Oxalic acid cocrystal of parp7 inhibitor and preparation method therefor

Abstract

A cocrystal, comprising a compound of formula 1 and oxalic acid.

Description

An oxalate cocrystal of a PARP7 inhibitor and its preparation method Technical Field

[0001] This invention relates to the pharmaceutical field, and in particular to an oxalate cocrystal of a PARP7 inhibitor and its preparation method. Background Technology

[0002] PARP (poly-ADP-ribose polymerase) is a family of 17 enzymes that use nicotinamide adenine dinucleotide (NAD+) as a substrate to transfer ADP-ribose (ADPR) to target proteins. It is a multifunctional post-translational modification enzyme present in most eukaryotic cells. It is activated by recognizing structurally damaged DNA fragments and is considered a DNA damage sensor, participating in a series of cellular processes such as DNA repair and genome stability.

[0003] The PARP family is divided into two subclasses: polyPARPs and monoPARPs. PolyPARPs add multiple ADPR (ADP-ribose) molecules sequentially to proteins, resulting in ADPR chains that can reach hundreds of units. In contrast, monoPARPs modify proteins by attaching only one ADPR molecule. Therefore, polyPARPs and monoPARPs represent two different types of therapeutic targets because they have different ADP-ribosylated protein substrates and play different roles in cell signal transduction and protein function regulation.

[0004] PARP7 (TIPARP) is a monoPARP that is a key factor regulating innate immunity, transcription factor activity, and cellular stress responses. Multiple studies have shown that PARP7 plays a crucial role in innate immune signaling pathways, particularly as a negative regulator of type I interferon antiviral responses; knocking out PARP7 can enhance the expression of nucleic acid sensor agonists or virus-induced interferon-β (IFN-β) in different cell types. PARP7 acts as an inhibitor of aryl hydrocarbon receptor (AHR) activity and is upregulated in cellular stress induced by AHR activation following viral infection or exposure to cigarette smoke. Furthermore, PARP7 is also regulated by liver X receptors (LXRs) and hypoxia-inducible factor 1 (HIF-1).

[0005] Currently, there are relatively few reported PARP7 inhibitors, with the most advanced ones still in early clinical development stages, and they often suffer from poor in vivo pharmacokinetic properties. CN115785074B provides a PARP7 inhibitor that can improve in vivo pharmacokinetic properties, exhibit better anti-tumor activity and therapeutic efficacy, reduce clinical side effects, and can be expanded to more cancer indications.

[0006] Example 25 of CN115785074B discloses the synthesis of (S)-N-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridin-4-yl)acetamide (structure shown in Formula 1), yielding a white solid. Experiments confirmed that this compound exhibits good inhibitory activity against PARP7 enzymes and good inhibitory activity against the growth of NCI-H1373 cancer cells, and possesses superior in vivo pharmacokinetic properties, making it valuable for clinical development.

[0007] The crystal structure of a pharmaceutical active ingredient often affects its chemical and physical stability. Different crystal forms, preparation methods, and storage conditions can lead to changes in the compound's crystal structure, sometimes accompanied by polymorphism. Therefore, the stability of the crystal structure has varying impacts on the drug's manufacturing process, storage conditions, and usage methods. Developing relatively simple crystal structures is of great significance for the industrial production and application of active ingredients.

[0008] In the process of seeking a stable crystal form for the compound of Formula 1, the inventors discovered that the compound has at least 14 crystal forms, including 7 amorphous crystal forms and 7 solvate crystal forms. Furthermore, during the crystal form preparation process, there are interconversion phenomena and mixed crystal phenomena among the various crystal forms, and no significant dominant crystal form was found. Summary of the Invention

[0009] The purpose of this invention is to provide a stable crystalline structure of "(S)-N-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridin-4-yl)acetamide" (hereinafter referred to as "Compound 1"), which has a simple structure, high reproducibility in preparation, high stability, low hygroscopicity, and good solubility.

[0010] A first aspect of the present invention provides a eutectic, characterized in that it comprises a compound of formula 1 (i.e., compound 1) and oxalic acid.

