Baricitinib phthalate crystal form and preparation thereof

Abstract

The invention provides a baricitinib phthalate crystal form, and relates to the technical field of crystal form drug molecules. The crystal form is radiated by Cu-K alpha, and an X-ray diffraction pattern represented by 2 theta has characteristic peaks at 6.20 + / -0.2 degrees, 6.53 + / -0.2 degrees, 14.53 + / -0.2 degrees, 18.29 + / -0.2 degrees, 18.53 + / -0.2 degrees, 18.70 + / -0.2 degrees, 19.44 + / -0.2 degrees and 26.95 + / -0.2 degrees; the crystallographic measurement parameters are as follows: an orthorhombic system is adopted, and the space group is Pbcn; the cell parameters are as follows: # imgabs 0 # alpha = 90 degrees, beta = 90 degrees, gamma = 90 degrees, and the cell volume # imgabs 1 #. The invention also provides a related preparation method and application. The baricitinib phthalate crystal form disclosed by the invention is good in stability and relatively high in solubility and permeability.

Description

Technical Field

[0001] The present invention relates to the technical field of crystalline drug molecules, and in particular to a crystalline form of baricitinib phthalate. Background Art

[0002] Baricitinib is a JAK inhibitor compound that can be used to treat autoimmune diseases, inflammatory diseases or cancer diseases involving JAK. JAK1 is a new target in the field of immune-inflammatory diseases. JAK1 heterodimerizes with other JAKs to transduce cytokine-driven pro-inflammatory signaling. Therefore, it is expected that inhibition of JAK1 and or other JAKs will be of therapeutic benefit for a range of inflammatory conditions and other diseases driven by JAK-mediated signal transduction. The chemical name of baricitinib is {1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, as shown in formula (I):

[0003]

[0004] Baricitinib (trade name: ) was jointly developed by Eli Lilly and Incyte. On June 13, 2022, baricitinib was approved by the FDA for priority review and marketing for the treatment of severe alopecia areata in adult patients, and was recognized as a breakthrough therapy. This is the first time that the FDA has approved a systemic treatment for alopecia areata (i.e., treating the entire body rather than a specific part). Baricitinib tablets were approved in June 2019. It has been approved for marketing in China for the treatment of rheumatoid arthritis, and in March 2023, it was approved for the treatment of severe alopecia areata in adult patients in China. This is also the first and only innovative targeted drug approved for the systemic treatment of severe alopecia areata in China. Alopecia areata is stubborn, difficult to treat, and prone to relapse. Its previous treatment was mainly oral and topical hormones, which generally had poor efficacy and obvious side effects. The emergence of baricitinib has undoubtedly brought hope to patients with alopecia areata.

[0005] Specific medicinal activity is a basic prerequisite that must be met for pharmaceutical active substances to be approved for marketing. However, there are a variety of other requirements that must be followed by pharmaceutical active substances. These requirements are based on various parameters related to the properties of the active substances themselves. Without limitation, examples of these parameters are the chemical and solid stability and storage stability of the active ingredients under various environmental conditions, the stability during the manufacture of the pharmaceutical composition, and the stability of the active ingredients in the final pharmaceutical composition. In addition, although pharmaceutical active substances have clinical application prospects, their poor water solubility and permeability lead to their low bioavailability, which greatly limits their clinical application. According to statistics, more than 40% of candidate drugs in the drug development process cannot enter clinical research due to poor water solubility, poor permeability, and low bioavailability. Baricitinib is a white powder. Baricitinib is classified as a BCS Class III drug and is a low-permeability drug.

[0006] As we all know, the crystal form of the drug has a great influence on the stability, solubility, permeability, bioavailability, etc. of the solid drug preparation. The excellent crystal form suitable for the preparation of solid preparations generally needs to meet various requirements such as stability, solubility, and bioavailability. A new salt form of a drug refers to a new eutectic substance (CCF) introduced by proton transfer, which self-assembles with the active pharmaceutical ingredient (APT) under the action of hydrogen bonds to form a supramolecular crystal with a fixed stoichiometric ratio. In the preclinical drug development stage, new drug development companies usually use the active pharmaceutical ingredient (APT) to improve the drug's solubility, dissolution rate, permeability, hygroscopicity, stability, bioavailability, and other physical and chemical properties by salting. Compared with nanocrystals, solid dispersants, and new drug dosage form technologies, drug salt forms have obvious advantages in improving drug solubility, dissolution rate, permeability, hygroscopicity, stability, and bioavailability.

