The crystallization time in step 3) is preferably 0.5h to 8h.

[0019] The drying conditions in step 4) are preferably vacuum drying at 40-70°C for 3h-12h.

[0020] The present invention provides a pharmaceutical crystalline form B of nilotinib hydrochloride and a preparation method thereof, wherein the crystal is a spherical crystal.

[0021] The spherical crystals of the present invention have a median particle size of ≥20 μm, preferably 20-400 μm, more preferably 20-350 μm, and more preferably 20-300 μm, 20-295 μm, 20-290 μm, 20-285 μm, 20-280 μm, 20-275 μm, 20-270 μm, 20-265 μm, 20-260 μm, 20-255 μm, 20-250 μm, 20-245 μm, 20-240 μm, 20-235 μm, 20-230 μm, 20-225 μm, 20-220 μm, 20-215 μm, 20-210 μm, 20-205 μm, 20-200 μm , 20-195μm, 20-190μm, 20-185μm, 20-180μm, 20-175μm, 20-170μm, 20-16 5μm, 20-160μm, 20-155μm, 20-150μm, 20-145μm, 20-140μm, 20-135μm, 20- 130μm, 20-125μm, 20-120μm, 20-115μm, 20-110μm, 20-105μm, 20-100μm, 2 0-95μm, 20-90μm, 20-85μm, 20-80μm, 20-75, 20-70μm, 20-65μm, 20-60μm.

[0022] Compared with the prior art, the present invention has the following advantages:

[0023] 1) The spherical crystals of the pharmaceutical form B of nilotinib hydrochloride provided by the present invention have significantly improved fluidity and bulk density, good mechanical processing properties, and are conducive to the operation, transportation and storage of large-scale production of raw materials and preparations.

[0024] 2) The spherical crystals of nilotinib hydrochloride provided by the present invention have a more uniform particle size and a controllable size. The method can obtain spherical crystals with different particle size ranges and different powder properties by adjusting conventional crystallization process parameters, thereby overcoming the limitation that the raw material can only be obtained by a pulverization process to obtain a micronized product, and avoiding material loss, active dust pollution and product static electricity caused by the pulverization process.

[0025] 3) The main absorption site of nilotinib hydrochloride is the stomach. Compared with the pharmaceutically acceptable crystalline form B obtained in the prior art, the spherical crystalline form B of nilotinib hydrochloride provided by the present invention has significantly improved intrinsic dissolution in a dissolution medium at pH 1.0, which is beneficial to improving bioavailability.

[0026] 4) The preparation method provided by the present invention can stably control genotoxic impurities to below 3 ppm. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 Optical microscope image of Nilotinib hydrochloride Form B prepared in Comparative Example 1

[0028] Figure 2 Particle size distribution diagram of the sample prepared for comparative example 1

[0029] Figure 3 Optical microscope image of Nilotinib hydrochloride Form B prepared in Comparative Example 2

[0030] Figure 4 Optical microscope image of Nilotinib hydrochloride Form B prepared in Comparative Example 3

[0031] Figure 5 Optical microscope image of Nilotinib hydrochloride Form B prepared in Comparative Example 4

[0032] Figure 6 X-ray powder diffraction pattern of spherical crystals of Nilotinib hydrochloride Form B prepared in Screening Example 1

[0033] Figure 7 Optical microscope image of spherical crystals of Nilotinib hydrochloride Form B prepared in Screening Example 1

[0034] Figure 8 Optical microscope image of spherical crystals of Nilotinib hydrochloride Form B prepared in Screening Example 2

[0035] Fig. 9 Optical microscope image of spherical crystals of Nilotinib hydrochloride Form B prepared in Screening Example 3

[0036] Fig.10 Particle size distribution of samples prepared for screening examples 1, 2, and 3

[0037] Fig.11 Particle size distribution of samples prepared for screening example 4

[0038] Fig.12 Optical microscope image of Nilotinib hydrochloride Form B prepared in Screening Example 5

[0039] Fig.13 X-ray powder diffraction pattern of Nilotinib hydrochloride Form A prepared in Screening Example 6

[0040] Fig.14 Particle size distribution diagram of the sample prepared for Screening Example 8

[0041] Fig.15 Particle size distribution of the sample prepared for Screening Example 9

[0042] Fig.16 Comparison chart of intrinsic dissolution rate of API DETAILED DESCRIPTION

[0043] The following embodiments are used to describe the technical solution of the present invention in detail, which will help to further understand the advantages and effects of the technical solution of the present invention. The embodiments do not limit the protection scope of the present invention.