[0011] The active pharmaceutical ingredient (API) molecule (compound 1) and the small molecule ligand copolymer (CCF) molecule (oxalic acid) form a supramolecular network through hydrogen bonds. This network undergoes a series of stacking, assembly, and arrangement processes to form a three-dimensional crystal structure, i.e., a eutectic structure. Intermolecular interactions and spatial bonding influence the formation of the network supramolecular structure. The network supramolecular structure can improve the crystallization properties of the API by affecting crystal particle size and crystal purity. Since hydrogen bonds are essentially electrostatic interactions and possess directionality and saturation characteristics, they can maintain the equilibrium and stability of the crystal. The eutectic formed by compound 1 and oxalic acid has a stable structure.

[0012] In a preferred embodiment, the molar ratio of compound 1 to oxalic acid is (2.2-1.8):1, preferably (2.1-1.9):1, more preferably (2.05-1.95):1, even more preferably (2.02-1.98):1, and most preferably 2:1.

[0013] In another preferred embodiment, the eutectic of the present invention has a crystal structure of crystal form A, wherein the X-ray powder diffraction pattern of crystal form A has characteristic peaks at 2θ values ​​of 18.4±0.2°, 19.3±0.2°, 20.7±0.2° and 21.3±0.2°.

[0014] In a more preferred embodiment, the X-ray powder diffraction pattern of crystal form A also has one or more characteristic peaks at 2θ values ​​selected from the following: 13.4±0.2°, 19.9±0.2°, 22.1±0.2°, 27.5±0.2°, and 29.1±0.2°.

[0015] In a particularly preferred embodiment, the positions of the characteristic peaks shown in the X-ray powder diffraction pattern of crystal form A are substantially the same as those of the characteristic peaks shown in Figures 1, 5, or 8.

[0016] In a second aspect, the present invention provides a method for preparing a eutectic, comprising mixing a compound of Formula 1 with oxalic acid in a solvent to form a suspension, separating the suspension after thorough stirring, and drying the suspension under vacuum to obtain crystals.

[0017] In a preferred embodiment, during the mixing step, the molar ratio of compound 1 to oxalic acid is 1:1 to 1:10.

[0018] In another preferred embodiment, the solvent is one or more selected from ethyl acetate (EA), dichloromethane (DCM), acetonitrile (ACN), ethanol (EtOH), toluene, methyl isobutyl ketone (MIBK), methyl tert-butyl ether (MTBE), anisole, and isopropyl acetate (IPAc).

[0019] In other preferred embodiments, the drying step includes placing the crystal in a vacuum at 40°C to 70°C for 2 to 24 hours.

[0020] By converting compound 1 into a eutectic with oxalic acid, the problems of compound 1 having many crystal types, poor crystal form product uniformity, and low reproducibility are effectively improved. Furthermore, its production process can be simplified, making it easier to achieve industrialization.

[0021] In addition, the eutectic formed by compound 1 and oxalic acid has good solubility, stable crystal form, and low hygroscopicity, and has good bioavailability and low requirements for storage environment.

[0022] The method of the present invention for preparing the eutectic is simple, controllable, and reproducible, making the eutectic promising for drug development. Attached Figure Description

[0023] Figure 1 shows the X-ray powder diffraction (XRPD) pattern of compound crystal form A obtained in Example 1;

[0024] Figure 2 shows the thermogravimetric analysis (TGA) spectrum of compound crystal form A obtained in Example 1;

[0025] Figure 3 shows the differential scanning calorimetry (DSC) spectrum of compound crystal form A obtained in Example 1;

[0026] Figure 4 shows the diffraction data obtained by microcrystalline electron diffraction (MicroED) of compound crystal form A obtained according to Example 1, thereby determining the crystal structure;

[0027] Figure 5 shows the X-ray powder diffraction (XRPD) pattern of compound crystal form A obtained in Example 2;

[0028] Figure 6 shows the thermogravimetric analysis (TGA) spectrum of compound crystal form A obtained in Example 2;

[0029] Figure 7 shows the differential scanning calorimetry (DSC) spectrum of compound crystal form A obtained in Example 2;

[0030] Figure 8 shows the X-ray powder diffraction (XRPD) pattern of compound crystal form A obtained in Example 3;

[0031] Figure 9 is a TGA and DSC overlay of the crystal form A of the compound obtained in Example 3;

[0032] Figure 10 shows the dynamic water adsorption (DVS) spectrum of compound crystal form A obtained in Example 1. Detailed Implementation

[0033] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that the following detailed description of the technical solutions of the present invention using embodiments will help to further understand the advantages and effects of the technical solutions of the present invention. The embodiments do not limit the scope of protection of the present invention, which is determined by the claims.