[0007] Currently, a large number of reports and studies on baricitinib crystal forms, salts and cocrystals have focused on improving their solubility, stability, hygroscopicity and other aspects.

[0008] Patent CN105924444A discloses five crystal forms of baricitinib, including crystal forms I and II and phosphate crystal form A, crystal form B, and crystal form C. The disclosed crystal forms have high hygroscopicity. At 80% humidity, the phosphate crystal form A gains weight by 0.99%, the phosphate crystal form C gains weight to 2.85%, the weight gains of crystal forms II and phosphate crystal form B both exceed 1%, and the crystal form I with the least weight gain, i.e. the best hygroscopic effect, has a slight hygroscopicity of 0.44% at 80% humidity. In terms of stability, crystal form II and phosphate crystal form B are unstable, and crystal transformation occurs after being placed at 40°C and 75% RH for 2 weeks. The above-mentioned reported crystal forms are not ideal in terms of hygroscopicity.

[0009] Patent CN105693731A discloses baricitinib crystal form A. It was found that no crystal transformation occurred under high temperature, high humidity and light conditions, which showed the stability of the crystal form. Preparation research found that crystal form A is the same crystal form as crystal form I recorded in patent CN105924444A. Patent CN105566332A discloses baricitinib trifluoroacetate crystal form A and crystal form B. It was found that no crystal transformation occurred under high temperature, high humidity and light conditions, and its solubility needs to be improved; trifluoroacetic acid semi-crystals all showed crystal transformation under high temperature and high humidity, showing instability.

[0010] Patent CN105601635A discloses baricitinib phosphate crystal form A, crystal form H, and crystal form I, wherein the solubility of crystal form A is increased to 4.2 mg / ml compared to crystal forms H and I, and phosphate crystal forms H and I are unstable under high humidity conditions. Patent CN108341818 A discloses baricitinib crystal form III and phosphate crystal form D, at 80% humidity, crystal form III gains weight by 0.15%, and phosphate crystal form D gains weight by 0.1%, showing that it does not attract moisture; the solubility of phosphate crystal form D in water is about 4.8 mg / ml.

[0011] Patent CN110799512A discloses baricitinib Form G and three solvates, Form D (1,4-dioxane solvate), Form E (chloroform solvate), and Form F (methyl tert-butyl ether solvate). The solvates are not suitable as pharmaceutical crystal forms due to their solvent toxicity problems. The solubility of baricitinib Form G recorded in it in water is 0.096 mg / ml after 24 hours. In terms of hygroscopicity, the weight gain is 0.21% at 80% humidity and 0.34% at 95% humidity. Form G has improved fluidity and adhesion. The solubility of baricitinib Form G needs to be improved.

[0012] Patent CN111278828A discloses baricitinib phosphate crystal form α and crystal form β. The phosphate crystal form α gains weight by 0.36% after equilibrium at 80% relative humidity. According to the definition standard of hygroscopic weight gain, crystal form α is slightly hygroscopic; the moisture weight gain of crystal form β is less than 0.2%, which is almost non-hygroscopic.

[0013] The document “Similarity and Diversity: Cocrystallization of Baricitinib with Four C4-Dicarboxylic Acids” discloses four crystalline forms of baricitinib, namely baricitinib maleate (MAL), baricitinib L-tartrate (TAR), baricitinib fumaric acid cocrystal (FUM), and baricitinib succinic acid cocrystal (SUC). The new solid forms all show excellent anti-hydration phase stability, reduced hygroscopicity, and slightly improved solubility; at 90% humidity, the moisture content of baricitinib maleate increased from 0.33% to 0.67%, an increase of 0.34 %, baricitinib-L-tartrate (TAR), baricitinib-fumaric acid cocrystal (FUM), and baricitinib-succinic acid cocrystal (SUC) increased by 0.67%, 0.66%, and 0.66%, respectively; in terms of solubility, the solubility of baricitinib-maleate and baricitinib-L-tartrate in phosphate buffer was 0.33mg / ml and 0.43mg / ml, respectively, which was significantly improved compared to the solubility of baricitinib 0.045mg / ml. Patent CN118561848A discloses a baricitinib-maleate, whose crystal data is consistent with the baricitinib-maleate (MAL) disclosed in the document "Similarity and Diversity: Cocrystallization of Baricitinib with Four C4-Dicarboxylic Acids", that is, it is judged to be the same crystal form, and the solubility in phosphate buffer tested by a technician in the field is about 0.46mg / ml.

