Eutectic of two sitagliptin medicines as well as preparation method and application of eutectic

Abstract

The invention relates to two sitagliptin pharmaceutical co-crystals as well as a preparation method and application thereof. The sitagliptin pharmaceutical co-crystal 1 (sitagliptin-CaCl2 co-crystal) is formed by combining the sitagliptin pharmaceutical co-crystal 1 (sitagliptin-CaCl2 co-crystal) according to the molar ratio of 2: 1, and the molecular formula of the sitagliptin pharmaceutical co-crystal 1 is C32H30CaCl2F12N10O2; the sitagliptin pharmaceutical co-crystal 2 (sitagliptin-ZnBr2 co-crystal) is formed by combining the sitagliptin pharmaceutical co-crystal 2 (sitagliptin-ZnBr2 co-crystal) according to the molar ratio of 1: 1, and the molecular formula of the sitagliptin pharmaceutical co-crystal 2 is C16H15ZnBr2F6N5O. The two Sitagliptin pharmaceutical co-crystals prepared by the invention are characterized by means of X-ray powder diffraction (PXRD), single crystal X-ray powder diffraction (SCXRD), differential scanning calorimetry (DSC), thermogravimetric analyzer (TGA) and the like. Compared with the prior art, the sitagliptin pharmaceutical co-crystal prepared by the invention has one or more improved characteristics compared with the existing compound, and has important value for optimization and development of the medicine in the future.

Description

Technical Field

[0001] The invention relates to the technical field of drug crystal chemistry, and in particular to two sitagliptin drug cocrystals and preparation methods and applications thereof. Background Art

[0002] Pharmaceutical cocrystals are based on supramolecular chemistry principles, i.e., molecular recognition and supramolecular self-assembly through the synergistic interaction between molecules. Active pharmaceutical ingredients (API) and suitable cocrystal formers (CCF) self-assemble through hydrogen bonds, or saturated and directional non-covalent bonds (such as van der Waals forces of aromatic hydrocarbons or benzene rings, π-π conjugation and halogen bonds) to form a new type of structure, namely, pharmaceutical cocrystals. Based on hydrogen bonds, it does not require the formation of new covalent bonds, nor does it require the destruction of existing covalent bonds. While retaining the pharmacological effects of the drug itself, it can also modify the physical and chemical properties of the drug, such as improving the stability of the drug, reducing its hygroscopicity, improving solubility, and improving bioavailability, etc., which provides broad development prospects for the application of pharmaceutical cocrystals in the pharmaceutical industry. In November 2011, the FDA issued the Guidance for Industry: Regulatory Classification of Pharmaceutical Cocrystals, which pointed out that when a drug forms a cocrystal with a certain excipient, the drug cocrystal can be managed and controlled as a "preparation intermediate", so the cocrystal does not need to be registered as a drug alone. In recent years, the research on drug cocrystals has attracted more and more attention. At present, the research on drug cocrystals abroad has gradually increased and deepened; while the research on it in China is relatively small. For generic drugs, the research on drug cocrystals can also break the patent protection of the original drug company on the drug crystal form, which is conducive to the introduction of generic drugs to the market. Therefore, it is of great practical significance to obtain more novel, practical and creative drug cocrystals, especially some water-insoluble drugs. Drug cocrystals can optimize the physical and chemical properties of drug molecules, such as stability and solubility, and are a potential new drug development technology.

[0003] Sitagliptin (STA), molecular formula is C 16 H 15F6N5O, its structure is shown in Formula I. Sitagliptin is the first dipeptidyl peptidase-IV (DPP-4) inhibitor drug approved by the FDA for the treatment of type II diabetes. The mechanism of action of sitagliptin is different from that of previous oral hypoglycemic drugs. It increases the activity of GLP-1 and GIP in plasma, slightly increases their content and weakens the antagonistic effect of GLP-1 metabolites, thereby improving the ability of diabetic patients' own pancreatic β cells to produce insulin and increasing insulin secretion when blood sugar rises, thereby controlling the blood sugar level of diabetic patients. In the biopharmaceutical classification system, sitagliptin has low solubility and high permeability, and belongs to BCS II class compounds.

