Tofacitinib citrate new crystal form compound and preparation method thereof

Abstract

The invention discloses a tofacitinib citrate new crystal form compound and a preparation method thereof, the crystal form compound has characteristic diffraction peaks at 8 degrees, 9.1 degrees, 10.0 degrees, 10.3 degrees, 11.7 degrees, 12.6 degrees, 14.0 degrees, 16.3 degrees, 16.8 degrees, 19.1 degrees, 20.0 degrees, 20.4 degrees, 21.0 degrees, 22.6 degrees, 24.0 degrees, 27.2 degrees, 27.5 degrees, 28.4 degrees, 29.6 degrees, 34.5 degrees, 35.3 degrees, 36.3 degrees and 39.3 degrees in an X-ray powder diffraction pattern represented by a diffraction angle of 2 theta + / -0.2 degrees, and the crystal form compound is obviously different from the prior art. Compared with the existing citric acid tofacitinib crystal form compound, the citric acid tofacitinib crystal form compound prepared by the invention has the advantages of lower dissolution rate, larger particle size and better flowability, and is expected to have better application prospects in the development of related solid preparation products.

Description

Technical Field

[0001] The present invention relates to a method for preparing a pharmaceutical crystalline compound, and in particular to a new crystalline compound of tofacitinib citrate and a method for preparing the same. Background Art

[0002] Tofacitinib citrate (also known as tofacitinib citrate) is a new oral small molecule JAK3 inhibitor and is currently the first choice for the treatment of moderate to severe rheumatoid arthritis that is intolerant or inadequately responsive to methotrexate. Its molecular structure is shown below. On March 16, 2017, the State Food and Drug Administration formally approved tofacitinib citrate for the treatment of RA patients in my country. Tofacitinib citrate ordinary tablets and sustained-release tablets developed by Pfizer Pharmaceuticals have been launched in my country. In the past five years of clinical treatment, other literature reports that it can also be used to treat other immune diseases, such as organ transplantation, lupus, multiple sclerosis, psoriasis, diabetic complications and other diseases.

[0003]

[0004] Polymorphism is a common phenomenon in APIs. APIs with different crystal forms can have different chemical and physical properties, such as melting point, solubility, dissolution rate, density, etc. When a compound has polymorphism, APIs with different crystal forms will affect the stability and bioavailability of the preparation. Pfizer Pharmaceuticals published a crystalline compound of tofacitinib citrate and a preparation method thereof in its original Chinese patent CN1325498C. The characteristic peaks of the X-ray powder diffraction pattern of the tofacitinib citrate API are 2θ±0.2°=5.7°、7.7°、8.9°、11.0°、11.5°、13.6°、13.9°、14.8°、15.2°、16.1°、16.6°、17.3°、18.7°、20.2°、20.5°、21.1°、21.4°、22. 0°, 23.0°, 23.4°, 24.0°, 25.0°, 25.5°, 26.2°, 27.0°, 27.5°, 28.1°, 28.7°, 29.4°, 30.1°, 30.3°, 31.1°, 32.0°, 32.8°, 33.6°, 34.4°, 34.8°, 35.3°, 35.9°, 36.5°, 37.8°, 38.5°, 39.2°, and the melting peak temperature in the differential scanning calorimeter (DSC) is 203.16°C. WO2012 / 135338A1 discloses a method for preparing a non-crystalline (amorphous) compound of tofacitinib citrate. Chinese patent CN105873931B discloses another method for preparing a crystalline form of tofacitinib citrate, wherein the average particle size of the crystal particles is 3 to 10 μm, which is smaller than the particle size of the raw material drug particles in the original patent (WO2003 / 048162), but still has good fluidity and can be used for direct tableting in preparation production. Chinese patent CN106967072B discloses a method for preparing a new crystalline form of tofacitinib citrate, and its X-ray characteristic peak diffraction peaks 2θ±0.2°=2.42°, 3.25°, 4.23°, 5.04°, 6.12°, 7.08°, 8.02°, 9.72°, 10.63°, 12.90°, 14.35°, 15.71°, 17.82°, 18.34°, 19.24°, 22.46°, 24.56°, 26.62°, 30.75°, 32.45°, which are obviously different from the original patent. The DSC spectrum under the same measurement conditions as CN1325498C shows that its melting point is 222°C, which is also obviously different from the 203.16°C reported in the original patent. In addition, Chinese patent CN103073552B discloses another method for preparing an amorphous form of tofacitinib citrate API. Compared with the original patent (WO2012 / 135338), this method has a simpler operation process, lower equipment requirements, and improves the stability and solubility of the API product.It can be seen that tofacitinib citrate raw material also has polymorphism. At present, there are few literatures on the research of tofacitinib citrate crystal forms at home and abroad. James A et al. used powder diffraction data to solve and refine the crystal structure of tofacitinib citrate published in the original patent, and optimized it using density function technology.