[0014] Patent CZ2017314A3 discloses two crystal forms of baricitinib formic acid solvate and baricitinib acetic acid solvate. Studies have found that at 80% humidity, their weight increases exceed 2%, and both are hygroscopic. EP3321267A1 discloses a series of baricitinib salt crystal forms, including hydrobromide, hydrochloride, sulfate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, L-tartrate, fumarate, and citrate amorphous. Studies have found that the solubility of the disclosed salt forms increases significantly, but the hygroscopicity is poor. EP3327020A1 discloses baricitinib monocitrate and biscitrate, wherein the solubility of baricitinib citrate is more than 2 times higher than that of baricitinib free base, and the solubility after 1 hour in 0.1N HCl solution medium is measured, the solubility of crystalline free base (WO 2015166434A1) is 25 mg / mL, the solubility of phosphate is 26 mg / ml, the solubility of baricitinib trifluoroacetate form A is 29 mg / ml, and the solubility of citrate crystalline forms disclosed in this patent is greater than 50 mg / ml.

[0015] Patent EP3502114A1 discloses baricitinib-lactic acid cocrystals, and baricitinib lactic acid cocrystals dissolve faster than pure crystalline baricitinib free base form A (comparing the values ​​at 1 minute, where the concentration of baricitinib dissolved in baricitinib lactic acid cocrystals is three times higher than that of baricitinib free base form A). Patent EP3771715A1 discloses PPH crystalline form I and crystalline form II, which have good stability. Studies have found that their solubility in aqueous solution is about 0.5 mg / ml, and there is no improvement in solubility. Patent EP3771716A1 discloses an amorphous baricitinib, which has a weight gain of 0.36% at about 80% humidity, showing slight hygroscopicity. Patent RU2644155C1 discloses baricitinib heminapthyl disulfonate salt, which has a solubility of about 1 mg / ml in water. In the Papp AB (CaCo-2) test (which evaluates the apparent permeability coefficient (Papp) of the compound by simulating intestinal epithelial cells (Caco-2 cells)), the ADME parameters of baricitinib heminapthyl disulfonate salt are twice that of baricitinib, showing better cell permeability. Patent US20220135566A1 discloses a series of salts or cocrystals, including baricitinib-orotic acid cocrystals (I, II, IV), baricitinib-naphthalene-2-sulfonate salt crystals, baricitinib-(+)-camphoric acid crystals, baricitinib-fumaric acid cocrystals, baricitinib-tartaric acid cocrystals (I, II), and baricitinib-succinic acid cocrystals. The baricitinib-naphthalene-2-sulfonate salt crystal has the most significant improvement in solubility among the above crystal forms and exhibits low hygroscopicity. Patent WO2017125772A1 discloses a series of salts formed by baricitinib with ethanesulfonic acid, methanesulfonic acid and benzenesulfonic acid, hydrochloric acid, 4-toluenesulfonic acid, oxalic acid, 2-hydroxyethanesulfonic acid, fumaric acid, tartaric acid and cyclohexylaminosulfonic acid; among them, the hydrochloride and cyclohexylaminosulfonic acid salt forms and their crystalline forms show a great degree of chemical instability. As for baricitinib oxalate, fumarate and tartrate, from a crystallographic point of view, these forms have low structural order and low thermodynamic stability. It is surprisingly found that the salts formed by baricitinib with sulfonic acids, especially ethanesulfonic acid, methanesulfonic acid and benzenesulfonic acid, are in the form of uniform crystal structure and can be reproducibly produced; the benzenesulfonate salt is hygroscopic, and the methanesulfonate salt is low in hygroscopicity. Patent WO2018113801A1 discloses a series of phosphate crystal forms, including phosphate crystal forms A, B, C, D, E, F, G and hemiphosphate crystal forms I and II. Studies have found that, except for phosphate type D, the phosphate crystal forms disclosed in this patent show a weight gain of 0.35% to 1.5% at 80% humidity.Patent WO2019003249A1 discloses a series of baricitinib solvates, including crystal form M1 (sulfolane solvate), crystal form M2 (propionic acid solvate), crystal form M3 (formic acid hemisolvate), crystal form M4 (formic acid solvate), crystal form M6 (cyclopentyl methyl ether solvate), and crystal form M7 (aniline solvate). Due to the toxicity of the solvent, the solvates are not suitable as pharmaceutical crystal forms. WO2015145286A1 discloses amorphous baricitinib. Although the amorphous form has higher solubility and dissolution rate than the crystalline form in most cases, it is unstable, highly hygroscopic, and prone to product transformation. Therefore, the amorphous form has problems with processing stability and storage stability, and in the production process, the amorphous particles have a low bulk density and high surface free energy, which can easily cause a series of formulation problems such as agglomeration, poor fluidity, and strong elastic deformation, which seriously affect the clinical use value of amorphous baricitinib. Patents CN116751204A and CN118561849A disclose baricitinib-gallic acid cocrystals and baricitinib-aminosulfonic acid cocrystals, which have improved solubility.

