New crystal form of rucotinib phosphate and preparation method thereof

Abstract

The invention discloses a new crystal form of rucotinib phosphate and a preparation method thereof, the characteristic peak of the X-ray powder diffraction spectrum of the new crystal form is represented by 2theta and is located at 4.2 degrees + / -0.2 degrees, 11.6 degrees + / -0.2 degrees, 12.7 degrees + / -0.2 degrees, 13.1 degrees + / -0.2 degrees, 16.9 degrees + / -0.2 degrees, 18.0 degrees + / -0.2 degrees, 20.7 degrees + / -0.2 degrees, 21.2 degrees + / -0.2 degrees and 22.2 degrees + / -0.2 degrees; the method comprises the following steps: dissolving rucotinib phosphate in a mixed solvent of methanol and dichloromethane; and carrying out rotary evaporation on the filtrate at 50-60 DEG C to obtain the product. The new crystal form of the rucotinib phosphate, disclosed by the invention, has better apparent solubility, higher chemical thermal stability and better physical stability; in addition, the nodules of the novel crystal form are in a short rod shape, good in fluidity and easy to disperse, and the difficulty of a preparation process is reduced. The preparation process of the new crystal form of rukotinib phosphate is simple, the recovery rate is high, industrial amplification is easy, and the new crystal form of rukotinib phosphate has a very good application prospect.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and more specifically, relates to a new crystal form of ruxolitinib phosphate and a preparation method thereof. Background Art

[0002] Ruxolitinib, also known as Ruxolitinib in English, is a Janus kinase (JAK1 / JAK2) inhibitor. Its original research company is Incyte and it is jointly developed by Incyte and Novartis. Ruxolitinib phosphate cream (trade name Opzelura) is the first topical Janus kinase (JAK) inhibitor approved by the FDA for the treatment of mild to moderate atopic dermatitis (AD) and for the local treatment of non-segmental vitiligo patients aged 12 years and above. In addition, ruxolitinib tablets are also the first FDA-approved drug for the treatment of diseases such as myelofibrosis (MF).

[0003] At present, various crystal forms or salt forms of ruxolitinib phosphate have been reported. CN 201310367212.9 discloses that the crystalline salt is a 1:1 R-type ruxolitinib phosphate, and its melting point is reported to be 198.66°C. The product shows almost no mass loss at 200°C by thermogravimetric analysis (TGA), and it is an anhydrous substance. WO 2016 / 063294 discloses amorphous, crystal form M, crystal form S, crystal form N, and crystal form I of ruxolitinib phosphate. WO2017125097A1 discloses crystal form 1 of the phosphate.

[0004] Drug polymorphism is the different solid forms formed by the same drug molecule in different arrangements. Due to the difference in this stacking method, differences in thermodynamics, kinetics, mechanical properties, such as apparent solubility, intrinsic rate, fluidity, chemical stability, hygroscopicity, melting point, etc., may occur. Different crystal forms may have different stabilities, making a particular form less sensitive to heat, relative humidity (RH) or light. Similarly, different crystal forms of a compound may be easier or more difficult to absorb moisture, resulting in potential changes in chemical and / or physical stability.

[0005] The amorphous form of ruxolitinib phosphate is a metastable state, which is prone to crystal transformation during storage; the thermal stability of crystal form M is reduced relative to that of crystal form I; crystal form S involves multiple solvent systems, complex preparation processes, and multiple crystallization modes, and many process variables, which are not conducive to industrial production; the product yield of crystal form N is low; and the preparation time of crystal form 1 is long. It can be seen that the phosphate crystal form of ruxolitinib has different defects in thermodynamic stability, preparation process or industrialization. Therefore, it is very meaningful to develop a phosphate crystal form of ruxolitinib with higher solubility and higher thermal stability, and to provide more crystal forms for the application of different types of drug preparations. In addition, it is also very necessary to develop a new preparation method for ruxolitinib phosphate crystal forms that are more suitable for industrial production and have high economic benefits. Summary of the invention

[0006] Based on this, the object of the present invention is to provide a new crystal form of ruxolitinib phosphate with high solubility and high thermal stability, and the preparation method of the new crystal form of ruxolitinib phosphate has a simple process, a high recovery rate, and is easy to industrially scale up.

[0007] The technical solutions for achieving the above-mentioned invention objectives include the following.

[0008] In the first aspect of the present invention, a new crystal form of ruxolitinib phosphate is provided, and the characteristic peaks of its X-ray powder diffraction spectrum are expressed as 2θ and are located at 4.2°±0.2°, 11.6±0.2°, 12.7°±0.2°, 13.1°±0.2°, 16.9°±0.2°, 18.0°±0.2°, 20.7°±0.2°, 21.2°±0.2°, and 22.2°±0.2°.

