Baricitinib and isophthalic acid eutectic dichloromethane 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 isophthalic acid eutectic dichloromethane solvate. The eutectic compound is high in stability, good in solubility and simple in preparation process. And the bioavailability of the baricitinib is obviously improved. Good medical industrial application prospects are realized.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of crystal form drug molecules, and in particular to a preparation method and application of a baricitinib and isophthalic acid co-crystal dichloromethane solvate. BACKGROUND

[0002] 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). Baricitinib is an oral anti-inflammatory drug developed by Lilly and Incyte. In February 2017, it was approved for marketing in the European Union and was 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. In China, baricitinib was approved for marketing in July 2019 and is suitable for adult patients with moderate to severe active rheumatoid arthritis who have not responded well or are intolerant to one or more disease-modifying antirheumatic drugs. In March 2023, the new indication of baricitinib was approved by the National Medical Products Administration, and it is used for the systemic treatment of severe alopecia areata in adults, and the trade name is Ailiming. It is also the first and only innovative targeted drug approved for the systemic treatment of severe alopecia areata in China. Alopecia areata is a common inflammatory non-scarring alopecia, and it is also the second highest incidence of alopecia symptoms in the world (only next to androgenetic alopecia), with about 147 million patients worldwide and about 4 million patients in China.

[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, it should be provided with a crystal form that is as stable as possible, convenient to produce and pharmaceutically acceptable. Although there have been many reports of 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 of 0.045 mg / ml.

[0006] WO2019121290A1 discloses baricitinib-lactic acid co-crystal, baricitinib lactic acid co-crystal dissolves faster than pure crystalline baricitinib free base Form A, as in Figure 7, (e.g. compare the values at 1 minute, where baricitinib dissolved in baricitinib lactic acid co-crystal is three times higher than when compared to 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-orthophthalic 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 best 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. The baricitinib-sulfamic acid co-crystal exhibits excellent dissolution performance, especially in dissolution experiments.

[0008] The prior art has studied a series of baricitinib salts or co-crystals, although certain progress has been made in solubility, but there are still defects in the stability of baricitinib crystal form, hygroscopicity, solubility, bioavailability and the like.

[0009] The baricitinib and isophthalic acid co-crystal dichloromethane solvate crystal form developed by the present application has not been reported, which provides a better basis for the application of baricitinib in drug treatment, so as to more efficiently play 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-isophthalic acid co-crystal dichloromethane solvate; the co-crystal has exact crystallographic main parameters and atomic spatial positions; and great improvement has been made in stability, solubility and the like.

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

[0012] Preferably, the baricitinib-isophthalic acid co-crystal dichloromethane solvate has an X-ray diffraction pattern expressed in 2 theta using Cu-Ka radiation characterized by peaks at 14.27±0.2°, 14.85±0.2°, 16.27±0.2°, 18.95±0.2°, 28.50±0.2°.

[0013] Preferably, the baricitinib-isophthalic acid co-crystal dichloromethane solvate has an X-ray diffraction pattern expressed in 2 theta using Cu-Ka radiation characterized by peaks at 10.80±0.2°, 14.27±0.2°, 14.85±0.2°, 16.27±0.2°, 16.50±0.2°, 18.55±0.2°, 18.95±0.2°, 22.41±0.2°, 22.69±0.2°, 23.44±0.2°, 24.73±0.2°, 26.75±0.2°, 28.50±0.2°.

[0014] Preferably, the baricitinib-isophthalic acid co-crystal dichloromethane solvate has an X-ray diffraction pattern expressed in 2 theta using Cu-Ka radiation characterized by peaks at 10.80±0.2°, 14.27±0.2°, 14.85±0.2°, 16.27±0.2°, 16.50±0.2°, 18.55±0.2°, 18.95±0.2°, 22.41±0.2°, 22.69±0.2°, 23.44±0.2°, 24.73±0.2°, 26.75±0.2°, 28.50±0.2°. Figure 1 and the X-ray powder diffraction pattern and detection data shown in Table 1.

