Two sitagliptin pharmaceutical co-crystals, preparation method and application thereof

Abstract

The present application relates to two kinds of sitagliptin pharmaceutical cocrystals and preparation methods and applications thereof. The sitagliptin pharmaceutical cocrystal 1 (sitagliptin-CaCl2 cocrystal) is combined according to a molar ratio of 2:1, and has a molecular formula of C 32 H 30 CaCl2F 12 N 10 O2; the sitagliptin pharmaceutical cocrystal 2 (sitagliptin-ZnBr2 cocrystal) is combined according to a molar ratio of 1:1, and has a molecular formula of C 16 H 15 ZnBr2F6N5O. The two kinds of sitagliptin pharmaceutical cocrystals prepared by the present application are characterized by X-ray powder diffraction (PXRD), single crystal X-ray powder diffraction (SCXRD), differential scanning calorimetry (DSC), and thermogravimetric analyzer (TGA). Compared with the prior art, the sitagliptin pharmaceutical cocrystals prepared by the present application have one or more improved properties compared with the prior art, and have important value for the optimization and development of the drug in the future.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical crystal chemistry, in particular to two kinds of sitagliptin pharmaceutical cocrystals and a preparation method and application thereof. BACKGROUND

[0002] Pharmaceutical cocrystals are based on the principle of supramolecular chemistry, that is, molecular recognition and supramolecular self-assembly through intermolecular synergistic effect. A new structure, i.e. pharmaceutical cocrystals, is formed by self-assembly of active pharmaceutical ingredients (API) and suitable cocrystal formers (CCF) through hydrogen bonds or non-covalent bonds with saturation and directionality (such as van der Waals force of aromatic hydrocarbons or benzene ring, π-π conjugation and halogen bond). It is based on hydrogen bond, without the need to form new covalent bond or destroy existing covalent bond, while retaining the pharmacological effect of the drug itself, and modifying the physical and chemical properties of the drug, such as improving the stability of the drug, reducing its hygroscopicity, improving the solubility and bioavailability, etc., which provides a broad development prospect for the application of pharmaceutical cocrystals in the pharmaceutical industry. In November 2011, 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 pharmaceutical cocrystal can be managed and controlled as a “formulation intermediate”, so the cocrystal does not need to be registered as a drug. In recent years, the research on pharmaceutical cocrystals has attracted more and more attention. At present, the research on pharmaceutical cocrystals abroad has gradually increased and deepened; while the research on pharmaceutical cocrystals in China is still relatively less. For generic drugs, the research on pharmaceutical cocrystals can also break the patent protection of the original drug company on the crystal form of the drug, which is beneficial to the marketing of generic drugs. Therefore, it is of important practical significance to obtain more novel, practical and creative pharmaceutical cocrystals, especially for some water-insoluble drugs. Pharmaceutical cocrystals can optimize the physicochemical 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, which is shown in formula I, is the first dipeptidyl peptidase-IV (DPP-4) inhibitor drug approved by FDA for treating type II diabetes. The mechanism of action of sitagliptin is different from that of the previous oral hypoglycemic drugs. Sitagliptin can increase the activity of GLP-1 and GIP in plasma, slightly increase the content of GLP-1 and GIP, and weaken the antagonism of GLP-1 metabolites, thereby improving the ability of the beta cells of the islets of Langerhans of the diabetes patient to produce insulin, increasing the secretion of insulin when the blood glucose is high, and thereby controlling the blood glucose level of the diabetes patient. Sitagliptin has low solubility and high permeability in the biopharmaceutical classification system, and belongs to the BCS II class of compounds.

