In vitro dissolution evaluation method for montelukast sodium pharmaceutical composition

Abstract

The present invention belongs to the field of medicine, and specifically relates to an in vitro dissolution evaluation method for a montelukast sodium pharmaceutical composition, wherein the montelukast sodium pharmaceutical composition is dissolved in a dissolution medium, samples are taken at different time points, the dissolution amount at each time point is measured, and a dissolution curve of the montelukast sodium is drawn; the dissolution medium is a hydrochloric acid or acetate buffer with a pH of 1.2 to 4.5, and 0.2 to 0.5% of Triton is added; the above percentages are mass / volume percentages. The method of the present invention monitors the rate and degree of in vitro release of a drug preparation in a suitable in vitro dissolution evaluation manner, and truly reflects the quality of the preparation sample.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and particularly relates to an in vitro dissolution evaluation method for a montelukast sodium pharmaceutical composition. Background Art

[0002] At present, the in vitro dissolution evaluation method of drugs generally uses the traditional paddle method and basket method. A good dissolution medium can reflect the changes in the product formulation process, reduce the risk of bioequivalence testing, and improve the efficiency of drug development. For APIs with poor solubility, such as BCS Class II and Class IV, the solubility of the API is pH-dependent, or it is difficult to dissolve in various media. After the preparations made of such APIs are made, the medium selection is more important in the in vitro dissolution evaluation.

[0003] Montelukast sodium is a cysteinyl leukotriene receptor 1 (CysLT1) antagonist that can inhibit the binding of LTC4, LTD4, LTE4 to cysteinyl leukotriene receptor 1 and reduce airway inflammation. For this reason, Montelukast sodium has anti-inflammatory and antiasthmatic pharmacological effects, and is suitable for patients with asthma and allergic rhinitis, and has good efficacy in patients with aspirin asthma and exercise-induced asthma. At present, the dissolution test conditions of Montelukast sodium tablets are 0.5% sodium dodecyl sulfate (SDS) aqueous solution, paddle method, 75rpm. Under this condition, Montelukast sodium dissolves more than 85% in 15 minutes, with almost no discrimination. In addition, the solubility of montelukast sodium in slightly acidic media is low, and the dissolution platform is below 40%. In acidic aqueous solutions, montelukast sodium will be converted into montelukast acid with lower solubility and precipitate. The solubilization effect of commonly used surfactants (such as SDS) is not obvious, resulting in the current evaluation methods of montelukast sodium in acidic dissolution media. There are problems such as insufficient accuracy and poor repeatability. The pharmacokinetic data of montelukast sodium tablets show that the peak time (Tmax) after oral administration is less than 3h, indicating that the dissolution curve in the pH range of 1.0-4.5 is more relevant in vitro and in vivo. Therefore, it is urgent to provide an in vitro dissolution evaluation method for montelukast sodium under low pH conditions to evaluate the rate and extent of drug dissolution or release in acidic media in order to assess the in vivo risk of oral solid preparations. Summary of the invention

[0004] In order to solve the above technical problems, the present invention provides an in vitro dissolution evaluation method for a montelukast sodium pharmaceutical composition. The method of the present invention can significantly increase the solubility of montelukast sodium in an acidic medium, and can reflect the changes in the formulation process of the montelukast sodium oral solid preparation through the dissolution curve, and fully evaluate the in vitro dissolution of homemade samples and reference preparations to reduce the risk of bioequivalence tests.

[0005] The technical solution provided by the present invention is as follows:

[0006] An in vitro dissolution evaluation method for a montelukast sodium pharmaceutical composition comprises dissolving the montelukast sodium pharmaceutical composition with a dissolution medium, sampling at different time points, measuring the dissolution amount at each time point, and drawing a dissolution curve of the montelukast sodium; the dissolution medium is a hydrochloric acid or acetate buffer with a pH of 1.2 to 4.5 in which 0.2 to 0.5% of Triton is added; the above percentages are mass / volume percentages.

[0007] Furthermore, the dissolution medium includes: pH 1.2 hydrochloric acid solution plus 0.2% Triton, pH 4.5 acetate buffer plus 0.5% Triton, and the above percentages are mass / volume percentages.

[0008] Furthermore, the dissolution medium includes: 0.5% SDS aqueous solution, pH 6.8 phosphate buffer, pH 1.2 hydrochloric acid solution plus 0.2% Triton, pH 4.5 acetate buffer plus 0.5% Triton, and the above percentages are mass / volume percentages.