[0034] During extensive experiments, the inventors discovered that compound 1 exhibits polymorphism, and that the structures of each of the multiple crystal forms are unstable, with no single crystal form showing a clear advantage. For example, the inventors found that the compound has at least 14 crystal forms, including 7 amorphous forms and 7 solvate forms (summarized in Table 1 below). Because polymorphism often coexists during synthesis, unstable and reproducible preparations are encountered during repeated preparations. Therefore, if compound 1 is to be produced and applied, a single-structure, stable, and reproducible crystal form is required.

[0035] Table 1 Summary of polymorphs of compound 1

[0036] Table 1 (continued) Summary of polymorphs of compound 1

[0037] Table 1 (continued) Summary of polymorphs of compound 1

[0038] Table 1 (continued) Summary of polymorphs of compound 1

[0039] Table 1 (continued) Summary of polymorphs of compound 1

[0040] Table 1 (continued) Summary of polymorphs of compound 1

[0041] Drug cocrystals are an important form of multi-component drug crystals. They refer to crystals formed by the bonding of a drug (API) with a pharmaceutically acceptable small-molecule ligand copolymer (CCF), which is solid at room temperature, through non-covalent bonds such as hydrogen bonds, van der Waals forces, π-π stacking interactions, and halogen bonds, in a fixed stoichiometric ratio. Cocrystals can improve the physicochemical properties of drugs without affecting their internal structure, particularly enhancing the solubility, dissolution rate, and bioavailability of oral solid dosage forms, thus attracting widespread attention in the industry.

[0042] In order to solve the problems of polymorphism and lack of a dominant stable crystal form of compound 1, a first aspect of the present invention provides a eutectic, characterized in that it comprises the compound of formula 1 (i.e., compound 1) and oxalic acid.

[0043] The functional groups on the dihydropyridazine structure of the active pharmaceutical ingredient (API) molecule (compound 1) and the carboxyl groups of the copolymer (CCF) molecule (oxalic acid) form hydrogen bond structures such as O…H…O and N…H…O (as shown by the light blue lines in Figure 4). These hydrogen bonds allow the API and CCF to form a supramolecular network, which, through a series of ordered stacking, assembly, and arrangement, forms a three-dimensional crystal structure, i.e., a eutectic structure. Intermolecular interactions and spatial bonding influence the formation of the network supramolecular structure, which can affect crystal particle size and crystal purity, thereby improving the crystallization properties of the API. Since hydrogen bonds are essentially an electrostatic interaction with directional and saturable characteristics, they can maintain the equilibrium and stability of the crystal. The eutectic formed by compound 1 and oxalic acid exhibits a well-stable structure.

[0044] In a preferred embodiment, the molar ratio of the compound to oxalic acid is essentially 2:1.

[0045] As described above, since oxalic acid contains two carboxyl groups, the "=O" and "-OH" in each carboxyl group can form hydrogen bonds with the "-NH" and "=O" functional groups on the dihydropyridazine ring of compound 1, respectively. Therefore, theoretically, one oxalic acid molecule can form a stable eutectic structure with two molecules of compound 1. Although theoretically the molar ratio of compound 1 to oxalic acid in the eutectic of the present invention is 2:1, the existence of eutectic structural units that do not conform to this molar ratio is not excluded. Therefore, "basically 2:1" means that the measured molar ratio of the two is (2.2 to 1.8):1, preferably (2.1 to 1.9):1, more preferably (2.05 to 1.95):1, even more preferably (2.02 to 1.98):1, and most preferably 2:1.

[0046] Considering the saturation of hydrogen bonds, the ratio between each copolymer (CCF) molecule and the active pharmaceutical ingredient (API) molecule can only guarantee the stability of the eutectic structure within a certain range.

[0047] According to the present invention, the eutectic has a crystal structure of crystal form A, and the X-ray powder diffraction pattern of crystal form A has characteristic peaks at 2θ values ​​of 18.4±0.2°, 19.3±0.2°, 20.7±0.2° and 21.3±0.2°.

