Baricitinib and saccharin eutectic crystal and preparation method thereof

Abstract

The invention belongs to the technical field of crystal form medicine molecules, and particularly relates to a preparation method and application of a baricitinib-saccharin eutectic crystal. Compared with eutectic crystals disclosed in the prior art, the baricitinib-saccharin eutectic crystal disclosed by the invention is high in stability, good in solubility and simple in preparation process. The bioavailability of the baricitinib can be obviously improved, and the baricitinib has a relatively good medical industrial application prospect.

Description

TECHNICAL FIELD

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

[0002] 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. 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] A drug co-crystal is a hydrogen bond or other non-covalent bond formed between a drug active ingredient and a co-crystal former (CCF) to improve the physicochemical properties of the drug, such as hygroscopicity, dissolution rate, stability, etc., thereby improving the bioavailability of the drug. Therefore, the study of drug co-crystals is an important task in the field of biomedicine to improve the physical and chemical properties of drugs. 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- 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", i.e. it is judged to be the same crystal form, and the solubility of the phosphate buffer thereof is about 0.46 mg / ml. It is found that the salt form 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. The baricitinib-sulfamic acid co-crystal exhibits excellent dissolution performance, especially in dissolution experiments.

[0008] In addition, WO2015145286A1 discloses amorphous baricitinib. Although amorphous has higher solubility and dissolution rate than crystal in most cases, it is unstable, highly hygroscopic, and prone to phase transformation. Therefore, amorphous has problems of processing stability and storage stability.

[0009] 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 baricitinib crystal form stability, hygroscopicity, solubility, bioavailability, etc.

[0010] Saccharin (SAC) is an artificial sweetener, which is used in the production of pharmaceutical products and various foods as a low-calorie sugar substitute. Studies have found that SAC can be used as a safe multi-drug salt or co-crystal conformation agent to improve the dissolution and bioavailability of the drug substance.

[0011] CZ31155U1 studies the co-crystal of baricitinib and saccharin, and obtains two crystal forms Sn1 and Sn2.

[0012] The baricitinib-saccharin co-crystal developed in the application has not been reported, and the application is committed to researching a baricitinib-saccharin co-crystal to solve the stability and dissolution of baricitinib. The application provides a better basis for the application of baricitinib in drug treatment, so that the medicinal value of baricitinib can be more efficiently played. SUMMARY

[0013] In view of the deficiencies of the prior art, one object of the application is to provide a baricitinib-saccharin co-crystal; the baricitinib-saccharin co-crystal has exact crystallographic main parameters and atomic spatial positions; and great improvement has been achieved in stability, solubility and the like.

[0014] The specific technical content of the application is as follows: In a first aspect, the application provides a baricitinib-saccharin co-crystal, wherein one molecule of baricitinib and one molecule of saccharin constitute the basic unit of the crystal form.

[0015] Preferably, the baricitinib-saccharin co-crystal has characteristic peaks at least at 9.59±0.2°, 15.61±0.2°, 17.39±0.2°, 18.96±0.2°, 20.71±0.2°, 22.57±0.2° in the X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation.

[0016] Preferably, the baricitinib-saccharin co-crystal has characteristic peaks at least at 9.59±0.2°, 11.49±0.2°, 13.85±0.2°, 15.61±0.2°, 16.14±0.2°, 17.39±0.2°, 18.13±0.2°, 18.96±0.2°, 20.71±0.2°, 22.57±0.2°, 25.20±0.2°, 26.68±0.2°, 27.76±0.2°, 28.48±0.2°, 30.98±0.2° in the X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation.

[0017] Preferably, the baricitinib-saccharin co-crystal has characteristic peaks in the X-ray powder diffraction spectrum and detection data shown in Table 1 and Table 2 using Cu-Kα radiation. Figure 1

[0018] Preferably, the baricitinib-saccharin co-crystal has the following crystallographic parameters: monoclinic crystal system, chiral space group P21 / n; cell parameters: a = 10.18130(10) Å, b = 23.8139(3) Å, c = 10.42840(10) Å, α = 90°, β = 98.7430(10) °, γ = 90°, cell volume V = 2499.05(5) Å 3 . ​

[0019] Preferably, the baricitinib-saccharin co-crystal has an endothermic peak at 185.49°C in the differential scanning calorimetry curve (DSC).

[0020] The second aspect of the present application provides a preparation method of the baricitinib-saccharin co-crystal, and the specific preparation steps include: The baricitinib and saccharin are added into the solvent A, heated and stirred, filtered, and then the baricitinib-saccharin co-crystal is obtained by cooling, standing, volatilization and crystallization, and filtration and drying.

