Determination method for dissolution curve of diclofenac sodium sustained release tablet

Abstract

The invention belongs to the technical field of pharmaceutical preparation analysis and detection, and particularly relates to a determination method of a dissolution curve of diclofenac sodium sustained release tablets. According to the method, a sample dissolution method is optimized, and a reciprocating cylinder method is used for dissolving out the sample, so that the determination method is not influenced by the release speed of the diclofenac sodium sustained release tablet in an acid medium and the degradation degree of the released raw material medicine, the in-vivo release environment of the medicine is better simulated, the accuracy is high, the reliability and the repeatability are good, and the method is suitable for industrial production. The method can be used for judging whether a self-made preparation of a BE test is equivalent to a reference or not, and the method for determining the dissolution curve established by the invention can provide guidance for the process research of a preparation prescription required by the declaration of a generic drug.

Description

Technical Field

[0001] The present invention belongs to the technical field of analysis and detection of pharmaceutical preparations, and particularly relates to a method for determining the dissolution curve of diclofenac sodium sustained-release tablets. Background Art

[0002] Diclofenac sodium is a non-steroidal compound, which has obvious anti-rheumatic, anti-inflammatory, analgesic and antipyretic effects. Experiments have proved that the main mechanism of the pharmacological action of diclofenac sodium is to inhibit the synthesis of prostaglandins, and prostaglandins are the main factors leading to inflammation, pain and fever. Clinical studies in animals and humans have shown that by inhibiting the synthesis of prostaglandins in the hypothalamic thermoregulatory center, the antipyretic effect can be achieved. Diclofenac sodium can be clinically used to treat rheumatoid and rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and pain and fever caused by various reasons.

[0003] In order to extend the dosing interval, maintain a stable blood drug concentration and reduce side effects, many manufacturers have developed diclofenac sodium into a sustained-release preparation. The sustained-release preparation can maintain the required blood drug concentration in the human body for a longer time, avoiding the large fluctuations in blood drug concentration caused by frequent daily medication in clinical practice, and improving the effectiveness, safety and patient compliance of medication. Determining the release rate of the sustained-release preparation and improving the requirements for release rate determination are very necessary to ensure the clinical efficacy of the preparation. The present invention proposes a reciprocating cylinder method for determining the dissolution degree that is more suitable for the detection of diclofenac sodium sustained-release preparations, better simulates the in vivo release environment of diclofenac sodium sustained-release tablets, is used to judge whether the self-made preparation and the reference preparation in the BE test are equivalent, and can provide guidance for the research on the formulation and process of the preparation required for the application of generic drugs. Summary of the Invention

[0004] The purpose of the present invention is to provide a reciprocating cylinder method for determining the dissolution degree that is more suitable for the detection of diclofenac sodium sustained-release preparations, reduce the influence of the difference in the release rate of diclofenac sodium sustained-release tablets in acidic medium and the degradation degree of the released active ingredient, better simulate the in vivo release environment of diclofenac sodium sustained-release tablets, is used to judge whether the self-made preparation and the reference preparation in the BE test are equivalent, and can provide guidance for the research on the formulation and process of the preparation required for the application of generic drugs.

