A new crystalline form of ulixertinib and a method for preparing the same

Abstract

The present application provides a new crystalline form of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and a method for preparing the same. The new crystalline form is a hydrate, designated as Form H, which has better solubility and thermal stability. These properties can improve the crystal form stability of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide under high temperature granulation conditions in its formulation process, and can improve its bioavailability in the human body to some extent.

Description

Technical Field

[0001] This invention belongs to the fields of organic chemistry and medicinal chemistry, and relates to a novel crystalline form of utpatinib and its preparation method. More specifically, this invention relates to a novel crystalline form of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and its preparation method. Background Technology

[0002] Upatinib (Rinvoq), chemically named (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, is an oral JAK inhibitor developed by AbbVie for the treatment of atopic dermatitis, psoriatic arthritis, and rheumatoid arthritis. In August 2019, utpatinib was first approved for marketing in the United States for the treatment of rheumatoid arthritis. Since then, it has been gradually approved for multiple indications in Europe and the United States, such as psoriasis, ankylosing spondylitis, and atopic dermatitis.

[0003] Compared to first-generation JAK inhibitors, which have side effects such as infection and anemia, second-generation JAK inhibitors offer greater advantages in safety and tolerability due to their higher selectivity. Upatinib, a second-generation JAK inhibitor, has seen its sales rise sharply since its market launch. Statistics show that sales reached $1.651 billion in 2021, a 125% increase from the previous year, and it is projected that sales will further increase to $2.57 billion by 2024.

[0004]

[0005] Crystal form refers to the ordered arrangement of compound molecules with the same chemical structure to form a crystal lattice. A compound may exist in multiple crystal forms, and may also form eutectics with solvents or salts with acids and bases to form stable crystal forms. For the same drug molecule, when different crystal forms are formed, it may exhibit completely different physicochemical properties, resulting in significant differences in dissolution, bioavailability, and other aspects, thus affecting the drug's efficacy. Therefore, crystal form plays a crucial role in the quality, stability, solubility, and other parameters of active pharmaceutical ingredients (APIs), and crystal form research is an important part of API research.

[0006] Currently, there are more than 10 patents related to the crystal forms of utpatinib (or its salts). AbbVie, the original manufacturer, reported several crystalline forms of utpatinib in patent WO2017066775, which can be summarized as follows:

[0007] (1) Amorphous form in free base form: It has acceptable chemical stability and is stable under light or oxide conditions, but has obvious hygroscopicity.

[0008] (2) Crystal form B in the form of free alkali hydrate: PXRD pattern shows that its 2θ has significant characteristic peaks at 3.1±0.2, 9.3±0.2, 12.0±0.2, 20.8±0.2, and 25±0.2. In addition, DSC results show that it has obvious endothermic curves between 134.70℃ and 167.53℃ and between 109.31℃ and 132.94℃.

[0009] (3) Crystal form C in the form of free alkali hydrate: PXRD pattern shows that its 2θ has significant characteristic peaks at 13.4±0.2, 15.1±0.2, 21.7±0.2, etc. In addition, DSC results show that it has obvious endothermic curves between 134.70℃ and 167.53℃. Meanwhile, hygroscopicity test shows that it has no hygroscopicity in the range of 0 to 90%.

[0010] (4) Crystal form D of free alkali anhydrous form: PXRD pattern shows that its 2θ has significant characteristic peaks at 8.0±0.2, 9.7±0.2, 14.2±0.2, 14.5±0.2, 20.3±0.2, etc. The hygroscopic results show that it is hygroscopic and it is easy to transform into crystal form C after absorbing water or in aqueous solvent.

[0011] (5) Crystal form of tartrate hydrate: PXRD patterns show significant characteristic peaks at 2θ of 3.9±0.2, 6.8±0.2, and 14.1±0.2, and a distinct endothermic curve in the range of 75.74℃ to 110.26℃. Similar to crystal form C, it exhibits good stability under light and oxidizing conditions and has no significant hygroscopicity. However, its preparation process has certain limitations, making it unsuitable for large-scale production.