[0004] SUMMARY

[0005] The purpose of the present application is to provide two sitagliptin pharmaceutical cocrystals and a preparation method and application thereof. In order to improve the stability and efficacy of sitagliptin molecules, the present application carries out cocrystal-related research on sitagliptin, which is beneficial to improving the therapeutic effect. The present application prepares sitagliptin pharmaceutical cocrystal 1 (sitagliptin-CaCl2 cocrystal) and sitagliptin pharmaceutical cocrystal 2 (sitagliptin-ZnBr2 cocrystal) by cocrystallizing the DPP-4 inhibitor drug sitagliptin with inorganic salts CaCl2 / ZnBr2 through crystal engineering technology, without changing the covalent structure of the active pharmaceutical ingredient sitagliptin, while optimizing the drug properties of sitagliptin and enhancing the drug efficacy.

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

[0007] The first purpose of the present application is to provide a sitagliptin pharmaceutical cocrystal 1, which takes sitagliptin as an active pharmaceutical ingredient and takes inorganic salt CaCl2 as a cocrystal ligand, and the basic structural unit of the sitagliptin pharmaceutical cocrystal 1 is composed of two sitagliptin molecules and one inorganic salt CaCl2 molecule, and the chemical structural formula of the sitagliptin pharmaceutical cocrystal 1 is C 32 H 30 CaCl2F 12 N 10 O2。

[0008] Further, the X-ray diffraction of the sitagliptin pharmaceutical cocrystal 1 expressed in 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°, and the like.

[0009] As a preferred technical scheme, the X-ray diffraction of the Sitagliptin pharmaceutical co-crystal 1 in terms of angle 2 theta (°) ± 0.2° comprises 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°, 36.2°.

[0010] Further, the crystal form of the Sitagliptin pharmaceutical co-crystal 1 belongs to monoclinic I121 space group, and the cell parameters are α = 90, β = 92.853, γ = 90.

[0011] As a preferred technical scheme, the ORTEP ellipsoid diagram of a single crystal in the Sitagliptin pharmaceutical co-crystal 1 is as shown in Figure 7 .

[0012] A second object of the present application is to provide a preparation method of the Sitagliptin pharmaceutical co-crystal 1, which is prepared by a suspension stirring method, a mechanical ball milling method or a gas diffusion method.

[0013] Further, the molar ratio of the Sitagliptin to CaCl2 is 2:1.

[0014] Further, the specific steps of preparing the Sitagliptin pharmaceutical co-crystal 1 by the suspension stirring method are as follows:

[0015] The Sitagliptin and CaCl2 are added into a solvent, and after stirring for a period of time, filtration is performed, and the filter cake is dried to obtain the Sitagliptin pharmaceutical co-crystal 1.

[0016] Further, the Sitagliptin: CaCl2: solvent = 1g: (0.1-0.2g): (3-25mL);

[0017] The solvent comprises isopropyl alcohol, ethyl acetate, acetonitrile, acetone and n-heptane.

[0018] As a preferred technical scheme, the stirring temperature is 15-40°C, and the stirring time is 2-48h;

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

[0020] Further, the specific steps of preparing the Sitagliptin pharmaceutical co-crystal 1 by the mechanical ball milling method are as follows:

[0021] After mixing sitagliptin and CaCl2 in a ball mill, zirconium oxide grinding balls and additives are added, and after mechanical grinding, sitagliptin pharmaceutical cocrystal 1 is obtained.

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

[0023] The additive includes methanol, ethyl acetate, acetonitrile, acetone and n-heptane.

[0024] Further, the specific steps of the gas diffusion method for preparing sitagliptin pharmaceutical cocrystal 1 are as follows:

[0025] After adding sitagliptin and CaCl2 into a solvent and stirring for a period of time, the filtrate is placed in sample bottle A, the hole is sealed with a sealing film, sample bottle A is placed in sample bottle B containing ethyl ether with the same liquid level as sample bottle A, and after sealing and standing, sitagliptin pharmaceutical cocrystal 1 is obtained after crystallization.

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

[0027] The solvent includes isopropyl alcohol, methanol, acetonitrile and n-heptane.