[0009] Furthermore, the dissolution amount at each time point was determined by high performance liquid chromatography, and the chromatographic conditions included: the chromatographic column was a C18 column; the flow rate was 1.2 mL·min -1 ; Column temperature was 25 ℃; Detection wavelength was 238 nm; Injection volume was 25 μL.

[0010] Furthermore, the dissolution curve was determined using a paddle method or a basket method.

[0011] Furthermore, the speed of the dissolution curve test was 50 r·min -1 .

[0012] Furthermore, 10 mL of the sample was taken at 5, 10, 15, 30, 45, and 60 min, respectively, filtered through a 0.22-0.45 μm microporous membrane, and the filtrate was used as the test solution, and the same temperature and volume of the dissolution medium were added.

[0013] Furthermore, the dissolution amount at each time point was calculated by the external standard method.

[0014] Furthermore, gradient elution is performed.

[0015] Furthermore, in the gradient elution, the mobile phase includes mobile phase A and mobile phase B, wherein mobile phase A is a 0.15% trifluoroacetic acid aqueous solution, and mobile phase B is a 0.15% trifluoroacetic acid acetonitrile solution.

[0016] Further, the gradient elution program is as follows:

[0017] From 0 to 3 min, the volume fraction of mobile phase A was maintained at 60%, and the volume fraction of mobile phase B was maintained at 40%;

[0018] Within 3-16 min, the volume fraction of mobile phase A gradually changed to 49%, and the volume fraction of mobile phase B gradually changed to 51%;

[0019] From 16 to 16.1 min, the volume fraction of mobile phase A gradually changed to 60%, and the volume fraction of mobile phase B gradually changed to 40%;

[0020] From 16.1 to 26 min, the volume fraction of mobile phase A was maintained at 60%, and the volume fraction of mobile phase B was maintained at 40%.

[0021] Beneficial Effects

[0022] The present invention can significantly improve the dissolution of the oral solid preparation of montelukast sodium in an acidic medium by adding a suitable surfactant to the dissolution medium, especially in the range of pH 1.0-4.5, and sensitively reflect the changes in the product prescription process; according to the pharmacokinetic data of the oral solid preparation of montelukast sodium, it is judged that its dissolution and absorption process in the body is mainly completed under the environment of pH 1.0-4.5, so the method can better predict the absorption of the drug in the body, thereby reducing the risk of bioequivalence testing, achieving the goal of improving research and development efficiency and reducing research and development costs. At the same time, the method is simple to operate, more suitable for quality monitoring in the daily production process of the product, and can more truly reflect the key quality attributes of the product, as well as the prescription process of the product, to ensure the safety and effectiveness of the drug. DETAILED DESCRIPTION

[0023] Example 1

[0024] Montelukast Sodium Tablets Sample Preparation

[0025] (1) Product prescription

[0026]

[0027] (2) Preparation process:

[0028] 1) Accurately weigh the raw and auxiliary materials for dry granulation, place them in a stainless steel powder mixer and mix them evenly;

[0029] 2) Place the mixed materials in a dry granulator for dry granulation: granulation pressure 0.25-0.35MP, feeding speed: roller speed 10:1, primary granulation 50-100rpm, secondary granulation 120-200rpm, secondary granulation screen aperture 1.0-1.5mm;

[0030] 3) The granules obtained by dry granulation are mixed with externally mixed cross-linked polyvinylpyrrolidone and magnesium stearate in a mixer to obtain a uniform mixed powder to be compressed into tablets.

[0031] 4) Compress the mixed powder to be compressed into tablets, use an 8mm punch, adjust the appropriate compression parameters, and control the tablet weight difference to ±7.5% and the friability to <1%.

[0032] 5) Prepare a coating solution with a solid content of 5-10%, start coating, and make the coating weight gain reach 2-4%, to obtain a montelukast sodium tablet sample.