[0012] The phosphate crystalline form of utpatinib described in patent WO2020115212 has significant characteristic peaks in its XRD pattern at 2θ = 7.4±0.2, 17.6±0.2 and 19.3±0.2, and also exhibits obvious endothermic peaks in the temperature range of 170 to 180 °C.

[0013] Patent WO20222217257 reports eutectic forms of various benzoic acid salts, which have significant characteristic peaks at 2θ = 5.1 ± 0.2, 10.2 ± 0.2, and 12.5 ± 0.2.

[0014] Suzhou Keruisi Pharmaceutical Co., Ltd. described the CSⅡ crystal form of utpatinib free base in ether solvent in patent WO2020177645, and the DSC endothermic curve showed that its melting point was 195-197℃; at the same time, patent WO2022007629 disclosed the CSVI crystal form of utpatinib free base and succinic acid and the CSVI crystal form of adipic acid.

[0015] Among the many reported crystal forms of utpatinib active pharmaceutical ingredient (API), crystal form C is the primary pharmaceutically acceptable form. However, crystal form C, as a pharmaceutically acceptable crystal form, still has certain shortcomings in terms of solubility and stability. During the study of the thermal stability of crystal form C, the present inventors found that it exhibits a significant tendency to lose its water of crystallization at higher temperatures (65°C), resulting in a change in crystal form. This is not a desirable phenomenon for formulation processes involving granulation at higher temperatures. Furthermore, the present inventors found that the solubility of crystal form C is low in various media, which may further affect the bioavailability of its formulation in humans. Therefore, preparing a pharmaceutically acceptable crystal form of utpatinib API with better thermal stability and higher solubility is of great significance. Summary of the Invention

[0016] This invention provides a novel crystalline form of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidin-1-carboxamide. This novel crystalline form is referred to as crystal form H in this invention, and is characterized in that it is a hydrate, as shown in Formula I:

[0017]

[0018] The X-ray powder diffraction pattern of the hydrate crystal form, when measured with monochromatic Kα1 radiation at approximately 25°C, shows characteristic peaks at 13.3±0.2°2θ, 15.4±0.2°2θ, and 21.5±0.2°2θ. The melting point was determined by DSC and evaluated based on the initial temperature. With a heating rate of 10°C / min, the melting point was 167°C±3°C.

[0019] The novel crystalline form described in this invention is characterized by having no characteristic peaks at 7.9±0.2 degrees 2θ, 17.2±0.2 degrees 2θ, and 21.9±0.2 degrees 2θ when measured with monochromatic Kα1 radiation at approximately 25°C.

[0020] The novel crystalline form described in this invention is characterized by the crystallization water being detected by TGA thermogravimetric analysis and evaluated at the initial temperature, with a heating rate of 10°C / min, and a weight loss of 2% ± 0.2% at 105°C to 150°C.

[0021] The novel crystalline form described in this invention is characterized by the following key steps in its preparation method: a mixture containing (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide is pressurized to P1 at temperature T1 and stirred for time t1 to form crystal nuclei.

[0022] The novel crystalline form described in this invention is characterized by the following steps in its preparation method:

[0023] a) Dissolve crude (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in V1 volume (mL / g) of ethyl acetate, and then add V2 volume (mL / g) of water to the solution;

[0024] b) Heat the mixture obtained in step a to temperature T1, and add V3 volumes (mL / g) of n-heptane to the solution;

[0025] c) The mixture obtained in step b is pressurized to P1 at temperature T1 and stirred for time t1;

[0026] d) Continue to add V4 volume (mL / g) of n-heptane to the mixture obtained in step c. After the addition is complete, cool down to temperature T2 and continue stirring at temperature T2 for time t2.

[0027] e) After solid-liquid separation, the mixture obtained in step d is dried at temperature T3 to obtain the new crystalline form.

