Baricitinib and glutaric acid eutectic acetonitrile solvate and preparation method thereof

Abstract

The invention belongs to the technical field of crystal form drug molecules, and particularly relates to a preparation method and application of a baricitinib and glutaric acid eutectic acetonitrile solvate. The eutectic compound disclosed by the invention is good in solubility, and the bioavailability of the baricitinib is remarkably improved. The preparation process is simple. Good medical industrial application prospects are realized.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of crystal form of drug molecules, and particularly relates to a baricitinib and glutaric acid co-crystal acetonitrile solvate, a preparation method and application thereof. BACKGROUND

[0002] Baricitinib is an oral anti-inflammatory drug developed by Lilly and Incyte. In 2017, it was approved for marketing in the European Union and became the first JAK inhibitor drug approved by the European Union for the treatment of rheumatoid arthritis (RA). So far, FDA has approved baricitinib tablets for the treatment of rheumatoid arthritis, atopic dermatitis, severe alopecia areata and other indications. Alopecia areata is a common inflammatory non-scarring alopecia, and is the second highest incidence of alopecia symptoms in the world (only next to androgenetic alopecia), with about 147 million patients worldwide. Baricitinib, molecular formula: C 16 H 17 N7O2S, CAS: 1187594-09-7, chemical name: {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] Drug molecules usually have different solid forms, including salts, polymorphs, etc. Different crystal forms of the same drug molecule usually have different physical properties, including solubility, hygroscopicity, flowability, stability and bioavailability, etc. These differences can directly affect the efficacy and developability of the drug. Stable crystal forms are beneficial to increase the safety of the drug in clinical application. Therefore, when a drug is commercially produced, a crystal form with high stability, convenient production and pharmaceutically acceptable drug molecules should be provided as much as possible. Although there are many reports on baricitinib crystals and salts, there are relatively few reports on co-crystals.

[0005] The document“Similarity and Diversity: Cocrystallization of Baricitinib with Four C4-Dicarboxylic Acids. Cryst. Growth Des. 2022, 22, 3218-3227” discloses four crystal forms of baricitinib, namely baricitinib-maleate (MAL), baricitinib-L-tartrate (TAR), baricitinib-fumarate co-crystal (FUM), baricitinib-succinate co-crystal (SUC), the moisture content of baricitinib-maleate increased from 0.33% to 0.67% under 90% humidity, an increase of 0.34%, baricitinib-L-tartrate (TAR), baricitinib-fumarate co-crystal (FUM), baricitinib-succinate co-crystal (SUC) increased by 0.67%, 0.66%, 0.66% respectively; the new solid forms all showed excellent anti-hydrated phase stability, reduced hygroscopicity and slight improvement of solubility; in terms of solubility, baricitinib-maleate and baricitinib-L-tartrate had a solubility of 0.33 mg / ml and 0.43 mg / ml in phosphate buffer, respectively, which was significantly improved compared with the solubility of baricitinib 0.045 mg / ml.

[0006] WO2019121290A1 discloses baricitinib-lactic acid co-crystal, baricitinib-lactic acid co-crystal dissolves faster than pure crystal baricitinib free base form A, for example, compare the value at 1 minute, wherein baricitinib-lactic acid co-crystal dissolves three times more baricitinib than when compared with baricitinib free base form A.

