CN113311092A - Method for measuring dissolution curve of tacrolimus capsule - Google Patents
Method for measuring dissolution curve of tacrolimus capsule Download PDFInfo
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- CN113311092A CN113311092A CN202110581457.6A CN202110581457A CN113311092A CN 113311092 A CN113311092 A CN 113311092A CN 202110581457 A CN202110581457 A CN 202110581457A CN 113311092 A CN113311092 A CN 113311092A
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- G—PHYSICS
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Abstract
The invention discloses a method for measuring a tacrolimus capsule dissolution curve, which comprises the following steps: respectively adding a neutral dissolution medium, an acidic dissolution medium and a medium acidic dissolution medium into three dissolution instruments, respectively putting tacrolimus capsule samples into the three dissolution instruments, sampling after the samples are dissolved out, filtering out 2-6mL of samples, and taking subsequent filtrate; taking a subsequent filtrate as a solution to be detected for the neutral dissolution medium and the medium acidic dissolution medium, and adding acetonitrile into the subsequent filtrate as the solution to be detected for the acidic dissolution medium; and detecting the solution to be detected by adopting a high performance liquid chromatograph, and calculating and analyzing. The method has the advantages of simple operation, good repeatability of detection results and low requirement on detection instruments, improves the accuracy of the analysis method, makes up for the dissolution curve analysis method lacking the pH1.0 (acidic) medium, improves the discrimination of the dissolution curve analysis method of the neutral medium, and solves the problem of low response of tacrolimus in the dissolution medium.
Description
Technical Field
The invention relates to a method for measuring a tacrolimus capsule dissolution curve, and belongs to the technical field of drug analysis.
Background
Dissolution rate refers to the rate and extent of release of a solid dosage form drug in a defined medium; meanwhile, the dissolution curve is a drug release dynamic model established aiming at the environment of the simulated human digestive tract system of the oral solid preparation, so as to predict the pharmacokinetic and pharmacodynamic results of the drug in the human body. The two are important indexes for controlling the quality of the medicine, thereby effectively ensuring the bioavailability of the medicine in vivo; the dissolution curve has wide application and plays a vital role in the prescription process screening of the solid preparation imitation pharmaceutical product, and a good dissolution curve method has stronger distinguishing force for different process prescriptions, so that the optimal process prescription is screened out.
Tacrolimus (FK506), a product obtained by fermentation and separation from streptomyces, is a macrolide compound, is a novel immunosuppressant, and is 100 times of the drug effect of cyclosporine. At present, the traditional Chinese medicine composition is mainly used for treating dermatitis, autoimmune eye diseases, immune rejection reaction of organ transplantation and other fields.
Tacrolimus has a large individual difference in bioavailability in vivo and an extremely low response in analytical instruments because: 1) tacrolimus is a poorly soluble drug; 2) the concentration of the main drug in the dissolution medium is extremely low; 3) it has very low dissolution rate under the condition of pH1.0 (acidity) and is not loaded by pharmacopoeia standards.
At present, the quality detection standard of tacrolimus capsules is not included in China. Of the 5 dissolution methods recommended in the united states pharmacopeia, 4 methods employ pH4.5 (moderately acidic), and 1 method employs pH7.0 (neutral) as the dissolution pH, and no dissolution medium method of pH1.0 (acidic) has been proposed, but the examination of dissolution curves should not be performed with dissolution media having less than 3 pH values according to the requirements of general dissolution curve analysis methods.
The existing method has the problems of complex operation, poor repeatability, high requirements on instruments and the like, and the analysis and judgment of technical personnel on the detection results are seriously influenced. Wherein, the dissolution curve of the neutral medium (pH7.0 or 6.8) method has poor distinguishing force and the raw material medicine (main medicine) is very unstable in the dissolution curve.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a method for measuring the dissolution curve of a tacrolimus capsule, which has the advantages of simple operation, good repeatability of a detection result, low requirement on a detection instrument, improvement of the accuracy of an analysis method, compensation of a dissolution curve analysis method lacking a medium with pH1.0, improvement of the discrimination of a neutral medium dissolution curve analysis method and solution of the problem of low response of tacrolimus in a dissolution medium.
In order to solve the technical problems, the invention provides a method for measuring a tacrolimus capsule dissolution curve, which comprises the following steps:
taking a hydroxypropyl cellulose solution without a buffering agent as a neutral dissolution medium, adjusting the pH of the hydroxypropyl cellulose solution to 1.0 by using hydrochloric acid as an acidic dissolution medium, and adjusting the pH of the hydroxypropyl cellulose solution to 4.5 by using phosphoric acid as a medium acidic dissolution medium;
respectively adding a neutral dissolution medium, an acidic dissolution medium and a medium acidic dissolution medium into three dissolution instruments, respectively putting tacrolimus capsule samples into the three dissolution instruments, sampling after the samples are dissolved out, filtering out 2-6mL of samples, and taking subsequent filtrate;
taking a subsequent filtrate as a solution to be detected for the neutral dissolution medium and the medium acidic dissolution medium, and adding acetonitrile into the subsequent filtrate as the solution to be detected for the acidic dissolution medium;
detecting the solution to be detected by adopting a high performance liquid chromatograph;
and (4) calculating the dissolution rate of the tacrolimus capsule, making a dissolution curve, and calculating a similarity factor between the tacrolimus capsule and the original capsule.
