A co-amorphous valsartan-2-aminopyridine and a method of preparation

Abstract

The present application relates to a kind of valsartan-2-amino pyridine co-amorphous and preparation method, the co-amorphous of valsartan-2-amino pyridine of the present application is with 2-amino pyridine according to specific proportion mixed, using solvent evaporation method to prepare single-phase amorphous binary system, the present application uses the interaction between 2-amino pyridine and valsartan, forms ternary hydrogen bond connection mode, greatly improves the solubility and dissolution of valsartan, improves bioavailability, and cost is low, energy consumption is low, can large-scale industrial production.

Description

Technical Field

[0001] This invention relates to a co-amorphous form of valsartan-2-aminopyridine and its preparation method, belonging to the field of pharmaceutical technology. Background Technology

[0002] Valsartan is an angiotensin II receptor antagonist, a drug that blocks the activity of angiotensin II, promoting arterial vasodilation and lowering blood pressure, making it easier for the heart to pump blood. It can be used to improve heart failure and hypertension, and is therefore also known as an ARB antihypertensive drug. Due to the excellent antihypertensive effect and good drug safety of ARB antihypertensive drugs, they were listed as first-line drugs for hypertension treatment by the World Health Organization and my country's hypertension treatment guidelines in early 1999.

[0003] Valsartan, also known as N-valeryl-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl-L-valine, has the following chemical structure:

[0004]

[0005] Valsartan is a white crystalline powder or a white or off-white powder; it is hygroscopic and belongs to the BCS II class of compounds in the biopharmaceutics classification system. It is characterized by low solubility and high permeability, with low water solubility and poor dissolution. Its oral bioavailability is low, only about 10-35%, which is the main reason limiting its application and poor patient tolerance. The low bioavailability of valsartan in the human body is mainly due to its low solubility under acidic conditions in the stomach. Valsartan is a carboxylic acid compound with good solubility at pH > 5. However, in the stomach, especially on an empty stomach, the pH value is very low, generally about 1-3. Under these acidic conditions, the solubility of valsartan is very low. For such a poorly soluble drug, low solubility leads to very poor absorption in the stomach, which is also the reason for the low bioavailability of valsartan in the human body.

[0006] Co-amorphous pharmaceuticals refer to single-phase binary amorphous systems with a single glass transition temperature formed by the combination of active pharmaceutical ingredients with other small molecules (sugars, carboxylic acids, amino acids). As a novel solid form for drugs, co-amorphous pharmaceuticals can improve properties such as solubility, dissolution rate, stability, and bioavailability, and have become a promising approach in drug development.

[0007] Chinese patent document CN116655511A discloses a vildagliptin-valsartan co-amorphous compound, its preparation method, and its application. The co-amorphous compound includes vildagliptin and valsartan. 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 exudation of valsartan. Compared to the valsartan raw material, the solubility and dissolution rate of valsartan in this co-amorphous compound are improved to a certain extent, 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. However, this co-amorphous compound requires another drug to interact with it and improve solubility, resulting in high cost and energy consumption, which greatly limits its industrial-scale production, and its bioavailability is generally low. Summary of the Invention

[0008] To address the shortcomings of existing technologies, this invention provides a co-amorphous form of valsartan-2-aminopyridine and its preparation method.

[0009] The amorphous form of valsartan-2-aminopyridine of the present invention is prepared by mixing valsartan and 2-aminopyridine in a specific ratio and using a solvent evaporation method to obtain a single-phase amorphous binary system. The present invention utilizes the interaction between 2-aminopyridine and valsartan to form a ternary hydrogen bond connection, which greatly improves the solubility and dissolution rate of valsartan, improves bioavailability, and has low cost and low energy consumption, and can be produced on a large scale industrially.

[0010] This invention is achieved through the following technical solution:

[0011] The first object of the present invention is to provide a co-amorphous form of valsartan-2-aminopyridine.

