A co-amorphous of vildagliptin-valastran, its preparation method and application

Abstract

This invention belongs to the field of pharmaceutical technology, and specifically relates to a vildagliptin-valsartan co-amorphous compound, its preparation method, and its application. The co-amorphous compound comprises vildagliptin and valsartan; the molar ratio of vildagliptin to valsartan in the co-amorphous compound is 1:0.5-3. In this invention, vildagliptin and valsartan interact to form hydrogen bonds. This interaction not only prevents solvent-mediated drug recrystallization but also accelerates the dissolution and exudation of valsartan. Compared to the valsartan raw material, the solubility and dissolution rate of valsartan in this co-amorphous compound are significantly improved, while the solubility and dissolution rate of vildagliptin are reduced. This is beneficial for improving the bioavailability of valsartan, delaying the release and absorption of vildagliptin in vivo, and the co-amorphous compound exhibits good stability.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, and specifically relates to a co-amorphous compound of vildagliptin-valsartan, its preparation method, and its application. Background Technology

[0002] Valsartan, chemically named N-valeryl-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-L-valine, has the following chemical structure:

[0003]

[0004] Valsartan is a tetrazolium derivative, belonging to the non-peptide, orally effective angiotensin II (AT) receptor antagonist class. It is primarily used to treat hypertension, mild to moderate essential hypertension, and congestive heart failure, and can reduce mortality during heart attacks in patients with left ventricular dysfunction, demonstrating good clinical efficacy. However, it belongs to Class II compounds in the biopharmaceutics classification system, characterized by low solubility and high permeability. It has low water solubility, poor dissolution, and low oral bioavailability, only about 25%.

[0005] Vildagliptin, chemically named 1-[(3-hydroxy-adamantyl-1-ylamino)-acetyl]-pyrrolidin-2(S)-nitrile, has the following chemical structural formula:

[0006]

[0007] Vildagliptin is another orally administered dipeptidyl peptidase-IV (DPP-IV) inhibitor following sitagliptin. Its mechanism of action involves promoting insulin secretion and inhibiting glucagon secretion. Clinically, it is mainly used for the treatment of type 2 diabetes. Vildagliptin belongs to Class I compounds in the biopharmaceutics classification system. It has high water solubility (approximately 170 mg / mL), is rapidly absorbed after oral administration, reaching peak plasma concentrations 1.5-1.7 hours after administration, and has a short half-life. 1 / 2 The dosage is 100 mg twice daily, morning and evening, for 3 hours. Frequent administration may further exacerbate side effects and increase patient safety risks. Additionally, long-term hyperglycemia increases angiotensin II levels, leading to elevated blood pressure. Furthermore, angiotensin II can activate glomerulonephrase C activity, resulting in decreased glomerular filtration function.

[0008] Cocrystals and coamorphs can improve the dissolution and bioavailability of poorly soluble drugs, representing a new technological trend in combination drug therapy.

[0009] Cocrystals refer to crystals formed by the bonding of an active pharmaceutical ingredient (API) and a cocrystal former (CCF) through hydrogen bonds or other non-covalent bonds. Both API and CCF are solids at room temperature in their pure states, and the components have a fixed stoichiometric ratio. Forming cocrystals can significantly improve the properties of APIs, such as increasing solubility, dissolution rate, bioavailability, and improving release characteristics. Drug-drug cocrystals are a subset of drug cocrystals, where the cocrystal former is also a drug-active molecule with independent pharmacological activity. Drug-drug cocrystals are an important research direction for crystalline drugs, offering advantages such as good homogeneity and small batch-to-batch variability. They can also improve the shortcomings of the physicochemical properties of the two raw materials, allowing cocrystal drugs to serve as a novel drug combination method, achieving a synergistic effect in clinical applications. Commonly used methods for preparing drug-drug cocrystals include: solvent evaporation, solvothermal methods, cooling crystallization, sublimation crystallization, melting, suspension crystallization, grinding, and ultrasonication.

[0010] Co-amorphous drug systems are single-phase amorphous binary systems formed by combining a drug with another molecule through methods such as grinding, quenching, cryogenic grinding, and solvent evaporation (co-precipitation). Currently, co-amorphous drug systems are proposed as a potential drug delivery system that can improve the stability, solubility, and tablet compressibility of amorphous single drugs. When a drug forms a co-amorphous form with another drug, it has the potential to simultaneously optimize the physicochemical properties of both drugs, achieving better combined drug efficacy. Furthermore, the resulting system is a homogeneous phase, exhibiting better homogeneity and stability compared to physical mixtures of two drugs, providing new insights for combination drug therapy.