[0048] In a preferred embodiment, the X-ray powder diffraction pattern of crystal form A also has one or more characteristic peaks at 2θ values ​​selected from the following: 13.4±0.2°, 19.9±0.2°, 22.1±0.2°, 27.5±0.2°, and 29.1±0.2°.

[0049] The X-ray powder diffraction pattern of crystal form A of oxalic acid eutectic exhibits subtle differences due to minute variations in crystal structure, which are primarily influenced by specific crystallization conditions. In certain embodiments, the characteristic peak positions displayed in the X-ray powder diffraction pattern of crystal form A are substantially the same as those shown in Figures 1, 5, or 8.

[0050] According to a second aspect of the present invention, a method for preparing a eutectic as described in the first aspect of the present invention is provided, comprising mixing a compound of formula 1 with oxalic acid in a solvent to form a suspension, separating the suspension after thorough stirring, and drying the suspension under vacuum to obtain crystals.

[0051] API and CCF molecules are coupled together via hydrogen bonds, without forming covalent or ionic bonds, thus requiring relatively mild reaction conditions. However, sufficient contact between the two molecules must be ensured to reach the distance necessary for hydrogen bonding.

[0052] The suspension can be formed by any method known in the art; the present invention uses a stirring and slurrying method to form the suspension.

[0053] In some preferred embodiments, the pulping experiment is usually carried out at room temperature to 50°C, and the pulping time is usually 6 hours to 2 weeks.

[0054] In a preferred embodiment, during the mixing step, the molar ratio of the compound to oxalic acid is 1:1 to 1:10.

[0055] An appropriate excess of CCF molecules is beneficial for the formation of sufficient hydrogen bonds between CCF and API molecules. Extensive experiments have shown that even with an excess of CCF molecules, the structural uniformity of the resulting eutectic crystal is not affected. This is attributed to the saturation of hydrogen bonds, which maintains a relatively stable ratio of CCF to API molecules within the crystal.

[0056] In another preferred embodiment, the solvent is selected from one or more of ethyl acetate (EA), dichloromethane (DCM), acetonitrile (ACN), ethanol (EtOH), toluene, methyl isobutyl ketone (MIBK), methyl tert-butyl ether (MTBE), anisole, and isopropyl acetate (IPAc).

[0057] Oxalic acid, due to its strong acidity, readily ionizes into ionic form in highly polar solvents such as water or ethanol. To ensure that oxalic acid forms a eutectic with API molecules in its molecular form, solvents with poor solubility or weak polarity are required to fully disperse the oxalic acid molecules.

[0058] The method for separating crystals mentioned in this invention can be any separation method known in the art, such as decantation, filtration, centrifugation, gravity sedimentation, etc. Generally, a suitable separation method is selected based on the fluidity of the suspension and the particle size of the solid particles. Commonly used methods are filtration and centrifugation.

[0059] In yet another preferred embodiment, the drying step includes placing the separated crystals in a vacuum at 40°C to 70°C for 2 to 24 hours, preferably at 40°C to 60°C for 8 to 20 hours, and more preferably at about 50°C for 12 to 18 hours.

[0060] Unless otherwise specified, the experimental methods described in the following examples are generally performed under standard conditions or as recommended by the manufacturer.

[0061] Unless otherwise specified, all raw materials or reagents used in the examples were purchased from commercial suppliers.

[0062] Unless otherwise specified, the reagents described shall be used directly without purification.

[0063] Experimental instruments and conditions

[0064] X-ray powder diffractometer (XRPD)

[0065] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)

[0066] Microcrystalline Electron Diffraction (MicroED)

[0067] 1H NMR (1H NMR) 1 H-NMR)

[0068] High-performance liquid chromatography (HPLC)

[0069] Ion chromatography (IC)

[0070] Preparation of the compound of Formula 1 (i.e., compound 1): prepared according to the method described in Example 25 of Chinese Invention Patent CN115785074B.

[0071] Example

[0072] Eutectic preparation experiment

[0073] Example 1

[0074] 1 g of compound 1 and 1.1 equivalents of oxalic acid were weighed and added to a 20 mL flask. 10 mL of ethyl acetate (EA) was added, and the resulting suspension was stirred at 50 °C for 6 h. After naturally cooling to room temperature, the suspension was filtered to obtain a wet product. The wet product was then vacuum dried at 50 °C for 18 h to obtain 805 mg of the product. The obtained product was subjected to XRPD, TGA, DSC, and other tests. 1 H-NMR, HPLC, IC and MicroED tests.