[0012] A co-amorphous compound of valsartan-2-aminopyridine, formed by combining valsartan and 2-aminopyridine in a molar ratio of 1:(1-5), exhibits no characteristic absorption peaks at 6.02, 6.40, 13.99, 17.73, 21.46, 7.76, 15.31, 19.51, 21.88, 23.98, 30.46, 30.80, and 34.59 using Cu-Kα radiation and a DSC glass transition temperature of 80 °C.

[0013] According to a preferred embodiment of the present invention, the co-amorphous form of valsartan-2-aminopyridine has a 15-minute dissolution rate that increases from 3.4% of the valsartan active pharmaceutical ingredient to 88.7%.

[0014] According to a preferred embodiment of the invention, the co-amorphous compound is formed by combining valsartan and 2-aminopyridine in a molar ratio of 1:2.

[0015] A second objective of this invention is to provide a method for preparing the co-amorphous form of the above-mentioned valsartan-2-aminopyridine.

[0016] The method for preparing the above-mentioned co-amorphous product of valsartan-2-aminopyridine includes the following steps:

[0017] 1) Add valsartan and 2-aminopyridine to anhydrous methanol, and dissolve them by magnetic stirring at a constant temperature to obtain a clear solution.

[0018] 2) The clear solution was placed under nitrogen and stirred at a constant temperature. After the reaction, the solvent was evaporated and the remaining solid was dried under vacuum to obtain a white co-amorphous powder of valsartan-2-aminopyridine.

[0019] According to a preferred embodiment of the present invention, in step 1), the molar ratio of valsartan to 2-aminopyridine is 1:(1-5).

[0020] Most preferably, in step 1), the molar ratio of valsartan to 2-aminopyridine is 1:2.

[0021] According to a preferred embodiment of the present invention, in step 1), the mass-to-volume ratio of valsartan to anhydrous methanol is (0.1-0.5):(5-25), in g / mL.

[0022] More preferably, in step 1), the mass-to-volume ratio of valsartan to anhydrous methanol is (0.1-0.3):(5-15), in g / mL.

[0023] According to a preferred embodiment of the present invention, in step 1), the temperature of the constant temperature magnetic stirring is 30-50°C.

[0024] According to a preferred embodiment of the present invention, in step 2), the constant temperature stirring temperature is 30-50℃ and the stirring time is 15-30h.

[0025] According to a preferred embodiment of the present invention, in step 2), the solvent is evaporated by filtering the solution after the reaction, and the solvent is rapidly evaporated from the filtrate using a nitrogen blower.

[0026] According to a preferred embodiment of the present invention, in step 2), vacuum drying is performed by vacuum drying the remaining solids at 30-40°C for 3-6 days.

[0027] The application of the co-amorphous form of valsartan-2-aminopyridine represents a new solid form of valsartan.

[0028] Technical features and advantages of the present invention:

[0029] 1. The co-amorphous solid form of valsartan-2-aminopyridine of the present invention is a new form that is completely different from valsartan and 2-aminopyridine monomers. The co-amorphous solid form has a different DSC spectrum from valsartan and 2-aminopyridine, and is a new solid substance.

[0030] 2. The amorphous form of valsartan-2-aminopyridine of the present invention is prepared by mixing valsartan and 2-aminopyridine in a specific ratio and using a solvent evaporation method to obtain a single-phase amorphous binary system. The interaction between 2-aminopyridine and valsartan forms a ternary hydrogen bond connection, which greatly improves the solubility and dissolution rate of valsartan and improves bioavailability.

[0031] 3. The solubility of the co-amorphous form of valsartan-2-aminopyridine of the present invention in water and 0.1N hydrochloric acid media is significantly improved compared to valsartan.

[0032] 4. The co-amorphous form of valsartan-2-aminopyridine of the present invention has strong stability and remains unchanged for 28 days in an environment with a relative humidity of less than 30% RH.

[0033] 5. This invention uses a conventional solvent evaporation method, which is simple, low-cost, low-energy, and suitable for large-scale industrial production. Attached Figure Description

[0034] Figure 1 This is a powder X-ray diffraction pattern of valsartan raw material.