[0011] Generally, the two drugs are determined by their respective structural characteristics. During the preparation process, they may form eutectic or amorphous substances, or they may not interact and only form a simple physical mixture. Therefore, the prepared product is unpredictable.

[0012] Therefore, there is an urgent need to provide a co-amorphous compound that, compared with valsartan raw material, significantly improves the solubility and dissolution rate of valsartan and reduces the solubility and dissolution rate of vildagliptin. This is beneficial to improving the bioavailability of valsartan, delaying the release and absorption of vildagliptin in vivo, avoiding frequent administration of vildagliptin and reducing the side effects caused by frequent administration, and the co-amorphous compound has good stability. Summary of the Invention

[0013] This invention aims to solve one or more technical problems existing in the prior art, and at least provide a beneficial alternative or create conditions. This invention provides a vildagliptin-valsartan co-amorphous compound. Compared with valsartan raw material, the solubility and dissolution rate of valsartan in this co-amorphous compound are significantly improved, while the solubility and dissolution rate of vildagliptin are reduced. This is beneficial for improving the bioavailability of valsartan, delaying the release and absorption of vildagliptin in vivo, avoiding frequent dosing of vildagliptin and reducing the side effects caused by frequent dosing, and the co-amorphous compound has good stability.

[0014] The inventive concept of this invention: In the vildagliptin-valsartan co-amorphous compound of this invention, the molar ratio of vildagliptin to valsartan is 1:0.5-3. In the co-amorphous compound, vildagliptin and valsartan interact to form hydrogen bonds. This interaction not only prevents solvent-mediated drug recrystallization but also accelerates the dissolution and release of valsartan while slowing down the dissolution and release of vildagliptin. Compared to the valsartan and vildagliptin raw materials, the solubility and dissolution rate of valsartan in this co-amorphous compound are significantly improved, while the solubility and dissolution rate of vildagliptin are reduced. This is beneficial for improving the bioavailability of valsartan in the co-amorphous compound, delaying the release and absorption of vildagliptin in vivo, avoiding frequent dosing of vildagliptin, and reducing the side effects caused by frequent dosing.

[0015] Therefore, a first aspect of the present invention provides a co-amorphous product of vildagliptin-valsartan.

[0016] Specifically, a vildagliptin-valsartan co-amorphous compound, the co-amorphous compound comprising vildagliptin and valsartan; wherein the molar ratio of vildagliptin to valsartan in the co-amorphous compound is 1:0.5-3.

[0017] Preferably, the molar ratio of vildagliptin to valsartan in the co-amorphous material is 1:0.5-2.5.

[0018] More preferably, the molar ratio of vildagliptin to valsartan in the co-amorphous material is 1:0.5-1.5.

[0019] More preferably, the molar ratio of vildagliptin to valsartan in the co-amorphous material is 1:1.

[0020] Preferably, the glass transition temperature of the co-amorphous material is 105-120°C.

[0021] More preferably, the glass transition temperature of the co-amorphous material is 105-115°C.

[0022] Preferably, the dissolution rate of valsartan in the co-amorphous material is 0.06-0.10 mg / cm³. -2 min-1 The dissolution rate of vildagliptin in the co-amorphous material was 0.01-0.20 mg / cm³. -2 min -1 .

[0023] More preferably, the dissolution rate of valsartan in the co-amorphous material is 0.06-0.09 mg / cm³. -2 min -1 The dissolution rate of vildagliptin in the co-amorphous material was 0.02-0.18 mg / cm³. -2 min -1 .

[0024] More preferably, the dissolution rate of valsartan in the co-amorphous material is 0.06-0.08 mg / cm³. -2 min -1 The dissolution rate of vildagliptin in the co-amorphous material was 0.03-0.16 mg / cm³. -2 min -1 .

[0025] Preferably, the amorphous material maintains a stable amorphous form after being stored at 40°C and 75% relative humidity for more than 28 days.

[0026] More preferably, the amorphous material maintains a stable amorphous form when stored for more than 28 days under open conditions of 40°C and 75% relative humidity.

[0027] A second aspect of the present invention provides a method for preparing the co-amorphous product of vildagliptin-valsartan as described in the first aspect of the present invention.

[0028] Specifically, a method for preparing a co-amorphous product of vildagliptin-valsartan includes grinding, solvent method, and ion liquid conversion method.

[0029] Preferably, the grinding method includes the following steps: mixing vildagliptin and valsartan, grinding them, and obtaining the product.