[0028] As a preferred technical solution, the stirring temperature is 15-40℃, and the stirring time is 2-48h;

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

[0030] The crystallization temperature is 15-35℃, and the crystallization time is 1-3 days.

[0031] A third object of the present application is to provide a sitagliptin pharmaceutical cocrystal 2, which takes sitagliptin as a pharmaceutical active ingredient and takes inorganic salt ZnBr2 as a cocrystal ligand, and a sitagliptin molecule and an inorganic salt ZnBr2 molecule constitute the basic structural unit of the sitagliptin pharmaceutical cocrystal 2, and the chemical structural formula of the sitagliptin pharmaceutical cocrystal 1 is C 16 H 15 ZnBr2F6N5O.

[0032] Further, the X-ray diffraction of the sitagliptin pharmaceutical cocrystal 2 expressed in 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 scheme, the X-ray diffraction of the sitagliptin pharmaceutical cocrystal 2 in terms of angle 2 theta (°) ± 0.2° comprises 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° and the like.

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

[0035] As a preferred technical scheme, the ORTEP ellipsoidal diagram of a single crystal in the sitagliptin pharmaceutical cocrystal 2 is as shown in Figure 8 .

[0036] A fourth object of the present application is to provide a preparation method of the sitagliptin pharmaceutical cocrystal 2, wherein the sitagliptin pharmaceutical cocrystal 2 suspension stirring method, mechanical ball milling method or gas diffusion method is used for preparation.

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

[0038] Further, the specific steps of the suspension stirring method for preparing the sitagliptin pharmaceutical cocrystal 2 are as follows:

[0039] The sitagliptin and ZnBr2 are added into a solvent, and after stirring for a period of time, filtration is performed, and the filter cake is dried to obtain the sitagliptin pharmaceutical cocrystal 2.

[0040] Further, the sitagliptin: ZnBr2: solvent = 1g: (0.5-0.6g): (3-25mL).

[0041] The solvent comprises isopropyl alcohol, ethyl acetate, acetonitrile, acetone and n-heptane.

[0042] As a preferred technical scheme, the stirring temperature is 15-40°C, and the stirring time is 2-48h,

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

[0044] Further, the specific steps of the mechanical ball milling method for preparing the sitagliptin pharmaceutical cocrystal 2 are as follows:

[0045] After mixing sitagliptin and ZnBr2 in a ball mill, adding zirconium oxide grinding balls, and mechanically grinding, sitagliptin pharmaceutical co-crystal 2 is obtained.

[0046] Further, sitagliptin:ZnBr2 = 1g:(0.5-0.6g).

[0047] Further, the specific steps for preparing sitagliptin pharmaceutical co-crystal 2 by the gas diffusion method are as follows:

[0048] After adding sitagliptin and ZnBr2 into a solvent and stirring for a period of time, filtration is performed, the filtrate is placed in sample bottle A, the hole is sealed with a sealing film, sample bottle A is placed in sample bottle B containing ethyl ether at the same liquid level as sample bottle A, and after sealing and standing, sitagliptin pharmaceutical co-crystal 2 is obtained after crystallization.

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

[0050] The solvent includes isopropyl alcohol, methanol, acetonitrile, and n-heptane.

[0051] As a preferred technical solution, the stirring temperature is 15-40℃, and the stirring time is 2-48h;

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

[0053] The crystallization temperature is 15-35℃, and the crystallization time is 1-3 days.

[0054] In addition, the application also provides a use of sitagliptin pharmaceutical co-crystals, and the sitagliptin pharmaceutical co-crystal 1 and the sitagliptin pharmaceutical co-crystal 2 are used for preparing a drug for treating hyperglycemia.

