A Dissolution Detection Method for Dotenoxetine Tablets

Abstract

This invention discloses a dissolution detection method for dotenoradine tablets, comprising the following steps: S1, preparing a dissolution medium: the dissolution medium is an aqueous solution containing a surfactant and a buffer salt, wherein the surfactant is a compound system of sodium dodecyl sulfate and poloxamer 407, and the buffer salt is used to maintain the pH of the medium at 6.8±0.05; S2, dissolution determination: using the dissolution medium prepared in step S1 as the medium, a dissolution test is performed using the paddle method at 37.0℃±0.5℃ and a rotation speed of 70-80 rpm; S3, sample collection and processing: samples are taken at specified time points, filtered, and the filtrate is used as the test solution; S4, HPLC analysis: the concentration of dotenoradine in the test solution is determined by high performance liquid chromatography, and the cumulative dissolution rate is calculated. This invention addresses the problems of incomplete drug dissolution, poor data repeatability, and inability to effectively distinguish between products of different quality in existing dotenoradine tablet dissolution detection methods.

Description

Technical Field

[0001] This invention relates to the technical field of drug detection, specifically a dissolution detection method for dotenoradine tablets. Background Technology

[0002] Dotinurad is a novel, highly selective uric acid reabsorption transporter 1 (URAT1) inhibitor. It effectively lowers serum uric acid levels by specifically inhibiting the reabsorption of uric acid in the proximal convoluted tubules of the kidneys, thereby promoting uric acid excretion in urine. Clinically, it is primarily used to treat gout and related hyperuricemia. Unlike traditional xanthine oxidase inhibitors such as allopurinol and febuxostat, dotinurad acts directly on the uric acid excretion process, offering significant therapeutic advantages for patients with uric acid excretion disorders.

[0003] However, dotenorazole belongs to Biopharmaceutical Class II drugs, characterized by poor water solubility and high permeability. This low solubility is a major challenge in the development of its oral solid dosage forms (such as tablets), as it not only directly affects the rate and extent of drug absorption in vivo, potentially leading to lower bioavailability, but also poses significant difficulties for dissolution testing in its quality control.

[0004] Existing dissolution methods are unable to sensitively distinguish the quality differences of dotenoradine tablets prepared with different formulations or processes. For example, tablets prepared using conventional formulation technology (CN120305210A) and advanced technologies such as solid dispersions (CN121102211A) aim to improve dissolution through formulation optimization. However, if the dissolution detection method itself is not sensitive enough, two products with vastly different qualities may show similar dissolution profiles. This makes dissolution testing unable to provide effective guidance for formulation screening and process optimization in the formulation development stage, and also unable to identify deviations in key manufacturing processes during quality control.

[0005] Dissolution rate is a core indicator for evaluating the quality of solid oral dosage forms, and it is crucial for ensuring batch-to-batch consistency, assessing the impact of formulation and process changes, and predicting in vivo bioavailability. Currently, for dissolution testing of dotenoradine tablets, the art typically refers to the general rules of the Chinese Pharmacopoeia and uses conventional dissolution methods, but these methods have significant problems and limitations.

[0006] Existing technologies typically use water, hydrochloric acid solutions (e.g., pH 1.0), or phosphate buffers with different pH values ​​(e.g., pH 4.5, 6.8) as dissolution media. Due to the inherent strong hydrophobicity of dotenorazole, it is difficult to effectively wet and dissolve in these conventional media. For example, dotenorazole is almost insoluble in a pH 1.0 medium simulating the acidic environment of the stomach; and its solubility is still limited in a pH 6.8 buffer. This results in slow dissolution rates of dotenorazole tablets when tested using conventional methods, often leading to low final dissolution rates (e.g., dissolution rates often below 70% after 45 minutes), failing to accurately reflect the dissolution potential of the formulation itself, and making it difficult to meet the clinical need for rapid onset of action.

[0007] Because drug dissolution is incomplete and susceptible to accidental factors (such as drug particle aggregation and adsorption), dissolution data obtained using conventional methods often fluctuate significantly, resulting in high relative standard deviations (RSDs). This poor repeatability and intermediate precision reduce the reliability of the detection method, making it unsuitable as a release standard or a stable indicator for stability testing, thus introducing uncertainty into product quality control.