[0035] Figure 2 This is a powder X-ray diffraction pattern of 2-aminopyridine crystals.

[0036] Figure 3 This is a powder X-ray diffraction pattern of the valsartan-2-aminopyridine co-amorphous compound prepared in Example 1.

[0037] Figure 4 This is the infrared spectrum of valsartan raw material.

[0038] Figure 5 It is the infrared spectrum of 2-aminopyridine crystal.

[0039] Figure 6 The infrared spectrum is that of the valsartan-2-aminopyridine co-amorphous compound prepared in Example 1.

[0040] Figure 7 This is a DSC diagram of valsartan raw material.

[0041] Figure 8 This is a DSC diagram of 2-aminopyridine crystals.

[0042] Figure 9 This is a DSC chromatogram of the valsartan-2-aminopyridine coamorph obtained in Example 1.

[0043] Figure 10 This is a comparison of the dissolution curves of valsartan raw material and valsartan-2-aminopyridine co-amorphous compound prepared in Example 1 in hydrochloric acid solution at pH 1.0.

[0044] Figure 11 This is a comparison of the dissolution curves of valsartan raw material and valsartan-2-aminopyridine co-amorphous compound prepared in Example 1 in phosphate buffer medium at pH 7.4.

[0045] Figure 12 The results are PXRD values ​​for the stability of the valsartan-2-aminopyridine co-amorphous compound prepared in Example 1 after being stored at 40°C for 3 months.

[0046] Figure 13 The supramolecular microstructure of the valsartan-2-aminopyridine coamorph obtained in Example 1 is obtained using DFT calculations. Detailed Implementation

[0047] The present invention will be further described below through specific embodiments, but these are not intended to limit the scope of the invention.

[0048] The raw materials used in the examples are commercially available or can be prepared using existing technologies.

[0049] Example 1

[0050] Preparation of the co-amorphous form of valsartan-2-aminopyridine:

[0051] 1) Accurately weigh 0.2352 g of valsartan and 0.1017 g of 2-aminopyridine (molar ratio 1:2) into a 25 mL wide-mouth bottle, add 10 mL of anhydrous methanol, and dissolve by magnetic stirring at a constant temperature of 40 °C to obtain a clear solution.

[0052] 2) The solution was stirred at a constant temperature of 40℃ for 24 hours under nitrogen protection to ensure complete reaction. The solution was filtered, and the solvent in the filtrate was rapidly evaporated using a nitrogen blower. The remaining solid was vacuum dried at 35℃ for 5 days to obtain a white powder. The product was removed under relative humidity less than 30% RH and stored in a desiccator for later use.

[0053] Experimental Example 1

[0054] To verify the successful preparation of the co-amorphous product of valsartan-2-aminopyridine and its high solubility and dissolution rate in this invention, the experimental examples were tested using X-ray diffraction, infrared spectroscopy, differential scanning calorimetry, equilibrium solubility, dissolution rate, and DFT calculations of supramolecular structure, as detailed below:

[0055] 1. Powder X-ray diffraction

[0056] Instrument: D / max2550_18KW rotating target X-ray diffractometer (Rigaku, Japan)

[0057] Target: Cu-Kα radiation

[0058] wavelength:

[0059] Pipe pressure: 40KV

[0060] Pipe current: 30mA

[0061] Step size: 0.02°

[0062] Scanning speed: 10° / min

[0063] Test results: The powder X-ray diffraction patterns of valsartan, 2-aminopyridine, and the valsartan-2-aminopyridine co-amorphous product from Example 1 are shown in the figure. Figure 1 , 2 3. Valsartan exhibits characteristic diffraction peaks at 6.02, 6.40, 13.99, 17.73, and 21.46; 2-aminopyridine shows characteristic absorption peaks at 7.76, 15.31, 19.51, 21.88, 23.98, 30.46, 30.80, and 34.59. Figure 3 It can be seen that the crystal diffraction peaks in the powder X-ray diffraction pattern of the valsartan-2-aminopyridine co-amorphous compound all disappeared, and were replaced by a single amorphous diffraction bulge, indicating that the co-amorphous compound was successfully prepared by valsartan and 2-aminopyridine at a molar ratio of 1:2.