[0015] Preferably, the baricitinib-isophthalic acid co-crystal dichloromethane solvate has crystallographic parameters: triclinic crystal system, chiral space group P-1; cell parameters: a = 6.91800(10) Å, b = 16.1911(4) Å, c = 20.4640(3) Å, α = 91.026(2) °, β = 99.6660(10) °, γ = 99.586(2) °, cell volume V = 2225.60(7) Å 3 .

[0016] Preferably, the baricitinib-isophthalic acid co-crystal dichloromethane solvate has three endothermic peaks in the differential scanning calorimetry curve (DSC), respectively 155.95 °C, 174.33 °C and 202.03 °C.

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

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

[0019] Preferably, the volume ratio of the organic solvent to dichloromethane in the solvent A is 1.3-1.8:1.

[0020] Preferably, the molar ratio of baricitinib to isophthalic acid is 1:0.5-1.2; further preferably, the molar ratio of baricitinib to isophthalic acid is 1:0.6-0.9.

[0021] Preferably, the mass-volume ratio of baricitinib to solvent A is 10.9-12.5:1, wherein the mass is in mg and the volume is in mL.

[0022] Preferably, the temperature for cooling and crystallization is 5-20°C, and further preferably, the temperature for cooling and crystallization is 10-15°C.

[0023] Preferably, the crystallization time is 48-60 hours.

[0024] Preferably, the drying temperature is 45-50°C, and the drying time is 4-7 hours.

[0025] Preferably, the solvent for washing the filter cake is selected from one of methanol, ethanol, and acetone.

[0026] The third aspect of the present application provides a pharmaceutical composition comprising the baricitinib-isophthalic acid co-crystal dichloromethane solvate prepared above and other pharmaceutically acceptable excipients or active ingredients that can be used in combination.

[0027] 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.

[0028] 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.

[0029] Preferably, the dosage form of the pharmaceutical composition is tablets, capsules, granules, and pills, and the like.

[0030] The fourth aspect of the present application provides a use of the baricitinib-isophthalic acid co-crystal dichloromethane solvate as an active ingredient in the preparation of a medicament for treating a JAK-related disease.

[0031] The JAK-related disease includes but is not limited to autoimmune diseases, inflammatory diseases, cancer.

[0032] Confirmation of crystal structure The X-ray powder diffraction testing instrument and testing conditions of the baricitinib-isophthalic acid co-crystal dichloromethane solvate of the present application in the test 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-Ka) are shown in the following Table 1 and Figure 1. Figure 1 and Table 1.

[0033] Table 1 Main PXRD peaks of baricitinib-isophthalic acid co-crystal dichloromethane solvate

[0034] X-ray crystal data was collected on a Rigaku XtaLAB Synergy model instrument, test temperature 293(2) K, with CuKa radiation, data was collected in omega scan mode and L p corrected. 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.

[0035] The crystallographic data of the baricitinib-isophthalic acid co-crystal dichloromethane solvate prepared by the present application was tested and analyzed, and the crystallographic parameters thereof are as follows: triclinic crystal system, chiral space group P-1; cell parameters are as follows: a = 6.91800(10) Å, b = 16.1911(4) Å, c = 20.4640(3) Å, α = 91.026(2) °, β = 99.6660(10) °, γ = 99.586(2) °, cell volume V = 2225.60(7) Å 3 . Molecular formula: C 41 H 42 C l2 N 14 O8S2, molecular weight: 993.90. The packing diagram of the baricitinib-isophthalic acid co-crystal dichloromethane solvate of the present application is shown in the following Figure 2. Figure 2The structural analysis ORTEP chart of the baricitinib-isophthalic acid co-crystal dichloromethane solvate of the present application shows that two molecules of baricitinib, one molecule of isophthalic acid and one molecule of dichloromethane exist in the crystal, as shown in the following figure: Figure 3

[0036] Table 2 Main crystallographic data of the baricitinib-isophthalic acid co-crystal dichloromethane solvate

[0037] 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: 50mL / min; crucible: aluminum crucible 40μl.

[0038] The TGA / DSC test results of the baricitinib-isophthalic acid co-crystal dichloromethane solvate prepared by the method of the present application are shown in the following figure: Figure 4 The DSC detection results have three endothermic peaks, respectively corresponding to temperatures of 155.95℃, 174.33℃ and 202.03℃. According to the TGA detection results, it can be seen that there are two weight loss steps, and the amount of loss of the two steps indicates that the crystal contains one molecule of dichloromethane. Combined with the DSC / TGA detection results, it is shown that the crystal form prepared in the present application is the baricitinib-isophthalic acid co-crystal dichloromethane solvate crystal form.