[0009] The second aspect of the present invention provides a method for preparing the above-mentioned new crystal form of Ruxolitinib phosphate, comprising the following steps: (1) dissolving ruxolitinib phosphate in a mixed solvent of methanol and dichloromethane; the volume ratio of methanol to dichloromethane is 1:5 to 5:1; (2) Filter and evaporate the filtrate at 50℃~60℃.

[0010] The third aspect of the present invention provides a preparation containing ruxolitinib phosphate, which is prepared from the above-mentioned new crystal form of ruxolitinib phosphate and pharmaceutically acceptable excipients.

[0011] The inventors of the present invention found that when preparing ruxolitinib phosphate, ruxolitinib phosphate was dissolved in a mixed solvent of methanol and dichloromethane in a specific volume ratio, and then the white solid obtained after rotary evaporation at 50°C to 60°C was characterized by PXRD. It is a new crystal form of ruxolitinib phosphate, which has better apparent solubility than the existing ruxolitinib phosphate crystal form I; the decomposition temperature is about 247.3°C, and it has higher chemical thermal stability; under accelerated conditions, no crystal transformation occurs for 30 days, and it has good physical stability; in addition, the crystal habit of the new crystal form is short rod-shaped, has good fluidity, is easy to disperse, and reduces the difficulty of the preparation process. Therefore, the new crystal form of ruxolitinib phosphate prepared by the present invention has a good application prospect.

[0012] The preparation process of the new crystal form of ruxolitinib phosphate of the present invention is simple, the recovery rate is high, and it is easy to scale up industrially. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 This is the PXRD pattern of the new crystal form of ruxolitinib phosphate prepared in Example 1 of the present invention.

[0014] Figure 2 This is a polarizing microscope image of the new crystal form of ruxolitinib phosphate prepared in Example 1 of the present invention.

[0015] Figure 3 This is the TGA chart of the new crystal form of ruxolitinib phosphate prepared in Example 1 of the present invention.

[0016] Figure 4 This is the DSC graph of the new crystal form of Ruxolitinib phosphate prepared in Example 1 of the present invention.

[0017] Figure 5 This is the Raman spectrum of the new crystal form of ruxolitinib phosphate prepared in Example 1 of the present invention.

[0018] Figure 6 The PXRD patterns of the new crystal form of ruxolitinib phosphate prepared in Example 1 of the present invention after 30 days of acceleration and 0 day. DETAILED DESCRIPTION

[0019] In order to facilitate the understanding of the present invention, the present invention will be described more fully below. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive.

[0020] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those commonly understood by those skilled in the art to which the present invention belongs. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used in the present invention includes any and all combinations of one or more of the related listed items.

[0021] The experimental methods in the following examples where specific conditions are not specified are generally carried out under conventional conditions, such as those described in Green and Sambrook et al., Molecular Cloning: A Laboratory Manual, 2013, or according to the conditions recommended by the manufacturer. The various commonly used chemical reagents used in the examples are all commercially available products.

[0022] In some embodiments of the present invention, a new crystal form of ruxolitinib phosphate is disclosed, and the characteristic peaks of its X-ray powder diffraction spectrum are expressed as 2θ and are located at 4.2°±0.2°, 11.6±0.2°, 12.7°±0.2°, 13.1°±0.2°, 16.9°±0.2°, 18.0°±0.2°, 20.7°±0.2°, 21.2°±0.2°, and 22.2°±0.2°.

[0023] In other embodiments of the present invention, a method for preparing the above-mentioned new crystal form of Ruxolitinib phosphate is disclosed, comprising the following steps: (1) dissolving ruxolitinib phosphate in a mixed solvent of methanol and dichloromethane; the volume ratio of methanol to dichloromethane is 1:5 to 5:1; (2) Filter and evaporate the filtrate at 50℃~60℃.

[0024] In some embodiments, the volume ratio of methanol to dichloromethane is 1:2~2:1.

[0025] In some embodiments, the volume ratio of methanol to dichloromethane is 1:1.

[0026] In some embodiments, the volume ratio of methanol to dichloromethane is 2:1.

[0027] In some embodiments, the volume ratio of methanol to dichloromethane is 1:2.

[0028] In some of the embodiments, the mass volume ratio of ruxolitinib phosphate to the mixed solvent is 5 g~30 g:1L.