[0028] The novel crystalline form described in this invention is characterized in that, in step a of the preparation method of the novel crystalline form, V1 is selected from 3 to 5, and V2 is selected from 0.5 to 1.5.

[0029] The new crystalline form described in this invention is characterized in that, in step b of the preparation method of the new crystalline form, T1 is selected from 30℃ to 50℃, and V3 is selected from 1 to 2.

[0030] The novel crystalline form described in this invention is characterized in that, in step c of the preparation method of the novel crystalline form, P1 is selected from 0.3MPa to 0.5MPa, and t1 is selected from 2 to 3 hours.

[0031] The novel crystalline form described in this invention is characterized in that, in step d of the preparation method of the novel crystalline form, V4 is selected from 2 to 3, T2 is selected from 20℃ to 30℃, and t2 is selected from 5 to 7 hours.

[0032] The novel crystalline form described in this invention is characterized in that, in step e of the preparation method of the novel crystalline form, T3 is selected from temperatures not exceeding 60°C.

[0033] It should be noted and emphasized that the novel crystalline form described in this invention is characterized by the step of "pressurizing a mixture containing (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide at temperature T1 and stirring for time t1" in the preparation method. This process is crucial for the formation of the H-type crystal nucleus; without this step, it is difficult to form the crystalline form described in this invention. Therefore, any practice that uses a different crystallization solvent to form the crystal nucleus through this crucial step is considered to be within the scope of this invention and is obvious to those skilled in the art.

[0034] It should be further explained and emphasized that the novel crystalline form of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide described in this invention is characterized by being significantly different from the hemihydrate crystal form C reported in patent document WO2017066775 in terms of both characterization and intrinsic properties. The XRD characteristic peaks and DSC endothermic peaks of this novel crystalline form under the same conditions as crystal form C show significant differences. Furthermore, the thermal stability of this novel crystalline form and its saturated solubility in different media also show significant differences compared to crystal form C under the same conditions.

[0035] The novel crystalline form described in this invention has the following advantages over the free alkali hydrate crystal form C reported in patent document WO2017066775:

[0036] (1) The crystal form described in this invention has better thermal stability at higher temperatures (65°C), which is more conducive to maintaining the stability of the crystal form of the active pharmaceutical ingredient during the formulation process and the drying process of the active pharmaceutical ingredient;

[0037] (2) The crystalline form described in this invention has greater solubility in acidic, alkaline or neutral media, which is more conducive to improving the bioavailability of the drug in the human body. Attached Figure Description

[0038] Appendix Figure 1 X-ray powder diffraction pattern of the new crystalline form described in this invention.

[0039] Appendix Figure 2 Differential scanning calorimetry of the new crystalline form described in this invention.

[0040] Appendix Figure 3 Thermogravimetric analysis diagram of the new crystalline form described in this invention.

[0041] Appendix Figure 4 Infrared spectrum of the new crystalline form described in this invention.

[0042] Appendix Figure 5 A comparison of the dissolution curves of the new crystalline form described in this invention with those of the sustained-release tablets of crystal form C. Detailed Implementation

[0043] The following specific embodiments will enable those skilled in the art to fully understand the present invention, but do not limit the present invention in any way.

[0044] In the following examples, unless otherwise specified, all temperatures are in Celsius; unless otherwise specified, all room temperatures are 20-30°C; unless otherwise specified, all starting materials and reagents are commercially available and used directly without further purification; unless otherwise specified, all solvents are industrial grade solvents and used directly without further processing; unless otherwise specified, commercially available manufacturers include, but are not limited to, Hangzhou Chemical Reagents, Sinopharm Reagents, etc.

[0045] time A B 0 95 5 5 95 5 30 15 85 40 15 85 42 95 5 50 95 5

[0046] Example 1: Preparation method of crude utpatinib free base:

[0047] (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (approximately 300 g) was dissolved in 10 L of water. 50% sodium hydroxide solution (160 g) was added dropwise over two hours to adjust the pH to >12. The mixture was filtered, and the filter cake was rinsed twice with 500 mL of water. Then, it was dried in a vacuum oven to obtain the crude free alkali product.

