Spherical crystal of tofacitinib citrate medicinal crystal form A and preparation method thereof

Abstract

The invention relates to a preparation method of a spherical crystal of a tofacitinib citrate medicinal crystal form A. The method comprises the following steps: 1) adding tofacitinib citrate into a mixed solvent of water, one or more of n-butyl alcohol, sec-butyl alcohol, isobutyl alcohol and tert-butyl alcohol and one or more of methanol, ethanol, n-propyl alcohol and isopropyl alcohol; heating and dissolving; 2) after stirring and cooling, adding one or a mixture of more of ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, dichloromethane, n-heptane, n-hexane, isopropyl ether and methyl tert-butyl ether; and 3) continuously cooling and crystallizing to obtain the tofacitinib citrate crystal form A spherical crystal.

Description

Technical Field

[0001] The invention relates to a method for preparing spherical crystals of tofacitinib citrate medicinal crystal form A, and belongs to the field of chemical pharmacy. Background Art

[0002] Tofacitinib Citrate is a novel oral JAK pathway inhibitor with the trade name XELJANZ, and its chemical structure is shown in Formula I:

[0003]

[0004] The product was developed by Pfizer and approved by the U.S. Food and Drug Administration (FDA) on November 6, 2012. It is mainly used for adult patients with moderate to severe active rheumatoid arthritis (RA) who have insufficient efficacy or intolerance to methotrexate. According to the biopharmaceutical classification system, this product belongs to BCS Class III drugs.

[0005] WO2003048162 discloses a method for crystallization using ethanol: water (1:1) and acetone, and the obtained product is recorded as crystal form A. 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. In large-scale production, it is often necessary to control the particle size of the raw material through a crushing process, which is easy to cause material loss, static electricity and dust pollution. The raw material before and after crushing is difficult to meet the requirements of direct compression of solid preparation powder. Poor material fluidity will increase the difficulty of feeding, thereby causing tablet weight differences and even affecting the efficacy of the drug.

[0006] Spherical crystals can obtain good post-processing characteristics and satisfactory bioavailability, and can also modify the drug crystals to be more regular and round, significantly improving their powder properties, making them have better filling and fluidity and suitable for direct tableting.

[0007] There is no report on spherical crystals of Tofacitinib Citrate Form A in the prior art. Summary of the invention

[0008] The object of the present invention is to overcome the shortcomings of the prior art and provide a tofacitinib citrate pharmaceutical crystal form A spherical crystal and a preparation method thereof. The specific scheme is as follows:

[0009] The first object of the present invention is to provide a method for preparing tofacitinib citrate pharmaceutical crystal form A spherical crystals, the method comprising the following steps:

[0010] 1) adding tofacitinib citrate into a mixed solvent of water and an alcohol solvent, and heating the mixture to dissolve;

[0011] 2) after stirring and cooling, add one or a mixture of ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, dichloromethane, n-heptane, n-hexane, isopropyl ether, and methyl tert-butyl ether;

[0012] 3) Continue to cool and crystallize to obtain spherical crystals of Tofacitinib citrate Form A.

[0013] In the step 1), there are two alcohol solvents, the first alcohol solvent is selected from one or more of n-butanol, sec-butanol, isobutanol, and tert-butanol, and the second alcohol solvent is selected from one or more of methanol, ethanol, n-propanol, and isopropanol.

[0014] In the step 1), the volume ratio of the first alcohol solvent to the second alcohol solvent is 1 to 6:1, preferably 2 to 4:1; more preferably 4:1.

[0015] In the step 1), the volume mass ratio of the alcohol solvent to tofacitinib citrate is 5 ml / g-25 ml / g, preferably 10 ml / g-25 ml / g, more preferably 10 ml / g, 14 ml / g, 15 ml / g, 20 ml / g, 25 ml / g.

[0016] The heating temperature in step 1) is 80°C-100°C.

[0017] The cooling temperature in step 2) is 15°C to 60°C, preferably 25°C to 45°C, and more preferably 30°C to 35°C.

[0018] The volume mass ratio of one or more of ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, dichloromethane, n-heptane, n-hexane, isopropyl ether, and methyl tert-butyl ether added in the step 2) to tofacitinib citrate is 1 ml / g to 12 ml / g, preferably 1 ml / g to 10 ml / g, more preferably 2 ml / g to 6 ml / g, and most preferably 5 ml / g.

[0019] The stirring rate of step 2) is 150-500 rpm.

[0020] The terminal crystallization temperature in step 3) is -5°C to 25°C, preferably 5°C to 10°C.