[0007] WO2020072870A1 discloses baricitinib and fumaric acid co-crystal dichloromethane solvate, baricitinib and fumaric acid co-crystal compound. WO2020163431A1 discloses a series of salts or co-crystals, including baricitinib- orotic acid co-crystal (I, II, IV), baricitinib-naphthalene-2-sulfonic acid co-crystal, baricitinib-(+)-camphoric acid crystal form, baricitinib-fumaric acid co-crystal, baricitinib-tartaric acid co-crystal (I, II), baricitinib-succinic acid co-crystal. CN202310175161.3 discloses a baricitinib-maleate salt, the crystal data of which is consistent with the baricitinib-maleate salt (MAL) disclosed in the literature "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 of the phosphate buffer thereof is about 0.46mg / ml. And research found that the salt type with the optimal solubility in the co-crystals disclosed in WO2020163431A1 is baricitinib-naphthalenesulfonic acid I co-crystal. CN202310699162.8 discloses a baricitinib-gallic acid co-crystal and a preparation method and application thereof, and the solubility of the co-crystal is improved. CN202310175163.2 discloses a baricitinib-sulfamic acid co-crystal and a preparation method and application thereof. Baricitinib-sulfamic acid co-crystal, especially in the dissolution experiment, shows excellent dissolution performance.

[0008] According to the prior art, the present researchers have studied a series of baricitinib salts or co-crystals, and the crystal form of the baricitinib salt or co-crystal has been improved in stability, hygroscopicity, solubility, bioavailability and the like, but still has defects.

[0009] The baricitinib and glutaric acid co-crystal acetonitrile solvate crystal form developed by the present application has not been reported, and the crystal form of the present application has improved stability, hygroscopicity, solubility, bioavailability and the like, so as to more efficiently exert the medicinal value of baricitinib. SUMMARY

[0010] In view of the deficiencies of the prior art, one object of the present application is to provide a baricitinib and glutaric acid co-crystal acetonitrile solvate and a preparation method thereof; the co-crystal has exact crystallographic main parameters and atomic spatial positions; and great improvement has been achieved in stability, solubility and the like, and the preparation method is simple.

[0011] The specific technical content of the present application is as follows: In a first aspect, the present application provides a baricitinib-malonic acid co-crystal acetonitrile solvate, wherein one molecule of baricitinib, one molecule of malonic acid and one molecule of acetonitrile form a basic unit of the crystal form.

[0012] Preferably, the baricitinib-malonic acid co-crystal acetonitrile solvate has an X-ray diffraction spectrum using Cu-Ka radiation, expressed in 2θ, with characteristic peaks at 13.89 ± 0.2°, 14.99 ± 0.2°, 19.21 ± 0.2°, 24.08 ± 0.2°, 25.42 ± 0.2°.

[0013] Preferably, the baricitinib-malonic acid co-crystal acetonitrile solvate has an X-ray diffraction spectrum using Cu-Ka radiation, expressed in 2θ, with characteristic peaks at 12.25 ± 0.2°, 13.64 ± 0.2°, 13.89 ± 0.2°, 14.99 ± 0.2°, 15.49 ± 0.2°, 16.57 ± 0.2°, 16.80 ± 0.2°, 18.19 ± 0.2°, 19.21 ± 0.2°, 24.08 ± 0.2°, 25.42 ± 0.2°, 27.40 ± 0.2°.

[0014] Preferably, the baricitinib-malonic acid co-crystal acetonitrile solvate has an X-ray diffraction spectrum using Cu-Ka radiation, expressed in 2θ, with characteristic peaks at 12.25 ± 0.2°, 13.64 ± 0.2°, 13.89 ± 0.2°, 14.99 ± 0.2°, 15.49 ± 0.2°, 16.57 ± 0.2°, 16.80 ± 0.2°, 18.19 ± 0.2°, 19.21 ± 0.2°, 24.08 ± 0.2°, 25.42 ± 0.2°, 27.40 ± 0.2°. Figure 1 and the X-ray powder diffraction spectrum and detection data shown in Table 1.

[0015] Preferably, the baricitinib-malonic acid co-crystal acetonitrile solvate has crystallographic parameters: triclinic crystal system, chiral space group P-1; cell parameters: a = 6.99000(10) Å, b = 15.6987(2) Å, c = 20.4545(3) Å, α = 87.5600(10) °, β = 80.7430(10) °, γ = 80.0650(10) °, cell volume V = 2181.85(5) Å 3 .