Preferably, for acidic dissolution media, the volume ratio of the secondary filtrate to acetonitrile is 3: 7.
preferably, the mass volume concentration of the hydroxypropyl cellulose solution is 0.005-0.05%, and the unit is kg/L.
Preferably, the chromatographic column of the high performance liquid chromatograph is a C18 chromatographic column: 150mm 4.6mm 5 μm.
Preferably, the chromatographic conditions of the high performance liquid chromatograph are as follows: the column temperature is 60 ℃; the volume ratio of mobile phase acetonitrile to 0.1ml/L trifluoroacetic acid is 50: 50; the wavelength is 205 nm; the sample injection volume is 400 ul; the flow rate was 1.5 ml/min.
Preferably, the specific method for sample dissolution is as follows: measuring 900mL of dissolution medium, and placing the dissolution medium in a 1000mL round bottom dissolution cup, wherein the temperature in the cup is 37.0 +/-0.5 ℃, and the rotating speed is 50 r/min.
Preferably, the specific method for sampling is as follows: sampling at 30min, 60min, 90min and 120min respectively.
Preferably, filtration is carried out using a needle glass fibre filter.
The invention achieves the following beneficial effects:
(1) for an acidic dissolution medium, the stability of tacrolimus is easily influenced due to more hydrochloric acid in the acidic dissolution medium, and the solubility of tacrolimus in acetonitrile is higher, so that acetonitrile is added into a subsequent filtrate to be used as a solution to be detected, and the acetonitrile is added to be used as a diluent, so that the stability of a sample solution is improved.
(2) The hydroxypropyl cellulose solution (without buffer salt) is used as a neutral dissolution medium, and because tacrolimus is extremely unstable in a phosphate buffer salt system and the ultraviolet absorption coefficient of the tacrolimus is influenced, the phosphate is not added as a pH regulator, and the system without buffer salt is directly used as a medium, so that the stability of the sample solution is improved.
(3) The chromatographic conditions of the invention are as follows: the column temperature is 60 ℃; the volume ratio of mobile phase acetonitrile to 0.1ml/L trifluoroacetic acid is 50: 50; the wavelength is 205 nm; the sample injection volume is 400 ul; the flow rate is 1.5ml/min, and the stability of the sample, the applicability of the analysis method and the precision are improved by improving the parameters of the chromatographic conditions.
(4) Makes up for the lacking dissolution curve analysis method of the pH1.0 medium, improves the discrimination of the dissolution curve analysis method of the neutral medium, and solves the problem of low response of the tacrolimus in the dissolution medium.
Drawings
FIG. 1 is a flow chart of the tacrolimus capsule dissolution profile determination method of the present invention;
FIG. 2 is the dissolution profile of example 1 in medium at pH 1.0;
FIG. 3 is the dissolution profile of example 2 in media at pH 4.5;
figure 4 is the neutral medium dissolution profile of example 3.
Detailed Description
The invention is further described below with reference to the accompanying drawings. The following examples are only for illustrating the technical solutions of the present invention more clearly, and the protection scope of the present invention is not limited thereby.
FIG. 1 is a flow chart of the method for measuring the dissolution curve of tacrolimus capsules according to the present invention. In examples 1 to 3, the dissolution profiles were measured using 1 lot of the original drug (tacrolimus capsules manufactured by ansteli pharmaceuticals, ltd.) and 3 lots of the drug from the original drug. The formulations of the three self-ground drugs are shown in table 1.
TABLE 1 formulation of three batches of self-ground drugs
Example 1 (dissolution in medium pH 1.0)
1) Sample dissolution: preparing 900mL of dissolution medium (0.005% hydroxypropyl cellulose solution is adjusted to pH value of 1.0 by hydrochloric acid), placing the dissolution medium in a 1000mL round bottom dissolution cup, setting the temperature in the dissolution instrument cup to be 37.0 +/-0.5 ℃, and setting the rotating speed to be 50 r/min; taking 12 tacrolimus capsules from each batch, putting the tacrolimus capsules into 12 dissolving cups, sampling 10mL from each dissolving cup in 30min, 60min, 90min and 120min, filtering out 2mL by using a GF needle filter, taking 1.4mL of subsequent filtrate into a sample injection vial, adding 0.6mL of acetonitrile, and uniformly mixing to obtain a sample solution.
2) Analyzing by an instrument: detecting the sample solution by using a high performance liquid chromatograph; the chromatographic column was C18150 mm × 4.6mm × 5 μm, the mobile phase was acetonitrile-0.1 ml/L trifluoroacetic acid (50: 50) solution, the temperature of the column was 60 deg.C, the flow rate was 1.5ml/min, the wavelength was 205nm, and the sample volume was 400 ul.