[0021] Preferably, the solvent A is selected from two or more mixed solvents of methanol, ethanol, isopropanol, acetonitrile, acetone and trifluoroethanol, and particularly preferably two or more mixed solvents of methanol, ethanol and acetone. Preferably, the volume ratio of methanol to acetone is 1-8:1.

[0022] Preferably, the molar ratio of the baricitinib to the saccharin is 1:0.9-1.7, and preferably the molar ratio of the baricitinib to the saccharin is 1:1.1-1.4.

[0023] Preferably, the mass-volume ratio of the baricitinib to the solvent A in the system is 7.1-9.2:1, wherein the mass is in mg and the volume is in ml.

[0024] Preferably, the temperature of the dissolution heating is 40-50°C.

[0025] Preferably, the temperature of the cooling and crystallization is 0-25°C, and preferably the temperature of the cooling and crystallization is 10-20°C.

[0026] Preferably, the crystallization time is 45-72 hours.

[0027] Further preferably, the preparation method includes the following steps: The baricitinib and saccharin are dissolved in the solvent A at 40-50°C, stirred and reacted for 1 hour, cooled to 10-20°C, crystallized for 45-72 hours, filtered, and vacuum dried to obtain the baricitinib-saccharin co-crystal.

[0028] Preferably, the vacuum drying temperature is 45-50°C, and the drying time is 5-8 hours.

[0029] The third aspect of the present application provides a pharmaceutical composition, which includes the above-prepared baricitinib-saccharin co-crystal and other pharmaceutically acceptable excipients or active ingredients that can be used in combination.

[0030] Preferably, the other components include other active ingredients that can be used in combination; and the pharmaceutically acceptable excipients include fillers, binders, disintegrants, lubricants, etc.

[0031] Further preferably, the filler is selected from one or more of starch, sucrose, dextrin, lactose, microcrystalline cellulose, mannitol, sorbitol; the binder is selected from one or more of methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, 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, microfine silica, talc and sodium lauryl sulfate.

[0032] Preferably, the dosage form of the pharmaceutical composition is tablets, capsules, granules and pills, etc.

[0033] The fourth aspect of the present application provides a use of the baricitinib-saccharin co-crystal as an active ingredient in the preparation of a medicament for treating JAK-related diseases.

[0034] The JAK-related diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, cancers.

[0035] Confirmation of crystal structure

[0036] X-ray crystal data were collected on a Rigaku XtaLAB Synergy model instrument, test temperature 293(2) K, with Cu-Ka radiation, data were collected in ω scan mode and processed with p correction. The structure was solved by direct methods, all non-hydrogen atoms were found by difference Fourier methods, all hydrogens on carbon and nitrogen were placed using theoretical hydrogen addition, and the structure was refined by least squares method. L

[0037] The crystallographic data obtained by testing and analyzing the baricitinib-saccharin crystal prepared by the present application are shown in Table 1: The crystallographic parameters are: monoclinic crystal system, chiral space group P21 / n; the unit cell parameters are: a = 10.18130(10) Å, b = 23.8139(3) Å, c = 10.42840(10) Å, α = 90°, β = 98.7430(10) °, γ = 90°, the unit cell volume V = 2499.05(5) Å 3 23 22 N8O5S2, the molecular weight is: 554.60. The packing diagram of the baricitinib-saccharin co-crystal of the present application is shown in the attached Figure 2 The structure analysis ORTEP diagram of the baricitinib-saccharin co-crystal of the present application shows that there is one molecule of baricitinib and one molecule of saccharin in the crystal, and no solvent, as shown in the attached Figure 3

[0038] Table 1 Main crystallographic data of baricitinib-saccharin crystal ​​​​

[0039] The X-ray powder diffraction tester and test conditions for the baricitinib-saccharin co-crystal tested in the present application are as follows: PANalytical Empyrean X-ray powder diffraction tester; light source Cu target, flat sample stage, incident light path: BBHD, diffraction light path: PLXCEL, 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°.

[0040] According to crystallographic data, the characteristic peaks in the X-ray powder diffraction pattern (Cu-Ka) thereof are shown in Table 2. Figure 1 and Table 2.

[0041] Table 2 Main PXRD peaks of baricitinib-saccharin crystal

[0042] The TGA / DSC thermal analysis tester and test conditions for the baricitinib-saccharin co-crystal of the present application are as follows: TGA / DSC thermal analyzer: METTLER TOLEDO TGA / DSC3+; dynamic temperature section: 30-350°C; heating rate: 10°C / min; program section gas N2; gas flow: 50 mL / min; crucible: aluminum crucible 40 μl.

