Method for detecting related substances of valsartan and levamlodipine pharmaceutical composition

Abstract

The present application relates to a kind of detection methods of valsartan amlodipine besylate composition related substances, belong to detection and analysis field, the present application uses high performance liquid chromatography to detect valsartan amlodipine besylate composition and its related substances;Active ingredient of detection includes pharmacodynamic component valsartan and amlodipine besylate, other related detection substances include valsartan degradation impurity, amlodipine degradation impurity and valsartan related substance 2a~2f, the method of the present application is simple to operate, related substances can reach baseline separation, sensitivity is good, injection precision and repeatability are good and low to instrument equipment, suitable for the detection of valsartan amlodipine besylate pharmaceutical composition related substances.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a method for detecting related substances in a valsartan-levamlodipine pharmaceutical composition. Background Technology

[0002] Impurities in pharmaceuticals are substances not required for the drug's production. These include organic impurities, inorganic impurities, and residual solvents. Organic impurities may arise during the production or storage of the active pharmaceutical ingredient (API), including starting materials, byproducts, intermediates, degradation products, reagents, ligands, and catalysts. Inorganic impurities generally originate from the production process and include reagents, ligands, catalysts, heavy metals or other residual metals, inorganic salts, and other substances. Controlling impurities is primarily based on safety and process stability. Some impurities are inherently toxic to humans and are considered harmful, such as elemental impurities and genotoxic impurities, which have received widespread attention in recent years. This is a significant cause of adverse drug reactions in clinical practice. Some impurities may not have obvious toxicity but are meaningless to the drug itself; their excess can affect the product's process stability, and therefore should be controlled as an indicator of process stability. In short, limiting impurity content is crucial for drug safety and quality control. Drug quality standards are an important component of the quality control system that ensures the quality and consistency of APIs and formulations, and are also the fundamental starting point for daily scientific supervision of products.

[0003] Valsartan-Amlodipine Tablets (I) are Novartis's first single-tablet, immediate-release combination formulation of angiotensin II receptor antagonist (ARB) and dihydropyridine calcium channel blocker (CCB). The main components are the angiotensin receptor antagonist valsartan and the calcium channel blocker amlodipine. Valsartan is a non-peptide, orally effective angiotensin II (AT) receptor antagonist, while amlodipine is a dihydropyridine calcium channel blocker (calcium ion antagonist or slow channel blocker) that selectively inhibits calcium ion transmembrane entry into smooth muscle cells and cardiomyocytes. Valsartan-Amlodipine Tablets (I) are used for patients whose blood pressure is not adequately controlled by monotherapy.

[0004] Levoamlodipine is a single isomer of amlodipine. In China, it was first marketed in 1999 by Shihui Pharmaceutical Co., Ltd. as levamlodipine besylate tablets. Compared to amlodipine, levamlodipine has twice the antihypertensive effect of the 1:1 racemic isomer, and its half-life is significantly longer. The dextrorotatory isomer has almost no antihypertensive effect but can cause adverse reactions such as headache, dizziness, peripheral edema, and facial flushing. Therefore, it is essential to develop a method for detecting related substances in the pharmaceutical composition of valsartan-levamlodipine tablets. Summary of the Invention

[0005] This invention provides a method for detecting related substances in a valsartan-levamlodipine pharmaceutical composition. The method employs high-performance liquid chromatography (HPLC) to detect these related substances. The active ingredients to be detected include valsartan and levamlodipine, and the impurities to be detected include valsartan impurity B, valsartan impurity G, valsartan impurity H, valsartan impurity F, valsartan impurity E, and amlodipine impurity D; valsartan related substances 2a, valsartan related substances 2b, valsartan related substances 2c, valsartan related substances 2d, valsartan related substances 2e, and valsartan related substances 2f.

[0006] In this invention, high performance liquid chromatography is used to detect related substances in the valsartan-levamlodipine pharmaceutical composition.

[0007] In some embodiments, the high performance liquid chromatography uses a reversed-phase column, preferably an octadecyl bonded silica column, more preferably a Luna® C18 (2) 100Å (150mm × 4.6mm × 3μm) or an Xbridge® C18 (150mm × 4.6, 3.5μm).