[0005] The study of the polymorphic form of raw materials is an important task in pre-formulation research, and the properties of raw materials also have a great influence on the final quality of the finished product. In order to better develop products related to tofacitinib citrate, Yang Qun and others studied the relevant physical and chemical properties of the crystalline form of tofacitinib citrate. The results of the study confirmed that tofacitinib citrate belongs to Class III drugs in the biopharmaceutics (BCS) classification. The crystalline form of tofacitinib citrate is stable and relatively stable under high temperature, high humidity and strong light conditions. Finding the advantageous crystal form of the drug is extremely important for the development of finished products and improving the efficacy of the drug. Summary of the invention

[0006] The technical problem to be solved by the present invention is to provide a new crystalline compound of tofacitinib citrate and a preparation method thereof. Compared with the existing crystalline compound of tofacitinib citrate, the new crystal has a lower dissolution rate and better fluidity, and is expected to have obvious advantages in the development of related solid dosage forms, especially in the development of sustained-release preparations.

[0007] In order to solve the above technical problems, the technical solutions adopted are:

[0008] The invention provides a new crystal compound of tofacitinib citrate. The crystal compound has characteristic diffraction peaks at 8°, 9.1°, 10.0°, 10.3°, 11.7°, 12.6°, 14.0°, 16.3°, 16.8°, 19.1°, 20.0°, 20.4°, 21.0°, 22.6°, 24.0°, 27.2°, 27.5°, 28.4°, 29.6°, 34.5°, 35.3°, 36.3° and 39.3° in an X-ray powder diffraction pattern represented by a diffraction angle of 2θ±0.2°.

[0009] Preferably, the X-ray powder diffraction pattern is measured using Cu-Ka radiation.

[0010] The X-ray powder diffraction pattern of the new crystal form of tofacitinib citrate provided by the present invention measured using Cu-Ka rays is as follows: Figure 1 As shown, the DSC / TG (differential thermal / thermogravimetric) graph is as follows Figure 2 shown.

[0011] The present invention also provides a method for preparing the above-mentioned tofacitinib citrate new crystal compound, the specific steps of which are:

[0012] (a) The tofacitinib citrate raw material is dissolved in the mixed solvent A, and the solution is heated to 65-85° C. and refluxed to completely dissolve the tofacitinib citrate crude product, and the heating and reflux are continued for 1 hour, and then filtered while hot.

[0013] (b) When the temperature of the above obtained solution is lowered to 20-30°C, the mixed solvent B is added dropwise to the solution, and after crystals are precipitated, the temperature is further lowered to -5-5°C, and the temperature is maintained for 12-24 hours until crystallization is complete.

[0014] (c) filtering, collecting crystals, washing and drying the filter cake to obtain a tofacitinib citrate crystalline compound (white crystalline powder).

[0015] Preferably, in step (a), the mixed solvent A is a mixed solvent of methanol, acetonitrile and water, the volume ratio of methanol to acetonitrile is 1:1-3, and the volume ratio of acetonitrile to water is 1-3:1-2.

[0016] Preferably, in step (a), the mass volume ratio of tofacitinib citrate API and mixed solvent A is 1 g:15-30 ml.

[0017] Preferably, in step (b), the mixed solvent B is a mixed solvent of ethanol and acetone, and the volume ratio of ethanol to acetone is 1 to 3: 1. The volume ratio of mixed solvent A to mixed solvent B is 1: 1 to 3. More preferably, in step (b), the crystal precipitation temperature is -5 to 5°C, and the duration is 12 to 24 hours.

[0018] Preferably, in step (b), the dropping speed of the mixed solvent B is 0.5 to 2.0 ml / min.

[0019] Preferably, in step (b), the mixed solvent B is a mixed solvent B precooled to 5-10°C, that is, a mixed solvent of ethanol and acetone precooled to 5-10°C.

[0020] Preferably, in step (c), the washing is performed using a small amount of mixed solvent B.

[0021] Preferably, in step (c), the drying conditions are: vacuum drying at 20-50° C. for 5-10 hours.