[0075] The final XRPD spectrum of the dried product is shown in Figure 1, the TGA spectrum is shown in Figure 2, the DSC spectrum is shown in Figure 3, and the crystal structure obtained by MicroED is shown in Figure 4.

[0076] XRPD analysis revealed that the dried product was oxalic acid eutectic form A, obtained by vacuum drying the wet product at 50°C for 18 hours. The XRPD chromatogram analysis data for oxalic acid eutectic form A are shown in Table 2.

[0077] Table 2. XRPD pattern analysis of oxalic acid eutectic form A

[0078] As can be seen from the TGA spectrum in Figure 2, the product experiences almost no weight loss before 105℃, indicating good thermal stability of the product structure. As can be seen from the DSC spectrum in Figure 3, the obtained dried product exhibits an endothermic peak at 175.2℃. 1 ¹H-NMR analysis confirmed the absence of organic reagent residues in the obtained crystal structure. HPLC testing showed that the purity of the dried product reached 99.3%, a result consistent with the absence of impurity peaks in the XRPD spectrum. IC analysis revealed that the oxalate ion content in the dried product was 7.7%, indicating a molar ratio of approximately 2.05:1 between compound 1 and oxalate, close to the theoretical molar ratio of 2:1.

[0079] The crystal structure of the obtained dried product was determined using MicroED experiments. The crystal belongs to the monoclinic crystal system, space group P21 (No. 4), and the unit cell parameters are as follows. α = 90°, β = 94.2(3)°, γ = 90°, cell volume Z' is 2. The asymmetric unit consists of 2 API molecules and one oxalic acid (C2H2O4) molecule. The crystal structure obtained by the diffraction results is shown in Figure 4.

[0080] Example 2

[0081] Weigh 50 mg of compound 1 and 1.1 equivalents of oxalic acid into a 2 mL vial. Add 0.5 mL of EA to the vial. Stir at 50 °C for 17 h, then cool to 5 °C at a rate of 0.1 °C / min and continue stirring for 3 days. Centrifuge and filter the sample, then vacuum dry at 50 °C for 18 h and measure the XRPD of the dried product. The XRPD spectrum is shown in Figure 5, and the XRPD spectrum resolution data is shown in Table 3. The TGA and DSC test results are shown in Figures 6 and 7.

[0082] Table 3. XRPD pattern analysis of oxalic acid eutectic crystal form A

[0083] XRPD results showed that the crystals obtained by this pulping method were identified as oxalic acid eutectic crystals of type A.

[0084] As shown in the TGA spectrum in Figure 6, the product exhibits almost no weight loss before 105℃, indicating good thermal stability. The DSC spectrum in Figure 7 shows an endothermic peak at 176℃. HPLC analysis revealed a product purity of 99.4%, and IC analysis showed an oxalate ion content of 7.5% in the dried product, indicating a molar ratio of approximately 2.11:1 between compound 1 and oxalate, close to the theoretical molar ratio of 2:1.

[0085] Example 3

[0086] 0.5 g of compound 1 and 2.0 equivalents of oxalic acid were weighed and added to a 20 mL bottle. 15 mL of DCM was added, and the mixture was stirred at room temperature for 12 h. After filtration, the wet sample was placed in a vacuum dryer at 50 °C for 4 h. The XRPD of the obtained dry sample was measured. The XRPD spectrum is shown in Figure 8, the XRPD spectrum resolution data is shown in Table 4, and the TGA and DSC test results are shown in Figure 9.

[0087] Table 4. XRPD pattern analysis of oxalic acid eutectic crystal form A

[0088] XRPD results showed that the crystals obtained by this pulping method were identified as oxalic acid eutectic crystals of type A.

[0089] As shown in the TGA spectrum in Figure 9, the product exhibits almost no weight loss before reaching 120℃, indicating good thermal stability of the product structure. The DSC spectrum in Figure 9 shows an endothermic peak at 175.6℃ in the obtained dried product. IC analysis revealed that the oxalate ion content in the obtained dried product was 7.5%, meaning the molar ratio between compound 1 and oxalate was approximately 2.13:1, close to the theoretical molar ratio of 2:1.