[0044] Instruments and testing methods:

[0045] Method for detecting base toxic impurities:

[0046] Instrument and equipment: Liquid chromatograph Agilent 1260InfinityⅡ; Detection method: Accurately measure the test solution and the base toxic impurity B6 reference solution, and inject them into the liquid chromatograph respectively. The chromatographic conditions are as follows: octadecyl bonded silica gel (ProntoSIL 120-3-C18ACE-EPS 3.0×150mm 3μm or a chromatographic column with equivalent performance) as the filler, 0.1% phosphoric acid as phase A, acetonitrile as phase B, flow rate of 0.8 ml per minute, column temperature of 40°C, injection volume of 10μl, detection wavelength of 240nm, and gradient elution according to the table below.

[0047]

[0048] Calculated by the external standard method based on the peak area of ​​each impurity, the base toxic impurity B6 shall not exceed 3ppm.

[0049] Related substance detection methods:

[0050] Instruments and equipment: Liquid chromatograph Agilent 1260 InfinityⅡ. Detection method: Determined according to high performance liquid chromatography (General Rules 0512 of Part IV of the Chinese Pharmacopoeia).

[0051] Crystal morphology detection method:

[0052] Instrument and equipment: polarizing microscope Olympus BX53; Detection method: Take the sample and observe it under a polarizing microscope.

[0053] Crystal form detection method:

[0054] Instruments and equipment: X-ray powder diffractometer PANalytical Empyrean; detection methods are shown in the table below:

[0055]

[0056]

[0057] Particle size detection method:

[0058] Instruments and equipment: Laser particle size analyzer Masterszier 3000; detection methods are shown in the table below:

[0059] Refractive index (%) 1.52 Absorption rate (%) 0.1 Particle density 1g / cm3 Background / sample measurement time 10s Shading 0.1％-6.0％ Feed rate 30％ Air pressure 3.0bar

[0060] Comparative Example 1

[0061] 20.0 g of nilotinib free base was weighed and a sample of nilotinib hydrochloride crystal form B was prepared according to the method described in Example 1 disclosed in CN101228151B. The optical microscopic morphology of the obtained sample is shown in the attached figure. Figure 1 As shown, the obtained product is a non-spherical crystalline product with uneven particle size distribution. The particle size distribution results are shown in the attached Figure 2 , D507.79μm, D9079.6μm. Yield 80.42%, HPLC purity 99.91%, base poison impurity B6 content 10.05ppm.

[0062] Comparative Example 2

[0063] Weigh 20.0 g of nilotinib hydrochloride, add 300.0 ml of anhydrous methanol, reflux to dissolve, cool and crystallize, add 0.2 g of seed crystals at 40-43 ° C, keep at 25 ± 5 ° C and stir to crystallize for 3 h, cool to 10-15 ° C and stir to crystallize for 1 h, take samples for testing, and the optical microscope morphology of the obtained sample is as shown in the attached figure. Figure 3 As shown, the obtained product is a non-spherical crystalline product.

[0064] Comparative Example 3

[0065] Weigh 20.0 g of nilotinib hydrochloride, add 240.0 ml of anhydrous methanol, reflux to dissolve, cool to 10-15 ° C, stir and crystallize, then heat to 40 ° C, stir and crystallize for 3.5 h, take samples for testing, and the optical microscope morphology of the obtained sample is as shown in the attached figure. Figure 4 As shown, the obtained product is a non-spherical crystalline product.

[0066] Comparative Example 4

[0067] Weigh 20.0 g of nilotinib hydrochloride, add 240.0 ml of anhydrous methanol, reflux to dissolve, then cool to 10-15 ° C, stir and crystallize, then heat to 50 ° C, stir and crystallize for 2 h, take samples for testing, and the optical microscope morphology of the obtained sample is as shown in the attached figure. Figure 5 As shown, the obtained product is a non-spherical crystalline product.

[0068] Screening Example 1

[0069] Weigh 20.0 g of nilotinib hydrochloride raw material (content of base toxic impurity B6: 7.98 ppm), add 240.0 ml of anhydrous methanol, heat to 60°C-65°C, stir to dissolve, cool to 40°C-50°C, add 10.0 ml of purified water, continue to cool to 10°C-15°C, stir to crystallize for 2 h, filter, and vacuum dry the filter cake at 60°C for 3 h to obtain 16.29 g of spherical crystals of nilotinib hydrochloride form B. The X-ray powder diffraction pattern is shown in the attached figure. Figure 6 As shown in the optical microscope picture Figure 7 The particle size distribution is uniform. See the attached Fig.10 , D5032.1μm, D9075.9μm, yield 81.45%, HPLC purity 99.97%, base toxic impurity B6 content 1.08ppm.