[0033] Example 2

[0034] Detection method of dissolution curve of montelukast sodium tablets

[0035] According to the second paddle method of the dissolution determination method in the appendix of the 2020 edition of the Chinese Pharmacopoeia, 12 tablets were tested, each with 900 mL of dissolution medium and a rotation speed of 50 r·min -1 , according to the pharmacopoeia. Take 10 mL of sample at 5, 10, 15, 30, 45, and 60 min, filter through a 0.45 μm microporous filter membrane, take the filtrate as the test solution, and add the same temperature and volume of dissolution medium. Take an appropriate amount of montelukast sodium reference substance, accurately weigh it, dissolve it with dissolution medium and dilute it to a mass concentration of about 10 μg mL -1 Reference solution: 10 μL of each of the above test sample and reference solution was taken, and the dissolution amount at each time point was calculated by the external standard method according to the following chromatographic conditions, and the dissolution curve of montelukast sodium was drawn. Finally, the cumulative release of the montelukast sodium tablet sample (self-made preparation) prepared by the method of Example 1 at each time point was calculated.

[0036] Chromatographic conditions:

[0037] The chromatographic column was a C18 column (Kromasil C18 column, 4.6 mm × 50 mm, 1.8 μm); the flow rate was 1.2 mL min -1 ; Column temperature 25 ℃; Detection wavelength 238 nm; Injection volume 25 μL, mobile phase and linear gradient elution program are shown in the table below, and the chromatogram is recorded.

[0038]

[0039] Example 3

[0040] Dissolution curves of montelukast sodium tablets in various media

[0041] Montelukast sodium belongs to BSC II drugs. According to the results of the solubility test, montelukast sodium is easily soluble in aqueous solution, but its solubility is low in aqueous solution with a pH range of 1.0 to 6.8. Since the import registration standard JX20100276 for montelukast sodium raw materials stipulates that the dissolution medium is a 0.5% SDS aqueous solution, this example prepares a 0.5% SDS aqueous solution, a pH 1.2 hydrochloric acid solution (7.65 mL hydrochloric acid, add water to 1 L), a pH 4.5 acetate buffer solution (2.99 g sodium acetate, 1.6 mL glacial acetic acid, add water to 1 L), and a pH 6.8 phosphate buffer solution (6.8 g potassium dihydrogen phosphate, 0.9 g sodium hydroxide, add water to 1 L), and investigates the dissolution of the montelukast sodium tablet sample (self-made preparation) and the reference preparation prepared by the method of Example 1 in these four dissolution media. The reference preparation is a commercially available product, montelukast sodium tablets, specification 10 mg, batch number X026344, trade name: Singulair, manufacturer: Merck Pharmaceuticals Co., Ltd., and sub-packaged by Hangzhou Merck Pharmaceuticals Co., Ltd.

[0042] The dissolution rates of the self-made preparation and the reference preparation prepared by the method of Example 1 were respectively investigated according to the above-mentioned dissolution curve determination method. The results are shown in the table below.

[0043]

[0044] The results show that the average dissolution of the reference preparation and the self-developed preparation in aqueous media within 15 minutes is greater than 85%, and it is inferred that the dissolution behaviors of the two are similar and both belong to rapid dissolution; the dissolution rate and final dissolution amount of the reference preparation and the self-developed preparation in the two acidic media of pH 1.2 and pH 4.5 are both low, and the dissolution behaviors of the two are judged to be similar, but they are not suitable as in vitro dissolution evaluation media; the dissolution rate of the reference preparation and the self-developed preparation in the alkaline medium of pH 6.8 is appropriate, and the final dissolution amount reaches 80%, which can be used as in vitro dissolution evaluation media.

[0045] Example 4

[0046] Dissolution conditions of montelukast sodium tablets in slightly acidic medium with surfactant

[0047] The results of Example 3 show that the dissolution rate and dissolution degree of montelukast sodium in buffer solutions of pH 1.2 and 4.5 are relatively low. Considering the evaluation of the in vitro dissolution curve, it is necessary to improve the dissolution rate and final dissolution amount of the Montelukast tablets in a slightly acidic medium. Therefore, in this embodiment, pH 1.2 hydrochloric acid solution plus 0.2% Triton (7.65 mL of hydrochloric acid, 2 g Triton, add water to 1 L), pH 1.2 hydrochloric acid solution plus 0.5% Triton (7.65 mL of hydrochloric acid, 5 g Triton, add water to 1 L), pH 1.2 hydrochloric acid solution plus 1.0% SDS (7.65 mL of hydrochloric acid, 10 g SDS, add water to 1 L), pH 4.5 acetate buffer plus 1.0% SDS (2.99 g sodium acetate, 10 g SDS, 1.6 mL glacial acetic acid, add water to 1 L), pH 4.5 acetate buffer plus 0.2% Triton (2.99 g sodium acetate, 2 g Triton, 1.6 mL glacial acetic acid, add water to 1 L), pH 4.5 The solubility of the self-developed preparation and the reference preparation was investigated in acetate buffer plus 0.5% Triton (2.99 g sodium acetate, 5 g Triton, 1.6 mL glacial acetic acid, add water to 1 L).