[0055] Compared with the prior art, the application has the following beneficial effects:

[0056] 1. The two kinds of sitagliptin pharmaceutical co-crystals prepared by the application are characterized by X-ray powder diffraction (PXRD), single crystal X-ray powder diffraction (SCXRD), differential thermal scanning method (DSC), and thermogravimetric analyzer (TGA). The sitagliptin pharmaceutical co-crystals prepared by the application have one or more improved properties than the existing compounds, and have important value for the optimization and development of the drug in the future.

[0057] 2. The sitagliptin pharmaceutical co-crystals provided by the application have the following advantages: the purity of the crystal form is high, reaching more than 99.9%, and the stability is good. The targeting binding fraction of sitagliptin-ZnBr2 co-crystal on DPP-4 (PDB ID: 7XNM) is 2.422 times higher than that of sitagliptin, and the binding energy is higher than that of sitagliptin by 22.445 kcal / mol.

[0058] 3. The sitagliptin pharmaceutical cocrystal has wide application prospect in the preparation of drugs for preventing or treating hyperglycemia.

[0059] 4. The targeting docking effect of the sitagliptin pharmaceutical cocrystal is greatly improved, and a modified sitagliptin preparation with higher bioavailability and better efficacy can be developed. BRIEF DESCRIPTION OF DRAWINGS

[0060] Figure 1 X-ray powder diffraction pattern of sitagliptin pharmaceutical cocrystal 1 (sitagliptin-CaCl2 cocrystal form);

[0061] Figure 2 X-ray powder diffraction pattern of sitagliptin pharmaceutical cocrystal 2 (sitagliptin-ZnBr2 cocrystal form);

[0062] Figure 3 Simulated X-ray powder diffraction pattern of sitagliptin pharmaceutical cocrystal 1 (sitagliptin-CaCl2 cocrystal form);

[0063] Figure 4 Simulated X-ray powder diffraction pattern of sitagliptin pharmaceutical cocrystal 2 (sitagliptin-ZnBr2 cocrystal form);

[0064] Figure 5 TG-DSC pattern of sitagliptin pharmaceutical cocrystal 1 (sitagliptin-CaCl2 cocrystal ligand);

[0065] Figure 6 TG-DSC pattern of sitagliptin pharmaceutical cocrystal 2 (sitagliptin-ZnBr2 cocrystal ligand);

[0066] Figure 7 ORTEP ellipsoidal diagram of sitagliptin pharmaceutical cocrystal 1 (sitagliptin-CaCl2 cocrystal ligand);

[0067] Figure 8 ORTEP ellipsoidal diagram of sitagliptin pharmaceutical cocrystal 2 (sitagliptin-ZnBr2 cocrystal ligand);

[0068] Figure 9 Targeted binding diagram of sitagliptin raw material and DPP-4 (PDB ID: 7XNM) protein complex;

[0069] Figure 10 Targeted binding diagram of sitagliptin pharmaceutical cocrystal 2 (sitagliptin-ZnBr2 cocrystal) and DPP-4 (PDB ID: 7XNM) protein complex;

[0070] Figure 11A unit cell diagram of a sitagliptin pharmaceutical co-crystal 1 (sitagliptin-CaCl2 co-crystal ligand);

[0071] Figure 12 A unit cell diagram of a sitagliptin pharmaceutical co-crystal 2 (sitagliptin-ZnBr2 co-crystal ligand). DETAILED DESCRIPTION

[0072] The application will be described in greater detail with reference to the accompanying drawings and specific embodiments. The embodiments are implemented on the premise of the technical solutions of the application, and detailed implementation and specific operation processes are given, but the protection scope of the application is not limited to the following embodiments.

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

[0074] The application will be described in greater detailed with reference to the accompanying drawings and specific embodiments. The following embodiments and features in the embodiments can be combined with each other without conflict.