[0016] Preferably, the baricitinib-malonic acid co-crystal acetonitrile solvate has two endothermic peaks in the differential scanning calorimetry curve (DSC), which are 75.03°C and 99.16°C, respectively.

[0017] The second aspect of the present application provides a preparation method of a baricitinib-malonic acid co-crystal acetonitrile solvate, and the specific preparation steps include: dissolving baricitinib and malonic acid in solvent A, heating and dissolving to obtain a transparent solution, cooling and standing to crystallize, filtering, washing, and vacuum drying to obtain the baricitinib-malonic acid co-crystal acetonitrile solvate.

[0018] Preferably, the solvent A is a mixed solvent of an organic solvent and acetonitrile, wherein the organic solvent is one or two of methanol, ethanol, acetone, and isopropanol. The solvent A is further preferably selected from acetonitrile-acetone, acetonitrile-methanol, and acetonitrile-ethanol mixed solvents.

[0019] Preferably, the volume ratio of the organic solvent to acetonitrile in the solvent A is 1-2:1.

[0020] Preferably, the molar ratio of baricitinib to glutaric acid is 1:1.1-1.7; further preferably, the molar ratio of baricitinib to glutaric acid is 1:1.2-1.4.

[0021] Preferably, the mass-volume ratio of baricitinib to solvent A is 14.3-17.5:1, wherein the mass is in mg and the volume is in mL.

[0022] Preferably, the temperature of the dissolution and heating is 45-55°C.

[0023] Preferably, the temperature of the cooling and crystallization is 10-30°C, further preferably, the temperature of the cooling and crystallization is 10-25°C.

[0024] Preferably, the crystallization time is 48-72 hours.

[0025] Preferably, the drying temperature is 50-55°C, and the drying time is 5-9 hours.

[0026] Preferably, the solvent for washing the filter cake is selected from one of methanol, ethanol, and acetone.

[0027] The third aspect of the present application provides a pharmaceutical composition comprising the baricitinib-glutaric acid co-crystal acetonitrile solvate prepared above and other pharmaceutically acceptable excipients or active ingredients that can be used in combination.

[0028] Preferably, the other components include other active ingredients that can be used in combination; and the pharmaceutically acceptable excipients include fillers, binders, disintegrants, lubricants, and the like.

[0029] Further preferably, the fillers are selected from one or more of starch, sucrose, dextrin, lactose, microcrystalline cellulose, mannitol, and sorbitol; the binders are selected from one or more of methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium hydroxymethyl cellulose, ethyl cellulose, and povidone; the disintegrants are selected from one or more of sodium carboxymethyl starch, low-substitution hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, and cross-linked povidone; and the lubricants are selected from one or more of magnesium stearate, microfine silica, talc, and sodium dodecyl sulfate.

[0030] Preferably, the pharmaceutical composition is in the form of tablets, capsules, granules, pills and the like.

[0031] The fourth aspect of the present application provides a use of the baricitinib-glutaric acid co-crystal acetonitrile solvate as an active ingredient in the preparation of a medicament for treating JAK-related diseases.

[0032] The JAK-related diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, cancers.

[0033] Confirmation of crystal structure The X-ray powder diffraction testing instrument and testing conditions of the baricitinib-glutaric acid co-crystal acetonitrile solvate in the present application are as follows: PANalytical Empyrean X-ray powder diffraction instrument; light source Cu target, flat sample stage, incident light path: BBHD, diffraction light path: PIXCEL, voltage 45 KV, current 40 mA, divergence slit 1 / 4°, anti-scattering slit 1°, Soller slit 0.04 rad, counting time per step 0.5 s, scanning range 3-50°. According to the crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Kα) are shown in Table 1 and FIG. 2. Figure 1 and Table 1.