[0008] More preferably, the chromatographic column is a Luna® C18 (2) 100Å (150mm × 4.6mm × 3μm).

[0009] In some embodiments, the mobile phase A in the high-performance liquid chromatography is a mixed solution of triethylamine-phosphoric acid-water with a pH of 2.4-3.0, and the mobile phase B is a mixed solution of methanol and acetonitrile with a volume ratio of methanol to acetonitrile of 70:30, and elution is performed using a gradient elution method.

[0010] In some implementations, the gradient elution procedure is as follows:

[0011]

[0012] In some embodiments, the mobile phase A is prepared by taking 10 ml of triethylamine, adding water to 1000 ml, and adjusting the pH to 2.4-3.0 with phosphoric acid.

[0013] In some embodiments, the detection wavelength of the high-performance liquid chromatography is 235 nm to 240 nm, preferably 237 nm.

[0014] In some embodiments, the column temperature of the high-performance liquid chromatography column is 20°C to 30°C.

[0015] In some embodiments, the injection volume of the high-performance liquid chromatography column is 10 μl.

[0016] In some embodiments, a method for detecting related substances in a valsartan-levamlodipine pharmaceutical composition includes the following steps:

[0017] (1) Preparation of test solution: Take the valsartan-amlodipine tablet composition, grind it, add solvent to dissolve it, sonicate it and cool it, and take the supernatant as the test solution;

[0018] (2) Preparation of mixed impurity reference solution: Accurately weigh appropriate amounts of amlodipine besylate reference standard and valsartan reference standard, dissolve them in solvent and dilute quantitatively to obtain mixed impurity reference solution;

[0019] (3) Preparation of mixed impurity reference stock solution: Accurately weigh appropriate amounts of levamlodipine besylate, valsartan, valsartan impurities B, C, D, E, F, G, H, I, and amlodipine impurities A, B, D, E, F, G, H reference standards, dissolve them in solvent and dilute quantitatively to obtain mixed impurity reference stock solution.

[0020] (4) Preparation of system suitability solution: Weigh out amlodipine besylate and valsartan, then transfer an appropriate amount of mixed reference stock solution, add solvent to make up to volume, and the system suitability solution is obtained.

[0021] (5) Inject 10 μl each of the test solution, mixed impurity reference solution, and system suitability solution into the liquid chromatograph and record the chromatogram; take the chromatogram of the test solution. If there are impurity peaks in the chromatogram of the test solution, except for the benzenesulfonic acid peak and the valsartan impurity B peak, calculate the content of each impurity by the corrected peak area according to the external standard method.

[0022] In some embodiments, the valsartan-levamlodipine pharmaceutical composition comprises valsartan, levamlodipine besylate, a diluent, a disintegrant, a flow aid, and a lubricant, wherein the mass percentages of each component are as follows: levamlodipine besylate is 1-2.0% by mass, valsartan is 47%-50% by mass, the diluent is 28%-32.7% by mass, the disintegrant is 12.5%-18% by mass, the flow aid is 0.8%-0.9% by mass, and the lubricant is 2.7%-2.8% by mass.

[0023] In some embodiments, the diluent is microcrystalline cellulose, preferably microcrystalline cellulose M101, microcrystalline cellulose M102, or microcrystalline cellulose M105.

[0024] In some embodiments, the disintegrant is selected from one or a combination of two of crospovidone and crospovidone sodium carboxymethyl cellulose.

[0025] In some embodiments, the flow aid is colloidal silica.

[0026] In some embodiments, the lubricant is magnesium stearate.

[0027] In some embodiments, the valsartan-levamlodipine pharmaceutical composition may optionally further comprise a coating agent.

[0028] Furthermore, the coating agent is preferably a gastrointestinal soluble film coating material, and the weight of the coating agent accounts for 4.6% to 5.8% of the weight of the tablet core.

[0029] In some embodiments, the valsartan-levamlodipine pharmaceutical composition comprises: 3.47 parts levamlodipine besylate, 160 parts valsartan, 104.53 parts microcrystalline cellulose M102, 40 parts crospovidone, 3 mg of silica, and 9 parts magnesium stearate.