[0005] The technical solution of the present invention is as follows: A method for determining the dissolution curve of diclofenac sodium sustained-release tablets, characterized by comprising the following steps: S1. Preparation of dissolution medium: Dissolution medium 1: 0.1 mol / L hydrochloric acid solution, and its preparation: Take an appropriate amount of hydrochloric acid, dilute it with water, shake well, and it is ready; Dissolution medium 2: Phosphate buffer solution with a pH of 6.8, and its preparation: Weigh an appropriate amount of potassium dihydrogen phosphate and sodium hydroxide, stir and dissolve with an appropriate amount of degassed water and dilute, and stir evenly to obtain. S2. Preparation of the test solution: The dissolution was carried out using the reciprocating cylinder method. An appropriate amount of 0.1 mol / L hydrochloric acid solution was used as dissolution medium 1, and the dipping speed was 30 dpm. After 2 h, the reciprocating cylinder of the dissolution device was moved to an appropriate amount of phosphate buffer solution with a pH of 6.8 as dissolution medium 2 for continued dissolution, and the dipping speed was 15 dpm. At 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, and 16 h, appropriate amounts were sampled, filtered through a membrane filter. An appropriate amount of the subsequent filtrate at each time point was placed in a centrifuge tube or test tube, filtered through a membrane filter, and then diluted with an appropriate amount of dissolution medium 2 and shaken well to obtain the test solution; S3. Preparation of the reference solution: An appropriate amount of diclofenac sodium reference substance was accurately weighed and placed in a volumetric flask. An appropriate amount of dissolution medium 2 was added, sonicated, diluted to the mark with diluent, and shaken well. An appropriate amount was accurately measured and placed in a volumetric flask, diluted to the mark with diluent, and shaken well to obtain the reference solution. Two portions were prepared in the same manner, namely reference solution ① and reference solution ②; S4. Determination: Appropriate amounts of the blank solution, reference solution, and test solution were taken. According to the ultraviolet-visible spectrophotometry, the absorbance was measured at a wavelength of 276 nm. After the system was stabilized, the blank solution was measured once, reference solution ① was measured 5 times, reference solution ② was measured once, and the test solution was measured once for each. Before the end of the sequence, reference solution ① was measured once again, and the readings were recorded and calculated; Furthermore, the specific dilution in step S2 is as follows:

[0006] Furthermore, in step S2, the sampling was carried out using an automatic sampler: the sampling volume was 5 ml, the volume discarded at the front end of the sampling needle was 0.5 ml, and at the same time, 5.5 ml of the dissolution medium at the same temperature was replenished.

[0007] Furthermore, the filter membrane material in step S2: PVDF or others with equivalent efficacy, and the pore size is 0.45 μm.

[0008] Furthermore, the concentration of diclofenac sodium prepared in step S3 is 0.02 mg / ml.

[0009] Furthermore, in step S2, the test sample was dissolved using the reciprocating cylinder method to obtain the test solution.

[0010] The beneficial effects of the present invention are: The present invention applies the reciprocating cylinder method to the dissolution determination of diclofenac sodium sustained-release tablets. The reciprocating cylinder method has a stronger shearing force, is more suitable for the detection of sustained-release preparations, and can better reflect the correlation between the in vitro and in vivo dissolution of diclofenac sodium sustained-release tablets. The dissolution method of the present invention first dissolves in 0.1 mol / L for 2 h and then transfers to a pH 6.8 medium for dissolution, simulating the in vivo drug release process. The results of the dissolution curve detection of the sustained-release tablets are consistent with the pre-BE data results, to a certain extent simulating the in vivo release environment of the drug. By optimizing the sample dissolution method, the determination method of the present invention is not affected by the release rate of diclofenac sodium sustained-release tablets in acidic media and the degradation degree of the released active pharmaceutical ingredient, with high accuracy, good reliability and repeatability. Therefore, the dissolution curve determination method established by the present invention can provide guidance for the research of the formulation prescription process required for the declaration of generic drugs. Description of the Drawings

[0011] Figure 1 Dissolution curve graph of the pH 6.8 dissolution medium (reciprocating cylinder method) after over-acidification Embodiments

[0012] The present invention will be further described in detail below in conjunction with the drawings and specific embodiments.