[0075] Embodiment 1

[0076] The embodiment provides a preparation method of a sitagliptin pharmaceutical co-crystal 1 (sitagliptin-CaCl2 co-crystal), and the specific steps are as follows:

[0077] Add 407.31 g of sitagliptin and 55.49 g of CaCl2 to 3 L of isopropyl alcohol, and stir at 25°C for 48 h, then filter, and dry the filter cake at 45°C for 2 h to obtain white crystals of the sitagliptin pharmaceutical co-crystal 1, i.e., the sitagliptin-CaCl2 co-crystal. The sample mass of the obtained sitagliptin-CaCl2 co-crystal is 329.62 g.

[0078] The sitagliptin-CaCl2 co-crystal is characterized by XRPD and TG-DSC, and the sitagliptin-CaCl2 co-crystal has X-ray powder diffraction characteristics as shown in Figure 1 The differential scanning calorimetric spectrum of the crystal form of the sitagliptin-CaCl2 co-crystal is as shown in Figure 3

[0079] Embodiment 2

[0080] The embodiment provides a preparation method of a sitagliptin pharmaceutical co-crystal 1 (sitagliptin-CaCl2 co-crystal), and the specific steps are as follows:

[0081] ​Put 60 mg of Sitagliptin and 8.17 mg of CaCl2 in a ball mill adapter in a molar ratio of 2:1, add 3 zirconium oxide grinding balls of 4 mm, drop 10 μL of methanol, mix thoroughly using a ball mill for 0.5 h, collect the sample, and obtain Sitagliptin pharmaceutical co-crystal 1, i.e., Sitagliptin-CaCl2 co-crystal.

[0082] The Sitagliptin-CaCl2 co-crystal is characterized by XRPD and TG-DSC, and has X-ray powder diffraction characteristics as shown in Figure 1 The differential scanning calorimetric pattern of the crystal form of the Sitagliptin-CaCl2 co-crystal is as shown in Figure 3

[0083] Example 3

[0084] This example provides a preparation method of Sitagliptin pharmaceutical co-crystal 2 (Sitagliptin-ZnBr2 co-crystal), and the specific steps are as follows:

[0085] Put 407.31 g of Sitagliptin and 225.2 g of ZnBr2 into 4 L of isopropanol to form a supersaturated solution, stir at 25 °C for 24 h, filter, dry the filter cake at 45 °C for 2 h, and obtain white crystalline Sitagliptin pharmaceutical co-crystal 2, i.e., Sitagliptin-ZnBr2 co-crystal, and the mass of the obtained Sitagliptin-ZnBr2 co-crystal sample is 447.07 g.

[0086] The Sitagliptin-ZnBr2 co-crystal is characterized by XRPD and TG-DSC, and has X-ray powder diffraction characteristics as shown in Figure 2 The differential scanning calorimetric pattern of the crystal form of the Sitagliptin-ZnBr2 co-crystal is as shown in Figure 4

[0087] Example 4

[0088] This example provides a preparation method of Sitagliptin pharmaceutical co-crystal 2 (Sitagliptin-ZnBr2 co-crystal), and the specific steps are as follows:

[0089] Put 30 mg of Sitagliptin and 16.59 mg of ZnBr2 in a ball mill adapter in a molar ratio of 2:1, add 3 zirconium oxide grinding balls of 4 mm, mix thoroughly using a ball mill for 1 h, collect the sample, and obtain Sitagliptin pharmaceutical co-crystal 2, i.e., Sitagliptin-ZnBr2 co-crystal.

[0090] The Sitagliptin-ZnBr2 co-crystal is characterized by XRPD and TG-DSC, and has X-ray powder diffraction characteristics as shown in Figure 2 ​​X-ray powder diffraction characteristics shown; the differential scanning calorimetry of the crystalline form of the sitagliptin-ZnBr2 co-crystal is shown in Figure 4

[0091] Performance test

[0092] The sitagliptin pharmaceutical co-crystal 1 (sitagliptin-CaCl2 co-crystal) and the sitagliptin pharmaceutical co-crystal 2 (sitagliptin-ZnBr2 co-crystal) obtained by different ways in the above examples were subjected to targeting molecular docking study with DPP-4 (PDB ID: 7XNM) protein complex, and compared with the targeting molecular docking of sitagliptin raw material with DPP-4 (PDB ID: 7XNM) protein complex.