[0030] In some embodiments, the valsartan-levamlodipine pharmaceutical composition comprises: 3.47 parts levamlodipine besylate, 80.00 parts valsartan, 47.53 parts microcrystalline cellulose M105, 20.00 parts crospovidone, 10.00 parts crospovidone sodium carboxymethyl cellulose, 1.50 parts silica, and 4.50 parts magnesium stearate.

[0031] In some embodiments, the formulation of the valsartan-levamlodipine pharmaceutical composition includes: 3.47 parts levamlodipine besylate, 80.00 parts valsartan, 47.53 parts microcrystalline cellulose, 20.00 parts crospovidone, 10.00 parts crospovidone sodium carboxymethyl cellulose, 1.50 parts silica, and 4.50 parts magnesium stearate.

[0032] In some embodiments, the formulation of the valsartan-levamlodipine pharmaceutical composition includes: 3.47 parts levamlodipine besylate, 80.00 parts valsartan, 101.47.53 parts microcrystalline cellulose, 20.00 parts crospovidone, 10.00 parts crospovidone sodium carboxymethyl cellulose, 1.50 parts silica, and 4.50 parts magnesium stearate.

[0033] Furthermore, the valsartan-levamlodipine pharmaceutical composition can be prepared by dry granulation comprising the following steps:

[0034] (i) Place amlodipine besylate, valsartan, diluent, disintegrant, glidant, and lubricant (added internally) in a mixer, mix, and sieve;

[0035] (ii) The mixture obtained in step (i) is granulated into granules by dry granulation: the premixed powder is added to a dry granulator and dry granulation is performed; the fine powder is collected and granulated a second time with the same process parameters, and the granules from the two granulations are combined as dry granules;

[0036] (iii) Blending: Place the dry granules obtained in step (ii) and the lubricant (added) in a mixer and blend them together;

[0037] (iv) Tableting: Using a rotary tablet press, tablets are compressed according to the target tablet weight and hardness.

[0038] Compared with the prior art, the present invention identifies the related substances of the valsartan-amlodipine pharmaceutical composition based on impurity research experiments, and provides corresponding detection methods and steps for the related substances.

[0039] The detection method of the present invention has good specificity and robustness. When the chromatographic conditions fluctuate to a certain extent, it does not affect the accurate detection and quantification of impurities, and can effectively control the quality of products. Attached Figure Description

[0040] Figure 1 This is a gradient 1 system applicability map for Example 3.

[0041] Among them, peak 1 is valsartan impurity G, peak 2 is valsartan impurity I, peak 3 is amlodipine impurity D, peak 4 is amlodipine impurity F, peak 5 is valsartan 2b, peak 6 is levamlodipine, peak 7 is amlodipine impurity E, peak 8 is valsartan impurity B, peak 9 is valsartan 2c, peak 10 is amlodipine impurity G, peak 11 is valsartan 2e, peak 12 is valsartan, peak 13 is amlodipine impurity B, peak 14 is valsartan impurity F, peak 15 is amlodipine impurity H, peak 16 is valsartan impurity E, and peak 17 is valsartan impurity D.

[0042] Figure 2 This is a gradient 2 system applicability map for Example 3.

[0043] Among them, peak 1 is valsartan impurity G, peak 2 is valsartan impurity I, peak 3 is amlodipine impurity D, peak 4 is amlodipine impurity F, peak 5 is valsartan 2b, peak 6 is levamlodipine, peak 7 is amlodipine impurity E, peak 8 is valsartan impurity B, peak 9 is valsartan impurity 2c, peak 10 is valsartan impurity 2d, peak 11 is valsartan impurity G, peak 12 is valsartan impurity 2e, peak 13 is valsartan, peak 14 is amlodipine impurity B, peak 15 is valsartan impurity E, peak 16 is amlodipine impurity F, peak 17 is valsartan impurity H, peak 18 is valsartan impurity D, peak 19 is valsartan impurity C, and peak 20 is amlodipine impurity A.

[0044] Figure 3 This is a gradient 3 system applicability map for Example 3.