[0004] Summary of the invention

[0005] The purpose of the present invention is to provide two sitagliptin drug cocrystals and their preparation methods and applications. In order to improve the molecular stability and drug efficacy of sitagliptin, the present invention conducts cocrystal-related research on sitagliptin, which will be beneficial to improving its therapeutic effect. The present invention cocrystallizes the DPP-4 inhibitor drug sitagliptin with the inorganic salt CaCl2 / ZnBr2 through crystal engineering technology to prepare sitagliptin drug cocrystal 1 (sitagliptin-CaCl2 cocrystal) and sitagliptin drug cocrystal 2 (sitagliptin-ZnBr2 cocrystal), while not changing the covalent structure of the active drug component sitagliptin, optimizes the drug properties of sitagliptin and enhances the drug efficacy.

[0006] The purpose of the present invention can be achieved by the following technical solutions:

[0007] The first object of the present invention is to provide a sitagliptin drug cocrystal 1, wherein sitagliptin is used as a drug active ingredient, an inorganic salt CaCl2 is used as a cocrystal ligand, and two sitagliptin molecules and one inorganic salt CaCl2 molecule constitute a basic structural unit of the sitagliptin drug cocrystal 1, and the chemical structural formula of the sitagliptin drug cocrystal 1 is C 32 H 30 CaCl2F 12 N 10 O2.

[0008] Furthermore, the X-ray diffraction of the sitagliptin drug cocrystal 1 represented by an angle 2θ (°) ± 0.2° includes characteristic diffraction peaks at 6.96°, 7.88°, 13.84°, 14.76°, 15.90°, 18.72°, 21.24°, 22.02°, 22.74°, 24.28°, 26.46°, etc.

[0009] As a preferred technical solution, the X-ray diffraction of the sitagliptin drug cocrystal 1 expressed by an angle 2θ (°) ± 0.2° includes characteristic diffraction peaks at 6.96°, 7.88°, 13.84°, 14.76°, 15.90°, 17.34°, 18.72°, 20.02°, 21.24°, 22.02°, 22.74°, 24.28°, 25.42°, 26.46°, 27.74°, 28.66°, 29.56°, 30.14°, 31.64°, 33.02°, 33.4°, 34.84°, and 36.2°.

[0010] Furthermore, the crystal form of the sitagliptin drug cocrystal 1 belongs to the I121 space group of the monoclinic system, and the unit cell parameters are α=90, β=92.853, γ=90.

[0011] As a preferred technical solution, the ORTEP ellipsoid diagram of the single crystal in the sitagliptin drug cocrystal 1 is as follows: Figure 7 shown.

[0012] The second object of the present invention is to provide a method for preparing sitagliptin drug cocrystal 1, wherein the sitagliptin drug cocrystal 1 is prepared by a suspension stirring method, a mechanical ball milling method or a gas diffusion method.

[0013] Furthermore, the molar ratio of sitagliptin to CaCl2 is 2:1.

[0014] Furthermore, the specific steps of preparing sitagliptin drug cocrystal 1 by the suspension stirring method are as follows:

[0015] Sitagliptin and CaCl2 are added to a solvent, stirred for a period of time, and then filtered. After the filter cake is dried, sitagliptin drug cocrystal 1 is obtained.

[0016] In the above, further, sitagliptin: CaCl2: solvent = 1 g: (0.1-0.2 g): (3-25 mL);

[0017] The solvents include isopropanol, ethyl acetate, acetonitrile, acetone and n-heptane.

[0018] As a preferred technical solution, the stirring temperature is 15 to 40°C, and the stirring time is 2 to 48 hours;

[0019] The drying temperature is 30-60°C.

[0020] Furthermore, the specific steps of preparing sitagliptin drug cocrystal 1 by mechanical ball milling are as follows:

[0021] Sitagliptin and CaCl2 were mixed in a ball mill, and then zirconium oxide grinding balls and additives were added, and the sitagliptin drug cocrystal 1 was obtained after mechanical grinding.