[0016] An analysis of the prior art shows that in order to overcome the problem of low solubility of baricitinib in water, a series of baricitinib salts or cocrystals have been studied, which have made certain progress in solubility, but most of them have not overcome the hygroscopicity problem, resulting in storage difficulties. Some baricitinib crystal forms developed and studied subsequently still have defects in terms of drug safety, stability, hygroscopicity, solubility, bioavailability, etc.

[0017] In summary, further research and development of superior crystalline forms of baricitinib suitable for pharmaceutical use is still a problem that needs to be solved. Summary of the invention

[0018] In order to overcome the shortcomings of the prior art, the present invention provides a new pharmaceutically acceptable salt crystalline form of baricitinib and a preparation method thereof.

[0019] The specific technical solutions of the present invention are as follows:

[0020] A baricitinib phthalate crystalline form, wherein the molar ratio of baricitinib to phthalic acid in the crystalline form is 1:1, and one molecule of baricitinib and one molecule of phthalic acid constitute a basic unit of the crystalline form, and the specific structure is as shown in Formula I:

[0021]

[0022] Preferably, the baricitinib phthalate crystalline form uses Cu-Kα radiation, and the X-ray diffraction spectrum expressed in 2θ has characteristic peaks at 6.20±0.2°, 6.53±0.2°, 18.53±0.2°, 18.70±0.2°, and 19.44±0.2°.

[0023] Preferably, the baricitinib phthalate crystalline form uses Cu-Kα radiation, and the X-ray diffraction spectrum expressed as 2θ has characteristic peaks at 6.20±0.2°, 6.53±0.2°, 14.53±0.2°, 18.29±0.2, 18.53±0.2, 18.70±0.2°, 19.44±0.2°, and 26.95±0.2°.

[0024] Preferably, the baricitinib phthalate crystalline form, using Cu-Kα radiation, has characteristic peaks that meet the following Figure 1 The X-ray powder diffraction pattern is shown.

[0025] Preferably, the crystal form of baricitinib phthalate has the following crystallographic parameters: orthorhombic system, space group Pbcn; unit cell parameters: α=90°,β=90°,γ=90°,unit cell volume

[0026] A method for preparing a crystalline form of baricitinib phthalate comprises the following steps:

[0027] Baricitinib and phthalate are added to an organic solvent, dissolved by ultrasonication, filtered, allowed to stand, evaporated and crystallized, filtered, and dried to obtain baricitinib phthalate.

[0028] Preferably, the organic solvent is one or two of acetonitrile, acetone, tetrahydrofuran, methanol, ethanol, and isopropanol; more preferably, it is one or a combination of isopropanol and tetrahydrofuran; if the organic solvent is a mixed solvent of two kinds, the volume ratio of the less polar solvent to the more polar solvent is preferably 1:1.5 to 2.

[0029] Preferably, the molar ratio of baricitinib to phthalate is 1:1.0 to 3.0, preferably 1:1.5.

[0030] Preferably, the mass-to-volume ratio of baricitinib to the organic solvent is 3 to 5:1, wherein the mass is measured in mg and the volume is measured in mL.

[0031] Preferably, the volatilization and crystallization temperature is 10 to 30°C, more preferably 10 to 25°C.

[0032] The baricitinib phthalate crystalline form of the present invention can be used as an active ingredient in the preparation of drugs for treating autoimmune diseases, inflammatory diseases or cancer diseases involving JAK.

[0033] A pharmaceutical composition comprising the baricitinib phthalate crystalline form of the present invention and mixed with other components.