[0093] The targeting molecular docking method is as follows: the DPP-4 protein complex (PDB ID: 7XNM) is downloaded 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 as (-47.699, 37.012, 11.26), and the edge length of the docking grid box is set as 29.775, 29.775, 29.775.

[0094] The docking effect of sitagliptin raw material with DPP-4 (PDB ID: 7XNM) is shown in Figure 9 The docking effect of sitagliptin-ZnBr2 co-crystal with DPP-4 (PDB ID: 7XNM) is shown in Figure 10 The interaction residues of sitagliptin raw material with protein are mainly TRP629, HIS740, GLY741, mainly relying on hydrogen bond, π bond and cation and π-π stacking interaction; the interaction residues of sitagliptin-ZnBr2 co-crystal with protein are mainly TYR48, LYS554, TRP563, mainly relying on hydrogen bond and π-π stacking interaction.

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

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

[0097]

[0098] ​As shown in Table 1, sitagliptin-ZnBr2 co-crystal shows better docking effect compared with single sitagliptin raw material. The docking force of sitagliptin-ZnBr2 co-crystal and DPP-4 (PDB ID: 7XNM) is mainly hydrogen bond and π bond stacking interaction, and the binding energy is -57.164 kcal / mol, and the docking score is -7.186; the docking interaction force of sitagliptin raw material and DPP-4 (PDB ID: 7XNM) is mainly hydrogen bond, π bond and cation and π-π stacking interaction, and the binding energy is -34.719 kcal / mol, and the docking score is -4.764.

[0099] The docking score of the targeting docking of the sitagliptin-ZnBr2 co-crystal on DPP-4 (PDB ID: 7XNM) is 2.422 points higher than that of sitagliptin raw material; the docking binding energy is 22.445 kcal / mol higher than that of sitagliptin. In comparison, the docking result of sitagliptin-ZnBr2 co-crystal and DPP-4 (PDB ID: 7XNM) is better than that of sitagliptin raw material.

[0100] The above description of the embodiments is for the purpose of enabling a person of ordinary skill in the art to understand and use the application. Those skilled in the art can easily make various modifications to these embodiments, and apply the general principles described herein to other embodiments without having to go through creative labor. Therefore, the present application 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 application without departing from the scope of the present application should be within the scope of protection of the present application.

Claims

1. A sitagliptin drug cocrystal 2, characterized in that, Sitagliptin is the active pharmaceutical ingredient, and ZnBr2 is the inorganic salt as the co-crystal ligand. The basic structural unit of sitagliptin co-crystal 2 consists of one sitagliptin molecule and one ZnBr2 molecule. The chemical structural formula of sitagliptin co-crystal 2 is C. 16 H 15 ZnBr2F6N5O; The X-ray diffraction of the sitagliptin drug cocrystal 2, expressed in terms of 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°.

2. The sitagliptin drug cocrystal 2 according to claim 1, characterized in that, The sitagliptin drug cocrystal 2 has a crystal form belonging to the monoclinic C16 crystal system. 2 / c The space group has the following cell parameters: a = 13.901(2) Å, b = 29.846(7) Å, c = 13.6466(15) Å, α = 90, β = 95.701(11), γ = 90.

3. A method for preparing sitagliptin drug cocrystal 2 as described in claim 1 or claim 2, characterized in that, The sitagliptin drug eutectic 2 is prepared by suspension stirring, mechanical ball milling or gas diffusion; the molar ratio of sitagliptin to ZnBr2 is 1:

1.

4. The application of a sitagliptin cocrystal, characterized in that, The sitagliptin drug cocrystal 2 as described in claim 1 or claim 2 is used to prepare a drug for treating hyperglycemia.

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