[0022] In the above, further, sitagliptin: CaCl2: additive = 1 g: (0.1-0.2 g): (0.1-0.2 μL);

[0023] The additives include methanol, ethyl acetate, acetonitrile, acetone and n-heptane.

[0024] Furthermore, the specific steps of preparing sitagliptin drug cocrystal 1 by the gas diffusion method are as follows:

[0025] Sitagliptin and CaCl2 are added to the solvent, stirred for a period of time and then filtered, the filtrate is placed in sample bottle A, sealed with a sealing film and pierced with a hole, sample bottle A is placed in sample bottle B containing ether at the same liquid level as sample bottle A, sealed and allowed to stand, and sitagliptin drug cocrystal 1 is obtained after crystallization.

[0026] In the above, further, sitagliptin: CaCl2: solvent = 1 g: (0.1-0.2 g): (3-25 mL);

[0027] The solvents include isopropanol, methanol, acetonitrile and n-heptane.

[0028] As a preferred technical solution, the stirring temperature is 15 to 40°C, and the stirring time is 2 to 48 hours;

[0029] The sealing film is a PE sealing film;

[0030] The crystallization temperature is 15 to 35° C., and the crystallization time is 1 to 3 days.

[0031] The third object of the present invention is to provide a sitagliptin drug cocrystal 2, wherein sitagliptin is used as a drug active ingredient, an inorganic salt ZnBr2 is used as a cocrystal ligand, and a sitagliptin molecule and an inorganic salt ZnBr2 molecule constitute a basic structural unit of the sitagliptin drug cocrystal 2, wherein the chemical structural formula of the sitagliptin drug cocrystal 1 is C 16 H 15 ZnBr2F6N5O.

[0032] Furthermore, the X-ray diffraction of the sitagliptin drug cocrystal 2 represented by an angle 2θ (°) ± 0.2° includes characteristic diffraction peaks at 6.02°, 8.98°, 10.98°, 11.90°, 13.68°, 14.50°, 15.50°, 16.28°, 17.56°, 18.98°, 20.06°, 21.06°, 22.92°, 24.6°, etc.

[0033] As a preferred technical solution, the X-ray diffraction of the sitagliptin drug cocrystal 2 expressed by an angle 2θ (°) ± 0.2° includes characteristic diffraction peaks at 6.02°, 7.44°, 8.98°, 10.98°, 11.9°, 12.46°, 13.68°, 14.5°, 15.5°, 16.28°, 16.84°, 17.56°, 18.47°, 18.98°, 20.06°, 21.06°, 22.92°, 24.6°, 26.3°, 27.44°, 29.82°, 32.58°, 35.96°, 38.46°, 39.66°, etc.

[0034] Furthermore, the crystal form of the sitagliptin drug cocrystal 2 belongs to the C2 / c space group of the monoclinic system, and the unit cell parameters are α=90, β=95.701(11), γ=90.

[0035] As a preferred technical solution, the ORTEP ellipsoid diagram of the single crystal in the sitagliptin drug cocrystal 2 is as follows: Figure 8 shown.

[0036] The fourth object of the present invention is to provide a method for preparing sitagliptin drug cocrystal 2, wherein the sitagliptin drug cocrystal 2 is prepared by a suspension stirring method, a mechanical ball milling method or a gas diffusion method.

[0037] Furthermore, the molar ratio of sitagliptin to ZnBr2 is 1:1.

[0038] Furthermore, the specific steps of preparing sitagliptin drug cocrystal 2 by the suspension stirring method are as follows:

[0039] Sitagliptin and ZnBr2 are added to a solvent, stirred for a period of time, and then filtered. After the filter cake is dried, sitagliptin drug cocrystal 2 is obtained.

[0040] In the above, further, sitagliptin: ZnBr2: solvent = 1 g: (0.5-0.6 g): (3-25 mL);

[0041] The solvents include isopropanol, ethyl acetate, acetonitrile, acetone and n-heptane.