[0045] Among them, peak 1 is valsartan impurity G, peak 2 is valsartan impurity I, peak 3 is amlodipine impurity D, peak 4 is amlodipine impurity F, peak 5 is valsartan 2b, peak 6 is levamlodipine, peak 7 is amlodipine impurity E, peak 8 is valsartan impurity B, peak 9 is valsartan impurity 2c, peak 10 is valsartan impurity 2d, peak 11 is valsartan impurity G, peak 12 is valsartan impurity 2e, peak 13 is valsartan, peak 14 is amlodipine impurity B, peak 15 is valsartan impurity E, peak 16 is valsartan impurity F, peak 17 is amlodipine impurity H, peak 18 is valsartan impurity H, peak 19 is valsartan impurity D, peak 20 is valsartan impurity C, and peak 21 is amlodipine impurity A. Detailed Implementation

[0046] The invention will be further described through the following embodiments; however, the scope of the invention is not limited to the following embodiments. Those skilled in the art will understand that various changes and modifications can be made to the invention without departing from its spirit and scope. Unless otherwise stated, the reagents, materials, and instruments used in the following embodiments are all available through conventional commercial means, but the invention is still described in detail herein. The following embodiments further illustrate the invention, but are not intended to limit it.

[0047] The relevant test samples and reference samples are shown in Table 1 and Table 2, respectively.

[0048] Table 1. Preparation and source of test samples

[0049]

[0050] Table 2. Sources of reference standards

[0051]

[0052]

[0053] All active pharmaceutical ingredients and excipients involved in the embodiments of this invention are commercially available. The film-coating premix (gastric-soluble type) in the embodiments of this invention comprises hydroxypropyl methylcellulose, titanium dioxide, talc, polyethylene glycol 400, and yellow iron oxide, purchased from Shanghai Carvac Coating Technology Co., Ltd.; microcrystalline cellulose (M105 type) purchased from Mingtai Chemical Co., Ltd.; microcrystalline cellulose (101 and 102 types) purchased from Ruidenmeier Natural Fiber Manufacturing (Changzhou) Co., Ltd.; crospovidone purchased from ISP Technologies Inc.; crospovidone sodium carboxymethyl cellulose purchased from Aminste (Shanghai) Trading Co., Ltd.; and silica and magnesium stearate purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.

[0054] Example 1: Formulation and preparation method of the compositions of samples 1-3.

[0055] Table 3 Formulations of Compositions for Samples 1 to 3

[0056]

[0057] Preparation methods of samples 1-3:

[0058] (i) Premixing: Place amlodipine besylate, valsartan, microcrystalline cellulose, crospovidone, crospovidone sodium carboxymethyl cellulose, silica, and magnesium stearate (3.0 mg / tablet) in a mixer and mix at 12 rpm for 3 min. Then, manually pass the mixture through a 60-mesh sieve.

[0059] (ii) Dry granulation: Add the premixed powder to a dry granulator, with a hydraulic pressure of 30 bar, screw speed of 30 rpm, roller speed of 6 rpm, roller gap of 0.6 mm, granulation screen aperture of 0.8 mm, and granulation speed of 100 rpm for dry granulation. Collect fine powder smaller than 60 mesh, and perform secondary granulation with the same process parameters. Combine the granules from the two granulations as dry granules; (iii) Total mixing: Place the dry granules and magnesium stearate (additional 1.5 mg / tablet) in a mixer for total mixing, and mix at a mixing speed of 12 rpm for 5 min;

[0060] (iv) Tableting: Using a rotary tablet press and an 8.0mm tableting punch, tablets are compressed according to the target tablet weight and hardness.

[0061] Example 2: Composition formulation and preparation method of sample 4

[0062] Table 4. Formulation of composition for sample 4

[0063]

[0064] Preparation method of sample 4:

[0065] (i) Premixing: Place amlodipine besylate, valsartan, microcrystalline cellulose, crospovidone, crospovidone sodium carboxymethyl cellulose, silica, and magnesium stearate (3.0 mg / tablet) in a mixer and mix at 12 rpm for 20 min;

[0066] (ii) Dry granulation: Add the premixed powder to the dry granulator, set the hydraulic pressure to 50 bar, screw speed to 60 rpm, roller speed to 20 rpm, roller gap to 1.0 mm, upper granulation screen aperture to 4.6 mm, lower granulation screen aperture to 0.8 mm, and upper and lower granulation speeds to 80 rpm for dry granulation; collect the fine powder smaller than 60 mesh, and perform secondary granulation with the same process parameters. Combine the granules from the two granulations as dry granules.