[0090] Examples 4-10

[0091] 50 mg of compound 1 and 2.0 equivalents of oxalic acid were weighed and added to 2 mL vials. 0.8 mL of each of the following solvents was added: (solvent selection is shown in Table 5). The resulting suspensions were stirred at 50 °C for 2 h, and then stirred again at room temperature for 12 h. After centrifugation and filtration, the wet product was obtained and then vacuum dried at 50 °C for 4 h. The XRPD of the dried product was measured. The results are shown in Table 5.

[0092] Table 5. Slurrying results of Compound 1 and oxalic acid in different solvents.

[0093] The results above show that both compound 1 and oxalic acid, after being slurried in different solvents and dried under vacuum, yielded oxalic acid eutectic crystal form A. Furthermore, the XRPD diffraction patterns of the crystals obtained in different solvents were essentially the same.

[0094] Examples 11-13

[0095] 50 mg of compound 1 and different equivalents of oxalic acid were weighed and added to 10 mL vials. 5 mL of DCM was added to each vial, and the resulting suspensions were stirred at room temperature for 12 h. The wet product was obtained by centrifugation and filtration, and then dried under vacuum at 50 °C for 24 h. The XRPD of the dried product was measured. The results are shown in Table 6.

[0096] Table 6. Slurrying results of compound 1 and different equivalents of oxalic acid in DCM.

[0097] The results above show that compound 1 and different proportions of oxalic acid, when slurried in DCM, all yielded oxalic acid eutectic crystal form A after vacuum drying. Furthermore, the XRPD diffraction patterns of the crystals obtained from reactions with different proportions of oxalic acid were essentially the same.

[0098] Performance testing of oxalic acid eutectic form A

[0099] Example 14: Rough Solubility Test

[0100] Approximately 5 mg of oxalic acid eutectic form A was weighed and added to 20 μL of each of the different solvents (solvent selection is shown in Table 7) until the solid dissolved or the solvent volume exceeded 1.5 mL. The approximate solubility was measured at room temperature, and the results are summarized in the table below:

[0101] Table 7. Approximate solubility of oxalic acid eutectic form A

[0102] From a chemical perspective, API molecules do not change after forming a eutectic structure, thus retaining their original efficacy. As shown in the table above, oxalic acid eutectic form A exhibits good solubility in various solvents, which is very beneficial for the development of some oral drug formulations.

[0103] Example 15: Solubility determination at different pH values

[0104] 1.7 mg of oxalic acid eutectic form A2 (containing approximately 20 mg of compound 1) was weighed and added to 10 mL of buffer solutions at pH 1.2, pH 4.5, and pH 6.8, respectively, to form suspensions. The suspensions were incubated at 37°C with stirring. Samples were taken and centrifuged after 2 hours, 6 hours, and 24 hours, respectively. The supernatant was collected, and the content of the sample in the solution was determined by high-performance liquid chromatography (HPLC). The solubility results are shown in Table 8 below.

[0105] Table 8 Solubility of Oxalic Acid Eutectic Form A

[0106] The results in the table show that the oxalic acid co-crystal A has good solubility, which is beneficial to increasing the concentration of the drug in the body and thus promoting the absorption of the drug in the body. Therefore, it can be considered that the co-crystal structure of compound 1 has good drug development prospects.

[0107] Example 16 Stability Test

[0108] Approximately 30 mg of oxalic acid eutectic crystal form A was placed in an open container at 25℃ / 60%RH, 40℃ / 75%RH, and 25℃ / 92.5%RH for one week and one month, respectively. XRPD was measured to determine the crystal morphology, and chemical purity was determined by HPLC. The reaction conditions and results are shown in Table 9.

[0109] Table 9. Stability assessment of oxalic acid eutectic form A under different temperatures and humidity conditions.

[0110] Characterization results from crystal structure analysis show that after one month of storage, the crystal form of oxalic acid cocrystal A did not change significantly, and the chemical purity did not decrease significantly. This indicates that compound 1 has good physical and chemical stability after forming oxalic acid cocrystal, which is beneficial to the stable preservation of the drug formed by this compound.