[0048] The dissolution curve determination method is the same as in Example 2.

[0049] Dissolution curve similarity evaluation:

[0050] The dissolution rates of the self-developed preparation prepared in Example 1 and the reference preparation were respectively investigated according to the dissolution curve determination method described in Example 2. The results are shown in the table below.

[0051]

[0052] The results show that the dissolution results of the reference preparation and the self-developed preparation in the two slightly acidic media of pH 1.2 and pH 4.5 with different proportions and types of surfactants can be judged to be similar; after the proportion of surfactant SDS in the two media of pH 1.2 and pH 4.5 was increased to 1%, the final dissolution amount of the reference preparation and the self-developed preparation was 48%, which was not significantly improved compared with the SDS dosage of 0.5%, and it is not suitable as an in vitro dissolution evaluation medium; after changing the type of surfactant to Triton, in the pH 1.2 hydrochloric acid solution, 0.2% Triton was added, the solubility range of the reference preparation was 42%~85%, and the addition of When 0.5% Triton was added, the dissolution range of the reference preparation was 52%~91%, and the final dissolution amount was increased, so it could be used as an in vitro dissolution evaluation medium, and the dissolution of the self-prepared preparation in these two media could be judged to be similar to that of the reference preparation; in pH 4.5 acetate solution, when 0.2% Triton was added, the dissolution range of the reference preparation was 31%~45%, which was short and not suitable as an in vitro dissolution evaluation medium; when 0.5% Triton was added, the dissolution range of the reference preparation was 47%~87%, and the final dissolution amount was increased, so it could be used as an in vitro dissolution evaluation medium, and the dissolution of the self-prepared preparation in this medium could be judged to be similar to that of the reference preparation.

[0053] Since Montelukast sodium tablets are immediate release preparations, pH 1.2 hydrochloric acid solution plus 0.2% Triton was selected to simulate the acidic environment in vivo, and the dissolution behavior of three batches of self-developed preparations (the prescription and preparation process are the same as those in Example 1) was measured. The results are shown in the table below. It can be seen from the results that the self-developed Montelukast sodium tablet preparation process is stable and the batch-to-batch difference is small.

[0054]

[0055] 0.5% SDS aqueous solution medium, pH 6.8 phosphate buffer medium, pH 1.2 + 0.2% Triton medium, and pH 4.5 + 0.5% Triton medium can be used as suitable media for in vitro evaluation of the dissolution curve of Montelukastner tablets, with a wide dissolution range and high final dissolution amount; the dissolution of the homemade preparation in each medium is similar to that of the reference, and the process is stable for multiple batches with small batch differences.

[0056] Example 5

[0057] Raw materials with different particle sizes were taken and samples were prepared according to the recipe and process of Example 1, and the differences in dissolution curves in different media were compared. The raw material particle size distribution and dissolution curve results are shown in the table below.

[0058] Raw material particle size distribution table

[0059]

[0060] Comparison of dissolution in different media

[0061]

[0062] From the above data, it can be seen that in the pH 6.8 medium, the dissolution curves of raw materials with different particle sizes are highly similar to the reference preparation. In the pH 1.2 + 0.2% Triton medium, the samples prepared with large particle size raw materials have a significantly slower dissolution; the samples prepared with raw materials with D90 below 24μm have a higher dissolution curve similar to the reference preparation and a lower risk of bioequivalence. The above data further prove that the use of pH 1.2 hydrochloric acid solution plus 0.2% Triton has a greater advantage as a dissolution medium than pH 6.8 phosphate buffer.

[0063] Example 6

[0064] The dosage of key auxiliary materials in the prescription of Example 1 was adjusted, the process parameters remained unchanged, and the prepared samples were used to compare the dissolution in different media.