[0030] Specifically, grinding is a common method for the interconversion of solid states. It uses mechanical force to uniformly mix different vildagliptin and valsartan drug molecules. The two drug molecules generate different intensities of forces such as hydrogen bonds, dipole moments, and van der Waals forces according to their own structural characteristics, thereby changing the state of the sample and forming a co-amorphous form.

[0031] Preferably, the grinding process is selected from either ball milling or vibratory milling.

[0032] Specifically, the grinding method is not limited to ball milling or vibratory milling; any method that can uniformly mix vildagliptin and valsartan through mechanical force is acceptable.

[0033] Preferably, vildagliptin and valsartan are passed through a 100-mesh sieve before mixing.

[0034] Preferably, the grinding time is 3.5-6.5 hours; more preferably, the grinding time is 4-6 hours.

[0035] Preferably, the solvent method includes the following steps: adding vildagliptin and valsartan to a solvent, dissolving them, removing the solvent, and vacuum drying to obtain the product.

[0036] Preferably, the solvent includes at least one of methanol, ethanol, acetone, isopropanol, n-butanol, tert-butanol, acetonitrile, ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, tert-butyl acetate, isobutyl acetate, dichloromethane, chloroform, tetrahydrofuran, and water.

[0037] More preferably, the solvent is ethanol.

[0038] Specifically, there is no particular limitation on the amount of solvent added, as long as it can completely dissolve vildagliptin and valsartan.

[0039] Preferably, the dissolution is performed using ultrasonic treatment.

[0040] Specifically, the dissolution method of the present invention is not limited to ultrasonic treatment, as long as it can completely dissolve vildagliptin and valsartan.

[0041] Preferably, the dissolution temperature is 25-85℃; more preferably, the dissolution temperature is 25-80℃.

[0042] Preferably, the solvent removal is performed by rotary evaporation; the temperature of the rotary evaporation is 25-80℃, and the rotation speed of the rotary evaporation is 50-160 rpm.

[0043] More preferably, the temperature of the rotary evaporation is 45-55°C, and the rotation speed of the rotary evaporation is 55-65 rpm.

[0044] More preferably, the temperature of the rotary evaporation is 50°C and the rotation speed of the rotary evaporation is 60 rpm.

[0045] Preferably, the rotary evaporation is performed using a rotary evaporator.

[0046] Specifically, rotary evaporators are mainly used for the continuous distillation of large quantities of volatile solvents under reduced pressure.

[0047] Preferably, the vacuum drying temperature is room temperature; the vacuum drying time is 10-50 hours.

[0048] More preferably, the vacuum drying time is 12-48 hours.

[0049] Preferably, the ionic liquid conversion method includes the following steps: mixing vildagliptin and valsartan, adding water, heating and stirring until a transparent viscous liquid is obtained, and then vacuum drying to obtain the liquid.

[0050] Preferably, the water is ultrapure water.

[0051] Preferably, the heating and stirring is performed using a magnetic stirrer.

[0052] Preferably, the heating and stirring temperature is 25-85℃; the heating and stirring speed is 200-800 rpm. More preferably, the heating and stirring temperature is 50-80℃; the heating and stirring speed is 550-650 rpm.

[0053] Preferably, the heating and stirring time is determined by stirring the mixture of vildagliptin and valsartan until a transparent, viscous liquid is obtained.

[0054] Preferably, the liquid is heated and stirred until it becomes a transparent, viscous liquid, then cooled to room temperature before being vacuum dried.

[0055] Specifically, the transparent viscous liquid is cooled to room temperature and remains clear, transparent, and viscous without any solid precipitation, and then vacuum dried.

[0056] Preferably, the vacuum drying time is 10-50 hours.

[0057] More preferably, the vacuum drying time is 12-48 hours.

[0058] Specifically, the co-amorphous form of the vildagliptin-valsartan is a white powder.

[0059] A third aspect of the present invention provides the use of the co-amorphous product of vildagliptin-valsartan described in the first aspect of the present invention in the preparation of a medicament for treating diabetes and cardiovascular and cerebrovascular diseases.

[0060] Compared with the prior art, the beneficial effects of the technical solution provided by the present invention are as follows:

[0061] (1) Compared with valsartan, the solubility and dissolution rate of valsartan in the co-amorphous form of vildagliptin-valsartan are significantly improved, which is beneficial to improving the bioavailability of valsartan.