[0064] 2. Infrared Spectroscopy

[0065] Instrument: NICOLET 380 infrared spectrometer (Thermo Electron corporation), 4000-400 cm⁻¹, KBr pellet method, resolution 2 cm⁻¹

[0066] Determination results: The infrared spectra of valsartan, 2-aminopyridine, and the valsartan-2-aminopyridine co-amorphous compound from Example 1 are shown below. Figure 4 , 5 6. By Figure 6The infrared wavenumbers (cm⁻¹) of the amorphous valsartan-2-aminopyridine (molar ratio 1:2) co-form were found to be: 3327, 3151, 3081, 2964, 2931, 2871, 1676, 1628, 1491, 1458, 1385, 1202, 1165, 1105, 978, 938, 848, 815, 764, 665, 622, 552, 514, and 434 cm⁻¹. The infrared spectrum of the prepared amorphous valsartan-2-aminopyridine co-form differed significantly from the infrared spectra of valsartan and 2-aminopyridine alone, indicating that it is a novel solid substance.

[0067] 3. Differential scanning calorimetry

[0068] Instrument: TGA / DSC 1 Differential Scanning Thermal Analyzer (Mettler Toledo, Switzerland)

[0069] Range: Room temperature - 200℃

[0070] Heating rate: 10℃ / min

[0071] Results: The DSC chromatograms of the amorphous compounds of valsartan, 2-aminopyridine, and valsartan-2-aminopyridine (molar ratio 1:2) from Example 1 are shown below. Figure 7 , 8 9. As shown in the figure, the endothermic transition peak of valsartan is at 116℃, the endothermic transition peak of 2-aminopyridine is at 145℃, and the glass transition temperature of the valsartan-2-aminopyridine co-amorphous compound is 80℃. The co-amorphous compound prepared in this invention has different DSC spectra from those of valsartan and 2-aminopyridine, indicating that a new solid substance has been prepared.

[0072] 4. Equilibrium solubility determination

[0073] The concentrations of valsartan and the valsartan-2-aminopyridine co-amorphous compound from Example 1 were determined in water and 0.1N hydrochloric acid, respectively. 10 mL of each medium (water and 0.1 mol / L HCl solution) was measured into 15 mL test tubes. An excess of the analyte was added, and the test tubes were sealed and placed in a water bath with a constant temperature shaker at 25°C for 24 hours to reach equilibrium. The supernatant was filtered through a 0.45 μm filter membrane, and the filtrate was diluted appropriately before solubility was determined using dual-wavelength ultraviolet spectrophotometry. Each sample was measured in triplicate.

[0074] The conditions for a UV-Vis spectrophotometer are as follows:

[0075] Instrument: UV-5200 UV-Vis spectrophotometer (Shanghai Yuanxi Instrument Equipment Co., Ltd.)

[0076] Cuvette material: Quartz

[0077] Cuvette optical path: 10mm

[0078] Measurement wavelengths: 238nm and 254nm

[0079] Standard curve preparation: Take 0.0106 g of valsartan reference standard and place it in a 1000 mL volumetric flask. Dilute to the mark with water and 0.1 N hydrochloric acid solution respectively, shake well to dissolve, and prepare the stock solution. Dilute the stock solution with water and hydrochloric acid to 10%, 20%, 40%, and 80% respectively, and measure the absorbance at 238 nm and 254 nm respectively. The linear equations for valsartan are A = 0.03C + 0.0806 (238 nm, R² = 0.9942); A = 0.0242C + 0.0763 (254 nm, R² = 0.9904). The relative standard deviations of parallel measurements are all less than 2.5%, indicating good repeatability and high accuracy of the method.

[0080] Test results: The equilibrium solubility of valsartan raw material and the co-amorphous product of Example 1 in water and 0.1N hydrochloric acid solution is shown in Table 1.