[0043] The TGA / DSC test results of the baricitinib-saccharin co-crystal of the present application are shown in Table 1, and the DSC detection results have one endothermic peak with a temperature of 185.49°C. According to the TGA detection results, there is no weight loss step before the melting point, indicating that the prepared crystal form is a solvent-free compound. Figure 4

[0044] Compared with the prior art, the present application has the following technical effects: The present application first provides a baricitinib-saccharin co-crystal, which has the advantages of simple preparation method, easy control of crystallization process, and good reproducibility. The co-crystal formed by the two can significantly enhance the solubility of baricitinib, improve the oral bioavailability, and has good drug value. BRIEF DESCRIPTION OF DRAWINGS

[0045] Figure 1 : X-ray powder diffraction pattern of baricitinib-saccharin co-crystal.

[0046] Figure 2 : Baricitinib-saccharin co-crystal stacking diagram.

[0047] Figure 3 : ORTEP diagram of baricitinib-saccharin co-crystal. ​

[0048] Figure 4 DSC-TGA graph of baricitinib-saccharin co-crystal DETAILED DESCRIPTION

[0049] The application will be further described by the following examples. It should be understood that the examples of the application are only used to illustrate the application, but not to limit the application. Therefore, any simple improvement of the application under the premise of the application is within the scope of the application.

[0050] 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 test 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.

[0051] Example 1

[0052] Dissolve 73.7 mg of baricitinib and 45.3 mg of saccharin in 6 mL of a mixed solvent of methanol and acetone, heat in a water bath at 40°C, stir for 1 hour until completely dissolved, slowly cool to 10-20°C, crystallize for 45-72 hours, filter, and vacuum dry at 45°C for 5-8 hours to obtain baricitinib-saccharin co-crystal. Yield: 94.6%, purity: 99.91%.

[0053] Example 2 Dissolve 70.2 mg of baricitinib and 44.7 mg of saccharin in 5 mL of a mixed solvent of ethanol and acetone, heat in a water bath at 50°C, stir for 1 hour until completely dissolved, slowly cool to 10-20°C, crystallize for 45-72 hours, filter, and vacuum dry at 50°C for 5-8 hours to obtain baricitinib-saccharin co-crystal. Yield: 93.5%, purity: 99.87%.

[0054] Example 3 Dissolve 74.1 mg of baricitinib and 50.5 mg of saccharin in 4 mL of a mixed solvent of methanol and ethanol, heat in a water bath at 50°C, stir for 1 hour until completely dissolved, slowly cool to 10-20°C, crystallize for 45-72 hours, filter, and vacuum dry at 50°C for 5-8 hours to obtain baricitinib-saccharin co-crystal. Yield: 93.2%, purity: 99.79%.

[0055] Example 4 73.7 mg of baricitinib and 45.3 mg of saccharin were dissolved in a mixed solvent of 8 mL of methanol and 1 mL of acetone, heated in a water bath at 40℃, stirred for 1 hour until completely dissolved, slowly cooled to 10-20℃, crystallized for 45-72 hours, filtered, and dried at 45℃ under vacuum for 5-8 hours to obtain the baricitinib-saccharin co-crystal. Yield: 94.4%, purity: 99.90%.

[0056] Preparation of comparative crystal form Two crystal forms Sn1 and Sn2 were obtained by repeating CZ31155U1.

[0057] Verification example:

[0058] Stability experiment

[0059] The specific stability test method refers to the guidance method for stability investigation in Chinese Pharmacopoeia 2020 Volume IV. The purity is detected by HPLC method, and the specific detection results are shown in Table 3.

[0060] Table 3 Purity results of stability test of crystal forms of various samples

[0061] From the stability experiment results, it can be seen that the baricitinib-saccharin co-crystal prepared by the present application does not have a relatively obvious change in purity and appearance under the conditions of light, high temperature and high humidity, and the crystal form does not change after sampling for 30 days and testing by XPRD. It shows good stability.

[0062] Hygroscopicity test:

[0063] Referring to the guidance principle for drug hygroscopicity test in Chinese Pharmacopoeia 2020 Volume IV General Principles 9103-Drug Hygroscopicity Test Guidance Principle for Judging Hygroscopicity Characteristics.