[0034] Table 1 Main PXRD peaks of baricitinib-glutaric acid co-crystal acetonitrile solvate

[0035] X-ray crystal data were collected on a Rigaku XtaLAB Synergy model instrument at a test temperature of 293(2) K, using CuKa radiation, in an omega scan mode and L p correction. The structure was solved by direct methods, all non-hydrogen atoms were found by difference Fourier methods, all hydrogen atoms on carbon and nitrogen were obtained by theoretical hydrogenation, and the structure was refined by least squares method.

[0036] The crystallographic data of the baricitinib-glutaric acid co-crystal acetonitrile solvate prepared in the present application were tested and analyzed, and the crystallographic parameters were as follows: triclinic crystal system, chiral space group P-1; cell parameters: a = 6.99000(10) Å, b = 15.6987(2) Å, c = 20.4545(3) Å, α = 87.5600(10) °, β = 80.7430(10) °, γ = 80.0650(10) °, cell volume V = 2181.85(5) Å 3 . Molecular formula: C 39 H 45 N 15O8S2, molecular weight: 916.02. The packing diagram of the baricitinib-glutaric acid co-crystal acetonitrile solvate of the present application is shown in FIG. 8. The structure analysis ORTEP diagram of the baricitinib-glutaric acid co-crystal acetonitrile solvate of the present application shows that there is one molecule of baricitinib, one molecule of glutaric acid and one molecule of acetonitrile in the crystal, as shown in FIG. 9. Figure 2 Figure 3

[0037] Table 2 Main crystallographic data of the baricitinib-glutaric acid co-crystal acetonitrile solvate

[0038] The TGA / DSC thermal analysis tester and test conditions in the present application: TGA / DSC thermal analyzer: METTLER TOLEDO TGA / DSC3+; dynamic temperature section: 30-300℃; heating rate: 10℃ / min; program section gas: N2; gas flow: 50 mL / min; crucible: aluminum crucible 40 μl.

[0039] The TGA / DSC test results of the baricitinib-glutaric acid co-crystal acetonitrile solvate prepared by the method of the present application are shown in FIG. 10. The DSC detection results have two endothermic peaks, corresponding to temperatures of 75.03℃ and 99.16℃, respectively. According to the TGA detection results, there are two weight loss steps, and the first step indicates that the crystal contains one molecule of acetonitrile. The DSC / TGA detection results show that the crystal form prepared in the present application is the baricitinib-glutaric acid co-crystal acetonitrile solvate crystal form. Figure 4

[0040] All the samples prepared in the examples have the same crystallographic parameters and X-ray powder diffraction spectra described above.

[0041] The baricitinib-glutaric acid co-crystal acetonitrile solvate prepared in the present application has been greatly improved in stability, solubility, etc. After long-term investigation of light stability, the co-crystal has good light stability. The baricitinib-glutaric acid co-crystal acetonitrile solvate crystal form is regular, the particle size is uniform, has clear crystallographic main parameters and exact atomic spatial positions, and the preparation method is simple, which provides a material basis for improving the oral bioavailability of baricitinib, and is suitable for industrialized production and large-scale popularization and application. BRIEF DESCRIPTION OF DRAWINGS

[0042] Figure 1 FIG. 7: X-ray powder diffraction spectrum of the baricitinib-glutaric acid co-crystal acetonitrile solvate.

[0043] Figure 2 FIG. 8: Packing diagram of the baricitinib-glutaric acid co-crystal acetonitrile solvate.​​​

[0044] Figure 3 ORTEP diagram of baricitinib-malonic acid co-crystal acetonitrile solvate.

[0045] Figure 4 DSC-TGA diagram of baricitinib-malonic acid co-crystal acetonitrile solvate. DETAILED DESCRIPTION

[0046] The present application is further illustrated by the following examples, it should be understood that the examples of the present application are only used to illustrate the present application, but not limit the present application, so, the simple improvement of the present application under the premise of the method of the present application is within the scope of the present application.

[0047] Materials used in the experiment: baricitinib can be purchased, also can be prepared according to the method disclosed in patent WO2009114512. Baricitinib crystal form required for comparative test can be prepared according to the prior art, also can be purchased; other materials used in the experiment not marked source and specification are commercially available analytical pure or chemical pure.