[0111] Example 17 Hygroscopicity Test

[0112] The moisture adsorption and desorption properties of the oxalic acid co-crystal form A obtained according to Example 1 were evaluated by DVS. 15 mg of the oxalic acid co-crystal form A was placed in a metal container, and the metal container was placed in an Intrinsic DVS instrument. A cyclic humidity gradient change of 40% RH - 0% RH - 90% RH - 0% RH - 90% RH was set at 25 °C, and the sample underwent two consecutive adsorption - desorption cycles. The steps differed by 5% RH from each other. At each stage, the following equilibrium criteria were used: the mass change dm / dt < 0.002% over a period of 5 min, and the minimum and maximum equilibrium times at each stage were 60 min and 360 min, respectively. The results are shown in Table 10 and Figure 10.

[0113] Table 10 Hygroscopicity experiment of oxalic acid co-crystal

[0114] From the results of the hygroscopicity test, it can be seen that under the condition of 25 °C, for the oxalic acid co-crystal form A, when the relative humidity < RH 70%, the moisture absorption weight gain is less than 0.2%, and there is almost no hygroscopicity. When the relative humidity is in the range of 70% - 90% RH, the moisture absorption weight gain is less than 0.32%, and there is slightly hygroscopicity. Therefore, the oxalic acid co-crystal form A has slight hygroscopicity. It shows that when the compound exists in the form of the oxalic acid co-crystal form A, it can maintain stability without strict humidity control during the production and storage of drugs. The requirements for the drug preparation process and storage conditions are reduced.

[0115] According to the present invention, the oxalic acid co-crystal form A has advantages such as good homogeneity, high structural stability, good solubility, low hygroscopicity, and can be prepared repeatedly, and thus has good application prospects.

[0116] It should be noted that this application is not limited to the above-mentioned embodiments. The above-mentioned embodiments are only examples, and embodiments having the same structure and the same function and effect as the technical idea within the scope of the technical solution of this application are all included in the technical scope of this application. In addition, within the scope not departing from the gist of this application, various modifications that can be thought of by those skilled in the art to the embodiments, and other ways constructed by combining some constituent elements of the embodiments are also included in the scope of this application.

[0117] Industrial availability

[0118] The present invention provides an oxalate co-crystal compound of "(S)-N-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-2-(1-(5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,6-tetrahydropyridin-4-yl)acetamide" with a single structure, high preparation repeatability, high stability, low hygroscopicity, and good solubility, which can be used as an active ingredient for preparing drugs. Therefore, the present invention is suitable for industrial applications.

Claims

1. A eutectic, characterized in that, The compound containing Formula 1 and oxalic acid, 2. The eutectic according to claim 1, characterized in that, The molar ratio of the compound to oxalic acid is (2.2-1.8):1, preferably (2.1-1.9):1, more preferably (2.05-1.95):1, even more preferably (2.02-1.98):1, and most preferably 2:

1.

3. The eutectic according to claim 1 or 2, characterized in that, The eutectic has a crystal structure of crystal form A, and the X-ray powder diffraction pattern of crystal form A has characteristic peaks at 2θ values ​​of 18.4±0.2°, 19.3±0.2°, 20.7±0.2° and 21.3±0.2°.

4. The eutectic according to claim 3, characterized in that, The X-ray powder diffraction pattern of crystal form A also has one or more characteristic peaks at 2θ values ​​selected from the following: 13.4±0.2°, 19.9±0.2°, 22.1±0.2°, 27.5±0.2°, and 29.1±0.2°.

5. The eutectic according to any one of claims 1 to 4, characterized in that, The positions of the characteristic peaks shown in the X-ray powder diffraction pattern of crystal form A are substantially the same as those shown in Figures 1, 5, or 8.

6. A method for preparing the eutectic as described in any one of claims 1 to 5, characterized in that, The compound of formula 1 is mixed with oxalic acid in a solvent to form a suspension. After thorough stirring, the mixture was separated and dried under vacuum to obtain crystals.

7. The method according to claim 6, characterized in that, In the mixing step, the molar ratio of the compound to oxalic acid is 1:1 to 1:

10.

8. The method according to claim 6 or 7, characterized in that, The solvent is selected from one or more of ethyl acetate, dichloromethane, acetonitrile, ethanol, toluene, methyl isobutyl ketone, methyl tert-butyl ether, anisole, and isopropyl acetate.

9. The method according to any one of claims 6 to 8, characterized in that, The drying step includes placing the crystals in a vacuum at 40°C to 70°C for 2 to 24 hours.

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