[0008] Therefore, there is an urgent need in this field to develop a novel method specifically for the dissolution testing of dotenoradine tablets. This method should effectively overcome the bottleneck of low solubility in dotenoradine. Summary of the Invention

[0009] This application provides a dissolution detection method for dotenoradine tablets to solve the problems of incomplete drug dissolution, poor data repeatability, and inability to effectively distinguish products of different quality in existing dotenoradine tablet dissolution detection methods.

[0010] This application provides a dissolution detection method for dotenoradine tablets, comprising the following steps: S1, preparing a dissolution medium: the dissolution medium is an aqueous solution containing a surfactant and a buffer salt, wherein the surfactant is a compound system of sodium dodecyl sulfate and poloxamer 407, and the buffer salt is used to maintain the pH of the medium at 6.8±0.05; S2, dissolution determination: using the dissolution medium prepared in step S1 as the medium, a dissolution test is performed using the paddle method at 37.0℃±0.5℃ and a rotation speed of 70-80 rpm; S3, sample collection and processing: samples are taken at specified time points, filtered, and the filtrate is used as the test solution; S4, HPLC analysis: the concentration of dotenoradine in the test solution is determined by high performance liquid chromatography, and the cumulative dissolution rate is calculated.

[0011] By adopting the above technical solution, the present invention significantly improves the apparent solubility of dotenoradine through the combination of sodium dodecyl sulfate (SDS) and poloxamer 407 and a pH 6.8 environment, ensuring that the drug can be completely released from the tablet.

[0012] Since water or buffer solutions alone cannot effectively wet and disperse hydrophobic dotenoramide crystals, sodium dodecyl sulfate (DSL) rapidly adsorbs onto the tablet surface and the hydrophobic interface of drug particles, significantly reducing solid-liquid interfacial tension. This allows the dissolution medium to quickly penetrate the tablet, strongly promoting tablet disintegration and drug particle dispersion, thus solving the problem of initial dissolution difficulties. Poloxamer 407 molecules spontaneously aggregate in aqueous solution to form micelles; their hydrophobic cores can encapsulate dissolved dotenoramide molecules, dissolving the drug within the micelles and significantly improving the apparent solubility of the drug in the medium. This prevents recrystallization of the dissolved drug after localized supersaturation, ensuring a continuous and complete dissolution process.

[0013] Preferably, in step S1, the concentration of sodium dodecyl sulfate is 0.4%-0.6% (w / v), and the concentration of poloxamer 407 is 0.4%-0.6% (w / v).

[0014] By adopting the above technical solution, the concentrations of sodium dodecyl sulfate and poloxamer 407 are strictly controlled in this application. If the concentration is too low, the solubilizing effect is insufficient and may not be able to completely overcome the hydrophobicity of the drug; if the concentration is too high, it will not only cause waste, but may also affect the dissolution kinetics or analytical process due to increased viscosity or the formation of complex micelles.

[0015] Preferably, in step S1, the buffer salt is a phosphate buffer pair.

[0016] Preferably, in step S2, the rotational speed is 60-80 rpm.

[0017] By adopting the above technical solution, this application increases the rotation speed from the conventional 50 rpm to 60-80 rpm, which can effectively reduce the thickness of the diffusion layer on the surface of drug particles, enhance the convection and mass transfer efficiency of the medium, and ensure the full and efficient dissolution process.

[0018] Preferably, in step S3, a 0.45 μm microporous membrane is used for filtration.

[0019] Preferably, in step S4, the chromatographic conditions of the high-performance liquid chromatography include a C18 column; a mobile phase of a mixed solution of acetonitrile and 0.1% phosphoric acid aqueous solution; and a detection wavelength of 270-280 nm.

[0020] Preferably, the volume ratio of acetonitrile to 0.1% phosphoric acid aqueous solution in the mobile phase is 55:45. One or more technical solutions provided in this application have at least the following technical effects or advantages: 1. This invention employs a surfactant system composed of SDS and poloxamer 407, which synergistically exerts rapid wetting and disintegration as well as micellar solubilization and stabilization. Combined with a buffer environment of pH 6.8, this greatly improves the apparent solubility of dotenoradine in the medium, ensuring that the drug can dissolve rapidly and completely.

[0021] 2. The optimized dissolution medium and conditions of this invention reduce the influence of accidental factors such as drug particle aggregation and adsorption, making the dissolution process more stable, significantly reducing the relative standard deviation of the measurement results, and providing good repeatability and intermediate precision of the method, which can be used as a stable quality release indicator.