[0034] Preferably, the pharmaceutical composition of the present invention is prepared by combining the compound of the present invention with a pharmaceutically acceptable solid or liquid carrier and optionally with a pharmaceutically acceptable excipient to prepare a usable dosage form using standard and conventional techniques.

[0035] Preferably, the other components include other active ingredients, fillers, diluents, binders, disintegrants, lubricants, etc. that can be used in combination.

[0036] More preferably, the diluent is selected from one or more of starch, sucrose, dextrin, lactose, microcrystalline cellulose, mannitol, and sorbitol; the binder is selected from one or more of methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium hydroxymethyl cellulose, ethyl cellulose, and povidone; the disintegrant is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, and cross-linked povidone; the lubricant is selected from one or more of magnesium stearate, micropowdered silica gel, talc, and sodium lauryl sulfate.

[0037] Preferably, the pharmaceutical composition is in the form of tablets, capsules, granules and pills.

[0038] Beneficial effects of the present invention:

[0039] The baricitinib phthalate crystalline form prepared by the present invention has achieved great improvements in stability, solubility, permeability, etc. After being inspected under high humidity conditions, the crystalline form is stable, has no crystal transformation, and is non-hygroscopic. The preparation method of the baricitinib phthalate crystalline form is simple, the obtained crystal has a regular crystalline form, uniform particle size, has clear main crystallographic parameters and exact atomic spatial positions, and single crystal diffraction data shows that it does not contain organic solvents, and the non-solvate crystalline form is safer for medicinal use and is suitable for large-scale promotion and application. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 : X-ray powder diffraction pattern of baricitinib phthalate crystalline form.

[0041] Figure 2 : ORTEP diagram of baricitinib phthalate crystalline form.

[0042] Figure 3 :Baricitinib phthalate crystal stacking diagram

[0043] Figure 4 : DSC-TGA diagram of baricitinib phthalate crystalline form. DETAILED DESCRIPTION

[0044] The present invention is further described below by way of examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention, so simple improvements to the present invention based on the method of the present invention are within the scope of protection claimed by the present invention.

[0045] Materials used in the experiment: Baricitinib can be purchased or prepared according to the method disclosed in patent WO2009114512. The crystal form of baricitinib required for the comparative experiment can be prepared according to the existing technology or purchased; the materials used in other experiments without indicating the source and specification are all commercially available analytically pure or chemically pure.

[0046] Example 1

[0047] 0.37 g of baricitinib and 0.25 g of phthalic acid were added to 100 mL of isopropanol, dissolved by ultrasonication, filtered, and allowed to stand at 20°C for natural evaporation and crystallization. After crystallization, the mixture was filtered and dried at 45°C for 10 h to obtain baricitinib phthalate with a purity of 99.85%.

[0048] Example 2

[0049] 0.37 g of baricitinib and 0.25 g of phthalic acid were added to 120 mL of acetonitrile, dissolved by ultrasonication, filtered, and allowed to stand at 20°C for natural evaporation and crystallization. After crystallization, the mixture was filtered and dried at 45°C for 10 h to obtain baricitinib phthalate with a purity of 99.54%.

[0050] Example 3

[0051] 0.37 g of baricitinib and 0.17 g of phthalic acid were added to 80 mL of tetrahydrofuran, dissolved by ultrasonication, filtered, and allowed to stand at 20°C for natural evaporation and crystallization. After crystallization, the mixture was filtered and dried at 45°C for 10 h to obtain baricitinib phthalate with a purity of 99.58%.

[0052] Example 4

[0053] 0.37 g of baricitinib and 0.49 g of phthalic acid were added to 120 mL of tetrahydrofuran / isopropanol (V 四氢呋喃 :V 异丙醇 =1:2), ultrasonically dissolved, filtered, and allowed to stand at 20°C for natural evaporation and crystallization. After crystallization, filtered, and dried at 45°C for 10 h to obtain baricitinib phthalate with a purity of 99.12%.

[0054] Crystalline characterization of baricitinib phthalate

[0055] The X-ray powder diffraction test instrument and test conditions involved in the present invention are as follows: X-ray powder diffractometer: PANalyticalEMPYREA; Cu-Kα; sample stage: flat plate; incident light path: BBHD; diffraction light path: PLXCEL; voltage 45kv, current 40mA; divergence slit: 1 / 4; anti-scattering slit: 1; Soller slit: 0.04rad; step length: 0.5s; scanning range: 3-50°. The characteristic peaks in the corresponding X-ray secretion diffraction pattern (Cu-Kα) are detailed in the attached Figure 1 And Table 1.