[0029] In some embodiments, the mass volume ratio of ruxolitinib phosphate to the mixed solvent is 10 g~20 g:1 L.

[0030] In some embodiments, the mass volume ratio of ruxolitinib phosphate to the mixed solvent is 17 g~18 g:1 L.

[0031] In some embodiments, the method for preparing the new crystal form of Ruxolitinib phosphate comprises the following steps: (1) Add ruxolitinib phosphate to a mixed solvent of methanol and dichloromethane in a volume ratio of 1:2 to 2:1, and dissolve it by ultrasonication; (2) Filter and evaporate the filtrate at 50℃~60℃.

[0032] In other embodiments of the present invention, a preparation containing ruxolitinib phosphate is disclosed, which is prepared from the above-mentioned new crystal form of ruxolitinib phosphate and pharmaceutically acceptable excipients. The new crystal form of ruxolitinib phosphate and pharmaceutically acceptable excipients are prepared into a preparation according to conventional techniques disclosed in the prior art.

[0033] In some embodiments, the auxiliary material is one or more of a filler, a disintegrant, a flavoring agent, a lubricant, and a surfactant.

[0034] In some embodiments, the formulation is a tablet or a cream.

[0035] In the following embodiments, the detection instruments and methods involved are as follows: X-ray diffraction (PXRD): PANalytical X-ray powder diffractometer (PW3040 / 60, PANalytical Analytical Instruments, the Netherlands), Cu-Kα radiation, wavelength , equipped with Bragg-Brentano High Definition. Incident light path: divergence slit 1 / 8°, Soller slit 0.04 rad, light shielding frame 10 mm, anti-scatter slit 1 / 2°; diffraction light path: anti-scatter slit P7.5; X-ray sample stage: rotation mode; scanning detector: PIXcel1D-Medipix3; X-ray tube voltage 45kV, X-ray tube current 40 mA, scanning range 2-40° (2θ), step length 0.026°, step time: 153.765 s. Data acquisition software Data Collector, data viewing software Data Viewer.

[0036] Raman spectroscopy: Renishaw inVia Raman microspectroscopy, equipped with a near-infrared diode laser source and a Rencam charge-coupled device (CCD) silicon detector. The sample was placed flat on a microscope slide, focused and observed under a 20x objective lens, and Raman single-point detection was performed. The detection conditions were as follows: detection wavelength 785 nm, detection range 200 cm -1 ~1800 cm-1 , laser intensity 100%, exposure time 3 s, cumulative number 2 times; data acquisition and analysis software wire 4.3.

[0037] Polarized light microscopy (PLM): The particle size and morphology of the samples were observed using a Nikon microscope with crossed polarizing filters, reflected light mode, Nikon DS-Fi1c camera, and NIS-Elements 4.50 analysis software.

[0038] Differential scanning calorimetry (DSC): The thermal properties of the samples were analyzed using a differential scanning calorimeter Q2000 (TA Instruments, USA). The sample chamber was set to have a nitrogen purge flow of 50 mL / min, balanced at 25°C, and heated to 230°C at a rate of 10°C / min. The data analysis software was TA Universal Analysis (TA Instruments, USA).

[0039] Thermogravimetric analyzer (TGA): Thermogravimetric analyzer Q500 was used to analyze the thermal weight loss of the samples. The nitrogen purge gas flow in the sample chamber was set to 60 mL / min, the heating rate was heated to 350°C at a rate of 10°C / min, and the data analysis software was TA Universal Analysis (TA Instruments, USA).

[0040] Ruxolitinib phosphate (the starting crystal form is the crystal form I in the original patent WO 2016 / 063294) was purchased from Jiangsu Aikon Biopharmaceutical Research and Development Co., Ltd.

[0041] The present invention is described in detail below with reference to the accompanying drawings and specific embodiments.

[0042] Example 1 Preparation of a new crystal form of Ruxolitinib phosphate

[0043] This embodiment provides a new crystal form of Ruxolitinib phosphate, and its preparation method comprises the following steps: 1. At room temperature, add 101.9 mg of ruxolitinib phosphate solid to 6 mL of a mixed solvent of methanol and dichloromethane (1:1, v / v), and sonicate to completely dissolve it; 2. Filter to remove the seed crystals, transfer the filtrate to a rotary evaporator, and rotary evaporate at 50°C to obtain a white solid with a recovery rate of about 98%.

[0044] Take the solid for PXRD characterization, the spectrum is as follows Figure 1 The main characteristic peak positions are shown in Table 1. The results show that a new crystal form of ruxolitinib phosphate was prepared in this example.