[0062] (2) In general, in co-amorphous drugs, the two drugs are determined by their respective structural characteristics. During the preparation process, they may form co-crystals or co-amorphous products. At the same time, the two drugs may not interact with each other and only form a simple physical mixture. Therefore, the co-amorphous product of vildagliptin-valsartan prepared by the present invention through the two drugs vildagliptin and valsartan is unpredictable.

[0063] (3) This invention investigated the effects of three different preparation methods on changes in drug-related properties such as solubility, dissolution rate, and stability, providing a theoretical basis for further exploration of methods to continuously generate effective co-amorphous compounds. Furthermore, the ionic liquid conversion method used in this invention is a novel method for preparing vildagliptin-valsartan co-amorphous compounds, developed by the inventors through long-term experimental research. DSC analysis also confirmed that this preparation method enables vildagliptin and valsartan to form a homogeneous co-amorphous system. Based on current technology, this invention's use of the ionic liquid conversion method to prepare vildagliptin-valsartan co-amorphous compounds has achieved unexpected technical effects.

[0064] (4) Under normal circumstances, the solubility of both raw materials increases after the formation of co-amorphous form. However, in this invention, compared with the raw material vildagliptin, the solubility and dissolution rate of vildagliptin in the co-amorphous form of vildagliptin-valsartan are reduced, thereby reducing the frequency of administration for diabetes and reducing the side effects caused by frequent administration. This is obviously an unexpected technical effect.

[0065] (5) The powder X-ray diffraction pattern, differential scanning calorimetry curve, and infrared spectrum of the co-amorphous vildagliptin-valsartan of the present invention are different from vildagliptin and valsartan alone, and are a completely different morphology from vildagliptin and valsartan. Attached Figure Description

[0066] Figure 1 Powder X-ray diffraction patterns of vildagliptin (VLG), valsartan (VAL), physical mixtures of VLG and VAL (VVPM), and co-amorphous materials (VVBM, VVSE, and VVILC) prepared in Examples 1, 4, and 7 of this invention.

[0067] Figure 2 DSC images of the co-amorphous materials prepared by VLG, VAL, and Examples 1, 4, and 7 of this invention;

[0068] Figure 3 Infrared spectra of VLG, VAL, and co-amorphous materials prepared in Examples 1, 4, and 7 of this invention;

[0069] Figure 4The powder X-ray diffraction patterns of the co-amorphous materials prepared in Examples 1, 4, and 7 of this invention during stability testing;

[0070] Figure 5 Dissolution curves of VLG and VAL in the co-amorphous compounds prepared in Examples 1, 4 and 7 of this invention. Detailed Implementation

[0071] To enable those skilled in the art to more clearly understand the technical solutions described in this invention, the following embodiments are provided for illustration. It should be noted that the following embodiments do not constitute a limitation on the scope of protection claimed by this invention.

[0072] Unless otherwise specified, the raw materials, reagents or devices used in the following examples are available from conventional commercial sources or can be obtained by existing known methods.

[0073] Examples 1-3 describe the preparation of vildagliptin-valsartan co-amorphous compounds using a grinding method.

[0074] Example 1

[0075] Weigh 320.0 mg of vildagliptin and 460.0 mg of valsartan (molar ratio 1:1), place them in a ball mill jar, and grind them at 20 Hz for 6 h using a Retsch MM 400 vibrating ball mill to obtain the vildagliptin-valsartan co-amorphous compound.

[0076] Example 2

[0077] Weigh 320.0 mg of vildagliptin and 920.0 mg of valsartan (molar ratio 1:2), place them in a ball mill jar, and grind them at 20 Hz for 6 h using a Retsch MM 400 vibrating ball mill to obtain vildagliptin-valsartan co-amorphous compound.

[0078] Example 3

[0079] Weigh 640.0 mg of vildagliptin and 460.0 mg of valsartan (molar ratio 2:1), place them in a ball mill jar, and grind them at 20 Hz for 6 h using a Retsch MM 400 vibrating ball mill to obtain vildagliptin-valsartan co-amorphous compound.

[0080] Examples 4-6 illustrate the preparation of vildagliptin-valsartan co-amorphous compounds using a solvent method.

[0081] Example 4

[0082] Weigh 320.0 mg vildagliptin and 460.0 mg valsartan (molar ratio 1:1), add them to 15 mL of anhydrous ethanol, sonicate at 25 °C until fully dissolved to obtain a clear solution, and use a rotary evaporator to evaporate the anhydrous ethanol under reduced pressure at 50 °C and 60 rpm, and then vacuum dry at 25 °C for 24 h to obtain the vildagliptin-valsartan co-amorphous compound.