[0048] Example 1 Add 111.4 mg of baricitinib and 40.1 mg of malonic acid into 4 mL of acetonitrile and 3 mL of acetone, heat to 45-55℃, stir to dissolve, react for 4 hours, slowly cool to 10-25℃, control temperature and stand for crystallization for 48-72 hours, filter, wash the filter cake with acetone, vacuum dry at 50℃ for 6 hours, to obtain baricitinib-malonic acid co-crystal acetonitrile solvate, yield 94.01%, purity 99.89%.

[0049] Example 2 Add 113.3 mg of baricitinib and 46.1 mg of malonic acid into 5 mL of acetonitrile and 3 mL of methanol, heat to 45-55℃, stir to dissolve, react for 4 hours, slowly cool to 10-25℃, control temperature and stand for crystallization for 48-72 hours, filter, wash the filter cake with methanol, vacuum dry at 60℃ for 6 hours, to obtain baricitinib-malonic acid co-crystal acetonitrile solvate, yield 94.51%, purity 99.87%.

[0050] Example 3 Add 110.7 mg of baricitinib and 38.5 mg of malonic acid into 4 mL of acetonitrile and 3 mL of ethanol, heat to 45-55℃, stir to dissolve, react for 4 hours, slowly cool to 10-25℃, control temperature and stand for crystallization for 48-72 hours, filter, wash the filter cake with ethanol, vacuum dry at 60℃ for 6 hours, to obtain baricitinib-malonic acid co-crystal acetonitrile solvate, yield 94.11%, purity 99.86%.

[0051] Preparation of comparative example crystal form Reference WO2020072870A1 to prepare baricitinib and fumaric acid co-crystal dichloromethane solvate crystal form I (referred to as fumaric acid co-crystal dichloromethane solvate), baricitinib and fumaric acid co-crystal crystal form II (referred to as fumaric acid co-crystal); reference CN202310699162.8 in the operation of example 4 to prepare baricitinib-gallic acid co-crystal; reference CN202411475639.5 in the operation of example 1 to prepare baricitinib phthalate crystal form.

[0052] Verification example:

[0053] Stability experiment

[0054] The specific stability test method refers to the guidance method for stability test in Chinese Pharmacopoeia 2020 fourth part, and the purity is detected by HPLC method. The specific detection results are shown in table 3.

[0055] Table 3 stability test purity results of each sample crystal form

[0056] From the stability experiment results, it can be seen that the baricitinib-glutaric acid co-crystal acetonitrile solvate prepared by the present application has no obvious change in purity and appearance under the conditions of light, high temperature and high humidity, and the crystal form of the sample taken after 30 days of investigation does not change. It shows good stability.

[0057] Hygroscopicity test:

[0058] Reference to "Guiding Principles for Drug Hygroscopicity Test, 9103 - General Principles of Chinese Pharmacopoeia 2020 Edition, Part IV".

[0059] Hygroscopicity judgment standard:

[0060] Take three groups of example 1 and comparative crystal form samples respectively, refer to the guiding principles for drug hygroscopicity test, and carry out hygroscopicity weight gain experiment at 25℃, 90% relative humidity (after equilibrium), use dynamic water adsorption (DVS) instrument to test the hygroscopicity of each sample, take the average value, and the experimental results are shown in table 4.

[0061] Table 4 hygroscopicity test results

[0062] The results show that the baricitinib-glutaric acid co-crystal acetonitrile solvate of the present application has slight hygroscopicity, and attention should be paid to moisture-proof and sealed storage in the manufacture and long-term storage of drug preparations.

[0063] Solubility test

[0064] Test method: Take each prepared baricitinib crystal form in excess, respectively, and add to the above-mentioned medium, stir at 37°C for 72 hours. Repeat sampling three times, filter, take the filtrate, dilute, and use HPLC to detect the solubility in each medium.