[0021] Furthermore, the alcohol solvent in step 1) is preferably sec-butanol and ethanol; the volume ratio of sec-butanol to ethanol is 2-4:1, preferably 4:1.

[0022] Furthermore, in the step 1), the volume mass ratio of sec-butyl alcohol and ethanol to tofacitinib citrate is 10-25 ml / g, preferably 10 ml / g.

[0023] Furthermore, n-heptane is preferably added in the step 2).

[0024] Furthermore, in the step 2), the volume mass ratio of n-heptane to tofacitinib citrate is 2 ml / g to 6 ml / g, preferably 5 ml / g.

[0025] The second object of the present invention is to provide a pharmaceutically acceptable crystal form A of tofacitinib citrate, characterized in that the crystal form is a spherical crystal.

[0026] The median particle size of the spherical crystals of the present invention is ≥10 μm, preferably 10 to 400 μm, and more preferably 10 to 350 μm. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 Optical microscope image of Tofacitinib citrate Form A prepared in Comparative Example 1

[0028] Figure 2 Optical microscope image of Tofacitinib Citrate Form A prepared in Comparative Example 2

[0029] Figure 3 Optical microscope image of tofacitinib citrate form A prepared in sequence number 1 for screening

[0030] Figure 4 Optical microscope image of tofacitinib citrate crystal form A prepared for screening No. 5

[0031] Figure 5 Optical microscope image of tofacitinib citrate form A prepared for screening No. 2

[0032] Figure 6 Optical microscope image of tofacitinib citrate form A prepared for screening No. 2

[0033] Figure 7 Optical microscope image of tofacitinib citrate form A prepared for screening No. 2

[0034] Figure 8 Optical microscopy image of tofacitinib citrate form A prepared for screening of the triisopropyl ether group

[0035] Fig. 9 Optical microscopy image of tofacitinib citrate form A prepared for screening isopropyl triacetate group

[0036] Fig.10 Optical microscopy image of tofacitinib citrate form A prepared for screening isopropyl pentaacetate group

[0037] Fig.11 Optical microscopy image of Tofacitinib citrate Form A prepared for screening of hexa-n-heptane groups

[0038] Fig.12 Optical microscopy image of tofacitinib citrate form A prepared for screening the hexaisopropyl ether group

[0039] Fig.13 Optical microscopy image of tofacitinib citrate form A prepared for screening isopropyl hexaacetate group

[0040] Fig.14 Optical microscopy image of Tofacitinib citrate Form A prepared for screening of seven n-hexane groups

[0041] Fig.15 Optical microscopy image of tofacitinib citrate form A prepared for screening of the seven dichloromethane groups

[0042] Fig.16 Optical microscopy image of tofacitinib citrate form A prepared for screening isopropyl heptaacetate group

[0043] Fig.17 Optical microscopy image of tofacitinib citrate form A prepared for screening of the octadichloromethane group

[0044] Fig.18 This is an optical microscope image of the spherical crystals of Tofacitinib Citrate Form A prepared in Example 1

[0045] Fig.19 This is an optical microscope image of the spherical crystals of Tofacitinib Citrate Form A prepared in Example 2

[0046] Fig. 20 X-ray powder diffraction pattern of the spherical crystals of Tofacitinib citrate Form A prepared in Example 3

[0047] Fig.21 This is an optical microscope image of the spherical crystals of Tofacitinib Citrate Form A prepared in Example 3

[0048] Fig. 22 This is an optical microscope image of the spherical crystals of Tofacitinib Citrate Form A prepared in Example 4

[0049] Fig.23 This is an optical microscope image of the spherical crystals of Tofacitinib Citrate Form A prepared in Example 5

[0050] Fig.24 This is an optical microscope image of the spherical crystals of Tofacitinib Citrate Form A prepared in Example 6

[0051] Fig.25 This is an optical microscope image of the spherical crystals of Tofacitinib Citrate Form A prepared in Example 7

[0052] Fig.26This is an optical microscope image of the spherical crystals of Tofacitinib Citrate Form A prepared in Example 8

[0053] Fig. 27 This is an optical microscope image of the spherical crystals of Tofacitinib Citrate Form A prepared in Example 9

[0054] Fig.28 This is an optical microscope image of the spherical crystals of Tofacitinib Citrate Form A prepared in Example 10 DETAILED DESCRIPTION

[0055] 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.

[0056] Related substance detection methods:

[0057] 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).

[0058] Crystal morphology detection: Instrument and equipment: polarizing microscope Olympus BX53; Detection: Take the sample and observe it under a polarizing microscope.