[0013] Example 1 A method for determining the dissolution curve of diclofenac sodium sustained-release tablets, characterized by comprising the following steps: S1. Preparation of the dissolution medium: Dissolution medium 1: 0.1 mol / L hydrochloric acid solution. Preparation method: Take 9 ml of hydrochloric acid, dilute it with water to 1000 ml, and shake well. Dissolution medium 2: Phosphate buffer solution with a pH of 6.8. Preparation method: Weigh 6.8 g of potassium dihydrogen phosphate and 0.896 g of sodium hydroxide, stir and dissolve with an appropriate amount of degassed water and dilute to 1000 ml, and stir evenly to obtain. S2. Preparation of the test solution: Use the reciprocating cylinder method for dissolution. Use 250 ml of 0.1 mol / L hydrochloric acid solution as dissolution medium 1, with an immersion speed of 30 dpm. After 2 h, the reciprocating cylinder of the dissolution device is moved to 250 ml of dissolution medium 2, phosphate buffer solution with a pH of 6.8, and continue to dissolve with an immersion speed of 15 dpm. At 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h, and 16 h, respectively, take 5.5 ml of samples (sampling method: using an automatic sampler, sampling volume 5 ml, discard 0.5 ml at the front end of the sampling needle, and simultaneously supplement 5.5 ml of dissolution medium at the same temperature), filter through a filter membrane (filter membrane material: PVDF or other materials with equivalent efficacy, pore size 0.45 μm), take an appropriate amount of the subsequent filtrate at each time point, place it in a centrifuge tube or test tube, filter through a filter membrane, and then add an appropriate amount of dissolution medium 2 to dilute, shake well, and use as the test solution. The specific dilution conditions are as follows:

[0014] S3. Preparation of reference solution (the concentration of diclofenac sodium prepared is 0.02 mg / ml): Take 20 mg of diclofenac sodium reference substance, weigh it accurately, place it in a 100-ml volumetric flask, add about 60 ml of dissolution medium 2, sonicate for 5 minutes, dilute to the mark with diluent, shake well, then accurately measure 5 ml and place it in a 50-ml volumetric flask, dilute to the mark with diluent, shake well to obtain the reference solution. Prepare 2 portions in the same way, namely reference solution ① and reference solution ②; S4. Determination: Take appropriate amounts of blank solution, reference solution and test solution, and determine the absorbance at the wavelength of 276 nm according to the ultraviolet-visible spectrophotometry. After the system is stable, measure the blank solution once, reference solution ① five times, reference solution ② once, and each test solution once. Measure reference solution ① once again before the end of the sequence, record the readings, and calculate according to the following formula:

[0015] In the formula: A s —— Peak area of the test solution; M r1 —— Quantity taken of reference substance ① (unit: mg); C r —— Content of the reference substance; N S —— Dilution factor of the test solution; N r —— Dilution factor of the reference solution; Q—— Specification of the test substance (0.1 g); A r1 —— Average peak area of the main peak of reference solution ① for 5 times;

[0016] In the formula: D n —— Dissolution rate measured at each time point; V1—— Fixed sampling volume at each time point (this volume includes the discarded volume); V2—— Volume of the dissolution medium.

[0017]

[0018] In the formula: A r1 —— Average peak area of the main peak of reference solution ① for 5 times; A r2 —— Peak area of the main peak of reference solution ②; M r1 —— Quantity taken of reference substance ① (unit: mg); M r2 —— Quantity taken of reference substance ② (unit: mg).

[0019] Example 2 The dissolution curve of the reference preparation of diclofenac sodium sustained release tablets (batch number: TJW04) in the pH 6.8 dissolution medium after peracidification (reciprocating cylinder method) was determined according to the method described in Example 1. The specific test data are shown in Table 1 below: Example 3

[0020] The dissolution curve of the reference preparation of diclofenac sodium sustained release tablets (batch number: TFJ97) in the pH 6.8 dissolution medium after peracidification (reciprocating cylinder method) was determined according to the method described in Example 1. The specific test data are shown in Table 2 below: Example 4

[0021] The dissolution curve of the self - made preparation of diclofenac sodium sustained release tablets in the pH 6.8 dissolution medium after peracidification (reciprocating cylinder method) was determined according to the method described in Example 1. The specific test data are shown in Table 3 below:

[0022] The dissolution curve graphs were made from the data obtained in the above - mentioned examples as Figure 1 shown. The dissolution curves of the self - made preparation of diclofenac sodium sustained release tablets and two batches of reference preparations (batch numbers: TJW04 and TFJ97, the license - holding company is Novartis Pharma GmbH, the trade name is VOLTAREN, and the specification is 0.1 g) in the pH 6.8 dissolution medium after peracidification (reciprocating cylinder method) are similar. Combining the data and results of clinical trials (pre - BE, fasting and post - prandial), (the blood drug concentration of the reference preparation reaches the peak state at 5 - 6 h in both fasting and post - prandial states), the dissolution curve in the pH 6.8 dissolution medium after peracidification (reciprocating cylinder method) simulates the in - vivo environment to a certain extent. Therefore, the USP3 reciprocating cylinder method dissolution curve of the above - mentioned diclofenac sodium sustained release tablets (specification: 0.1 g) can provide data guidance for the formulation development of this product.

[0023] Matters not covered in this invention are well - known techniques.

[0024] The above - mentioned examples are only for illustrating the technical concept and characteristics of the present invention. The purpose is to enable those skilled in the art to understand the content of the present invention and implement it accordingly, and it cannot be used to limit the protection scope of the present invention. All equivalent changes or modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.

Claims

1. A method for determining the dissolution curve of diclofenac sodium sustained release tablets, characterized in that: It includes the following steps: S1. Preparation of dissolution media: Dissolution medium 1: 0.1 mol / L hydrochloric acid solution. Preparation method: Take appropriate amount of hydrochloric acid, dilute with water, and shake well. Dissolution medium 2: Phosphate buffer solution with pH 6.

8. Preparation method: Weigh appropriate amounts of potassium dihydrogen phosphate and sodium hydroxide, stir and dissolve with appropriate amount of degassed water and dilute, stir evenly to obtain. S2. Preparation of test solution: Use the reciprocating cylinder method for dissolution. Use appropriate amount of 0.1 mol / L hydrochloric acid solution as dissolution medium 1, with an immersion speed of 30 dpm. After 2 h, move the reciprocating cylinder of the dissolution device to an appropriate amount of phosphate buffer solution with pH 6.8 as dissolution medium 2 and continue dissolution, with an immersion speed of 15 dpm. At the above time points, take appropriate amounts of samples respectively, filter through a membrane filter. Take appropriate amounts of the subsequent filtrates at each time point, place them in a centrifuge tube or test tube, filter through a membrane filter, then add appropriate amount of dissolution medium 2 to dilute, shake well, and use as the test solution. S3. Preparation of reference solution: Take appropriate amount of diclofenac sodium reference substance, weigh accurately, place it in a volumetric flask, add appropriate amount of dissolution medium 2, sonicate, dilute to the scale with diluent, shake well. Accurately measure an appropriate amount, place it in a volumetric flask, dilute to the scale with diluent, shake well, and use as the reference solution. Prepare 2 portions in the same way, namely reference solution ① and reference solution ②. S4. Determination: Take appropriate amounts of blank solution, reference solution and test solution, and determine the absorbance at a wavelength of 276 nm by ultraviolet-visible spectrophotometry. After the system is stable, measure the blank solution once, reference solution ① five times, reference solution ② once, and the test solution once each. Measure reference solution ① once again before the end of the sequence, record the readings, and calculate. Among them, the specific dilution situation in step S2 is as follows: ； In step S2, the sampling is carried out by an automatic sampler method: the sampling volume is 5 ml, the volume discarded at the front end of the sampling needle is 0.5 ml, and at the same time, 5.5 ml of dissolution medium at the same temperature is supplemented. The filter membrane material in step S2: PVDF or other materials with equivalent efficacy, with a pore size of 0.45 μm. The concentration of diclofenac sodium prepared in step S3 is 0.02 mg / ml.

2. The measurement method according to claim 1, characterized in that: In step S2, the test substance is dissolved to obtain the test solution by using the reciprocating cylinder method.

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