[0065] Table 5 Solubility of each crystal form of baricitinib in different media (mg / ml)

[0066] The solubility test results show that the baricitinib-glutaric acid co-crystal acetonitrile solvate prepared in the present application has higher solubility compared to the salt or co-crystal disclosed in the prior art. It can be seen that the development of the co-crystal helps to improve the bioavailability of baricitinib.

Claims

1. A baricitinib-malonic acid co-crystal acetonitrile solvate characterized by, The co-crystal is composed of one molecule of baricitinib, one molecule of glutaric acid and one molecule of acetonitrile as a basic unit of crystal form.

2. The baricitinib-malonic acid co-crystal acetonitrile solvate of claim 1, characterized by, The co-crystal has characteristic peaks at 13.89 ± 0.2°, 14.99 ± 0.2°, 19.21 ± 0.2°, 24.08 ± 0.2°, 25.42 ± 0.2° in the X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation.

3. The baricitinib-malonic acid co-crystal acetonitrile solvate of claim 1, characterized by, The co-crystal has characteristic peaks at 12.25 ± 0.2°, 13.64 ± 0.2°, 13.89 ± 0.2°, 14.99 ± 0.2°, 15.49 ± 0.2°, 16.57 ± 0.2°, 16.80 ± 0.2°, 18.19 ± 0.2°, 19.21 ± 0.2°, 24.08 ± 0.2°, 25.42 ± 0.2°, 27.40 ± 0.2° in the X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation.

4. The baricitinib-malonic acid co-crystal acetonitrile solvate of claim 1, characterized by, The co-crystal has an X-ray powder diffraction spectrum as shown in Figure 1.

5. The baricitinib-malonic acid co-crystal acetonitrile solvate of claim 1, characterized by, The co-crystal has the following crystallographic parameters: triclinic system, chiral space group P-1; cell parameters: a = 6.99000(10) Å, b = 15.6987(2) Å, c = 20.4545(3) Å, α = 87.5600(10) °, β = 80.7430(10) °, γ = 80.0650(10) °, cell volume V = 2181.85(5) Å 3 .

6. A process for preparing baricitinib-glutaric acid co-crystal acetonitrile solvate according to any one of claims 1-5, characterized in that, The method comprises the following steps: dissolving baricitinib and glutaric acid in solvent A, heating and dissolving to obtain a transparent solution, cooling and standing to crystallize, filtering, washing and vacuum drying to obtain the baricitinib-glutaric acid co-crystal acetonitrile solvate.

7. The process for preparing baricitinib-malonic acid co-crystal acetonitrile solvate according to claim 6, characterized in that, The solvent A is a mixed solvent of an organic solvent and acetonitrile, wherein the organic solvent is one or two of methanol, ethanol, acetone and isopropanol; the solvent A is preferably selected from acetonitrile-acetone, acetonitrile-methanol and acetonitrile-ethanol mixed solvents; the volume ratio of the organic solvent to acetonitrile in the solvent A is 1-2:

1.

8. The process for preparation of baricitinib-malonic acid co-crystal acetonitrile solvate as claimed in claim 6, wherein, The molar ratio of baricitinib to glutaric acid is 1:1.1-1.7; preferably, the molar ratio of baricitinib to glutaric acid is 1:1.2-1.4; the mass-volume ratio of baricitinib and solvent A is 14.3-17.5:1, wherein the mass is in mg and the volume is in mL.

9. The process for preparation of baricitinib-malonic acid co-crystal acetonitrile solvate as claimed in claim 6, wherein, The temperature of the heating and dissolving is 45-55°C; the temperature of the cooling and crystallization is 10-30°C, preferably 10-25°C.

10. Use of the baricitinib-glutaric acid co-crystal acetonitrile solvate of any one of claims 1-5 as an active ingredient for preparing a medicament for treating a JAK-involved autoimmune disease, an inflammatory disease or a cancer disease.

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