[0059] Particle size detection: Instrument: Laser particle size analyzer Masterszier 3000; set the instrument according to the parameters described in the following table:

[0060] Refractive index (%) 1.52 Absorption rate (%) 0.1 Particle density 1g / cm3 Background / sample measurement time 10s Shading 0.1％-6.0％ Feed rate 50％ Air pressure 3.0bar

[0061] Bulk density test method: Determine according to the Chinese Pharmacopoeia 2020 edition (0993 Bulk density and tap density determination method), the tapping frequency is 300 times ± 15 times per minute, and the amplitude is 14mm ± 2mm.

[0062] According to USP <1174> According to the guiding principle of Powder Flow, the flowability of powder can be evaluated by calculating the Hausner ratio and compression, and the calculation formula is Hausner ratio = tap density / bulk density, compression (%) = 100 × [(tap density - bulk density) / tap density]. For powders with good fluidity, the importance of interaction between particles is relatively low, and the bulk density and tap density are also close in value. For powders with poor fluidity, there is usually a strong interaction between particles, and the difference between bulk density and tap density is also large. The Hausner ratio can reflect the above differences. The corresponding relationship between the Hausner ratio and compression and fluidity evaluation is shown in the following table.

[0063] surface

[0064] Compression (%) Hausnaby Liquidity ≤10 1.00-1.11 very good 11-15 1.12-1.18 good 16-20 1.19-1.25 generally 21-25 1.26-1.34 qualified 26-31 1.35-1.45 Difference 32-37 1.46-1.59 Very bad ＞38 ＞1.60 Difficult to flow

[0065] The crystal forms obtained in the present invention are all crystal form A, and the X-ray powder diffraction pattern is as shown in the attached Fig. 20 shown.

[0066] Comparative Example 1

[0067] The tofacitinib citrate crystal form A sample was prepared according to the method described in Example 1 disclosed in CN1325498C. The optical microscopic morphology of the obtained sample is shown in the attached figure. Figure 1 As shown, the grains are in irregular powder form, with large particles agglomerated and needle-shaped fine crystals, a bulk density of 0.106 g / ml, a tap density of 0.264 g / ml, a Hausner ratio of 2.49, and a compression degree of 60%.

[0068] Comparative Example 2

[0069] The tofacitinib citrate crystal form A sample was prepared according to the method described in Example 1 disclosed in CN105873931A. The optical microscopic morphology of the obtained sample is shown in the attached figure. Figure 2 As shown, the grains are needle-shaped and fine, with a bulk density of 0.130 g / ml, a tap density of 0.280 g / ml, a Hausner ratio of 2.15, and a compression degree of 54%.

[0070] Filter 1

[0071] Weigh the tofacitinib citrate API or tofacitinib free base as shown in Table 1 (material column), add ethanol and water as shown in Table 1 (solvent dosage column), stir at 300 rpm, heat and reflux to dissolve, then quickly cool and crystallize, take samples during the process for microscopic observation, and the process and results are shown in Table 1: No. 1 See attached Figure 3 , No. 5, see attached Figure 4 .

[0072] Table 1

[0073]

[0074] Screening 2

[0075] Weigh 50 mg of tofacitinib citrate API, add alcohol solvent and water as shown in Table 2 (solvent dosage column), stir magnetically at 900 rpm, heat and reflux to dissolve, then cool naturally to crystallize, take samples for microscopic observation, the process and results are shown in Table 2: No. 2 See attached Figure 5 , serial number 3, see attached Figure 6 , No. 5, see attached Figure 7 .

[0076] Table 2

[0077]

[0078] Screening three

[0079] Weigh 50 mg of tofacitinib citrate raw material, add ethanol and water as shown in Table 3 (solvent dosage 1), and a bridging agent as shown in Table 3 (solvent dosage 2), stir at 300 rpm, heat up and reflux to dissolve, then cool naturally to crystallize, take samples during the process for microscopic observation, and the process and results are shown in Table 3: Isopropyl ether group see attached Figure 8 , isopropyl acetate group see attached Fig. 9 .

[0080] Table 3

[0081]

[0082] Screening 4

[0083] 50 mg of tofacitinib citrate raw material was weighed, and isopropanol and water as shown in Table 4 (solvent dosage 1) and a bridging agent as shown in Table 4 (solvent dosage 2) were added respectively. The mixture was stirred at 300 rpm, heated to reflux to dissolve, and then cooled naturally to crystallize. Samples were taken during the process for microscopic observation. The process and results are shown in Table 4.