[0056] Table 1 PXRD peaks of baricitinib phthalate crystalline form

[0057]

[0058] The baricitinib phthalate crystalline form provided by the present invention is subjected to X-ray single crystal diffraction test and analysis. The X-ray single crystal diffraction instrument and test conditions involved in the present invention are: Rigaku XtaLab Synergy X-ray single crystal diffractometer, test temperature 293 (2) K, CuKa radiation, ω scanning mode data collection and Lp correction. The structure is analyzed by direct method, the difference Fourier method is used to find all non-hydrogen atoms, all hydrogen atoms on carbon and nitrogen are obtained by theoretical hydrogenation, and the structure is refined by least squares method.

[0059] The crystallographic parameters of the baricitinib phthalate prepared by the present invention are tested and analyzed: orthorhombic system, chiral space group is Pbcn; unit cell parameters are: α=90°,β=90°,γ=90°,unit cell volume ORTEP of the crystal form of baricitinib phthalate of the present invention Figure 2 It shows that one molecule of baricitinib is combined with one molecule of phthalate. The stacking diagram of the crystalline form of baricitinib phthalate of the present invention is shown in the attached figure. Figure 3 shown.

[0060] Table 2 Main crystallographic data of baricitinib phthalate crystalline form

[0061]

[0062] The TGA / DSC thermal analysis tester and test conditions in the present invention are as follows: TGA / DSC thermal analyzer: METTLERTOLEDOTGA / DSC3+; dynamic temperature section: 30-300°C; heating rate: 10°C / mIVn; program section gas N2; gas flow: 50mL / mIVn; crucible: aluminum crucible 40μl.

[0063] The TGA / DSC test results of the baricitinib phthalate crystalline form prepared by the method of the present invention are as follows: Figure 4 As shown, the DSC detection results have an endothermic peak, and the peak temperature corresponds to 191.61°C.

[0064] The samples of Examples 1 to 4 all have the same X-ray powder diffraction patterns, crystallographic parameters, and DSC patterns.

[0065] Comparative crystal preparation

[0066] Baricitinib Form I was prepared with reference to patent CN105924444A; Baricitinib Form G was prepared with reference to patent CN110799512A; Baricitinib trifluoroacetic acid Form A and Form B were prepared with reference to patent CN105566332A; Baricitinib phosphate Form A was prepared with reference to patent CN105601635A; Baricitinib phosphate Form D was prepared with reference to patent CN108341818A; Baricitinib phosphate was prepared with reference to patent CN111278828A Crystal form α, phosphate crystal form β; refer to the document "Similarity and Diversity: Cocrystallization of Baricitinib with Four C4-Dicarboxylic Acids" to prepare baricitinib-maleate, baricitinib-L-tartrate, baricitinib-fumaric acid cocrystal, baricitinib-succinic acid cocrystal; refer to patent EP3321267A1 to prepare 9 salt forms of baricitinib (hydrobromide, hydrochloride, sulfate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, L-tartrate, fumarate, citrate amorphous), through investigation, the citrate amorphous with the best solubility, and the sulfate with the best stability and hygroscopicity; refer to patent EP3327020A1 to prepare baricitinib monocitrate and dicitrate; refer to patent EP3502114A1 to prepare baricitinib-lactic acid cocrystal; refer to patent EP3771716A 1. Preparation of amorphous baricitinib; preparation of baricitinib heminapthyl disulfonate salt with reference to patent RU2644155C1; preparation of baricitinib-naphthalene-2-sulfonate crystalline form with reference to patent US20220135566A1; preparation of baricitinib mesylate crystalline form with reference to patent WO2017125772A1; preparation of baricitinib-gallic acid cocrystal with reference to patent CN116751204A; preparation of baricitinib-aminosulfonic acid cocrystal with reference to patent CN118561849A.

[0067] Verification example:

[0068] The present invention investigates the baricitinib crystal form prepared above in terms of stability, solubility, permeability, etc., and the specific implementation contents are as follows:

[0069] Stability test

[0070] The specific stability test method was carried out in accordance with the guidance method for stability investigation specified in Part 4 of the Chinese Pharmacopoeia 2020 Edition. The specific experimental conditions and results are shown in Table 3.