[0048] Example 2: The technical solution described in this invention

[0049] 4 g of crude (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide was dissolved in 12 mL of ethyl acetate by stirring. 2 mL of water was added, and the mixture was heated to 35 °C. 8 mL of n-heptane was added dropwise. After the addition was complete, the mixture was stirred until a solid precipitated. The system pressure was increased to 0.3 MPa and stirred for 3 hours. 8 mL of n-heptane was added dropwise. After the addition was complete, the temperature was lowered to 20 °C and the mixture was stirred for 6 hours. The mixture was filtered, and the filter cake was dried at 50 °C for 8 hours to obtain 2.02 g of utpatinib crystal form H.

[0050] Example 3: The technical solution described in this invention

[0051] 4 g of crude (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide was dissolved in 12 mL of ethyl acetate by stirring. 2 mL of water was added, and the mixture was heated to 50 °C. 4 mL of n-heptane was added dropwise. After the addition was complete, the mixture was stirred until a solid precipitated. The system pressure was increased to 0.4 MPa and stirred for 2 hours. 8 mL of n-heptane was added dropwise. After the addition was complete, the temperature was lowered to 20 °C and the mixture was stirred for 7 hours. The mixture was filtered, and the filter cake was dried at 50 °C for 8 hours to obtain 2.02 g of utpatinib crystal form H.

[0052] Example 4: The technical solution described in this invention

[0053] 4 g of crude (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide was dissolved in 12 mL of ethyl acetate by stirring. 4 mL of water was added, and the mixture was heated to 40 °C. 8 mL of n-heptane was added dropwise. After the addition was complete, the mixture was stirred until a solid precipitated. The system pressure was increased to 0.5 MPa and stirred for 3 hours. Another 12 mL of n-heptane was added dropwise. After the addition was complete, the temperature was lowered to 25 °C and the mixture was stirred for 6 hours. The mixture was filtered, and the filter cake was dried at 50 °C for 8 hours to obtain 2.31 g of utpatinib crystal form H.

[0054] Example 5: The technical solution described in this invention

[0055] 4 g of crude (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide was dissolved in 12 mL of ethyl acetate by stirring. 6 mL of water was added, and the mixture was heated to 40 °C. 6 mL of n-heptane was added dropwise. After the addition was complete, the mixture was stirred until a solid precipitated. The system pressure was increased to 0.5 MPa and stirred for 2 hours. 10 mL of n-heptane was added dropwise. After the addition was complete, the temperature was lowered to 30 °C and the mixture was stirred for 5 hours. The mixture was filtered, and the filter cake was dried at 60 °C for 8 hours to obtain 2.13 g of utpatinib crystal form H.

[0056] Example 6: The technical solution described in this invention

[0057] 4 g of crude (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide was dissolved in 20 mL of ethyl acetate by stirring. 6 mL of water was added, and the mixture was heated to 50 °C. 4 mL of n-heptane was added dropwise. After the addition was complete, the mixture was stirred until a solid precipitated. The system pressure was increased to 0.5 MPa and stirred for 3 hours. 10 mL of n-heptane was added dropwise. After the addition was complete, the temperature was lowered to 30 °C and the mixture was stirred for 7 hours. The mixture was filtered, and the filter cake was dried at 60 °C for 8 hours to obtain 1.75 g of utpatinib crystal form H.

[0058] Example 7: The technical solution described in this invention

[0059] 4 g of crude (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide was dissolved in 20 mL of ethyl acetate by stirring. 6 mL of water was added, and the mixture was heated to 45 °C. 4 mL of n-heptane was added dropwise. After the addition was complete, the mixture was stirred until a solid precipitated. The system pressure was increased to 0.5 MPa and stirred for 3 hours. 12 mL of n-heptane was added dropwise. After the addition was complete, the temperature was lowered to 30 °C and the mixture was stirred for 7 hours. The mixture was filtered, and the filter cake was dried at 50 °C for 8 hours to obtain 1.86 g of utpatinib crystal form H.