[0081] Table 1. Solubility of valsartan in water and 0.1N hydrochloric acid (μg / mL)

[0082]

[0083] Therefore, it can be seen that the solubility of co-amorphous valsartan in the above buffer solutions is significantly higher than that of valsartan.

[0084] 5. Dissolution test

[0085] Valsartan raw material and valsartan-2-aminopyridine from Example 1 were both amorphously passed through a 100-mesh sieve (150 μm). A sample equivalent to 40 mg of valsartan was taken and dissolution was performed according to Method II (paddle method) of the General Chapter IV of the 2015 edition of the Chinese Pharmacopoeia. The dissolution medium was 0.1 mol / L hydrochloric acid solution and pH 7.4 phosphate buffer, with a medium volume of 900 mL, a rotation speed of 50 rpm, and a dissolution medium temperature of 37 °C. Samples were taken at 5, 10, 15, 30, 45, 60, 90, and 120 minutes after the start of the experiment, with 3 mL of sample taken each time and 3 mL of dissolution medium added. The collected solution was filtered through a 0.11 μm microporous membrane, and the filtrate was analyzed by HPLC. The experiment was repeated six times in parallel.

[0086] High performance liquid chromatography conditions:

[0087] Instrument: Shimadzu LC-10ADVP high-performance liquid chromatograph

[0088] Chromatographic column: CAPCELL PAK C18 column (4.6mm*150mm, 5μm)

[0089] Mobile phase: Acetonitrile-water (60 / 40, v / v, adjusted to pH 3.0 with phosphoric acid)

[0090] Flow rate: 1 mL / min

[0091] Detection wavelength: 247nm

[0092] The results show that after the present invention prepares the valsartan-2-aminopyridine co-amorphous compound by mixing valsartan and 2-aminopyridine in a specific ratio, the dissolution rate at 15 min increases from 3.4% of the valsartan raw material to 88.7% of the valsartan-2-aminopyridine co-amorphous compound, and the dissolution rate of valsartan is significantly improved.

[0093] 6. DFT calculation of supramolecular structure

[0094] Initial structures of valsartan and 2-aminopyridine were extracted from their crystal structures obtained using Conquest 1.8 software from the Cambridge Crystallography Database (CCDC). The CCDC codes for valsartan and 2-aminopyridine are KIPLEC and AMPYRD, respectively. To determine the multimolecular hydrogen-bonded configurations, four ternary configurations were constructed using infrared spectroscopy results and structural information from the visualization module. Simulations were performed on the co-amorphous system constructed based on hydrogen-bonded information, and optimization and frequency calculations were performed at the GGA / PW91 function level. Convergence criteria were independently defined for the maximum energy change, maximum force, and maximum displacement, with each parameter having a convergence criterion of 1x10⁻⁶. -5 Hartree, 0.002Hartree and All calculations were performed using the DMol3 module from the Material Studio 8.0 package.

[0095] Results: The calculated infrared spectra of all four configurations were compared with experimental values, and it was found that... Figure 13 The current configuration is closest to the experimental infrared spectrum results of valsartan-2-aminopyridine co-amorphous. Therefore, the ternary hydrogen bond connection mode of valsartan-2-aminopyridine co-amorphous is as follows: the carboxylic acid group of valsartan and the N element on the pyridine ring are connected to the side chain amino group; the -NH of the five-membered nitrogen ring of valsartan and its conjugated N are connected to the side chain amino group of 2-aminopyridine and its conjugated N element.

[0096] The raw materials used in the examples are commercially available or can be prepared using existing technologies.

[0097] Example 2

[0098] The preparation of the co-amorphous product of valsartan-2-aminopyridine as described in Example 1 differs from that in:

[0099] Valsartan and 2-aminopyridine were added to a 25 mL wide-mouth bottle at a molar ratio of 1:1.5, and other conditions and parameters were performed as in Example 1.