[0084] Table 4

[0085]

[0086] Screening 5

[0087] Weigh 50 mg of tofacitinib citrate raw material, add tert-butyl alcohol and water as shown in Table 5 (solvent dosage 1), and a bridging agent as shown in Table 5 (solvent dosage 2), stir at 300 rpm, heat up and reflux to dissolve, then cool naturally to crystallize, take samples during the process for microscopic observation, and the process and results are shown in Table 5: Isopropanol group see attached Fig.10 .

[0088] Table 5

[0089]

[0090] Screening Six

[0091] Weigh 50 mg of tofacitinib citrate raw material, add n-butanol and water as shown in Table 6 (solvent dosage 1), and a bridging agent as shown in Table 6 (solvent dosage 2), stir at 300 rpm, heat up and reflux to dissolve, then cool naturally to crystallize, take samples during the process for microscopic observation, and the process and results are shown in Table 6: n-heptane group see attached Fig.11 , isopropyl ether group see attached Fig.12 , isopropyl acetate group see attached Fig.13 .

[0092] Table 6

[0093]

[0094] Screening seven

[0095] Weigh 50 mg of tofacitinib citrate raw material, add isobutyl alcohol and water as shown in Table 7 (solvent dosage 1), and a bridging agent as shown in Table 7 (solvent dosage 2), stir at 300 rpm, heat up and reflux to dissolve, then cool naturally to crystallize, take samples for microscopic observation, and the process and results are as follows: n-hexane group see attached Fig.14 , dichloromethane group see attached Fig.15 , isopropyl acetate group see attached Fig.16 .

[0096] Table 7

[0097]

[0098] Screening eight

[0099] Weigh 50 mg of tofacitinib citrate raw material, add sec-butyl alcohol and water as shown in Table 8 (solvent dosage 1), and a bridging agent as shown in Table 8 (solvent dosage 2), stir at 300 rpm, heat and reflux to dissolve, then cool naturally to crystallize, take samples for microscopic observation, and the process and results are as follows: dichloromethane group see attached Fig.17 .

[0100] Table 8

[0101]

[0102]

[0103] Example 1

[0104] Weigh 4.0g of tofacitinib citrate raw material, add 80.0ml of sec-butyl alcohol and 80.0ml of purified water, heat to 80℃ and stir to dissolve. Stir mechanically at 200rpm, cool to 35℃, add 24.0ml of dichloromethane, continue to cool to 5-10℃ and stir to crystallize for 1h, filter, and vacuum dry the filter cake at 60℃ for 5h to obtain 3.22g of tofacitinib citrate type A spherical crystals, with a yield of 80.5%, HPLC purity of 99.98%, bulk density of 0.122g / ml, tap density of 0.248g / ml, Hausner ratio of 2.03, and compression of 51%. The optical microscope picture is as attached. Fig.18 shown.

[0105] Example 2

[0106] Weigh 2.0g of tofacitinib citrate raw material, add 50.0ml of sec-butyl alcohol and 50.0ml of purified water, heat to 80℃ and stir to dissolve. Stir mechanically at 200rpm, cool to 35℃, add 50ml of dichloromethane, continue to cool to 5-10℃ and stir to crystallize for 1h, filter, and vacuum dry the filter cake at 60℃ for 5h to obtain 1.48g of tofacitinib citrate type A spherical crystals, with a yield of 74.0%, HPLC purity of 99.98%, bulk density of 0.113g / ml, tap density of 0.198g / ml, Hausner ratio of 1.75, and compression of 43%. The optical microscope picture is as attached. Fig.19 shown.

[0107] Example 3

[0108] Weigh 50.0g of tofacitinib citrate raw material, add 400.0ml of sec-butanol, 100.0ml of ethanol, 500.0ml of purified water, heat to 80℃ and stir to dissolve. Mechanical stirring speed 300rpm, cool to 30℃, add 250.0ml of n-heptane, continue to cool to 5-10℃ and stir to crystallize for 1h, filter, and vacuum dry the filter cake at 60℃ for 5h to obtain 44.9g of spherical crystals of tofacitinib citrate form A, with a yield of 89.8%, HPLC purity of 99.98%, bulk density of 0.428g / ml, tap density of 0.484g / ml, Hausner ratio of 1.13, and compression of 12%. The optical microscope picture is as attached. Fig.21 shown.