[0060] Example 8: The technical solution described in this invention

[0061] 4 g of crude (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide was dissolved in 20 mL of ethyl acetate by stirring. 4 mL of water was added, and the mixture was heated to 40 °C. 6 mL of n-heptane was added dropwise. After the addition was complete, the mixture was stirred until a solid precipitated. The system pressure was increased to 0.5 MPa and stirred for 2.5 hours. 12 mL of n-heptane was added dropwise. After the addition was complete, the temperature was lowered to 25 °C and the mixture was stirred for 6 hours. The mixture was filtered, and the filter cake was dried at 50 °C for 8 hours to obtain 1.96 g of utpatinib crystal form H.

[0062] Example 9: The technical solution described in this invention

[0063] 4 g of crude (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide was dissolved in 20 mL of ethyl acetate by stirring. 2 mL of water was added, and the mixture was heated to 35 °C. 8 mL of n-heptane was added dropwise. After the addition was complete, the mixture was stirred until a solid precipitated. The system pressure was increased to 0.3 MPa and stirred for 3 hours. 8 mL of n-heptane was added dropwise again. After the addition was complete, the temperature was lowered to 20 °C and the mixture was stirred for 6 hours. The mixture was filtered, and the filter cake was dried at 50 °C for 8 hours to obtain 1.76 g of utpatinib crystal form H.

[0064] Example 10: The technical solution described in this invention

[0065] 4 g of crude (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide was dissolved in 16 mL of ethyl acetate by stirring. 4 mL of water was added, and the mixture was heated to 40 °C. 8 mL of n-heptane was added dropwise. After the addition was complete, the mixture was stirred until a solid precipitated. The system pressure was increased to 0.3 MPa and stirred for 3 hours. 12 mL of n-heptane was added dropwise. After the addition was complete, the temperature was lowered to 20 °C and the mixture was stirred for 6 hours. The mixture was filtered, and the filter cake was dried at 50 °C for 8 hours to obtain 2.09 g of utpatinib crystal form H.

[0066] Example 11: The technical solution described in this invention

[0067] 4 g of crude (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide was dissolved in 16 mL of ethyl acetate by stirring. 6 mL of water was added, and the mixture was heated to 50 °C. 8 mL of n-heptane was added dropwise. After the addition was complete, the mixture was stirred until a solid precipitated. The system pressure was increased to 0.4 MPa and stirred for 3 hours. 10 mL of n-heptane was added dropwise. After the addition was complete, the temperature was lowered to 30 °C and the mixture was stirred for 6 hours. The mixture was filtered, and the filter cake was dried at 60 °C for 8 hours to obtain 1.98 g of utpatinib crystal form H.

[0068] Example 12: Preparation of crystal form C as described in patent document WO2017066775:

[0069] 11.1 g of crude (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide was dissolved in 70 g of ethyl acetate containing 2% water. Seed crystals of crystal form C were added, and the mixture was stirred. Then, n-heptane was added dropwise, and the mixture was stirred overnight. The suspension was filtered, washed with water-saturated ethyl acetate / n-heptane (1:1, 100 mL), and dried under vacuum at 50 °C to obtain urpatinib crystal form C.

[0070] Example 12: Characterization test of crystal form H described in this invention

[0071] A solid sample of crystal form H was taken, and the powder of the solid sample was measured using monochromatic Kα1 radiation at 25°C. The results are summarized below, and details can be found in the appendix of the instruction manual. Figure 1 .

[0072]

[0073] Differential scanning calorimetry (DSC) was performed at the initial temperature, with a heating rate of 10 °C / min. The endothermic peak was detected, and the results showed that the sample initially exhibited an endothermic peak at approximately 156.8 °C, reaching its apex at 167.9 °C. The endothermic endpoint occurred at approximately 172.1 °C. See the appendix in the instruction manual for details. Figure 2 .