[0045] Table 1 PXRD characteristic peak positions of the new crystal form of ruxolitinib phosphate

[0046] Use polarizing microscope to observe its crystal habit, such as Figure 2 As shown, the new crystal form is in the shape of short rods and has good fluidity.

[0047] The thermal behavior was analyzed by thermogravimetric analyzer and differential scanning calorimeter, and the results were as follows: Figure 3 , Figure 4 As shown. The new crystal loses about 1.3% weight from room temperature to 100°C ( Figure 3 ), the decomposition temperature is about 247.3℃. The new crystal has an exothermic peak at about 110℃ ( Figure 4 ), its transition temperature is relatively high and can meet the requirements of formulation process.

[0048] Raman detection spectrum Figure 5 Its characteristic peaks are shown in Table 2.

[0049] Table 2 Raman characteristic peak positions of the new crystal form of ruxolitinib phosphate

[0050] Example 2 Preparation of a new crystal form of Ruxolitinib phosphate This embodiment provides a new crystal form of Ruxolitinib phosphate, and the preparation method thereof comprises the following steps: 1. At room temperature, add 51.2 mg of ruxolitinib phosphate solid to 3 mL of a mixed solvent of methanol and dichloromethane (1:1, v / v), and sonicate to completely dissolve it; 2. Filter to remove the seed crystals, transfer the filtrate to a rotary evaporator, and rotary evaporate at 50°C to obtain a white solid with a recovery rate of about 93%.

[0051] Take the solid for PXRD characterization, the spectrum is as follows Figure 1 The thermal behavior was analyzed by differential scanning calorimetry (DSC). Figure 4 The results show that a new crystal form of ruxolitinib phosphate was prepared in this example.

[0052] Example 3 Preparation of a new crystal form of Ruxolitinib phosphate This embodiment provides a new crystal form of Ruxolitinib phosphate, and the preparation method thereof comprises the following steps: 1. At room temperature, add 60.0 mg of ruxolitinib phosphate solid to 3 mL of a mixed solvent of methanol and dichloromethane (2:1, v / v), and sonicate to completely dissolve it; 2. Filter to remove the seed crystals, transfer the filtrate to a rotary evaporator, and rotary evaporate at 60°C to obtain a white solid with a recovery rate of about 94%.

[0053] Take the solid for PXRD characterization, the spectrum is as follows Figure 1 The results show that a new crystal form of ruxolitinib phosphate was prepared in this example.

[0054] Example 4 Preparation of a new crystal form of Ruxolitinib phosphate This embodiment provides a new crystal form of Ruxolitinib phosphate, and its preparation method comprises the following steps: 1. At room temperature, add 55.0 mg of ruxolitinib phosphate solid to 3 mL of a mixed solvent of methanol and dichloromethane (1:2, v / v), and sonicate to completely dissolve it; 2. Filter to remove the seed crystals, transfer the filtrate to a rotary evaporator, and rotary evaporate at 60°C to obtain a white solid with a recovery rate of about 93%.

[0055] Take the solid for PXRD characterization, the spectrum is as follows Figure 1 shown.

[0056] The results showed that a new crystal form of ruxolitinib phosphate was prepared in this example.

[0057] Example 5 Preparation of tablets containing a new crystal form of ruxolitinib phosphate This embodiment provides a tablet containing a new crystal form of ruxolitinib phosphate, and its prescription is shown in Table 2.

[0058]

[0059] The preparation method comprises the following steps: (1) Weighing: Weigh each component according to the prescription ratio in Table 2.

[0060] (2) Preliminary mixing: The new crystal form of ruxolitinib phosphate prepared in Example 1, microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose are mixed and passed through a 40-mesh sieve. The sieved powders are placed in a multi-directional motion mixer and mixed evenly.

[0061] (3) Dry granulation: The mixed materials are added into a dry granulator for granulation.

[0062] (4) Total mixing: Mix the dry granulated granules with colloidal silicon dioxide, pass through a 20-mesh sieve, add magnesium stearate, and mix well.

[0063] (5) Tablet pressing: Press the mixture into tablets using a tablet press.

[0064] Comparative Example This comparative example adopts the preparation method of Example 1, and uses different solvents to prepare ruxolitinib phosphate crystals. The solvents are grouped as follows: 1. Methanol 2. Dichloromethane 3. A mixed solvent of methanol and dichloromethane (20:1, v / v) 4. A mixed solvent of methanol and dichloromethane (1:20, v / v) 5. A mixed solvent of methanol and 1,4-dioxane (2:1, v / v) 6. A mixed solvent of dichloromethane and ethanol (1:1, v / v) Each solid was subjected to PXRD characterization to compare the crystal forms of the solid. The results are shown in Table 3.