[0067] (iii) Total mixing: Place the dry granules and magnesium stearate (additional 1.5 mg / tablet) in a mixer and mix for 10 min at a speed of 12 rpm;

[0068] (iv) Tableting: Using a rotary tablet press and an 8.0mm tableting punch, tablets are compressed according to the target tablet weight and hardness;

[0069] (v) Coating: Using a high-efficiency coating machine and setting reasonable coating parameters, the coating weight gain is 5.0%.

[0070] Example 3: Screening of elution procedures

[0071] (1) Amlodipine impurity D stock solution: Accurately weigh an appropriate amount of amlodipine impurity D reference standard, dissolve it in a solvent and quantitatively dilute it to prepare a solution containing approximately 500 μg of amlodipine impurity D per 1 ml;

[0072] (2) Stock solutions of amlodipine impurities A, B, E, F, G, and H: Accurately weigh appropriate amounts of amlodipine impurity A, B, E, F, G, and H reference standards, dissolve them in solvent, and quantitatively dilute them to prepare solutions containing approximately 125 μg of impurities per ml.

[0073] (3) Valsartan impurity reference standard stock solution: Accurately weigh appropriate amounts of valsartan and valsartan impurity G, B, C, D, H, E, F, I reference standards, dissolve them in solvents and quantitatively dilute them to prepare solutions containing approximately 1600 μg of each component per 1 ml.

[0074] (4) Mixed reference stock solution 1: Appropriate amounts of reference standards of levamlodipine besylate, valsartan, valsartan impurities B, C, D, E, F, G, H, I and amlodipine impurities A, B, D, E, F, G, H were dissolved in solvent and quantitatively diluted to prepare a mixed solution containing approximately 5 μg of levamlodipine, 5 μg of each of the following impurities per ml: 12.5 μg of amlodipine impurity D, 160 μg of valsartan, and 160 μg of each of the following impurities per ml: valsartan impurity B, C, D, E, F, G, H, I.

[0075] (5) Mixed reference stock solution 2: appropriate amounts of levamlodipine besylate, valsartan, valsartan impurities B, C, D, E, F, G, H, I and amlodipine impurity D reference standards were dissolved in solvent and quantitatively diluted to prepare a mixed solution containing approximately 5 μg of levamlodipine, 12.5 μg of amlodipine impurity D, 160 μg of valsartan, and 160 μg of each of valsartan impurities B, C, D, E, F, G, H, I per ml;

[0076] (6) Preparation of System Suitability Solution 1: Weigh 7 mg of amlodipine besylate and 160 mg of valsartan, place them in a 20 ml volumetric flask, then transfer 12 ml of the mixed reference stock solution into the same volumetric flask and add solvent to make up to volume. (Contains 0.25 mg / ml amlodipine, 8 mg / ml valsartan, 1.25 μg / ml amlodipine impurity D, 0.5 μg / ml amlodipine impurities A, B, E, F, G, and H, and 16 μg / ml valsartan impurities).

[0077] (7) Preparation of System Suitability Solution 2: Weigh 7 mg of amlodipine besylate and 160 mg of valsartan, place them in a 20 ml volumetric flask, then transfer 2 ml of mixed reference standard stock solution 2 into the same volumetric flask and add solvent to make up to volume. (Contains 0.25 mg / ml amlodipine, 8 mg / ml valsartan, 1.25 μg / ml amlodipine impurity D, and 16 μg / ml valsartan impurities).

[0078] Chromatographic conditions: Thermo high performance liquid chromatograph, Luna C18(2) (4.6×150mm, 3.0μm) column, with 1% triethylamine solution (pH adjusted to 2.6 with phosphoric acid) as mobile phase A and methanol-acetonitrile (70:30) as mobile phase B, gradient elution, detection wavelength 237nm, flow rate 1.0ml / min, column temperature 30℃, injection volume 10μl; gradient elution program is shown in Table 5.