[0070] Screening Example 2

[0071] Weigh 20.0 g of nilotinib hydrochloride raw material (content of base toxic impurity B6: 19.34 ppm), add 240.0 ml of anhydrous methanol, heat to 60°C-65°C, stir to dissolve, cool to 40°C-50°C, add 16.0 ml of purified water, continue to cool to 10°C-15°C, stir to crystallize for 2 h, filter, and vacuum dry the filter cake at 60°C for 3 h to obtain 16.68 g of spherical crystals of nilotinib hydrochloride form B with uniform particle size distribution. The particle size distribution results are shown in the attached Fig.10 , D5039.3μm, D9085.9μm, yield 83.40%, HPLC purity 99.97%, base toxic impurity B6 content 0.39ppm. Optical microscope picture as attached Figure 8 shown.

[0072] Screening Example 3

[0073] Weigh 20.0 g of nilotinib hydrochloride raw material (content of base toxic impurity B6: 28.16 ppm), add 240.0 ml of anhydrous methanol, heat to 60°C-65°C, stir to dissolve, cool to 40°C-50°C, add 20.0 ml of purified water, continue to cool to 10°C-15°C, stir to crystallize for 2 h, filter, and vacuum dry the filter cake at 60°C for 3 h to obtain 16.39 g of spherical crystals of nilotinib hydrochloride form B with uniform particle size distribution. The particle size distribution results are shown in the attached Fig.10, D5054.4μm, D90116μm, yield 81.95%, HPLC purity 99.97%, base toxic impurity B6 content 0.97ppm. Optical microscope picture as attached Fig. 9 shown.

[0074] Screening Example 4

[0075] Weigh 20.0 g of nilotinib hydrochloride raw material (content of base toxic impurity B6 9.43 ppm), add 240.0 ml of anhydrous methanol, heat to 60°C-65°C, stir to dissolve, cool to 30°C-40°C, add 6.0 ml of purified water, continue to cool to 5°C-10°C, stir to crystallize for 0.5 h, filter, and vacuum dry the filter cake at 60°C for 5 h to obtain 16.04 g of spherical crystals of nilotinib hydrochloride form B with uniform particle size distribution. The particle size distribution results are shown in the attached Fig.11 , D5022.2μm, D9082.9μm, yield 80.20%, HPLC purity 99.96%, base toxic impurity B6 content 0.89ppm.

[0076] Screening Example 5

[0077] Weigh 20.0g of nilotinib hydrochloride raw material, add 240.0ml of anhydrous methanol, heat to 60℃~65℃, stir to dissolve, cool to 40℃~50℃, add 2.0ml of purified water, continue to cool to 10℃~15℃, stir to crystallize for 2h, filter, and vacuum dry the filter cake at 60℃ for 3h to obtain 15.98g of nilotinib hydrochloride crystal form B product, with a yield of 79.90%, HPLC purity of 99.97%, non-spherical crystals, D5011.5μm, D90107μm. The optical microscope picture is as attached Fig.12 shown.

[0078] Screening Example 6

[0079] Weigh 20.0 g of nilotinib hydrochloride bulk drug, add 240.0 ml of anhydrous methanol, heat to 60°C-65°C, stir to dissolve, cool to 40°C-50°C, add 44.0 ml of purified water, continue to cool to 10°C-15°C, stir to crystallize for 2 h, filter, filter slowly, vacuum dry the filter cake at 60°C for 3 h, and crystallize to obtain nilotinib hydrochloride form A. The X-ray powder diffraction pattern is shown in the attached figure. Fig.13 shown.

[0080] Screening Example 7

[0081] Weigh 20.0 g of nilotinib hydrochloride raw material (content of base toxic impurity B6: 9.43 ppm), add 360.0 ml of anhydrous methanol, heat to 60°C-65°C, stir to dissolve, cool to 15°C-20°C, add 16.0 ml of purified water, continue to cool to 10°C-15°C, stir and crystallize for 1 h, then cool to 0°C-5°C, stir and crystallize for 2 h, filter, and vacuum dry the filter cake at 60°C for 5 h to obtain 15.00 g of nilotinib hydrochloride form B spherical crystals, D5048.5 μm, D90126 μm, yield 75.00%, HPLC purity 99.98%, and base toxic impurity B6 content 0.61 ppm.