[0022] X-ray powder diffraction is an important characterization method for detecting crystalline compounds. In the spectrum, the diffraction pattern obtained from the new crystalline form has a specific diffraction peak. Therefore, it can be determined whether it is a new crystalline compound based on the appearance of a specific diffraction peak. In addition, DSC / TG (differential thermal analysis and thermogravimetric analysis) as a commonly used thermal analysis technique can distinguish polymorphs based on the changes in peak values ​​such as melting peaks and crystallization peaks in the DSC / TG spectrum.

[0023] The X-ray powder diffraction pattern of the new crystal form of tofacitinib citrate provided by the present invention has obvious characteristic peaks compared with the existing crystal form of tofacitinib citrate, and the peak value of the melting endothermic peak of the compound in the DSC / TG spectrum is 263.17° C., indicating that it is a new crystal form different from the prior art.

[0024] The pH 1.0 hydrochloric acid solution with the maximum equilibrium solubility was selected as the dissolution medium, and the tofacitinib citrate crystals prepared by the present invention and the commercially available original tofacitinib citrate crystals were taken, and the content of the raw material drug was determined by liquid chromatography. The dissolution rate of the new crystal form of tofacitinib citrate prepared by the present invention is significantly lower than that of the existing commercially available tofacitinib citrate.

[0025] The particle size was measured by laser scattering method (dry method) using HELOS / RODOS dry particle size analyzer and VIBRI / ASPIROS dry sampler. The crystal particle size of the tofacitinib citrate prepared by the present invention was d(90)=29.59 μm, and the d(90) of the commercially available original tofacitinib citrate was 8.09 μm. The tofacitinib citrate crystalline compound prepared by the present invention has a larger particle size.

[0026] The Hausner ratio method is used to calculate the Hausner ratio and the Carr index according to the bulk density and the tap density. A smaller Hausner ratio or Carr index indicates that the powder has better fluidity. The tofacitinib citrate prepared by the present invention has a Hausner ratio of 1.21 and a Carr index of 17.39%, and the commercially available original tofacitinib citrate has a Hausner ratio of 1.36 and a Carr index of 26.67%. The tofacitinib citrate crystalline compound prepared by the present invention has good fluidity.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] (1) The tofacitinib citrate crystalline compound provided by the present invention is a new crystalline form different from the prior art;

[0029] (2) The dissolution rate of the new crystalline tofacitinib citrate compound provided by the present invention is reduced, and the particle size and fluidity are improved, which is conducive to the development of related solid dosage forms, especially oral sustained-release dosage forms, and has better application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 This is the X-ray powder diffraction pattern of the new crystalline compound of Tofacitinib citrate prepared in Example 1 of the present invention.

[0031] Figure 2 This is the DSC / TG spectrum of the new crystalline compound of Tofacitinib citrate prepared in Example 1 of the present invention.

[0032] Figure 3It is a dissolution rate curve diagram of the new crystalline tofacitinib citrate compound prepared in Example 1 of the present invention and the existing commercially available original crystalline tofacitinib citrate compound. DETAILED DESCRIPTION

[0033] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following embodiments. All technologies realized based on the above contents of the present invention belong to the scope of the present invention.

[0034] In the following examples, the commercially available original tofacitinib citrate API was purchased from Wuhan Xinxinjiali Biotechnology Co., Ltd.

[0035] Example 1

[0036] (1) Preparation of a new crystalline compound of tofacitinib citrate

[0037] Weigh 100 g of the commercially available original tofacitinib citrate raw material, dissolve it in 2000 ml of a mixed solvent of methanol: acetonitrile: water (volume ratio = 1:1:1), heat to 80 ° C and reflux for 1 h, filter it while hot, cool the filtrate to 20 ° C, add 2000 ml of a mixed solvent of ethanol: acetone (volume ratio = 1:1) precooled to 5 ° C to the solution dropwise at a rate of 2.0 ml / min, and continue to cool to -5 ° C under ice water bath conditions after crystals precipitate, and stand under this condition for crystallization for 24 h, filter, wash the filter cake with 300 ml of anhydrous ethanol three times, and then vacuum dry it at 50 ° C for 10 h to obtain a new crystalline compound of tofacitinib citrate (white crystalline powder).

[0038] (2) Crystal form detection

[0039] X-ray diffractometer detection conditions: Cu Ka radiation, graphite monochromator, tube voltage 40kV, tube current 150mA, scanning range 3-40°, scanning speed 5° / min, step length 0.02°, slit conditions: divergence slit 1°, anti-scattering slit 1°, receiving slit 0.6mm. The tofacitinib citrate crystals prepared in this example were measured under the above conditions to obtain an X-ray powder diffraction pattern. The results are as follows: Figure 1 As shown, 2θ±0.2°=8°, 9.1°, 10.0°, 10.3°, 11.7°, 12.6°, 14.0°, 16.3°, 16.8°, 19.1°, 20.0°, 20.4°, 21.0°, 22.6°, 24.0°, 27.2°, 27.5°, 28.4°, 29.6°, 34.5°, 35.3°, 36.3°, 39.3°.