[0079] Table 5. Gradient elution program table

[0080]

[0081] Based on the above chromatographic conditions, injections were performed on each impurity localization solution and system suitability solution 1. The system suitability solution was then analyzed using three gradient methods, and the chromatograms are shown below. Figures 1-3 As shown, the results indicate that in the gradient 1 method, neither valsartan impurity 2e nor valsartan achieved baseline separation; neither amlodipine impurities B nor H achieved baseline separation from valsartan impurity F; and neither valsartan impurity C nor amlodipine impurity A showed peaks within 25 minutes. In both the gradient 2 and gradient 3 methods, all impurities showed peaks. However, when using gradient 2 elution, valsartan impurity B and amlodipine impurity E could not be separated. In the system suitability solution using the gradient 3 method, not only were more impurities detected, but valsartan impurity B could also be separated from adjacent impurities.

[0082] The system applicability results of gradient 2 and gradient 3 methods are shown in Table 6.

[0083] Table 6: Applicability Results of Gradient 2 and Gradient 3 Systems

[0084]

[0085] Note: Valsartan 2b, 2c, 2d, and 2e are specific monohexies with uncertain structures.

[0086] Example 4: Investigation of different mobile phase pH and column temperature

[0087] Chromatographic conditions: Thermo high performance liquid chromatograph, Luna C18(2) (4.6×150mm, 3.0μm) column, with 1% triethylamine solution (pH adjusted to 2.4~3.0 with phosphoric acid) as mobile phase A and methanol-acetonitrile (70:30) as mobile phase B, gradient elution, detection wavelength 237nm, flow rate 1.0ml / min, column temperature 20℃~30℃, injection volume 10μl; gradient elution program is shown in Table 7.

[0088] Table 7 Gradient elution program

[0089]

[0090] The system suitability solution 2 prepared in step (7) of Example 3 was injected, and the results are shown in Table 8 below.

[0091] Table 8: Suitability Results of Mobile Phase A at Different pH Values ​​and Column Temperatures

[0092]

[0093] Based on the above test results for different pH mobile phases A and different temperatures, it can be seen that when the mobile phase pH is 2.4~2.8 and the column temperature is 20℃~30℃, the resolution of each peak meets the requirements.

[0094] Example 5: Investigation of different chromatographic columns

[0095] Table 9 Information on different chromatographic columns

[0096]

[0097] The system suitability solution 2 prepared in step (7) of Example 3 was injected, and the results are shown in Table 10 below:

[0098] Table 10: Suitability Results of Different Column Systems

[0099]

[0100] The suitability of the system was tested using different chromatographic columns, and the separation degree between each impurity met the requirements.

[0101] Example 6: Specificity Test

[0102] Levoamlodipine besylate feedstock is unstable under alkaline conditions; it is also unstable under acidic, oxidizing, and light-exposed conditions. The peak purity of the main peak under all degradation conditions is 1000, and the material balance is between -4.7% and 3.0%. Valsartan feedstock is relatively unstable at high temperatures; it is relatively stable under acidic, alkaline, oxidizing, and light-exposed conditions. The peak purity of the main peak under all degradation conditions is ≥990, and the material balance is between -4.9% and -2.3%, all meeting the requirements.

[0103] The valsartan-amlodipine drug combination is unstable under alkaline conditions; it is also unstable under acidic, oxidative, and light-induced conditions. The peak purity of the main peak under all degradation conditions is ≥990, and the material balance is within -3.7% to 4.2%. Degradation conditions and results under acid, alkali, oxidation, high temperature, and light-induced conditions are shown in Tables 11-13. This indicates that under these chromatographic conditions, the forced degradation experiment achieved a material balance (±5%) and a main peak purity that met the requirements (greater than 980), demonstrating the good specificity of this method. Impurity information is shown in Tables 14-15.

[0104] Table 11: Results of forced degradation of levamlodipine besylate

[0105]

[0106] Table 12: Results of forced degradation of valsartan

[0107]

[0108] Table 13: Forced Degradation Results of Valsartan-Levoamlodipine Tablets

[0109]

[0110] Table 14. Impurity Information

[0111]

[0112] Example 7: Determination of related substances - Determination of related substances in the compositions of samples 1-4

[0113] The detection of related substances in the valsartan-levamlodipine pharmaceutical composition includes the following steps:

[0114] (1) Solvent preparation: mobile phase A - mobile phase B (10:90);

[0115] (2) Preparation of test solution: Accurately weigh an appropriate amount of fine powder of this product (approximately equivalent to 5 mg of amlodipine and 160 mg of valsartan), place it in a 20 ml volumetric flask, add about 15 ml of solvent, sonicate to dissolve, cool, dilute to the mark with solvent, shake well, centrifuge, and take the supernatant.