[0109] Example 4

[0110] Weigh 50.0g of tofacitinib citrate raw material, add 500.0ml of sec-butyl alcohol, 250.0ml of ethanol, 500.0ml of purified water, heat to 80℃ and stir to dissolve. Mechanical stirring speed is 150rpm, cool to 40℃, add 150.0ml of isopropyl acetate, continue to cool to -5~5℃ and stir to crystallize for 0.5h, filter, and vacuum dry the filter cake at 60℃ for 5h to obtain 45.7g of spherical crystals of tofacitinib citrate form A, with a yield of 91.4%, HPLC purity of 99.99%, bulk density of 0.382g / ml, tap density of 0.429g / ml, Hausner ratio of 1.12, and compression of 11%. The optical microscope picture is as attached. Fig. 22 shown.

[0111] Example 5

[0112] Weigh 50.0g of tofacitinib citrate raw material, add 1000.0ml of sec-butyl alcohol, 250.0ml of ethanol, and 250.0ml of purified water, heat to 80℃ and stir to dissolve. Mechanical stirring speed is 500rpm, cool to 60℃, add 50.0ml of ethyl acetate, continue to cool to 20-25℃, stir and crystallize for 8h, filter, and vacuum dry the filter cake at 60℃ for 5h to obtain 43.8g of spherical crystals of tofacitinib citrate form A, with a yield of 87.6%, HPLC purity of 99.98%, bulk density of 0.240g / ml, tap density of 0.319g / ml, Hausner ratio of 1.33, and compression of 25%. The optical microscope picture is as attached. Fig.23 shown.

[0113] Example 6

[0114] Weigh 50.0g of tofacitinib citrate raw material, add 600.0ml of sec-butyl alcohol, 150.0ml of ethanol, 600.0ml of purified water, heat to 80℃ and stir to dissolve. Mechanical stirring speed 500rpm, cool to 15℃, add 100.0ml of methyl tert-butyl ether, continue to cool to 10-15℃ and stir to crystallize for 2h, filter, and vacuum dry the filter cake at 60℃ for 5h to obtain 44.4g of spherical crystals of tofacitinib citrate form A, with a yield of 88.8%, HPLC purity of 99.98%, bulk density of 0.200g / ml, tap density of 0.266g / ml, Hausner ratio of 1.33, and compression of 25%. The optical microscope picture is as attached. Fig.24 shown.

[0115] Example 7

[0116] Weigh 50.0g of tofacitinib citrate raw material, add 600.0ml of sec-butyl alcohol, 150.0ml of ethanol, 600.0ml of purified water, heat to 80℃ and stir to dissolve. Mechanical stirring speed 500rpm, cool to 15℃, add 100.0ml of dichloromethane, continue to cool to 10-15℃ and stir to crystallize for 2h, filter, and vacuum dry the filter cake at 60℃ for 5h to obtain 45.3g of spherical crystals of tofacitinib citrate form A, with a yield of 90.6%, HPLC purity of 99.98%, bulk density of 0.369g / ml, tap density of 0.424g / ml, Hausner ratio of 1.15, and compression of 13%. The optical microscope picture is as attached. Fig.25 shown.

[0117] Example 8

[0118] Weigh 50.0g of tofacitinib citrate raw material, add 450.0ml of n-butanol, 150.0ml of ethanol, 500.0ml of purified water, heat to 80℃ and stir to dissolve. Mechanical stirring speed 200rpm, cool to 35℃, add 150.0ml of dichloromethane, continue to cool to 5-10℃ and stir to crystallize for 5h, filter, and vacuum dry the filter cake at 60℃ for 5h to obtain 45.5g of spherical crystals of tofacitinib citrate form A, with a yield of 91.0%, HPLC purity of 99.98%, bulk density of 0.268g / ml, tap density of 0.340g / ml, Hausner ratio of 1.27, and compression of 21%. The optical microscope picture is as attached. Fig.26 shown.

[0119] Example 9

[0120] Weigh 50.0g of tofacitinib citrate raw material, add 600.0ml of isobutyl alcohol, 100.0ml of ethanol, 750.0ml of purified water, heat to 80℃ and stir to dissolve. Mechanical stirring speed 200rpm, cool to 45℃, add 500.0ml of dichloromethane, continue to cool to 5-10℃ and stir to crystallize for 1h, filter, and vacuum dry the filter cake at 60℃ for 5h to obtain 44.9g of spherical crystals of tofacitinib citrate form A, with a yield of 89.8%, HPLC purity of 99.97%, bulk density of 0.220g / ml, tap density of 0.288g / ml, Hausner ratio of 1.31, and compression of 24%. The optical microscope picture is as attached. Fig. 27 shown.