[0040] (3)DSC / TG analysis

[0041] DSC / TG detection conditions: air flow rate of 2.0 ml / min, temperature rise range of 40-300°C, and temperature rise rate of 10°C / min. The tofacitinib citrate crystals prepared in this example were measured under the above conditions to obtain a DSC / TG spectrum. The results are as follows: Figure 2 As shown, the melting endothermic peak of the product is 263.17° C., which further illustrates that the tofacitinib citrate compound prepared by the present invention is a new crystal form.

[0042] Example 2

[0043] Weigh 50g of the commercially available original tofacitinib citrate raw material drug, dissolve in 1000ml of a mixed solvent of methanol: acetonitrile: water (volume ratio = 1: 2: 1), heat to 70°C and reflux for 1h, filter while hot, add 1000ml of a mixed solvent of ethanol: acetone (volume ratio = 1: 2) precooled to 8°C dropwise at a rate of 1.5ml / min to the solution after the filtrate is cooled to 25°C, continue to cool to 0°C under ice-water bath conditions after crystals are precipitated, and stand crystallization for 18h under the conditions, filter, and wash the filter cake with 150ml of anhydrous ethanol 3 times and then vacuum dry at 40°C for 5h to obtain a new crystal compound of tofacitinib citrate (white crystalline powder). The X-ray powder diffraction spectra of the obtained tofacitinib citrate crystals are similar to those in Example 1.

[0044] Example 3

[0045] Weigh 30g of the commercially available original tofacitinib citrate raw material drug, dissolve in 600ml of a mixed solvent of methanol: acetonitrile: water (volume ratio = 1: 2: 2), heat to 65°C and reflux for 1h, filter while hot, add 600ml of a mixed solvent of ethanol: acetone (volume ratio = 1: 3) precooled to 10°C dropwise at a rate of 1.0ml / min to the solution after the filtrate is cooled to 30°C, continue to cool to 5°C under ice-water bath conditions after crystals are precipitated, and stand crystallization for 12h under the conditions, filter, and wash the filter cake with 100ml of anhydrous ethanol 3 times and then vacuum dry at 30°C for 5h to obtain a new crystal compound of tofacitinib citrate (white crystalline powder). The X-ray powder diffraction spectra of the obtained tofacitinib citrate crystals are similar to those in Example 1.

[0046] Example 4

[0047] The following specific experimental examples further illustrate that the new crystalline tofacitinib citrate compound prepared by the present invention has a low dissolution rate, a large particle size, and good powder fluidity, and is suitable for the development of oral sustained-release preparations and related products.

[0048] Experimental Example 1: Dissolution rate determination experiment

[0049] The pH 1.0 hydrochloric acid solution with the maximum equilibrium solubility was selected as the dissolution medium, and the tofacitinib citrate crystals prepared in Example 1 of the present invention and the commercially available original tofacitinib citrate crystals were taken, and the content of the raw material drug was determined by liquid chromatography. The content of the raw material drug was determined by sampling every 20 minutes, and a dissolution rate curve was drawn. Instrument detection conditions: the chromatographic column is C18 (250mm×4.6mm, 5μm), the mobile phase is methanol-water (volume ratio 45:55), and the volume flow rate is 1ml / min; the detection wavelength of the ultraviolet detector is 289nm, the column temperature is 30°C, and the injection volume is 20μl. The results are as follows: Figure 3 As shown, the dissolution rate of the new crystal form of tofacitinib citrate prepared by the present invention is significantly lower than that of the existing commercially available tofacitinib citrate.

[0050] Experimental Example 2: Particle Size Measurement Experiment

[0051] The particle size analysis of the tofacitinib citrate crystalline compound provided by the present invention and the commercially available original tofacitinib citrate crystalline compound was performed by laser scattering method (dry method) using HELOS / RODOS dry particle size analyzer and VIBRI / ASPIROS dry sampler. Instrument detection conditions: dispersion pressure 2.0×10 5 Pa, injection rate 70%, optical density ≤ 10%, slit width 2 mm. Take 6 batches of samples prepared in Example 1, measure the particle size respectively and calculate the average value and standard deviation (RSD). The experimental results are shown in Table 1-2.