[0074] Thermogravimetric analysis was performed using the initial temperature as the assessment method. The heating rate was 10℃ / min, and weight loss was measured below 105-150℃. Results showed a weight loss of approximately 2.0% in this region. See the instruction manual for details. Figure 3 .

[0075] Weigh 5 mg of sample powder and potassium bromide powder, mix well, compress into a tablet, and detect its infrared spectrum. The results show that the sample is at 3431 cm⁻¹. -1 2569cm -1 1780cm -1 Strong absorption is observed at constant wavenumbers; see the instruction manual for details. Figure 4 .

[0076] Example 13: Study on the hygroscopicity of crystal form H described in this invention

[0077] Weigh 500 mg of utpatinib crystal form H solid sample and spread it evenly at the bottom of a weighing bottle. Place the weighing bottle in a desiccator or artificial climate chamber (set temperature 25℃±1℃, relative humidity 80%±2%) for 24 hours and then weigh it. The weighing result shows 500 mg, so crystal form H is not hygroscopic.

[0078] Example 14: Comparative Study of the Crystalline Thermal Stability of Crystal Forms C and H

[0079] 1g of solid samples of utpatinib in crystal form C and crystal form H were weighed separately and spread evenly at the bottom of a weighing bottle. The weighing bottle was placed open at 65℃, and samples were taken at 5, 10, and 30 days to detect the change in water content of crystal form C and crystal form H, in order to evaluate the stability of its crystal form. The results are shown in the table below:

[0080]

[0081] The results show that crystal form C exhibits a significant decrease in water of crystallization at 65℃, losing more than 30% of its water after 30 days. In contrast, crystal form H demonstrates better stability, maintaining its original water content even after 30 days at 65℃. Therefore, crystal form H exhibits better thermal stability than crystal form C at 65℃.

[0082] Example 15: Comparative Study of Solubility of Crystal Form C and Crystal Form H

[0083] Equal amounts of solid samples of crystal form C and crystal form H were weighed and placed in 5 mL volumetric flasks. 5 mL of liquid medium at different pH values ​​were added and the solution was brought to volume. The mixture was shaken for 1 minute every 30 minutes for 6 hours until both solutions reached saturation and undissolved solids remained. 2 mL of the supernatant was filtered, and 1 mL of the filtrate was quantitatively transferred to a 5 mL volumetric flask and diluted to volume. The content of the main component of utpatinib in the saturated solution was quantitatively determined by HPLC external method, and the saturated equilibrium solubility of crystal forms C and H in different dissolving media was calculated. The results are summarized below:

[0084]

[0085] The above results indicate that, under the same medium and temperature, crystal form H has a significantly higher saturated equilibrium solubility than crystal form C.

[0086] Example 16: Comparative Study of Tablet Dissolution of Crystal Form C and Crystal Form H

[0087] Following the method described in Example 24 of patent document WO2017066775, utpatinib extended-release tablets of crystal form C and crystal form H were prepared, respectively. The dissolution rate (paddle method) of the main component of tablets containing crystal form C and crystal form H was measured over time in a medium at pH 6.8. The results showed that the main component of the utpatinib extended-release tablet containing crystal form H had a longer release time. For detailed dissolution curves, please refer to the appendix to the instruction manual. Figure 5 .

[0088] The method of this invention has been described through preferred embodiments. Those skilled in the art will readily understand, within the scope and content of this invention, the methods and applications described herein, and will make appropriate, common-sense adjustments, modifications, and combinations where necessary to implement and apply the technology of this invention. Those skilled in the art can also refer to the content of this invention and implement it by appropriately modifying process parameters. It should be particularly noted that all similar improvements and modifications are obvious to those skilled in the art and should be considered as included within this invention.