[0121] Example 10

[0122] Weigh 50.0g of tofacitinib citrate raw material, add 250.0ml of tert-butyl alcohol, 250.0ml of ethanol, 400.0ml of purified water, heat to 80℃ and stir to dissolve. Mechanical stirring speed 200rpm, cool to 40℃, add 100.0ml of dichloromethane, continue to cool to 5-10℃ and stir to crystallize for 1h, filter, and vacuum dry the filter cake at 60℃ for 5h to obtain 44.7g of spherical crystals of tofacitinib citrate form A, with a yield of 89.4%, HPLC purity of 99.98%, bulk density of 0.286g / ml, tap density of 0.355g / ml, Hausner ratio of 1.24, and compression of 19%. The optical microscope picture is as attached. Fig.28 shown.

[0123] Embodiment 11

[0124] Weigh 50.0 g of tofacitinib citrate raw material, add 750.0 ml of sec-butyl alcohol, 250.0 ml of methanol, 400.0 ml of purified water, heat to 80 ° C and stir to dissolve. Mechanical stirring speed 200 rpm, cool to 25 ° C, add 100.0 ml of n-heptane, continue to cool to 5-10 ° C and stir to crystallize for 1 h, filter, and vacuum dry the filter cake at 60 ° C for 5 h to obtain 43.6 g of tofacitinib citrate form A spherical crystals, regular spherical crystals, yield 87.2%, HPLC purity 99.98%, bulk density 0.245 g / ml, tap density 0.316 g / ml, Hausner ratio 1.29, compression 24%.

[0125] Example 12

[0126] Weigh 50.0g of tofacitinib citrate raw material, add 250.0ml of sec-butyl alcohol, 250.0ml of n-propanol, 400.0ml of purified water, heat to 80°C and stir to dissolve. Mechanical stirring speed 200rpm, cool to 35°C, add 300.0ml of n-heptane, continue to cool to 5-10°C and stir to crystallize for 1h, filter, and vacuum dry the filter cake at 60°C for 5h to obtain 47.4g of tofacitinib citrate form A spherical crystals, regular spherical crystals, yield 94.8%, HPLC purity 99.98%, bulk density 0.282g / ml, tap density 0.336g / ml, Hausner ratio 1.19, compression 16%.

[0127] Example 13

[0128] Weigh 50.0g of tofacitinib citrate raw material, add 250.0ml of sec-butyl alcohol, 250.0ml of isopropanol, 400.0ml of purified water, heat to 80°C and stir to dissolve. Mechanical stirring speed 200rpm, cool to 35°C, add 300.0ml of isopropyl ether, continue to cool to 5-10°C and stir to crystallize for 1h, filter, and vacuum dry the filter cake at 60°C for 5h to obtain 45.1g of tofacitinib citrate form A spherical crystals, regular spherical crystals, yield 90.2%, HPLC purity 99.98%, bulk density 0.296g / ml, tap density 0.361g / ml, Hausner ratio 1.22, compression 18%.

[0129] Embodiment 14

[0130] Weigh 50.0g of tofacitinib citrate raw material, add 750.0ml of sec-butyl alcohol, 250.0ml of n-propanol, 400.0ml of purified water, heat to 80°C and stir to dissolve. Mechanical stirring speed 200rpm, cool to 25°C, add 100.0ml of n-hexane, continue to cool to 5-10°C and stir to crystallize for 1h, filter, and vacuum dry the filter cake at 60°C for 5h to obtain 44.0g of tofacitinib citrate form A spherical crystals, regular spherical crystals, yield 88.0%, HPLC purity 99.99%, bulk density 0.312g / ml, tap density 0.368g / ml, Hausner ratio 1.18, compression 15%.

[0131] Embodiment 15

[0132] Weigh 50.0g of tofacitinib citrate raw material, add 600.0ml of isobutyl alcohol, 150.0ml of methanol, 750.0ml of purified water, heat to 80°C and stir to dissolve. Mechanical stirring speed 200rpm, cool to 45°C, add 500.0ml of methyl acetate, continue to cool to 0-5°C and stir to crystallize for 1h, filter, and vacuum dry the filter cake at 60°C for 5h to obtain 45.0g of tofacitinib citrate form A spherical crystals, regular spherical crystals, yield 90.0%, HPLC purity 99.98%, bulk density 0.253g / ml, tap density 0.324g / ml, Hausner ratio 1.28, compression 22%.