[0083] Example 5

[0084] Weigh 320.0 mg vildagliptin and 460.0 mg valsartan (molar ratio 1:1), add to 20 mL methanol, sonicate at 25 °C until fully dissolved to obtain a clear solution, use a rotary evaporator to evaporate the methanol under reduced pressure at 50 °C and 60 rpm, and then dry under vacuum at 25 °C for 24 h to obtain the vildagliptin-valsartan co-amorphous compound.

[0085] Example 6

[0086] Weigh 320.0 mg vildagliptin and 460.0 mg valsartan (molar ratio 1:1), add them to 20 mL acetonitrile, sonicate at 25 °C until fully dissolved to obtain a clear solution, and use a rotary evaporator to evaporate the acetonitrile under reduced pressure at 50 °C and 60 rpm, and then dry under vacuum at 25 °C for 24 h to obtain the vildagliptin-valsartan co-amorphous compound.

[0087] Examples 7-9 describe the preparation of vildagliptin-valsartan co-amorphous compounds using an ionic liquid conversion method.

[0088] Example 7

[0089] Weigh 320.0 mg vildagliptin and 460.0 mg valsartan (molar ratio 1:1), add them to 100 μL of ultrapure water, and heat and stir with a magnetic stirrer at 50 °C and 600 rpm to obtain a transparent viscous liquid. Cool the transparent viscous liquid to room temperature, and it will still remain clear, transparent and viscous without any solid precipitation. Dry it under vacuum at 25 °C for 48 h to obtain the vildagliptin-valsartan co-amorphous compound.

[0090] Example 8

[0091] Weigh 320.0 mg vildagliptin and 460.0 mg valsartan (molar ratio 1:1), add them to 200 μL of ultrapure water, and heat and stir with a magnetic stirrer at 50 °C and 600 rpm to obtain a transparent viscous liquid. Cool the transparent viscous liquid to room temperature, and it will still remain clear, transparent and viscous without any solid precipitation. Dry it under vacuum at 25 °C for 48 h to obtain the vildagliptin-valsartan co-amorphous compound.

[0092] Example 9

[0093] Weigh 320.0 mg of vildagliptin and 460.0 mg of valsartan (molar ratio 1:1), add them to 300 μL of ultrapure water, and heat and stir with a magnetic stirrer at 50 °C and 600 rpm to obtain a transparent viscous liquid. Cool the transparent viscous liquid to room temperature, and it will still remain clear, transparent and viscous without any solid precipitation. Dry it under vacuum at 25 °C for 48 h to obtain the vildagliptin-valsartan co-amorphous compound.

[0094] Performance testing

[0095] 1. Powder X-ray Diffraction (PXRD)

[0096] The PXRD analysis conditions were: Cu-Kα radiation; tube current: 150 mA; high voltage intensity: 40 kV; step size: 0.01°; scan range: 3-40.0°; scan speed: 20° / min.

[0097] X-ray diffraction analysis was performed on the co-amorphous compounds (VVBM, VVSE, and VVILC) prepared from VLG (active drug substance), VAL (active drug substance), a physical mixture of VLG and VAL in a simple mass ratio of 1:1 (VVPM), and Examples 1, 4, and 7. The powder X-ray diffraction patterns are shown below. Figure 1 As shown, the horizontal axis represents the diffraction angle 2θ, and the vertical axis represents the diffraction intensity.

[0098] from Figure 1 It can be seen that VLG has strong crystal-characteristic diffraction peaks at positions such as 10.04°, 11.71°, 13.17°, 16.39°, 16.85°, 19.88°, 20.39° and 24.25°, indicating that the raw material of VLG has a typical crystal structure. VAL is amorphous, and a halo pattern can be observed in Figure (1), with no Bragg peaks at all. In the diffraction pattern of VVPM, the characteristic diffraction peaks of VLG can be observed, indicating that VLG and VAL are only physically mixed, and VLG is not amorphized. In contrast, the powder X-ray diffraction patterns of the co-amorphous compounds VVBM, VVSE and VVILC prepared by three different preparation methods in Examples 1, 4 and 7 of this invention have no obvious diffraction peaks and all show halos, indicating that the long-range ordered structure of VLG and VAL is destroyed, and the co-amorphous compounds of vildagliptin-valsartan are obtained.

[0099] 2. Differential Scanning Calorimetry (DSC)

[0100] DSC analysis was performed on VLG, VAL, and the co-amorphous compounds VVBM, VVSE, and VVILC prepared in Examples 1, 4, and 7.