[0116] (3) Preparation of reference solution: Accurately weigh appropriate amounts of levamlodipine besylate reference standard and valsartan reference standard, dissolve them in solvent and quantitatively dilute them to prepare a solution containing approximately 0.5 μg of levamlodipine and 16 μg of valsartan per 1 ml;

[0117] (4) Preparation of sensitivity solution: Accurately measure 5 ml of the reference solution, place it in a 20 ml volumetric flask, dilute to the mark with solvent, and shake well;

[0118] (5) Preparation of system suitability solution: Take appropriate amounts of levamlodipine besylate, valsartan, valsartan impurity B, valsartan impurity E, valsartan impurity F, valsartan impurity G, valsartan impurity H and amlodipine impurity D reference standards, dissolve them in solvent and dilute quantitatively to prepare a mixed solution containing approximately 0.25 mg of levamlodipine, 8 mg of valsartan, 16 μg of each valsartan impurity and 1.25 μg of amlodipine impurity D per 1 ml.

[0119] Using the above method, the tablets (plain-coated and coated tablets) prepared in Examples 1 and 2 of this invention were tested for compatibility of raw materials and excipients. Samples 1-3 were subjected to influencing factor tests under high temperature (60°C) for 10 and 30 days and high humidity (92.5%RH) for 10 and 30 days. Sample 4 was subjected to high temperature (60°C) for 10 days, high temperature (40°C) for 10 and 30 days, high humidity (92.5%RH) for 10 and 30 days, and light exposure (total illuminance not less than 1.2 million lux and near-ultraviolet lamp energy not less than 200 W·hr / m²). 2 The compatibility of raw materials and auxiliary materials was investigated by conducting an influencing factor test under the following conditions: samples 1-4 were placed in double aluminum packaging under high humidity conditions, while the other samples were placed in the open. The test results of relevant substances are shown in Tables 15-18.

[0120] Table 15: Summary of Results of Related Substances Test on Influencing Factors of Sample 1

[0121]

[0122] Table 16: Summary of Results of Related Substances Test on Influencing Factors of Sample 2

[0123]

[0124] Table 17: Summary of Results of Related Substances Test on Influencing Factors of Sample 3

[0125]

[0126] Table 18: Summary of Results of Related Substances Tests for Influencing Factors of Sample 4

[0127]

[0128] Tables 15-17 show that the valsartan-amlodipine drug compositions of samples 1-3 are unstable under high temperature (60℃) conditions, mainly degrading into amlodipine impurity D and valsartan impurity G; they are relatively stable under high humidity conditions, without producing large impurities and without a significant increase in impurity content; Table 18 shows that after 10 days of storage at high temperature (60℃) for sample 4, amlodipine impurity D increased significantly. Compared with the results of day 0, after 10 days of storage at high temperature (60℃) for prescription 1, amlodipine impurity D increased significantly. After 30 days of storage at high temperature (40℃), amlodipine impurity D and total impurities increased slightly, but still within the limits. Under light and high humidity conditions, there were no significant changes in related substances. In the above-mentioned influencing factor tests, the chromatographic method for related substances can accurately determine the results of related substances in the samples.

[0129] The above-described embodiments are merely preferred embodiments provided to fully illustrate the present invention, and the scope of protection of the present invention is limited.

[0130] The scope is not limited thereto. All equivalent substitutions or modifications made by those skilled in the art based on this invention are within the scope of protection of this invention. The scope of protection of this invention is defined by the claims.

Claims

1. A method for detecting related substances in a valsartan-levamlodipine pharmaceutical composition, characterized in that, High performance liquid chromatography (HPLC) was used to detect the valsartan-levamlodipine combination and its related substances. The active ingredients to be detected included valsartan and levamlodipine, and the impurities to be detected included valsartan impurity B, valsartan impurity G, valsartan impurity H, valsartan impurity F, valsartan impurity E and amlodipine impurity D; valsartan related substances 2a, valsartan related substances 2b, valsartan related substances 2c, valsartan related substances 2d, valsartan related substances 2e and valsartan related substances 2f.