[0039] All the samples prepared in the examples have the same crystallographic parameters and X-ray powder diffraction spectra as described above.

[0040] The preparation of the baricitinib-isophthalic acid co-crystal dichloromethane solvate provided in the present application has achieved great improvement in stability, solubility, permeability and the like. After long-term investigation of light stability, the co-crystal has good light stability. The baricitinib-isophthalic acid co-crystal dichloromethane solvate crystal form is regular, the particle size is uniform, has clear crystallographic main parameters and exact atomic spatial position, 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

[0041] Figure 1 : X-ray powder diffraction spectrum of the baricitinib-isophthalic acid co-crystal dichloromethane solvate.

[0042] Figure 2 : Packing diagram of the baricitinib-isophthalic acid co-crystal dichloromethane solvate.

[0043] ​Figure 3 ORTEP diagram of baricitinib-isophthalic acid co-crystal dichloromethane solvate.

[0044] Figure 4 DSC-TGA diagram of baricitinib-isophthalic acid co-crystal dichloromethane solvate. DETAILED DESCRIPTION

[0045] The present application is further illustrated by the following examples, which should not be construed as limiting the present application. Any modification of the present application within the scope of the present application is intended to be included in the present application.

[0046] Materials used in the experiment: Baricitinib can be purchased or prepared according to the method disclosed in patent WO2009114512. Baricitinib crystal form required for comparative experiments can be prepared according to the prior art or purchased; the materials used in other experiments not marked with source and specifications are commercially available analytical or chemical pure.

[0047] Example 1 116.3 mg of baricitinib and 37.3 mg of isophthalic acid were added to 7 mL of ethanol and 4 mL of dichloromethane, stirred and dissolved at room temperature and reacted for 3 hours. After slowly cooling to 10-15°C, temperature control was maintained for crystallization for 48-60 hours. Filtration was performed, the filter cake was washed with acetone, and vacuum drying was performed at 50°C for 6 hours to obtain baricitinib-isophthalic acid co-crystal dichloromethane solvate, with a yield of 93.31% and a purity of 99.86%.

[0048] Example 2 118.1 mg of baricitinib and 29.1 mg of isophthalic acid were added to 6 mL of acetone and 4 mL of dichloromethane, stirred and dissolved at room temperature and reacted for 3 hours. After slowly cooling to 10-15°C, temperature control was maintained for crystallization for 48-60 hours. Filtration was performed, the filter cake was washed with methanol, and vacuum drying was performed at 50°C for 6 hours to obtain baricitinib-isophthalic acid co-crystal dichloromethane solvate, with a yield of 92.33% and a purity of 99.85%.

[0049] Example 3 110.8 mg of baricitinib and 44.6 mg of isophthalic acid were added to 6 mL of methanol and 4 mL of dichloromethane, stirred and dissolved at room temperature and reacted for 3 hours. After slowly cooling to 10-15°C, temperature control was maintained for crystallization for 48-60 hours. Filtration was performed, the filter cake was washed with ethanol, and vacuum drying was performed at 50°C for 6 hours to obtain baricitinib-isophthalic acid co-crystal dichloromethane solvate, with a yield of 92.12% and a purity of 99.79%.

[0050] Preparation of comparative crystal form Refer to 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).

[0051] Verification example:

[0052] Stability experiment

[0053] The specific stability test method refers to the guidance method for stability test in Chinese Pharmacopoeia 2020 Volume IV, and the purity detection is detected by HPLC method, and the specific detection results are shown in Table 3.

[0054] Table 3 Purity results of stability test of crystal form of each sample

[0055] From the stability experiment results, it can be seen that the purity and appearance of the baricitinib-isophthalic acid co-crystal dichloromethane solvate prepared by the present application do not change obviously 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.

[0056] Hygroscopicity test:

[0057] Refer to "Guiding Principles for Drug Hygroscopicity Test, China Pharmacopoeia 2020 Edition Volume IV General Rule 9103" to judge the hygroscopicity characteristics.