[0133] Example 16

[0134] Weigh 50.0g of tofacitinib citrate raw material, add 450.0ml of n-butanol, 150.0ml of ethanol, 500.0ml of purified water, heat to 80°C and stir to dissolve. Mechanical stirring speed 200rpm, cool to 35°C, add 150.0ml of ethyl formate, continue to cool to 5-10°C and stir to crystallize for 5h, filter, and vacuum dry the filter cake at 60°C for 5h to obtain 45.6g of tofacitinib citrate form A spherical crystals, regular spherical crystals, yield 91.2%, HPLC purity 99.99%, bulk density 0.248g / ml, tap density 0.308g / ml, Hausner ratio 1.24, compression 19%.

[0135] Embodiment 17

[0136] Weigh 10.0 g of tofacitinib citrate raw material, add 240.0 ml of sec-butyl alcohol, 60.0 ml of ethanol, and 100.0 ml of purified water, heat to 80 ° C and stir to dissolve. Mechanical stirring speed 300 rpm, cool to 30 ° C, add 50.0 ml of n-heptane, continue to cool to 5-10 ° C, stir and crystallize for 1 h, filter, and vacuum dry the filter cake at 60 ° C for 4 h to obtain 9.02 g of tofacitinib citrate crystal form A sample, the microscopic morphology shows hollow spherical crystals, the yield is 90.2%, the bulk density is 0.114 g / ml, the tap density is 0.168 g / ml, the Hausner ratio is 1.47, and the compression degree is 32%.

[0137] Embodiment 18

[0138] Weigh 10.0 g of tofacitinib citrate raw material, add 80.0 ml of sec-butanol, 20.0 ml of ethanol, and 100.0 ml of purified water, heat to 80 ° C and stir to dissolve. Mechanical stirring speed 300 rpm, cool to 30 ° C, add 120.0 ml of n-heptane, continue to cool to 5-10 ° C, stir and crystallize for 1 h, filter, and vacuum dry the filter cake at 60 ° C for 4 h to obtain 8.99 g of tofacitinib citrate crystal form A sample, the microscopic morphology shows spherical and small clusters of crystals, the yield is 89.9%, the bulk density is 0.104 g / ml, the tap density is 0.182 g / ml, the Hausner ratio is 1.75, and the compression degree is 43%.

[0139] Embodiment 19

[0140] Weigh 10.0 g of tofacitinib citrate raw material, add 100.0 ml of sec-butyl alcohol, 10.0 ml of ethanol, and 100.0 ml of purified water, heat to 80 ° C and stir to dissolve. Mechanical stirring speed 300 rpm, cool to 30 ° C, add 50.0 ml of n-heptane, continue to cool to 5-10 ° C and stir to crystallize for 1 h, filter, and vacuum dry the filter cake at 60 ° C for 4 h to obtain 9.01 g of tofacitinib citrate crystal form A sample, the microscopic morphology shows spherical and needle-shaped crystals, the yield is 90.1%, the bulk density is 0.105 g / ml, the tap density is 0.187 g / ml, the Hausner ratio is 1.78, and the compression degree is 44%.

[0141] Comparative test

[0142] Experiment 1: Comparison of equilibrium solubility of spherical crystals of tofacitinib citrate form A and existing products

[0143] The samples obtained in Comparative Example 1 and Comparative Example 2 and the spherical crystal samples obtained in Example 3, Example 4 and Example 5 were subjected to equilibrium solubility determination test, and the obtained data are shown in Table 1 below.

[0144] Table 1

[0145]

[0146]

[0147] As shown in Table 1, the spherical crystalline products obtained in Examples 3, 4 and 5 of the present invention are compared with the non-spherical crystalline products obtained in the prior art comparative example 1, and the equilibrium solubility in the pH 6.8 medium is increased by 202.9%, 156.1% and 145.1%, respectively, and the equilibrium solubility is increased by 279.5%, 220.9% and 207.1%, respectively, compared with the comparative example 2, and the equilibrium solubility is increased by 279.5%, 220.9% and 207.1%, respectively, which significantly increases its solubility performance. The main absorption site of the drug is the small intestine, and the in vitro dissolution is usually simulated in a medium of pH 6.8, and compared with other conventional dissolution media (pH 1.0, pH 4.5, etc.), the solubility of tofacitinib citrate in a pH 6.8 medium is the lowest, which is only 654 μg / ml. Under the premise of consistent crystal form, higher equilibrium solubility can increase the concentration gradient of the drug, which is beneficial to the passive diffusion of the drug in the intestinal tract (pH 6.8), and has a positive significance for the improvement of drug absorption and bioavailability.