2. The detection method according to claim 1, characterized in that, The high performance liquid chromatography method uses a reversed-phase column, preferably a Luna® C18 (2) 100Å (150mm×4.6mm×3μm) or an Xbridge® C18 (150mm×4.6, 3.5μm).

3. The detection method according to claim 2, characterized in that, In the high-performance liquid chromatography method, mobile phase A is a mixed solution of triethylamine-phosphoric acid-water with a pH of 2.4-3.0, and mobile phase B is a mixed solution of methanol and acetonitrile with a volume ratio of methanol to acetonitrile of 70:

30. Gradient elution is used for elution.

4. The detection method according to claim 3, characterized in that, The gradient elution procedure is as follows: 。 5. The detection method according to any one of claims 1-4, characterized in that, The detection wavelength of the high-performance liquid chromatography is 235nm~240nm, preferably 237nm.

6. The detection method according to any one of claims 2-5, characterized in that, The column temperature of the chromatographic column is 20℃~30℃.

7. The detection method according to any one of claims 2-6, characterized in that, The injection volume of the chromatographic column is 10 μl.

8. The detection method according to any one of claims 1-7, characterized in that: The valsartan-levamlodipine pharmaceutical composition comprises valsartan, levamlodipine besylate, a diluent, a disintegrant, a flow aid, and a lubricant, with the following mass percentages: levamlodipine besylate at 1-2.0%, valsartan at 47-50%, the diluent at 28-32.7%, the disintegrant at 12.5-18%, the flow aid at 0.8-0.9%, and the lubricant at 2.7-2.8%.

9. The detection method according to claim 8, characterized in that, The diluent is microcrystalline cellulose.

10. The detection method according to claim 8 or 9, characterized in that, The disintegrant is one or a combination of two of crospovidone and crospovidone sodium carboxymethyl cellulose.

11. The detection method according to any one of claims 8-10, characterized in that, The flow aid is colloidal silica.

12. The detection method according to any one of claims 8-11, characterized in that, The lubricant is magnesium stearate.

13. The detection method according to any one of claims 8-12, characterized in that, The valsartan-amlodipine pharmaceutical composition may optionally further include a coating agent, wherein the coating agent is a gastrosoluble film coating material and the weight of the coating agent accounts for 4.6% to 5.8% of the tablet core weight.

14. The detection method according to any one of claims 8-12, characterized in that: The pharmaceutical composition comprises: 3.47 parts of amlodipine besylate, 160 parts of valsartan, 104.53 parts of microcrystalline cellulose M102, 40 parts of crospovidone, 3 mg of silicon dioxide, and 9 parts of magnesium stearate.

15. The detection method according to any one of claims 8-12, characterized in that: The pharmaceutical composition comprises: 3.47 parts of amlodipine besylate, 80.00 parts of valsartan, 47.53 parts of microcrystalline cellulose M105, 20.00 parts of crospovidone, 10.00 parts of crospovidone sodium carboxymethyl cellulose, 1.50 parts of silica, and 4.50 parts of magnesium stearate.

16. The detection method according to any one of claims 8-12, characterized in that: The composition comprises: 3.47 parts of amlodipine besylate, 80.00 parts of valsartan, 47.53 parts of microcrystalline cellulose, 20.00 parts of crospovidone, 10.00 parts of crospovidone sodium carboxymethyl cellulose, 1.50 parts of silica, and 4.50 parts of magnesium stearate.

17. The detection method according to any one of claims 8-12, characterized in that: The composition comprises: 3.47 parts of amlodipine besylate, 80.00 parts of valsartan, 47.53 parts of microcrystalline cellulose, 20.00 parts of crospovidone, 10.00 parts of crospovidone sodium carboxymethyl cellulose, 1.50 parts of silica, and 4.50 parts of magnesium stearate.

18. The method for detecting related substances in the valsartan-levamlodipine pharmaceutical composition according to any one of claims 1 to 17 is used in the quality control of valsartan-levamlodipine.

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