[0022] 3. The steps of this method are clearly defined, and the reagents and instruments used are all routinely configured in pharmaceutical analysis laboratories. HPLC uses isocratic elution, making the method robust and easy to implement and promote in QC laboratories. Detailed Implementation

[0023] This application provides a dissolution detection method for dotenoradine tablets to solve the problems of incomplete drug dissolution, poor data repeatability, and inability to effectively distinguish products of different quality in existing dotenoradine tablet dissolution detection methods.

[0024] The technical solutions in the embodiments of this application will be clearly and completely described below with reference to the embodiments of this application. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments. Based on the embodiments of this application, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of this application.

[0025] It should be noted that the terms "first," "second," etc., in the specification and claims of this application are used to distinguish similar objects and are not necessarily used to describe a specific order or sequence. It should be understood that such data can be interchanged where appropriate so that the embodiments of this application described herein can be implemented in orders other than those described. Furthermore, the terms "comprising" and "having," and any variations thereof, are intended to cover non-exclusive inclusion; for example, a process, method, system, product, or server that comprises a series of steps or units is not necessarily limited to those steps or units explicitly listed, but may include other steps or modules not explicitly listed or inherent to such processes, methods, products, or devices.

[0026] Example 1 of this application provides a dissolution detection method for dotenoradine tablets, including preparation of dissolution medium, dissolution rate determination, sample collection and processing, and HPLC analysis.

[0027] S1. Preparation of dissolution medium: Taking the preparation of 1000 mL as an example, take sodium dodecyl sulfate (SDS): 5.0 g; poloxamer 407: 5.0 g; potassium dihydrogen phosphate (KH2PO4): 6.8 g; sodium hydroxide (NaOH): 10.0 g; purified water: add to 1000 mL.

[0028] The specific steps for preparing the dissolution medium are as follows: a. Measure about 800 mL of purified water and heat it to 40-45℃.

[0029] b. Accurately weigh 5.0g of SDS and 5.0g of poloxamer 407, add them to the above-mentioned warm water, and stir on a magnetic stirrer until completely dissolved to obtain a clear solution.

[0030] c. Add 6.8g of accurately weighed potassium dihydrogen phosphate to the solution and stir until completely dissolved.

[0031] d. Carefully adjust the pH of the solution to 6.80 ± 0.05 using 1 mol / L sodium hydroxide solution.

[0032] e. Transfer the solution completely to a 1000 mL volumetric flask, dilute to the mark with purified water, and shake well.

[0033] f. Before use, the prepared dissolution medium shall be subjected to ultrasonic degassing treatment.

[0034] S2. Dissolution test: Refer to Method II (paddle method) of General Chapter 0931 of the Chinese Pharmacopoeia. In Example 1 of this application, the volume of the dissolution medium was 900.0 mL, the medium temperature was maintained at 37.0℃±0.5℃, and the paddle speed was set to 75 rpm. Six tablets of dotenoradine were taken, each accurately weighed, and then steadily placed into dissolution vessels containing 900 mL of dissolution medium. The instrument was immediately started, and timing began.

[0035] S3. Sample Collection and Processing: At 10, 15, 20, 30, and 45 minutes after the start of dissolution, precisely aspirate approximately 5 mL of solution from the center of the dissolution vessel, at the midpoint of the liquid surface, using a syringe. Immediately after sampling, add blank dissolution medium of the same temperature and volume to the dissolution vessel. Filter the sample solution immediately through a 0.45 μm microporous membrane, discarding the first 1 mL of initial filtrate, and collect the subsequent clear filtrate as the test solution.

[0036] S4. HPLC Analysis: The chromatographic column used in Example 1 of this application was an octadecylsilane-bonded silica (C18) column (4.6 mm × 150 mm, 5 μm); the mobile phase was an aqueous solution of acetonitrile and 0.1% phosphoric acid (volume ratio 55:45); the flow rate was 1.0 mL / min; the column temperature was 30°C; the detection wavelength was 275 nm; and the injection volume was 10 μL.

[0037] Accurately measure the test solution and the dotenorazole reference solution of known concentration, inject them separately into the liquid chromatograph, and record the chromatograms. Calculate the concentration of dotenorazole in the solution at each time point using the external standard method based on peak area, then calculate the cumulative dissolution rate (%) of each tablet at each time point, and calculate the average value and relative standard deviation (RSD) of 6 tablets. Example 2

[0038] The difference between Example 2 and Example 1 is that the concentration of the surfactant in the dissolution medium was adjusted. The SDS concentration was 0.4% (w / v), and the poloxamer 407 concentration was 0.6% (w / v).