[0101] Take 5 mg of sample and place it in an aluminum sample crucible. Use an empty aluminum crucible as a reference. Increase the temperature from 20 °C to 300 °C at a rate of 10 °C / min under a nitrogen atmosphere. Perform DSC analysis. The DSC curves for each sample are shown below. Figure 2 As shown in the figure, the horizontal axis represents temperature and the vertical axis represents heat flow rate.

[0102] from Figure 2 It can be seen that VLG exhibits a sharp endothermic melting peak at 154℃, while amorphous VAL shows a glass transition at 65.8℃ and an endothermic melting peak after crystallization at 102℃. The three co-amorphous compounds prepared in Examples 1, 4, and 7 all show a single glass transition temperature: VVBM, VVSE, and VVILC have glass transition temperatures of 109.3℃, 113.4℃, and 106.8℃, respectively. This indicates that all three preparation methods yielded pure co-amorphous compounds, and VLG and VAL formed a homogeneous co-amorphous system. This also demonstrates that the co-amorphous compounds are not simply a physical mixture of drug monomers, but rather a uniform mixture at the drug molecule level, thus corresponding to only one glass transition temperature.

[0103] 3. Fourier transform infrared spectroscopy test

[0104] Infrared spectroscopy analysis was performed on VLG, VAL, and the co-amorphous compounds VVBM, VVSE, and VVILC prepared in Examples 1, 4, and 7.

[0105] Sample preparation was performed using the KBr pellet method. A small amount of sample was taken, mixed with KBr, and pelleted. The KBr pellet was used as a blank control. The pellets were prepared at 4000-4000 cm⁻¹. -1 Infrared absorption spectra were measured within the specified range. The infrared spectra of the above samples are shown below. Figure 3 As shown in the figure, the horizontal axis represents wavenumber and the vertical axis represents transmittance.

[0106] from Figure 3 It can be seen that VLG is at 3426cm -1 and 1658cm -1 The characteristic absorption peaks for the NH stretching vibration of the amine group and the C=O stretching vibration of the amide group are observed at 3417 cm⁻¹. The amorphous VAL shows a peak at 3417 cm⁻¹. -1 1603cm -1 and 1735cm -1 The peaks at these locations represent characteristic absorption peaks for the NH stretching and deformation vibrations of the amine group and the C=O stretching vibration of the amide group, respectively. After forming the emodinous form, the peaks at 1603 cm⁻¹ in the VVBM spectrum are also characteristic. -1 The characteristic peak at 3421 cm⁻¹ disappeared, and NH shifted to 3421 cm⁻ -1C=O shifts to 1724cm -1 The VVSE spectrum is located at 1603 cm. -1 The characteristic peak at 3428 cm⁻¹ disappeared, and NH shifted to 3428 cm⁻ -1 C=O shifts to 1721cm -1 The VVILC spectrum is located at 1603 cm⁻¹ -1 The characteristic peak at 3413 cm⁻¹ disappeared, and NH shifted to 3413 cm⁻ -1 C=O shifts to 1728cm -1 In summary, the hydrogen bonding strengths of the co-amorphous compounds obtained by the three preparation methods differ. This difference may affect some physicochemical properties of the co-amorphous compounds, such as stability, solubility, and dissolution rate. Therefore, the wavelengths corresponding to the main absorption peaks of VVBM / VVSE / VVILC are different. The wavelengths corresponding to the main absorption peaks of VVBM are: 3421, 2958, 2930, 2860, 1724, 1658, 1457, and 1409 cm⁻¹. -1 The wavelengths corresponding to the main absorption peaks of VVSE are: 3428, 2960, 2929, 2871, 1721, 1635, 1456, and 1403 cm⁻¹. -1 The wavelengths corresponding to the main absorption peaks of VVILC are: 3413, 2960, 2931, 2872, 1728, 1659, 1458, and 1410 cm⁻¹. -1 .

[0107] 4. Stability testing of co-amorphous materials

[0108] 10.0 mg of the co-amorphous compounds VVBM, VVSE, and VVILC prepared in Examples 1, 4, and 7 were weighed respectively and placed in 10 mL beakers. The beakers were left open and placed in a constant temperature and humidity chamber at 40°C and 75% RH (relative humidity) for 3 months. On the last day of each of the first, second, and third months, appropriate amounts of samples were taken out and their crystal phases were analyzed using PXRD. The powder X-ray diffraction patterns are shown below. Figure 4 As shown, the horizontal axis represents the diffraction angle 2θ, and the vertical axis represents the diffraction intensity. Figure 4 (a) is the powder X-ray diffraction pattern of VVBM in Example 1; Figure 4 (b) is the powder X-ray diffraction pattern of VVSE in Example 4; Figure 4 (c) is the powder X-ray diffraction pattern of VVILC in Example 7.