[0058] Hygroscopicity judgment standard:

[0059] Three groups of each of example 1 and comparative crystal form samples were taken, and the hygroscopicity weight gain test was carried out at 25℃, 90% relative humidity (after equilibrium), according to the guiding principles for drug hygroscopicity test, the hygroscopicity of each was tested by dynamic water adsorption (DVS) instrument, the average value was taken, and the experimental results are shown in Table 4.

[0060] Table 4 Hygroscopicity test results

[0061] The results show that the baricitinib-isophthalic acid co-crystal dichloromethane solvate of the present application has almost no hygroscopicity, good stability, and is suitable for the manufacture and long-term storage of drug preparations.

[0062] Solubility test

[0063] Test method: water and 0.1 mol / L hydrochloric acid solution, pH 6.8 PBS buffer were respectively taken as the medium, and each crystal form of the prepared baricitinib was taken in excess and added into the above-mentioned medium, and stirred at 37℃ for 72 hours. Sampling was repeated three times, filtered, and the filtrate was diluted and detected by HPLC to obtain the solubility in each medium.

[0064] Table 5 Solubility of each crystal form of baricitinib in different media (mg / ml)

[0065] The solubility test results show that the baricitinib-isophthalic acid co-crystal dichloromethane solvate prepared in the present application has higher solubility compared with the salt or co-crystal disclosed in the prior art, and the research and development of the co-crystal can help to improve the bioavailability of baricitinib.

Claims

1. A baricitinib-isophthalic acid co-crystal dichloromethane solvate, characterized by, The two molecules of baricitinib, one molecule of isophthalic acid and one molecule of dichloromethane constitute the basic unit of the crystal form in the co-crystal.

2. The baricitinib-isophthalic acid co-crystal dichloromethane solvate of claim 1, characterized by, The X-ray diffraction spectrum of the co-crystal has characteristic peaks at 14.27±0.2°, 14.85±0.2°, 16.27±0.2°, 18.95±0.2°, 28.50±0.2° using Cu-Kα radiation.

3. The baricitinib-isophthalic acid co-crystal dichloromethane solvate of claim 1, characterized by, The X-ray diffraction spectrum of the co-crystal has characteristic peaks at 10.80±0.2°, 14.27±0.2°, 14.85±0.2°, 16.27±0.2°, 16.50±0.2°, 18.55±0.2°, 18.95±0.2°, 22.41±0.2°, 22.69±0.2°, 23.44±0.2°, 24.73±0.2°, 26.75±0.2°, 28.50±0.2° using Cu-Kα radiation.

4. The baricitinib-isophthalic acid co-crystal dichloromethane solvate of claim 1, characterized by, The co-crystal has the following crystallographic parameters: triclinic system, chiral space group P-1; cell parameters: a = 6.91800(10) Å, b = 16.1911(4) Å, c = 20.4640(3) Å, α = 91.026(2) °, β = 99.6660(10) °, γ = 99.586(2) °, cell volume V = 2225.60(7) Å 3 .

5. The baricitinib-isophthalic acid co-crystal dichloromethane solvate of claim 1, characterized by, The crystal form of the co-crystal has an X-ray powder diffraction spectrum as shown in Figure 1.

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

7. A process for preparing baricitinib-mandelic acid co-crystal dichloromethane solvate according to claim 6, characterized in that, The molar ratio of baricitinib to isophthalic acid is 1:0.5-1.2; and the mass-volume ratio of baricitinib to solvent A is 10.9-12.5:1, wherein the mass is in mg and the volume is in mL.

8. A process for preparing baricitinib-mandelic acid co-crystal dichloromethane solvate according to claim 6, characterized in that, The cooling and crystallization temperature is 5-20°C, preferably 10-15°C.

9. A process for preparing baricitinib-mandelic acid co-crystal dichloromethane solvate according to claim 6, characterized in that, The solvent A is a mixed solvent of an organic solvent and dichloromethane, wherein the organic solvent is one or two of methanol, ethanol, acetone, and isopropanol.

10. Use of the baricitinib-isophthalic acid co-crystal dichloromethane 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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