[0039] S1. Preparation of dissolution medium: Taking the preparation of 1000 mL as an example, take sodium dodecyl sulfate (SDS): 4.0 g; poloxamer 407: 6.0 g; potassium dihydrogen phosphate (KH2PO4): 6.8 g; sodium hydroxide (NaOH): 10 g; and add purified water to 1000 mL.

[0040] The specific preparation steps are the same as in Example 1. The dissolution determination, sample preparation, and HPLC analysis steps and conditions are exactly the same as in Example 1. Example 3

[0041] The difference between Example 3 and Example 1 is that the rotation speed of the dissolution test was adjusted. The dissolution measurement parameters were adjusted so that the impeller speed was set to 70 rpm. All other conditions, including the dissolution medium formulation, preparation method, sample processing, and HPLC analysis conditions, were exactly the same as in Example 1.

[0042] Comparative Example 1 Comparative Example 1 used a standard pH 6.8 phosphate buffer solution as the dissolution medium.

[0043] Specifically, the dissolution medium was prepared according to the method in the Chinese Pharmacopoeia, using a phosphate buffer solution with a pH of 6.8, free of any surfactants. 6.8 g of potassium dihydrogen phosphate was dissolved in water, and the pH was adjusted to 6.8 with sodium hydroxide, bringing the volume to 1000 mL.

[0044] The dissolution test parameters used were the paddle method, with a medium volume of 900 mL, a temperature of 37°C, and a standard rotation speed of 50 rpm. Sample preparation and HPLC analysis conditions were the same as in Example 1.

[0045] Comparative Example 2 The difference between Comparative Example 2 and Example 1 is that a single surfactant (SDS) is used as the dissolution medium.

[0046] The dissolution medium was prepared in 1000 mL volume as follows: sodium dodecyl sulfate (SDS): 5.0 g; potassium dihydrogen phosphate (KH₂PO₄): 6.8 g; sodium hydroxide (NaOH): 10 g; purified water added to 1000 mL. This means the medium contained only 0.5% SDS and no poloxamer 407. The preparation steps were the same as in Example 1. The dissolution test parameters and subsequent analytical steps were the same as in Example 1.

[0047] The dissolution rates of Examples 1-3 and Comparative Examples 1-2 at 10, 15, 20, 30, and 45 minutes after the start of dissolution were statistically analyzed. Additionally, the average dissolution rate (%) over 45 minutes was measured; this was the average cumulative dissolution percentage of the six dotenoradine tablets tested at 45 minutes of the dissolution test. This measure further assesses the total amount of the active pharmaceutical ingredient (dotenoradine) released from the tablets under specified media and conditions after 45 minutes. A higher value indicates more complete and thorough drug dissolution.

[0048] The 45-minute RSD (%, n=6) is calculated based on the relative standard deviation (RSD) of six independent measurements (i.e., six tablets). It measures the dispersion of the dissolution data of the six tablets at 45 minutes. The smaller the RSD value, the closer the dissolution results of the six tablets are to each other and the smaller the fluctuation, indicating better repeatability and intermediate precision of the detection method, and more reliable data.

[0049] The detection data of Examples 1-3 and Comparative Examples 1-2 are summarized in Table 1 below.

[0050] Table 1. Dissolution data detection table for Examples 1-3 and Comparative Examples 1-2 Example 1 45.2 65.8 78.5 87.3 92.5 92.1 1.5 Example 2 40.1 61.5 75 85.2 90.8 90.3 1.8 Example 3 38.5 58.9 72.1 83.6 89.7 89.2 1.7 Comparative Example 1 5.2 9.8 15.3 22.1 28.5 28.1 12.5 Comparative Example 2 35.8 52.4 65 72.5 75.3 74.8 8.2 According to the table analysis, the average dissolution rate of all embodiments of the present invention at 45 minutes was close to or exceeded 90%, significantly higher than that of Comparative Example 1 and Comparative Example 2. This demonstrates that the solubilization system of SDS combined with poloxamer 407, combined with optimized pH and rotation speed, can ensure near-complete drug dissolution. Furthermore, Example 1 achieved a dissolution rate of 45.2% at 10 minutes, exhibiting rapid dissolution characteristics, which is attributed to the rapid wetting and disintegration effects of SDS. In contrast, Comparative Example 1 showed a dissolution rate of only 5.2% at 10 minutes, indicating that drug dissolution initiation is extremely difficult without surfactants.