[0042] As a preferred technical solution, the stirring temperature is 15 to 40° C., and the stirring time is 2 to 48 hours.

[0043] The drying temperature is 30-60°C.

[0044] Furthermore, the specific steps of preparing sitagliptin drug cocrystal 2 by mechanical ball milling are as follows:

[0045] Sitagliptin and ZnBr2 were mixed in a ball mill, and then zirconium oxide grinding balls were added and mechanical grinding was performed to obtain sitagliptin drug cocrystal 2.

[0046] Furthermore, in the above, sitagliptin: ZnBr2=1g: (0.5-0.6g).

[0047] Furthermore, the specific steps of preparing sitagliptin drug cocrystal 2 by the gas diffusion method are as follows:

[0048] Sitagliptin and ZnBr2 are added to the solvent, stirred for a period of time and then filtered, the filtrate is placed in sample bottle A, sealed with a sealing film and pierced with a hole, sample bottle A is placed in sample bottle B containing ether at the same liquid level as sample bottle A, sealed and allowed to stand, and sitagliptin drug cocrystal 2 is obtained after crystallization.

[0049] In the above, further, sitagliptin: ZnBr2: solvent = 1 g: (0.5-0.6 g): (3-25 mL);

[0050] The solvents include isopropanol, methanol, acetonitrile and n-heptane.

[0051] As a preferred technical solution, the stirring temperature is 15 to 40°C, and the stirring time is 2 to 48 hours;

[0052] The sealing film is a PE sealing film;

[0053] The crystallization temperature is 15 to 35° C., and the crystallization time is 1 to 3 days.

[0054] In addition, the present invention also provides an application of sitagliptin drug cocrystals, wherein the sitagliptin drug cocrystal 1 and the sitagliptin drug cocrystal 2 are used to prepare a drug for treating hyperglycemia.

[0055] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0056] 1. The two sitagliptin drug cocrystals prepared by the present invention are characterized by means of X-ray powder diffraction (PXRD), single crystal X-ray powder diffraction (SCXRD), differential scanning calorimetry (DSC), thermogravimetric analyzer (TGA), etc. The sitagliptin drug cocrystals prepared by the present invention have one or more improved properties compared with existing compounds, which is of great value to the future optimization and development of the drug.

[0057] 2. The sitagliptin drug cocrystal provided by the present invention has the following advantages: high purity of the crystal form, reaching more than 99.9%, good stability. The target binding score of sitagliptin-ZnBr2 cocrystal on DPP-4 (PDB ID: 7XNM) is 2.422 higher than that of sitagliptin, and the binding energy is 22.445 kcal / mol higher than that of sitagliptin.

[0058] 3. The sitagliptin drug co-crystal provided by the present invention has broad application prospects in the preparation of drugs for preventing or treating hyperglycemia.

[0059] 4. The targeted docking effect of the sitagliptin drug co-crystal provided by the present invention has been greatly improved, and improved sitagliptin preparations with higher bioavailability and better efficacy can be developed. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] Figure 1 It is an X-ray powder diffraction pattern of sitagliptin drug cocrystal 1 (sitagliptin-CaCl2 cocrystal form);

[0061] Figure 2 It is an X-ray powder diffraction pattern of sitagliptin drug cocrystal 2 (sitagliptin-ZnBr2 cocrystal form);

[0062] Figure 3 It is a simulated X-ray powder diffraction pattern of sitagliptin drug cocrystal 1 (sitagliptin-CaCl2 cocrystal form);

[0063] Figure 4 It is a simulated X-ray powder diffraction pattern of sitagliptin drug cocrystal 2 (sitagliptin-ZnBr2 cocrystal form);

[0064] Figure 5 TG-DSC graph of sitagliptin drug cocrystal 1 (sitagliptin-CaCl2 cocrystal form);

[0065] Figure 6 TG-DSC graph of sitagliptin drug cocrystal 2 (sitagliptin-ZnBr2 cocrystal form);

[0066] Figure 7 It is the ORTEP ellipsoid diagram of sitagliptin drug cocrystal 1 (sitagliptin-CaCl2 cocrystal ligand);