[0052] Table 1 Particle size measurement results of the tofacitinib citrate crystalline compound provided by the present invention (n=6)

[0053]

[0054] Note: d(10), d(50) and d(90) represent the particle sizes corresponding to the particles accounting for 10%, 50% and 90% of the total particles, respectively.

[0055] Table 2 Particle size determination results of commercially available original tofacitinib citrate crystalline compound (n=6)

[0056]

[0057] Note: Same as Table 1.

[0058] The crystal particle size of the tofacitinib citrate prepared by the present invention is d(90)=29.59 μm, and the d(90) of the commercially available original tofacitinib citrate is d(90)=8.09 μm.

[0059] Experimental Example 3: Fluidity Measurement Experiment

[0060] With reference to the general rules of the fourth part of the Chinese Pharmacopoeia in 2020, the bulk density, tap density, and calculation of the Hausner ratio and Carr index of the tofacitinib citrate crystalline compound and the commercially available tofacitinib citrate crystalline compound provided by the present invention are measured by the Hausner ratio method. Take 6 batches of samples prepared in Example 1, and calculate the mean value and standard deviation (RSD). The experimental results are shown in Tables 3-4.

[0061] Table 3 Fluidity determination results of the tofacitinib citrate crystalline compound provided by the present invention (n=6)

[0062]

[0063]

[0064] Note: Hausner ratio = tap density / bulk density; Carr index = (tap density-bulk density) / tap density.

[0065] Table 4 Results of fluidity determination of commercially available original tofacitinib citrate crystalline compound (n=6)

[0066]

[0067] Note: Same as Table 3.

[0068] The Hausner ratio of the tofacitinib citrate prepared by the present invention is 1.21, and the Carr index is 17.39%. The Hausner ratio of the commercially available original tofacitinib citrate is 1.36, and the Carr index is 26.67%.

Claims

1. A new crystalline compound of tofacitinib citrate, characterized in that: In the X-ray powder diffraction pattern expressed as a diffraction angle of 2θ±0.2°, there are characteristic diffraction peaks at 8°, 9.1°, 10.0°, 10.3°, 11.7°, 12.6°, 14.0°, 16.3°, 16.8°, 19.1°, 20.0°, 20.4°, 21.0°, 22.6°, 24.0°, 27.2°, 27.5°, 28.4°, 29.6°, 34.5°, 35.3°, 36.3° and 39.3°.

2. The tofacitinib citrate crystalline compound according to claim 1, characterized in that: X-ray powder diffraction pattern measured using Cu-Ka radiation.

3. The method for preparing the tofacitinib citrate crystalline compound according to claim 1 or 2, characterized in that: The steps include: (a) dissolving the tofacitinib citrate API in a mixed solvent A, heating to 65-85° C. and refluxing for 1 h to 3 h, and filtering while hot; wherein the mixed solvent A is a mixed solvent of methanol, acetonitrile and water, the volume ratio of methanol to acetonitrile is 1:1-3, and the volume ratio of acetonitrile to water is 1-3:1-2; (b) When the temperature of the solution obtained above is lowered to 20 to 30° C., a mixed solvent B is added dropwise to the solution, and after crystals are precipitated, the temperature is further lowered to -5 to 5° C., and the temperature is maintained for 12 to 24 hours until crystallization is complete; wherein the mixed solvent B is a mixed solvent of ethanol and acetone, and the volume ratio of ethanol to acetone is 1 to 3:1; and the volume ratio of the mixed solvent A to the mixed solvent B is 1:1 to 3; (c) filtering, collecting crystals, washing and drying the filter cake to obtain a tofacitinib citrate crystalline compound.

4. The method for preparing the tofacitinib citrate crystalline compound according to claim 3, characterized in that: In step (a), the mass volume ratio of tofacitinib citrate raw material and mixed solvent A is 1g:15-30ml.

5. The method for preparing the tofacitinib citrate crystalline compound according to claim 3, characterized in that: In step (b), the dropping speed of the mixed solvent B is 0.5 to 2.0 ml / min.

6. The method for preparing the tofacitinib citrate crystalline compound according to claim 3, characterized in that: In step (b), the mixed solvent B is a mixed solvent of ethanol and acetone precooled to 5-10°C.

7. The method for preparing the tofacitinib citrate crystalline compound according to claim 3, characterized in that: In step (c), the washing is performed using a mixed solvent B.

8. The method for preparing the tofacitinib citrate crystalline compound according to claim 3, wherein in step (c), the drying conditions are: vacuum drying at 20 to 50°C for 5 to 10 hours.

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