[0071] Table 3 Stability test results of the crystal form of the present invention

[0072]

[0073]

[0074] It can be seen from the experimental results that the purity and appearance of the baricitinib-phthalate prepared by the present invention do not undergo obvious changes under conditions of light, high temperature and high humidity, showing good stability.

[0075] In addition, after 30 days of the above-mentioned conditions, samples were taken for XPRD testing to examine the crystal stability of the samples under light, temperature, and humidity. The results showed that the baricitinib-phthalate crystal of the present invention was stable under strong light, high temperature, and high humidity conditions.

[0076] Moisture absorption test:

[0077] Three groups of samples of Example 1 and comparative crystal forms were taken respectively, and according to the guidelines for drug hygroscopicity test, hygroscopicity and weight gain experiments were carried out at 25°C and 90% relative humidity (after equilibrium). The hygroscopicity of each group was tested using a dynamic moisture sorption (DVS) instrument, and the average value was taken. The experimental results are shown in Table 4.

[0078] Table 4 Moisture absorption test results

[0079] Crystal form Average weight gain Crystal form Average weight gain Example 1 0.11％ Succinic acid eutectic 0.74％ Crystalline Form I 0.56％ Citrate amorphous 2.25％ Form G 0.35％ Sulfate 0.43％ Trifluoroacetic acid crystal form A 0.96％ Monocitrate 0.46％ Trifluoroacetic acid form B 1.14％ Biscitrate 0.53％ Phosphate Form A 0.94％ Lactic acid eutectic 0.67％ Phosphate Crystalline Form D 0.23％ Amorphous 0.44％ Phosphate crystal form α 0.42％ Semi-naphthyl disulfonate 0.42％ Phosphate crystal form β 0.18％ Naphthalene-2-sulfonate 0.26％ Maleate 0.38％ Methanesulfonate 0.17％ Tartrate 0.72％ Gallic acid eutectic 0.32％ Fumaric acid eutectic 0.68％ Sulfamic acid eutectic 0.94％

[0080] Refer to "Chinese Pharmacopoeia 2020 Edition Part 4 General Chapter 9103-Guidelines for Drug Hygroscopicity Tests to Determine Hygroscopicity Characteristics".

[0081] Table 5 Hygroscopicity judgment criteria

[0082] Moisture characteristics Weight gain definition deliquescence Absorbs enough water to form a liquid Highly hygroscopic The weight gain due to moisture absorption is not less than 15% There is dampness The weight gain due to moisture absorption is less than 15% but not less than 2% Slightly hygroscopic The weight gain due to moisture absorption is less than 2% but not less than 0.2% No or almost no hygroscopicity The weight gain due to moisture absorption is less than 0.2%

[0083] The results show that the baricitinib-phthalate crystalline form of the present invention has almost no hygroscopicity, good stability, and is suitable for the manufacture and long-term storage of pharmaceutical preparations; Examples 1 to 4 have similar hygroscopicity test results.

[0084] Solubility test

[0085] Test method: Take water, 0.1mol / L hydrochloric acid solution and pH 6.8 PBS buffer as the medium, take excess of each crystal form of baricitinib prepared, add them to the above medium, and stir at 37°C for 72 hours. Repeat the sampling three times, filter, take an appropriate amount of the filtrate, dilute, and use HPLC to detect the solubility in each medium.

[0086] Table 6 Solubility of baricitinib in different media (mg / ml)

[0087]

[0088]

[0089] The solubility test results show that the baricitinib phthalate crystalline form prepared by the present invention has a significantly improved solubility compared to the free base crystalline form disclosed in the prior art. It was found that Examples 1 to 4 have similar solubility test results.

[0090] Permeability test

[0091] Test conditions: The permeability test was carried out using the Franz diffusion cell method at a water temperature of (37±0.5)℃.

[0092] Dialysis membrane (model: MW14000Da, Himedia, India): treated with 10% sodium bicarbonate solution, 10 MmEDTA solution, and deionized water at 70 °C for 20 min respectively; the treated dialysis membrane was placed in a diffusion cell (effective surface area 4.15 cm 2 ); the donor chamber was filled with Example 1 and the comparative crystal form (10 mg in terms of baricitinib) and suspended in 2 ml of distilled water; the receptor chamber was filled with phosphate buffer (pH = 7.4), maintained at room temperature, bubbles were removed, and magnetic stirring was performed at 45 ± 5 RPM; the cumulative permeation amount was tested after 24 hours.