[0148] Experiment 2: Dissolution effect test of tofacitinib citrate form A spherical crystalline powder direct compression preparation

[0149] Prescription process: Referring to the prescription process of 11 mg tablet core in Example 1 of CN105101952B patent (see Table 2), spherical crystal products were used as raw materials, and the powder was directly compressed without granulation to prepare 11 mg tofacitinib citrate tablet cores. Then, the tablet coating and drilling processes were completed by continuing to refer to this example to complete the preparation of sustained-release tablets.

[0150] Table 2

[0151] Material Function composition(%) Tofacitinib citrate Active Agent 4.457 Sorbitol Osmogen 80.543 Hydroxyethyl Cellulose Thickener 8.000 KollidonVA64 (copolyvidone) Adhesives 6.000 Magnesium Stearate Lubricants 1.000 Core tablet weight —— 100

[0152] The sample of Example 3 was subjected to the above-mentioned formulation prescription process, and sustained-release tablets were prepared by powder direct compression. The dissolution method and dissolution acceptance standard of tofacitinib citrate sustained-release tablets are shown in Table 3. According to this method, the dissolution curve of the preparation product obtained by direct compression of the spherical crystal powder of Example 3 in the medium pH 6.8 was investigated, and the data are shown in Table 4.

[0153] Table 3

[0154]

[0155] Table 4

[0156]

[0157] Experiment 3: Stability test of spherical crystals of Tofacitinib citrate form A

[0158] (I) Stability test of influencing factors

[0159] The samples of Example 3 were placed under high temperature (60°C), high humidity (92.5%RH) and light (4500Lx±500Lx) conditions to conduct stability tests. The results collected after one month of observation are shown in Table 5.

[0160] Table 5

[0161]

[0162] It can be seen from Table 5 that the spherical crystal product of Example 3 obtained was observed for 1 month under high temperature 60° C., high humidity 92.5% RH and light conditions, and the impurities did not grow and the crystal form did not change.

[0163] (II) Accelerated stability test

[0164] The samples of Example 3 were simultaneously placed under accelerated conditions of 40°C ± 5°C and 75% ± 5% RH for accelerated stability testing. The results collected after 2 months of testing are shown in Table 6.

[0165] Table 6

[0166]

[0167] It can be seen from Table 6 that the spherical crystal product of Example 3 obtained was observed under accelerated conditions of 40°C±5°C and 75%±5%RH for 2 months, and the impurities did not grow and the crystal form did not change.

Claims

1. A method for preparing spherical crystals of tofacitinib citrate, It is characterized in that The method comprises the following steps: 1) adding tofacitinib citrate into a mixed solvent of water and an alcohol solvent, and heating the mixture to dissolve; 2) after stirring and cooling, add one or a mixture of ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, dichloromethane, n-heptane, n-hexane, isopropyl ether, and methyl tert-butyl ether; 3) Continue to cool and crystallize to obtain spherical crystals of Tofacitinib citrate Form A.

2. The preparation method according to claim 1, It is characterized in that In the step 1), there are two alcohol solvents, the first alcohol solvent is selected from one or more of n-butanol, sec-butanol, isobutanol, and tert-butanol, and the second alcohol solvent is selected from one or more of methanol, ethanol, n-propanol, and isopropanol.

3. The preparation method according to claim 3, It is characterized in that In the step 1), the volume ratio of the first alcohol solvent to the second alcohol solvent in the alcohol solvent is 1 to 6:1, preferably 2 to 4:

1.

4. The preparation method according to claim 1, It is characterized in that In the step 1), the volume mass ratio of the alcohol solvent to tofacitinib citrate is 5 ml / g-25 ml / g, preferably 10 ml / g-25 ml / g.

5. The preparation method according to claim 1, It is characterized in that The heating temperature in step 1) is 80°C-100°C.

6. The preparation method according to claim 1, It is characterized in that The cooling temperature in step 2) is 15°C to 60°C, preferably 25°C to 45°C, and more preferably 30°C to 35°C.

7. The preparation method according to claim 1, It is characterized in that The volume mass ratio of one or more of ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, dichloromethane, n-heptane, n-hexane, isopropyl ether, and methyl tert-butyl ether added in the step 2) to tofacitinib citrate is 1 ml / g to 12 ml / g, preferably 1 ml / g to 10 ml / g, and more preferably 2 ml / g to 6 ml / g.

8. The preparation method according to claim 1, It is characterized in that The stirring rate of step 2) is 150-500 rpm.

9. The preparation method according to claim 1, It is characterized in that The terminal crystallization temperature in step 3) is -5°C to 25°C, preferably 5°C to 10°C.

10. A crystal of tofacitinib citrate form A, It is characterized in that The crystals are spherical crystals.

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