[0051] Furthermore, in precision (RSD) testing, the three embodiments of this invention exhibited extremely low RSD values ​​at 45 minutes, ranging from 1.5% to 1.8%, demonstrating excellent method precision and repeatability. In contrast, Comparative Example 1 had an RSD as high as 12.5%, with significant data fluctuations; Comparative Example 2 had an RSD of 8.2%, which, while better than Comparative Example 1, was still far inferior to the embodiments of this application. This indicates that the combined effect of the compound surfactant system and optimized hydrodynamic conditions greatly stabilized the dissolution process and reduced random errors.

[0052] In addition, the dissolution curve of Comparative Example 2 showed a significant slowdown in growth after 30 minutes, eventually settling at approximately 75%, while the curve of the present invention continued to grow to over 90%. This clearly demonstrates that the micellar solubilizing and stabilizing effects of poloxamer 407 are crucial for achieving complete dissolution, and that this method can sensitively distinguish the advantages and disadvantages of two different formulation designs: one containing poloxamer 407 and the other not.

[0053] Finally, the dissolution curves of Example 1 and Example 3 showed distinguishable differences at each time point, such as a difference of about 3% at 45 minutes, indicating that the method can also sensitively reflect changes in the key process parameter of rotation speed and has the ability to provide guidance for process optimization.

[0054] It should be noted that the order of the embodiments described above is merely for descriptive purposes and does not represent the superiority or inferiority of the embodiments. Furthermore, specific embodiments have been described above. Other embodiments are within the scope of the appended claims. In some cases, the actions or steps described in the claims can be performed in a different order than those shown in the embodiments and still achieve the desired results. In some implementations, multitasking and parallel processing are also possible or may be advantageous.

[0055] The above description is only a preferred embodiment of this application and is not intended to limit this application. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the protection scope of this application.

[0056] This specification is merely an illustrative description of this application and is intended to cover any and all modifications, variations, combinations, or equivalents within the scope of this application. Clearly, those skilled in the art can make various alterations and modifications to this application without departing from its scope. Therefore, if such modifications and modifications fall within the scope of this application and its equivalents, this application intends to include such modifications and modifications.

Claims

1. A method for detecting the dissolution of dotenoradine tablets, characterized in that, Includes the following steps: S1. Preparation of dissolution medium: The dissolution medium is an aqueous solution containing a surfactant and a buffer salt, wherein the surfactant is a compound system of sodium dodecyl sulfate and poloxamer 407, and the buffer salt is used to maintain the pH of the medium at 6.8±0.

05. S2. Dissolution test: Using the dissolution medium prepared in step S1 as the medium, the dissolution test was carried out by paddle method at 37.0℃±0.5℃ and a rotation speed of 70-80 rpm. S3. Sample collection and processing: Samples are collected at specified time points, filtered, and the filtrate is used as the test solution. S4. HPLC analysis: The concentration of dotenoroxetine in the test solution was determined by high performance liquid chromatography, and the cumulative dissolution rate was calculated.

2. The dissolution detection method for dotenoradine tablets as described in claim 1, characterized in that, In step S1, the concentration of sodium dodecyl sulfate is 0.4%-0.6% (w / v), and the concentration of poloxamer 407 is 0.4%-0.6% (w / v).

3. The dissolution detection method for dotenoradine tablets as described in claim 1, characterized in that, In step S1, the buffer salt is a phosphate buffer pair.

4. The dissolution detection method for dotenoradine tablets as described in claim 1, characterized in that, In step S2, the rotational speed is 60-80 rpm.

5. The dissolution detection method for dotenoradine tablets as described in claim 1, characterized in that, In step S3, a 0.45 μm microporous membrane is used for filtration.

6. The dissolution detection method for dotenoradine tablets as described in claim 1, characterized in that, In step S4, the chromatographic conditions of the high-performance liquid chromatography include a C18 column; a mobile phase of a mixed solution of acetonitrile and 0.1% phosphoric acid aqueous solution; and a detection wavelength of 270-280 nm.

7. The dissolution detection method for dotenoradine tablets as described in claim 6, characterized in that, The volume ratio of acetonitrile to 0.1% phosphoric acid aqueous solution in the mobile phase is 55:45.