[0093] Table 7 Baricitinib permeation cumulative amount (mg / cm 2 )

[0094]

[0095]

[0096] From the above permeability test results, it can be seen that the permeability of the baricitinib phthalate crystalline form of the present invention is significantly improved, and its cumulative permeation amount is 3 times that of the free base crystalline form I, further improving the bioavailability. It was found that Examples 1 to 4 had similar permeability test results.

[0097] Bioavailability test

[0098] 60 healthy male rats were randomly divided into 10 groups. After fasting for 1 night, they were given Example 1 and the comparative crystal form (in terms of baricitinib) at 10 mg / kg by oral gavage. Blood samples of 0.25 ml were taken from the tail vein of the rats at 10 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, and 24 h before and after administration, respectively. After centrifugation, the plasma was subjected to liquid phase analysis to determine the concentration of baricitinib.

[0099] Table 8 Pharmacokinetic parameters of baricitinib in rats (n=6)

[0100]

[0101]

[0102] The above pharmacokinetic parameters show that the blood concentration of the baricitinib phthalate crystal prepared in Example 1 of the present invention can be significantly improved. It was found that Examples 1 to 4 had similar bioavailability test results.

[0103] The baricitinib phthalate crystalline form prepared by the present invention has achieved beneficial effects in terms of stability, solubility, permeability, bioavailability, etc., and its comprehensive performance has achieved significant improvement compared with the baricitinib crystalline form reported in the prior art, and is more suitable for pharmaceutical preparations. The ORTEP diagram of the baricitinib phthalate crystalline form of the present invention shows that the crystalline form does not contain an organic solvent, and is safer for pharmaceutical use than the solvate of baricitinib, and is more suitable for pharmaceutical preparations.

Claims

1. A crystalline form of baricitinib phthalate, characterized in that: The molar ratio of baricitinib to phthalic acid in the crystalline form is 1:

1.

2. The baricitinib phthalate crystalline form according to claim 1, characterized in that The basic unit of the crystal form is composed of one molecule of baricitinib and one molecule of phthalic acid, and its crystallographic parameters are: orthorhombic system, space group is Pbcn; unit cell parameters are: α=90°,β=90°,γ=90°,unit cell volume The structure is as follows:

3. The baricitinib phthalate crystalline form according to claim 1, characterized in that The crystal form uses Cu-Kα radiation, and the X-ray diffraction spectrum represented by 2θ has characteristic peaks at 6.20±0.2°, 6.53±0.2°, 18.53±0.2°, 18.70±0.2°, and 19.44±0.2°.

4. The baricitinib phthalate crystalline form according to claim 1, characterized in that The crystal form uses Cu-Kα radiation, and the X-ray diffraction spectrum represented by 2θ has characteristic peaks at 6.20±0.2°, 6.53±0.2°, 14.53±0.2°, 18.29±0.2, 18.53±0.2, 18.70±0.2°, 19.44±0.2°, and 26.95±0.2°.

5. The baricitinib phthalate crystalline form according to claim 1, characterized in that The crystal form has an X-ray powder diffraction pattern as shown in FIG1 .

6. A method for preparing the crystalline form of baricitinib phthalate according to any one of claims 1 to 5, characterized in that: The method comprises the following steps: adding baricitinib and phthalate into an organic solvent, dissolving by ultrasonication, filtering, standing, volatilizing and crystallizing, filtering, and drying to obtain baricitinib phthalate.

7. The method for preparing the crystalline form of baricitinib phthalate according to claim 6, characterized in that: The molar ratio of baricitinib to phthalate is 1:1.0 to 3.

0.

8. The method for preparing the crystalline form of baricitinib phthalate according to claim 6, characterized in that: The organic solvent is one or two of acetonitrile, acetone, tetrahydrofuran, methanol, ethanol and isopropanol.

9. The method for preparing the crystalline form of baricitinib phthalate according to claim 6, characterized in that: The mass-to-volume ratio of baricitinib to the organic solvent is 3 to 5:1, wherein the mass is measured in mg and the volume is measured in mL.

10. Use of the baricitinib phthalate crystalline form according to any one of claims 1 to 5 as an active ingredient in the preparation of a drug for treating autoimmune diseases, inflammatory diseases or cancer diseases involved in JAK.

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