[0100] Example 3

[0101] The preparation of the co-amorphous product of valsartan-2-aminopyridine as described in Example 1 differs from that in:

[0102] Valsartan and 2-aminopyridine were added to a 25 mL wide-mouth bottle at a molar ratio of 1:2.5, and other conditions and parameters were performed as in Example 1.

[0103] Comparative Example 1

[0104] The preparation of the co-amorphous product of valsartan-2-aminopyridine as described in Example 1 differs from that in:

[0105] Replace 2-aminopyridine with L-tryptophan.

[0106] Comparative Example 2

[0107] The preparation of the co-amorphous product of valsartan-2-aminopyridine as described in Example 1 differs from that in:

[0108] Replace 2-aminopyridine with L-proline.

[0109] Comparative Example 3

[0110] The preparation of the co-amorphous product of valsartan-2-aminopyridine as described in Example 1 differs from that in:

[0111] Replace 2-aminopyridine with gallic acid.

[0112] Experiment Example 2

[0113] The equilibrium solubility of the co-amorphous material of Example 1 and Comparative Examples 1-3 in water was tested according to the solubility determination method in Experimental Example 1. The test results are shown in Table 2.

[0114] Table 2. Solubility of samples in water (μg / mL)

[0115]

[0116] As can be seen from Table 2, neither amino acids nor gallic acid form amorphous compounds with valsartan, but rather reduce the solubility of valsartan technical. Comprehensive experiments show that amorphous compounds formed by valsartan and 2-aminopyridine greatly improve its solubility and bioavailability, and are low in cost and energy consumption, making them suitable for large-scale industrial production.

Claims

1. A co-amorphous compound of valsartan-2-aminopyridine, formed by combining valsartan and 2-aminopyridine in a molar ratio of 1:2, wherein the X-ray powder radiometric spectrum, expressed as 2θ, using Cu-Kα radiation, shows no characteristic absorption peaks at 6.02, 6.40, 13.99, 17.73, 21.46, 7.76, 15.31, 19.51, 21.88, 23.98, 30.46, 30.80, and 34.59, and its DSC glass transition temperature is 80 °C; The method for preparing the co-amorphous product of valsartan-2-aminopyridine includes the following steps: 1) Add valsartan and 2-aminopyridine to anhydrous methanol, and dissolve by magnetic stirring at a constant temperature to obtain a clear solution. 2) The clear solution was placed under nitrogen and stirred at a constant temperature. After the reaction, the solvent was evaporated and the remaining solid was dried under vacuum to obtain a white co-amorphous powder of valsartan-2-aminopyridine.

2. The co-amorphous product of valsartan-2-aminopyridine according to claim 1, characterized in that, The co-amorphous form of valsartan-2-aminopyridine showed an increase in dissolution rate from 3.4% of the valsartan active pharmaceutical ingredient to 88.7% within 15 minutes.

3. The method for preparing the co-amorphous product of valsartan-2-aminopyridine according to claim 1, comprising the following steps: 1) Add valsartan and 2-aminopyridine to anhydrous methanol, and dissolve by magnetic stirring at a constant temperature to obtain a clear solution. 2) The clear solution was placed under nitrogen and stirred at a constant temperature. After the reaction, the solvent was evaporated and the remaining solid was dried under vacuum to obtain a white co-amorphous powder of valsartan-2-aminopyridine.

4. The preparation method according to claim 3, characterized in that, In step 1), the molar ratio of valsartan to 2-aminopyridine is 1:

2.

5. The preparation method according to claim 3, characterized in that, In step 1), the mass-to-volume ratio of valsartan to anhydrous methanol is (0.1-0.5):(5-25), in g / mL.

6. The preparation method according to claim 3, characterized in that, In step 1), the temperature of the constant temperature magnetic stirring is 30-50℃.

7. The preparation method according to claim 3, characterized in that, In step 2), the constant temperature stirring temperature is 30-50℃, the stirring time is 15-30h, the solvent is evaporated by filtering the solution after the reaction, the filtrate is evaporated quickly by nitrogen blowing, and the remaining solids are vacuum dried at 30-40℃ for 3-6 days.

Images