[0067] Figure 8 It is the ORTEP ellipsoid diagram of sitagliptin drug cocrystal 2 (sitagliptin-ZnBr2 cocrystal ligand);

[0068] Fig. 9 This is the targeted binding map of the sitagliptin API and DPP-4 (PDB ID: 7XNM) protein complex;

[0069] Fig.10 This is the targeted binding diagram of the sitagliptin drug cocrystal 2 (sitagliptin-ZnBr2 cocrystal) and the DPP-4 (PDB ID: 7XNM) protein complex;

[0070] Fig.11It is the unit cell diagram of sitagliptin drug cocrystal 1 (sitagliptin-CaCl2 cocrystal ligand);

[0071] Fig.12 This is the unit cell diagram of sitagliptin drug cocrystal 2 (sitagliptin-ZnBr2 cocrystal ligand). DETAILED DESCRIPTION

[0072] The present invention is described in detail below in conjunction with the accompanying drawings and specific embodiments. This embodiment is implemented based on the technical solution of the present invention, and provides a detailed implementation method and specific operation process, but the protection scope of the present invention is not limited to the following embodiments.

[0073] The following test methods and detection methods, unless otherwise specified, are conventional methods; the reagents and raw materials, unless otherwise specified, are commercially available.

[0074] In conjunction with the accompanying drawings, some embodiments of the present invention are described in detail below. In the absence of conflict, the following embodiments and features in the embodiments may be combined with each other.

[0075] Example 1

[0076] This embodiment provides a method for preparing sitagliptin drug cocrystal 1 (sitagliptin-CaCl2 cocrystal), and the specific steps are as follows:

[0077] 407.31 g of sitagliptin and 55.49 g of CaCl2 were added to 3 L of isopropanol, stirred at 25 °C for 48 h and then filtered. The filter cake was dried at 45 °C for 2 h to obtain white crystalline sitagliptin drug cocrystal 1, i.e., sitagliptin-CaCl2 cocrystal. The sample mass of the obtained sitagliptin-CaCl2 cocrystal was 329.62 g.

[0078] The sitagliptin-CaCl2 co-crystal was characterized by XRPD and TG-DSC. The sitagliptin-CaCl2 co-crystal had Figure 1 The X-ray powder diffraction characteristics shown in FIG. 1 and FIG. 2 are shown in FIG. 3 ; the differential scanning calorimetry spectrum of the crystalline form of sitagliptin-CaCl2 cocrystal is shown in FIG. Figure 3 shown.

[0079] Example 2

[0080] This embodiment provides a method for preparing sitagliptin drug cocrystal 1 (sitagliptin-CaCl2 cocrystal), and the specific steps are as follows:

[0081] According to the molar ratio of 2:1, 60 mg of sitagliptin and 8.17 mg of CaCl2 were placed in the adapter of the ball mill, 3 4 mm zirconium oxide grinding balls were added, 10 μL of methanol was dropped, and after fully grinding and mixing for 0.5 h using the ball mill, the sample was collected to obtain sitagliptin drug cocrystal 1, i.e., sitagliptin-CaCl2 cocrystal.

[0082] The sitagliptin-CaCl2 co-crystal was characterized by XRPD and TG-DSC. The sitagliptin-CaCl2 co-crystal had Figure 1 The X-ray powder diffraction characteristics shown in FIG. 1 and FIG. 2 are shown in FIG. 3 ; the differential scanning calorimetry spectrum of the crystalline form of sitagliptin-CaCl2 cocrystal is shown in FIG. Figure 3 shown.

[0083] Example 3

[0084] This embodiment provides a method for preparing sitagliptin drug cocrystal 2 (sitagliptin-ZnBr2 cocrystal), and the specific steps are as follows:

[0085] 407.31 g of sitagliptin and 225.2 g of ZnBr2 were added to 4 L of isopropanol to form a supersaturated solution, which was stirred at 25 °C for 24 h and then filtered. The filter cake was dried at 45 °C for 2 h to obtain white crystalline sitagliptin drug cocrystal 2, i.e., sitagliptin-ZnBr2 cocrystal. The sample mass of the obtained sitagliptin-ZnBr2 cocrystal was 447.07 g.