Claims

1. A novel crystalline form of (3S,4R)-3-ethyl-4-(3H-imidazo[l,2-a]pyrrolo[2,3- e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine- 1 -carboxamide characterized by, The crystalline form is a hydrate, as shown in formula I: The X-ray powder diffraction pattern of the hydrate crystalline form has characteristic peaks at 13.3 ± 0.2 degrees 2-theta, 14.9 ± 0.2 degrees 2-theta, 15.4 ± 0.2 degrees 2-theta, 16.9 ± 0.2 degrees 2-theta, 20.4 ± 0.2 degrees 2-theta, 21.5 ± 0.2 degrees 2-theta, when measured at 25°C using monochromatic Kα1 radiation; the melting point is determined by DSC, and is evaluated as the onset temperature, with a heating rate of 10°C / min, and is 167°C ± 3°C.

2. The new crystalline form according to claim 1, characterized by, The X-ray powder diffraction pattern has no characteristic peaks at 7.9 ± 0.2 degrees 2-theta, 17.2 ± 0.2 degrees 2-theta, 21.9 ± 0.2 degrees 2-theta, when measured at 25°C using monochromatic Kα1 radiation.

3. The new crystalline form of claim 1, characterized by, The crystallization water is detected by TGA thermogravimetric analysis, and is evaluated as the onset temperature, with a heating rate of 10°C / min, and the weight loss between 105°C and 150°C is 2% ± 0.2%.

4. The new crystalline form of claim 1, characterized by, The method for preparing the new crystalline form comprises the following key steps: the mixed solution containing (3S, 4R)-3-ethyl-4-(3H-imidazo[1, 2-a]pyrrolo[2, 3-e]pyrazin-8-yl)-N-(2, 2, 2-trifluoroethyl) pyrrolidine-1-carboxamide is pressurized to P1 at T1, and is stirred for t1 to form crystal nuclei.

5. The new crystalline form of claim 1, characterized by, The method for preparing the new crystalline form specifically comprises the following steps: a) (3S, 4R)-3-ethyl-4-(3H-imidazo[1, 2-a]pyrrolo[2, 3-e]pyrazin-8-yl)-N-(2, 2, 2-trifluoroethyl) pyrrolidine-1-carboxamide crude is dissolved in V1 volume of ethyl acetate, and V2 volume of water is added to the solution, wherein the volumes are milliliters per gram; b) the mixed solution obtained in step a) is heated to T1, and V3 volume of n-heptane is added dropwise to the solution, wherein the volume is milliliters per gram; c) the mixed solution obtained in step b) is pressurized to P1 at T1, and is stirred for t1; d) V4 volume of n-heptane is continuously added dropwise to the mixture obtained in step c), after the dropwise addition is completed, it is cooled to T2, and is continuously stirred at T2 for t2, wherein the volumes are milliliters per gram; e) after the solid-liquid separation of the mixture obtained in step d) is achieved, it is dried at T3 to obtain the new crystalline form.

6. The novel crystalline form as claimed in claim 5, characterized in that, In step a) of the method for preparing the new crystalline form, V1 is selected from 3 to 5, and V2 is selected from 0.5 to 1.

5.

7. The novel crystalline form as claimed in claim 5, characterized in that, In step b) of the method for preparing the new crystalline form, T1 is selected from 30°C to 50°C, and V3 is selected from 1 to 2.

8. The novel crystalline form as claimed in claim 4 or 5, characterized in that, In step c) of the method for preparing the new crystalline form, P1 is selected from 0.3 MPa to 0.5 MPa, and t1 is selected from 2 to 3 hours.

9. The novel crystalline form as claimed in claim 5, characterized in that, In step d) of the method for preparing the new crystalline form, V4 is selected from 2 to 3, T2 is selected from 20°C to 30°C, and t2 is selected from 5 to 7 hours.

10. The novel crystalline form as claimed in claim 5, characterized in that, In step e) of the method for preparing the new crystalline form, T3 is selected to be not higher than 60°C.

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