[0065] Comparison of dissolution of samples from different formulations

[0066]

[0067] From the above data, it can be seen that the amount of SDS has increased to 1%, but the dissolution of the reference preparation and the homemade sample did not exceed 50%, and the difference between different prescriptions was small. When Triton was selected as a surfactant and added to the pH 1.2 medium, only 0.2% was added, and the dissolution of each sample was significantly improved, and the adjustment of the prescription can be shown in the dissolution curve. The above data further proves that compared with 0.5% SDS aqueous solution, the use of pH 1.2 hydrochloric acid solution plus 0.2% Triton as a dissolution medium has a greater advantage.

[0068] Example 7

[0069] The formulation of Example 1 was kept unchanged, and the granulation and tableting parameters were adjusted to prepare different samples, and their dissolution curves in different media were compared.

[0070] Comparison of dissolution of samples from different processes

[0071]

[0072] According to the dissolution test method of the import registration standard (medium: water + 0.5% SDS, paddle method 50rpm), the dissolution curve was tested. Both the reference preparation and the homemade sample were rapidly dissolved, and the changes in key process parameters could not be reflected under this dissolution condition. After changing the dissolution method (medium: pH4.5 + 0.5% Triton, basket method 100rpm), the dry granulation and tableting parameters changed, which were clearly reflected in the dissolution curve: the dry granulation pressure increased (prescription 6), the granule bulk density increased significantly, resulting in slower product dissolution, and the dissolution curve was not similar to the reference preparation, indicating that the dry granulation pressure should not be too large; the tableting hardness decreased (prescription 7), and the dissolution became faster, but it was still similar to the reference preparation, indicating that the tablet hardness was in the range of 40-90N, and the dissolution curve was similar to the reference preparation. The above data show that compared with the standard dissolution conditions (water + 0.5% SDS, paddle method 50rpm), pH4.5 + 0.5% Triton and basket method 100rpm are more able to distinguish changes in process parameters.

Claims

1. An in vitro dissolution evaluation method for a montelukast sodium pharmaceutical composition, characterized in that: The montelukast sodium pharmaceutical composition was dissolved in a dissolution medium, and samples were taken at different time points, the dissolution amount at each time point was determined, and a dissolution curve of montelukast sodium was drawn; the dissolution medium included: 0.5% SDS aqueous solution, pH 6.8 phosphate buffer, pH 1.2 hydrochloric acid solution plus 0.2% Triton, pH 4.5 acetate buffer plus 0.5% Triton, and the above percentages were mass / volume percentages; 10 mL of samples were taken at 5, 10, 15, 30, 45, and 60 min, respectively, filtered through a 0.22-0.45 μm microporous filter membrane, and the filtrate was taken as a test solution, and the dissolution medium of the same temperature and the same volume was supplemented; the rotation speed for testing the dissolution curve was 50 r·min -1 .

2. The in vitro dissolution evaluation method of the montelukast sodium pharmaceutical composition according to claim 1, characterized in that: The dissolution amount at each time point was determined by high performance liquid chromatography. The chromatographic conditions included: the chromatographic column was a C18 column; the flow rate was 1.2 mL min -1 ; Column temperature was 25 ℃; Detection wavelength was 238 nm; Injection volume was 25 μL.

3. The in vitro dissolution evaluation method of the montelukast sodium pharmaceutical composition according to claim 1, characterized in that: The dissolution amount at each time point was calculated by the external standard method.

4. The in vitro dissolution evaluation method of the montelukast sodium pharmaceutical composition according to claim 1, characterized in that: Elution was performed using gradient elution.

5. The in vitro dissolution evaluation method of the montelukast sodium pharmaceutical composition according to claim 4, characterized in that: In the gradient elution, the mobile phases include mobile phase A and mobile phase B, wherein mobile phase A is 0.15% trifluoroacetic acid aqueous solution, and mobile phase B is 0.15% trifluoroacetic acid acetonitrile solution.

6. The in vitro dissolution evaluation method of the montelukast sodium pharmaceutical composition according to claim 5, characterized in that: The gradient elution program is as follows: From 0 to 3 min, the volume fraction of mobile phase A was maintained at 60%, and the volume fraction of mobile phase B was maintained at 40%; Within 3-16 min, the volume fraction of mobile phase A gradually changed to 49%, and the volume fraction of mobile phase B gradually changed to 51%; From 16 to 16.1 min, the volume fraction of mobile phase A gradually changed to 60%, and the volume fraction of mobile phase B gradually changed to 40%; From 16.1 to 26 min, the volume fraction of mobile phase A was maintained at 60%, and the volume fraction of mobile phase B was maintained at 40%.

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