[0109] from Figure 4It can be seen that the co-amorphous compounds VVBM, VVSE and VVILC prepared in Examples 1, 4 and 7 maintained a stable amorphous morphology after being stored at constant temperature and humidity for 3 months, indicating that the co-amorphous compounds obtained in this invention have good stability.

[0110] 5. Solubility test

[0111] The co-amorphous materials used in this test were the co-amorphous materials VVBM, VVSE, and VVILC prepared in Examples 1, 4, and 7.

[0112] The solubility of VLG (active drug), VLG in VVBM (VVBM-VLG), VLG in VVSE (VVSE-VLG), VLG in VVILC (VVILC-VLG), VAL (active drug), VAL in VVBM (VVBM-VAL), VAL in VVSE (VVSE-VAL), and VAL in VVILC (VVILC-VAL) was determined in three solutions: acetate buffer (pH 4.5), phosphate buffer (pH 6.8), and ultrapure water.

[0113] Each of the above-mentioned test samples was suspended in 1 mL of the three solutions mentioned above, forming supersaturated solutions in each case. The solutions were then magnetically stirred in a 37℃ water bath for 24 h until equilibrium was reached. The solutions were then filtered through a 0.45 μm filter membrane. The filtrate was diluted appropriately and injected into a high-performance liquid chromatograph (HPLC) to determine the solubility. Three parallel operations were performed, and the average value was calculated.

[0114] The chromatographic conditions for high performance liquid chromatography are as follows:

[0115] Instrument: SHIMADZU LC-2030C 3D

[0116] Chromatographic column: Inertsil ODS C18 column (4.6mm × 150mm, 5μm)

[0117] Mobile phase: For VLG, the mobile phase is acetonitrile-20mM phosphate buffer (containing 2.72g potassium dihydrogen phosphate, adjusted to pH 3.0 with 85% phosphoric acid) (10:90, V / V); for VAL, the mobile phase is acetonitrile-0.3% triethylamine salt solution (adjusted to pH 7.0 with 85% phosphoric acid) (27:73, V / V).

[0118] Column temperature: 35℃

[0119] Flow rate: 1.0 mL / min

[0120] Detection wavelengths: VLG detection wavelength 210nm, VAL detection wavelength 254nm

[0121] Injection volume: 20 μL

[0122] The solubility of VLG and VAL in the three solutions in different samples is shown in Table 1.

[0123] Table 1

[0124]

[0125] As shown in Table 1, the equilibrium solubility of VLG in the co-amorphous compounds of Examples 1, 4, and 7 in the three different solutions was significantly lower than that of the active pharmaceutical ingredient VLG. Furthermore, the solubility trend in the three solutions was: VLG > VVBM-VLG > VVSE-VLG > VVILC-VLG. Specifically, in ultrapure water, the equilibrium solubility of VVBM-VLG, VVSE-VLG, and VVILC-VLG were 29.7±0.68, 13.6±1.20, and 13.5±1.40 mg / mL, respectively, representing reductions of 81.3%, 91.4%, and 91.5% compared to the active pharmaceutical ingredient VLG (159±1.44 mg / mL).

[0126] In acetate buffer (pH 4.5) and phosphate buffer (pH 6.8), the equilibrium solubility of VVBM-VAL, VVSE-VAL, and VVSE-VAL showed little change compared to the active pharmaceutical ingredient (VAL). However, in ultrapure water, VVBM-VAL, VVSE-VAL, and VVSE-VAL all exhibited significantly higher equilibrium solubility than the active pharmaceutical ingredient (VAL). Specifically, in ultrapure water, the equilibrium solubility of VVBM-VAL, VVSE-VAL, and VVSE-VAL was 43 times, 41 times, and 43 times that of the active pharmaceutical ingredient (VAL), respectively.

[0127] 6. Inherent Dissolution Rate (IDR)

[0128] The samples tested were VLG, VAL, and co-amorphous compounds VVBM, VVSE, and VVILC prepared in Examples 1, 4, and 7.