[0086] The sitagliptin-ZnBr2 cocrystal was characterized by XRPD and TG-DSC. The sitagliptin-ZnBr2 cocrystal had Figure 2 The X-ray powder diffraction characteristics shown in FIG. 1 and FIG. 2 are shown in FIG. 3 ; the differential scanning calorimetry spectrum of the crystalline form of sitagliptin-ZnBr2 cocrystal is shown in FIG. Figure 4 shown.

[0087] Example 4

[0088] This embodiment provides a method for preparing sitagliptin drug cocrystal 2 (sitagliptin-ZnBr2 cocrystal), and the specific steps are as follows:

[0089] 30 mg of sitagliptin and 16.59 mg of ZnBr2 were placed in the adapter of a ball mill at a molar ratio of 2:1, and 3 4 mm zirconium oxide grinding balls were added. After fully grinding and mixing for 1 hour using a ball mill, the sample was collected to obtain sitagliptin drug cocrystal 2, i.e., sitagliptin-ZnBr2 cocrystal.

[0090] The sitagliptin-ZnBr2 cocrystal was characterized by XRPD and TG-DSC. The sitagliptin-ZnBr2 cocrystal had Figure 2The X-ray powder diffraction characteristics shown in FIG. 1 and FIG. 2 are shown in FIG. 3 ; the differential scanning calorimetry spectrum of the crystalline form of sitagliptin-ZnBr2 cocrystal is shown in FIG. Figure 4 shown.

[0091] Performance Testing

[0092] Sitagliptin drug cocrystal 1 (sitagliptin-CaCl2 cocrystal) and sitagliptin drug cocrystal 2 (sitagliptin-ZnBr2 cocrystal) were obtained by different methods in the above embodiments, and targeted molecular docking studies were conducted on them with the DPP-4 (PDBID: 7XNM) protein complex, and compared with the targeted molecular docking of the sitagliptin raw material and the DPP-4 (PDB ID: 7XNM) protein complex.

[0093] The targeted molecular docking method is as follows: Download the DPP-4 protein complex (PDB ID: 7XNM) from the Protein Data Bank (PDB). After analysis, the large cavity of the protein A chain of DPP-4 is more suitable for docking, and the docking grid box ceter coordinates are set to (-47.699, 37.012, 11.26), and the side length of the docking grid box is set to 29.775, 29.775, 29.775.

[0094] The docking interaction between sitagliptin API and DPP-4 (PDB ID: 7XNM) is shown in Figure 2. Fig. 9 As shown; the docking interaction between sitagliptin-ZnBr2 cocrystal and DPP-4 (PDB ID: 7XNM) is shown Fig.10 As shown; the interacting residues of sitagliptin API and protein are mainly TRP629, HIS740, GLY741, which mainly rely on hydrogen bonds, π bonds with cations and π-π stacking; the interacting residues of sitagliptin-ZnBr2 cocrystal and protein are mainly TYR48, LYS554, TRP563, which mainly rely on hydrogen bonds and π-π stacking.

[0095] The docking binding energy and docking score of sitagliptin API / sitagliptin-ZnBr2 cocrystal with DPP-4 (PDB ID: 7XNM) are shown in Table 1.

[0096] Table 1 Docking binding energy and docking score results of sitagliptin API / sitagliptin-ZnBr2 cocrystal with DPP-4 (PDB ID: 7XNM)

[0097]

[0098] As shown in Table 1, the sitagliptin-ZnBr2 cocrystal exhibits a better docking effect than the single sitagliptin API. The docking interaction forces between the sitagliptin-ZnBr2 cocrystal and DPP-4 (PDB ID: 7XNM) are mainly hydrogen bonds and π-bond stacking interactions, with a binding energy of -57.164 kcal / mol and a docking score of -7.186; the docking interaction forces between the sitagliptin API and DPP-4 (PDBID: 7XNM) are mainly hydrogen bonds, π-bonds with cations and π-π stacking interactions, with a binding energy of -34.719 kcal / mol and a docking score of -4.764.