[0065]

[0066] Note: The PXRD spectra of Form I and Form M are shown in patent WO 2016 / 063294.

[0067] From the results in Table 3, it can be seen that the crystal form of ruxolitinib phosphate prepared by using methanol, a mixed solvent of methanol and dichloromethane (20:1, v / v), a mixed solvent of methanol and 1,4-dioxane (2:1, v / v), and a mixed solvent of dichloromethane and ethanol (1:1, v / v) is the existing crystal form I, and the crystal form of ruxolitinib phosphate prepared by using a mixed solvent of dichloromethane, methanol and dichloromethane (1:20, v / v) is the existing crystal form M. It can be seen that the new crystal form of the present invention cannot be obtained by using other solvents or other volume ratios of methanol and dichloromethane.

[0068] Test Example 1 Apparent solubility test in water According to the solubility test method in the 15th general rule of Part IV of the 2020 edition of the Chinese Pharmacopoeia, the apparent solubility test is carried out. The specific method is as follows: The new crystals of ruxolitinib phosphate and the crystal powder of Form I prepared in Example 1 were passed through a 100-mesh sieve, and 5 mg was weighed into a conical flask respectively. A certain volume of water was added at 25°C ± 2°C, and the mixture was vigorously shaken for 30 seconds every 5 minutes. The dissolution was observed within 30 minutes. When no solute particles were visually visible, the mixture was completely dissolved, and the apparent solubility was calculated.

[0069] The results showed that the solubility of the new crystal prepared in Example 1 was 5.68 mg / mL, and the apparent solubility of crystal form I was 3.08 mg / mL.

[0070] Experimental Example 2 Stability Study of the New Crystalline Form of Ruxolitinib Phosphate According to the 9001 Stability Guidelines for Drug Substances and Preparations of Part IV of the 2020 edition of the Chinese Pharmacopoeia, the new crystalline solid of ruxolitinib phosphate prepared in Example 1 was placed under accelerated conditions (40°C / 75%RH) for 30 days, and the sample was characterized by PXRD. The results are as follows: Figure 6 shown.

[0071] The results show that the new crystal form of ruxolitinib phosphate prepared by the present invention does not undergo crystal form transformation under accelerated and long-term conditions for 30 days.

[0072] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0073] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A new crystal form of ruxolitinib phosphate, characterized in that: The characteristic peaks of its X-ray powder diffraction spectrum are expressed as 2θ and are located at 4.2°±0.2°, 11.6±0.2°, 12.7°±0.2°, 13.1°±0.2°, 16.9°±0.2°, 18.0°±0.2°, 20.7°±0.2°, 21.2°±0.2°, and 22.2°±0.2°.

2. A method for preparing the new crystal form of Ruxolitinib phosphate according to claim 1, characterized in that: The following steps are involved: (1) dissolving ruxolitinib phosphate in a mixed solvent of methanol and dichloromethane; the volume ratio of methanol to dichloromethane is 1:5 to 5:1; (2) Filter and evaporate the filtrate at 50℃~60℃.

3. The method for preparing the new crystal form of Ruxolitinib phosphate according to claim 3, characterized in that: The volume ratio of the methanol to the dichloromethane is 1:2 to 2:

1.

4. The method for preparing the new crystal form of Ruxolitinib phosphate according to claim 3, characterized in that: The volume ratio of methanol to dichloromethane is 1:1, 1:2 or 2:

1.

5. The method for preparing the new crystal form of Ruxolitinib phosphate according to any one of claims 2 to 4, characterized in that: The mass volume ratio of the ruxolitinib phosphate to the mixed solvent is 5 g to 30 g: 1 L.

6. The method for preparing the new crystal form of Ruxolitinib phosphate according to claim 5, characterized in that: The mass volume ratio of the ruxolitinib phosphate to the mixed solvent is 10 g~20 g:1 L.

7. The method for preparing the new crystal form of Ruxolitinib phosphate according to claim 6, characterized in that: The mass volume ratio of the ruxolitinib phosphate to the mixed solvent is 17 g-18 g:1 L.

8. A preparation containing ruxolitinib phosphate, characterized in that: It is prepared from the new crystal form of ruxolitinib phosphate according to claim 1 and pharmaceutically acceptable excipients.

9. The preparation containing ruxolitinib phosphate according to claim 8, characterized in that: The auxiliary material is one or more of a filler, a disintegrant, a flavoring agent, a lubricant, and a surfactant; and / or the preparation is a tablet or a cream.

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