[0064] Hygroscopicity judgment standard:

[0065] Three groups of samples of example 1 and comparative crystal form were taken respectively, and the hygroscopicity weight gain experiment was carried out at 25℃ and 90% relative humidity (after equilibrium) according to the guidance principle for drug hygroscopicity test. The hygroscopicity of each was tested by dynamic water adsorption (DVS) instrument, and the average value was taken. The experimental results are shown in Table 4.

[0066] Table 4 Hygroscopicity test results

[0067] The results show that the baricitinib-saccharin co-crystal of the present application has almost no hygroscopicity, good stability, and is suitable for the manufacture and long-term storage of drug preparations.

[0068] Solubility test

[0069] Test method: water and 0.1 mol / L hydrochloric acid solution, pH 6.8 PBS buffer were used as medium respectively, each crystal form of baricitinib prepared was taken in excess and added into the above-mentioned medium, 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.

[0070] Table 5 solubility of each crystal form of baricitinib in different media (mg / ml)

[0071] The solubility test results show that the baricitinib-saccharin co-crystal prepared in the present application has higher solubility than the co-crystal disclosed in the prior art.

[0072] Through the above experimental results, although the baricitinib-saccharin co-crystal, but different crystal forms have different effects on the solubility, hygroscopicity and stability of the crystal. The solubility of baricitinib-saccharin co-crystal Sn2 is relatively good compared with baricitinib-saccharin co-crystal Sn1, but the hygroscopicity is large and the stability is poor. The baricitinib-saccharin co-crystal prepared in the present application is improved in stability, hygroscopicity and solubility, so the research and development of the co-crystal is helpful to improve the bioavailability of baricitinib.

Claims

1. A baricitinib-saccharin eutectic, characterized in that, In the eutectic, one molecule of baricitinib and one molecule of saccharin constitute the basic unit of the crystal structure.

2. The baricitinib-saccharin eutectic according to claim 1, characterized in that, The eutectic is subjected to Cu-Kα radiation, and the X-ray diffraction pattern expressed in 2θ has characteristic peaks at at least 9.59±0.2°, 15.61±0.2°, 17.39±0.2°, 18.96±0.2°, 20.71±0.2°, and 22.57±0.2°.

3. The baricitinib-saccharin eutectic according to claim 1, characterized in that, Using Cu-Kα radiation, the X-ray diffraction pattern, expressed as 2θ, has characteristic peaks at at least 9.59±0.2°, 11.49±0.2°, 13.85±0.2°, 15.61±0.2°, 16.14±0.2°, 17.39±0.2°, 18.13±0.2°, 18.96±0.2°, 20.71±0.2°, 22.57±0.2°, 25.20±0.2°, 26.68±0.2°, 27.76±0.2°, 28.48±0.2°, and 30.98±0.2°.

4. The baricitinib-saccharin eutectic according to claim 1, characterized in that, Its crystallographic parameters are: monoclinic system, chiral space group P21 / n; cell parameters are: a = 10.18130(10) Å, b = 23.8139(3) Å, c = 10.42840(10) Å, α = 90°, β = 98.7430(10)°, γ = 90°, cell volume V = 2499.05(5) Å. 3 .

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

6. A method for preparing the baricitinib-saccharin eutectic according to any one of claims 1-5, characterized in that, The method includes the following steps: adding baricitinib and saccharin to solvent A, heating and stirring, filtering, cooling and allowing to stand to volatilize and crystallize, filtering and drying to obtain baricitinib-saccharin co-crystals.

7. The method for preparing baricitinib-saccharin eutectic according to claim 6, characterized in that, Solvent A is selected from two or more mixed solvents selected from methanol, ethanol, isopropanol, acetonitrile, acetone, and trifluoroethanol; preferably, it is a mixture of two or more mixed solvents selected from methanol, ethanol, and acetone; preferably, the volume ratio of methanol to acetone is 1 to 8:

1.

8. The method for preparing baricitinib-saccharin eutectic according to claim 6, characterized in that, The molar ratio of baricitinib to saccharin is 1:0.9 to 1.7, preferably 1:1.1 to 1.4; the mass-to-volume ratio of baricitinib to solvent A in the system is 7.1 to 9.2:1, where mass is expressed in mg and volume in ml.

9. The method for preparing baricitinib-saccharin eutectic according to claim 6, characterized in that, The melting and heating temperature is 40-50°C; the cooling and crystallization temperature is 0-25°C, preferably 10-20°C.

10. The use of the baricitinib-saccharin cocrystal as described in any one of claims 1-5 as an active ingredient in the preparation of a medicament for treating JAK-related autoimmune diseases, inflammatory diseases, or cancers.

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