[0129] The above samples were ground and sieved to control the particle size between 75-150 μm. Then, 100.0 mg of each sample was weighed and pressed at 300 MPa for 15 seconds to form 5 mm diameter round tablets. One side of the sample was sealed with a candle, while the other side was exposed to 900 mL of ultrapure water. Samples were taken at 5 min, 10 min, 15 min, 20 min, 25 min, and 30 min, with 2 mL of solution taken each time. Immediately after each sample, 2 mL of the constant-temperature dissolution medium was added. The collected solutions were filtered through a 0.45 μm microporous membrane. The solution concentration at each time point was monitored using HPLC. Three parallel operations were performed, and the average value was taken to obtain the characteristic dissolution curves for each sample. Figure 5 As shown, the horizontal axis represents time, the vertical axis represents the cumulative release, and the slope of the curve is the inherent dissolution rate. Figure 5 (a) Dissolution curves of VLG in VLG (active drug), VVBM, VVSE and VVILC prepared in Examples 1, 4 and 7; Figure 5 (b) Dissolution curves of VLG in VVBM, VVSE and VVILC prepared in Examples 1, 4 and 7 at different ordinate scales; Figure 5 (c) Dissolution curves of VAL (active drug), VVBM, VVSE and VVILC prepared in Examples 1, 4 and 7.

[0130] The chromatographic conditions in the inherent dissolution test are the same as those in the solubility test.

[0131] from Figure 5 It can be concluded that the dissolution rates of VLG from VVBM, VVSE, and VVILC are 0.15, 0.07, and 0.04 mg / cm³, respectively. -2 ·min -1 The dissolution rate of the active pharmaceutical ingredient VLG was 15.61 mg / cm³, respectively. -2 min -1 The dissolution rates of VLG in the active pharmaceutical ingredient (VLG) were reduced by 99.0%, 99.5%, and 99.7%, respectively, and the dissolution rates of VLG in VVBM, VVSE, and VVILC were significantly higher than those in VVBM, VVSE, and VVILC. Meanwhile, the dissolution rates of VAL in VVBM, VVSE, and VVILC were 0.06, 0.07, and 0.08 mg / cm³, respectively. -2 min -1 These are the dissolution rates of the active pharmaceutical ingredient VAL (0.04 mg / cm³). -2 min -1 The dissolution rates of the active pharmaceutical ingredient (VAL) were 1.5, 1.8, and 2.0 times higher than those of VVBM, VVSE, and VVILC, respectively. This indicates that compared to the active pharmaceutical ingredient (VAL), the dissolution rate of VLG in the co-amorphous compounds was decreased, while the dissolution rate of VAL was significantly increased.

[0132] The above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A co-amorphous material, characterized in that, The co-amorphous material includes vildagliptin and valsartan; the molar ratio of vildagliptin to valsartan in the co-amorphous material is 1:0.5-3; The dissolution rate of valsartan in the co-amorphous material was 0.06-0.10 mg / cm³. -2 min -1 The dissolution rate of vildagliptin in the co-amorphous material was 0.01-0.20 mg / cm³. -2 min -1 .

2. The co-amorphous material according to claim 1, characterized in that, The glass transition temperature of the co-amorphous material is 105-120℃.

3. The co-amorphous material according to claim 1, characterized in that, When stored at 40°C and 75% relative humidity for more than 28 days, the amorphous material maintains a stable amorphous form.

4. The method for preparing the co-amorphous material according to any one of claims 1-3, characterized in that, The preparation methods include grinding, solvent method, and ionic liquid conversion method.

5. The preparation method according to claim 4, characterized in that, The grinding method includes the following steps: mixing vildagliptin and valsartan, grinding them, and obtaining the co-amorphous compound.

6. The preparation method according to claim 4, characterized in that, The solvent method includes the following steps: adding vildagliptin and valsartan to a solvent, dissolving them, removing the solvent, and vacuum drying to obtain the co-amorphous compound.

7. The preparation method according to claim 6, characterized in that, The solvent includes at least one of methanol, ethanol, acetone, isopropanol, n-butanol, tert-butanol, acetonitrile, ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, tert-butyl acetate, isobutyl acetate, dichloromethane, chloroform, tetrahydrofuran, and water.

8. The preparation method according to claim 4, characterized in that, The ionic liquid conversion method includes the following steps: Vildagliptin and valsartan were mixed, water was added, and the mixture was heated and stirred until a transparent viscous liquid was obtained. The liquid was then dried under vacuum to obtain the co-amorphous product.

9. The use of the co-amorphous material according to any one of claims 1-3 in the preparation of a medicament for treating diabetes and cardiovascular and cerebrovascular diseases.

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