[0099] The docking score of the targeted docking of the sitagliptin-ZnBr2 cocrystal on DPP-4 (PDB ID: 7XNM) was 2.422 points higher than that of the sitagliptin API; the docking binding energy was 22.445 kcal / mol higher than that of sitagliptin. In comparison, the docking result of the sitagliptin-ZnBr2 cocrystal with DPP-4 (PDB ID: 7XNM) was better than that of the sitagliptin API.

[0100] The above description of the embodiments is to facilitate the understanding and use of the invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be within the scope of protection of the present invention.

Claims

1. A sitagliptin drug cocrystal 1, characterized in that: Sitagliptin is used as the active ingredient of the drug, and the inorganic salt CaCl2 is used as the cocrystal ligand. The basic structural unit of the sitagliptin drug cocrystal 1 is composed of two sitagliptin molecules and one inorganic salt CaCl2 molecule. The chemical structural formula of the sitagliptin drug cocrystal 1 is C 32 H 30 CaCl2F 12 N 10 O2.

2. A sitagliptin drug cocrystal 1 according to claim 1, characterized in that: The X-ray diffraction of the sitagliptin drug cocrystal 1 expressed at an angle 2θ (°) ± 0.2° includes characteristic diffraction peaks at 6.96°, 7.88°, 13.84°, 14.76°, 15.90°, 18.72°, 21.24°, 22.02°, 22.74°, 24.28°, and 26.46°.

3. A sitagliptin drug cocrystal 1 according to claim 1, characterized in that: The crystal form of the sitagliptin drug cocrystal 1 belongs to the I121 space group of the monoclinic system, and the unit cell parameters are α=90, β=92.853, γ=90.

4. A method for preparing the sitagliptin drug cocrystal 1 as claimed in any one of claims 1 to 3, characterized in that: The sitagliptin drug cocrystal 1 is prepared by a suspension stirring method, a mechanical ball milling method or a gas diffusion method.

5. The method for preparing a sitagliptin drug cocrystal 1 according to claim 4, characterized in that: The molar ratio of sitagliptin to CaCl2 is 2:

1.

6. A sitagliptin drug cocrystal 2, characterized in that: Sitagliptin is used as the active ingredient of the drug, and the inorganic salt ZnBr2 is used as the cocrystal ligand. The basic structural unit of the sitagliptin drug cocrystal 2 is composed of one sitagliptin molecule and one inorganic salt ZnBr2 molecule. The chemical structural formula of the sitagliptin drug cocrystal 1 is C 16 H 15 ZnBr2F6N5O.

7. A sitagliptin drug cocrystal 2 according to claim 6, characterized in that: The X-ray diffraction of the sitagliptin drug cocrystal 2 expressed at an angle 2θ (°) ± 0.2° includes characteristic diffraction peaks at 6.02°, 8.98°, 10.98°, 11.90°, 13.68°, 14.50°, 15.50°, 16.28°, 17.56°, 18.98°, 20.06°, 21.06°, 22.92°, and 24.6°.

8. A sitagliptin drug cocrystal 2 according to claim 6, characterized in that: The crystal form of the sitagliptin drug cocrystal 2 belongs to the C2 / c space group of the monoclinic system, and the unit cell parameters are α=90, β=95.701(11), γ=90.

9. A method for preparing the sitagliptin drug cocrystal 2 as claimed in any one of claims 6 to 8, characterized in that: The sitagliptin drug cocrystal 2 is prepared by a suspension stirring method, a mechanical ball milling method or a gas diffusion method; the molar ratio of sitagliptin to ZnBr2 is 1:

1.

10. An application of sitagliptin drug cocrystal, characterized in that: The sitagliptin drug cocrystal 1 as described in any one of claims 1 to 3 and the sitagliptin drug cocrystal 2 as described in any one of claims 6 to 8 are used to prepare a drug for treating hyperglycemia.

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