[0082] Screening Example 8

[0083] Weigh 20.0 g of nilotinib hydrochloride raw material (content of base toxic impurity B6: 14.63 ppm), add 500.0 ml of anhydrous methanol, heat to 60°C-65°C, stir to dissolve, cool to 50°C-60°C, add 40.0 ml of purified water, continue to cool to 10°C-15°C, stir and crystallize for 2 h, then cool to -5°C-0°C, stir and crystallize for 6 h, filter, and vacuum dry the filter cake at 60°C for 5 h to obtain spherical crystals of nilotinib hydrochloride form B with uniform particle size distribution. The particle size distribution results are shown in the attached Fig.14 , 14.61g, D5061.1μm, D90134μm, yield 73.05%, HPLC purity 99.97%, base toxic impurity B6 content 0.90ppm.

[0084] Screening Example 9

[0085] Weigh 20.0 g of nilotinib hydrochloride raw material (content of base toxic impurity B6: 14.63 ppm), add 200.0 ml of anhydrous methanol and 16.0 ml of purified water, heat to 60°C-65°C, stir to dissolve, cool to 10°C-15°C, stir to crystallize for 1 h, cool to 0°C-5°C, stir to crystallize for 2 h, filter, and vacuum dry the filter cake at 60°C for 5 h to obtain spherical crystals of nilotinib hydrochloride form B with uniform particle size distribution. The particle size distribution results are shown in the attached Fig.15 , 16.94g, D5023.4μm, D9070.9μm, yield 84.70%, HPLC purity 99.97%, base toxic impurity B6 content 1.16ppm.

[0086] Example 1

[0087] Weigh 150.0g of nilotinib hydrochloride, add 2000ml of anhydrous methanol, heat and reflux to dissolve, cool to 40-50°C, add 100ml of purified water, continue to cool to 10-15°C, stir and crystallize for 1h, then cool to 0-5°C, stir and crystallize for 2h, filter, collect the obtained solid, and vacuum dry at 65°C for 4h-18h to obtain 130.56g of spherical crystals of nilotinib hydrochloride form B, with uniform particle size distribution, D5029.4μm, D9080.2μm, and yield of 87.04%. HPLC purity is 99.97%, and the content of base toxic impurity B6 is 0.35ppm.

[0088] Example 2 Comparison of intrinsic dissolution rates of bulk drugs

[0089] The coarse particle method was used to determine the intrinsic dissolution rate of the drug. Appropriate amounts of samples of Comparative Example 1, Screening Example 1, Screening Example 2, Screening Example 3, Screening Example 4, Screening Example 8, and Screening Example 9 were weighed and added to a dissolution medium preheated to 37°C and pH 1.0 to form a suspension. The stirring speed was 100 rpm. The dissolved solution was sampled at 15 min, 30 min, 60 min, 90 min, and 120 min, respectively, and the sample concentration was determined by filtering. The intrinsic dissolution rate curve is attached. Fig.16 It can be seen that the intrinsic dissolution of spherical crystalline API is significantly improved.

Claims

1. A method for preparing spherical crystals of nilotinib hydrochloride pharmaceutical form B, characterized in that: The method comprises the following steps: 1) adding nilotinib hydrochloride raw material into a methanol solvent system; 2) Add a certain amount of water and heat it up to dissolve it or dissolve it in methanol first and then cool it down to a certain temperature and add a certain amount of water; 3) Continue to lower the temperature to the end point and stir to crystallize for a certain period of time; 4) filtering, washing and drying the filter cake to obtain spherical crystals of Nilotinib hydrochloride Form B.

2. The preparation method according to claim 1, characterized in that: In the step 1), the volume mass ratio of the amount of methanol added to the bulk drug is 5 ml / g to 30 ml / g, preferably 10 ml / g to 25 ml / g, and more preferably 12 ml / g to 18 ml / g.

3. The preparation method according to claim 1, characterized in that: The cooling temperature in step 2) is preferably 15°C to 60°C, more preferably 30°C to 50°C.

4. The preparation method according to claim 1, characterized in that: In the step 2), the volume mass ratio of the amount of water added to the bulk drug is 0.1 ml / g to 5 ml / g, preferably 0.3 ml / g to 2 ml / g, and more preferably 0.5 ml / g to 1 ml / g.

5. The preparation method according to claim 1, characterized in that: The cooling end point temperature in step 3) is preferably -5°C to 15°C, more preferably 0°C to 10°C.

6. A crystal of Nilotinib hydrochloride Form B, characterized in that: The crystals are spherical crystals.

7. The spherical crystal according to claim 6, characterized in that: The median particle size of the spherical crystals is ≥20 μm, preferably 20-400 μm.

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