3) And (4) calculating a result: calculating the dissolution rate of the tacrolimus capsule. And a dissolution curve is made, and a similarity factor with the original ground capsule is calculated, and the result is shown in table 2.
TABLE 2 dissolution results of tacrolimus raw grinding and self-made capsule in PH1.0 medium
The dissolution curve is shown in fig. 2, and it can be seen that the dissolution method exhibits good discrimination power to discriminate the samples of different processes and formulas and judge the quality thereof.
Example 2(pH4.5 dissolution in Medium)
1) Sample dissolution: preparing 900mL of dissolution medium (0.005% hydroxypropyl cellulose solution is adjusted to pH4.5 by phosphoric acid), placing the dissolution medium in a 1000mL round bottom dissolution cup, setting the temperature in the dissolution instrument cup to be 37.0 +/-0.5 ℃, and setting the rotating speed to be 50 r/min; taking 12 tacrolimus capsules from each batch, putting the tacrolimus capsules into 12 dissolving cups, sampling 10mL from each dissolving cup in 30min, 60min, 90min and 120min, filtering out 2mL by using a GF needle filter, and taking a proper amount of subsequent filtrate to a sample injection vial to obtain a sample solution.
2) Analyzing by an instrument: detecting the sample solution by using a high performance liquid chromatograph; the chromatographic column was C18150 mm × 4.6mm × 5 μm, the mobile phase was acetonitrile-0.1 ml/L trifluoroacetic acid (50: 50) solution, the temperature of the column was 60 deg.C, the flow rate was 1.5ml/min, the wavelength was 205nm, and the sample volume was 400 ul.
3) And (4) calculating a result: calculating the dissolution rate of the tacrolimus capsule. And a dissolution curve was prepared, and the similarity factor with the original ground capsule was calculated, and the results are shown in table 3.
TABLE 3 dissolution results of tacrolimus raw grinding and self-made capsule in PH4.5 medium
The dissolution curve is shown in fig. 3, and it can be seen that the dissolution method exhibits good discrimination power to discriminate the samples of different processes and formulations and judge the quality thereof.
Example 3 (dissolution in neutral Medium)
1) Sample dissolution: preparing 900mL of dissolution medium (0.005% hydroxypropyl cellulose solution), placing the dissolution medium in a 1000mL round bottom dissolution cup, and setting the temperature in the dissolution instrument cup to be 37.0 +/-0.5 ℃ and the rotating speed to be 50r/min by a paddle method; taking 12 tacrolimus capsules from each batch, putting the tacrolimus capsules into 12 dissolving cups, sampling 10mL from each dissolving cup in 30min, 60min, 90min and 120min, filtering out 2mL by using a GF needle filter, and taking a proper amount of subsequent filtrate to a sample injection vial to obtain a sample solution.
2) Analyzing by an instrument: detecting the sample solution by using a high performance liquid chromatograph; the chromatographic column was C18150 mm × 4.6mm × 5 μm, the mobile phase was acetonitrile-0.1 ml/L trifluoroacetic acid (50: 50) solution, the temperature of the column was 60 deg.C, the flow rate was 1.5ml/min, the wavelength was 205nm, and the sample volume was 400 ul.
3) And (4) calculating a result: calculating the dissolution rate of the tacrolimus capsule. And a dissolution curve was prepared, and the similarity factor with the original ground capsule was calculated, and the results are shown in table 4.
TABLE 4 Tacrolimus raw grinding and self-made capsule dissolution rate results in neutral medium
The dissolution curve is shown in fig. 4, and it can be seen that the dissolution method exhibits good discrimination power to discriminate the samples of different processes and formulations and judge the quality thereof.
The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the protection scope of the present invention.
Claims (8)
1. The method for measuring the dissolution curve of the tacrolimus capsule is characterized by comprising the following steps:
taking a hydroxypropyl cellulose solution without a buffering agent as a neutral dissolution medium, adjusting the pH of the hydroxypropyl cellulose solution to 1.0 by using hydrochloric acid as an acidic dissolution medium, and adjusting the pH of the hydroxypropyl cellulose solution to 4.5 by using phosphoric acid as a medium acidic dissolution medium;
respectively adding a neutral dissolution medium, an acidic dissolution medium and a medium acidic dissolution medium into three dissolution instruments, respectively putting tacrolimus capsule samples into the three dissolution instruments, sampling after the samples are dissolved out, filtering out 2-6mL of samples, and taking subsequent filtrate;
taking a subsequent filtrate as a solution to be detected for the neutral dissolution medium and the medium acidic dissolution medium, and adding acetonitrile into the subsequent filtrate as the solution to be detected for the acidic dissolution medium;
detecting the solution to be detected by adopting a high performance liquid chromatograph;
and (4) calculating the dissolution rate of the tacrolimus capsule, making a dissolution curve, and calculating a similarity factor between the tacrolimus capsule and the original capsule.
2. The method for the determination of the dissolution profile of tacrolimus capsules according to claim 1, characterized in that the volume ratio of the secondary filtrate to acetonitrile with respect to the acidic dissolution medium is 3: 7.
3. the method for measuring a tacrolimus capsule dissolution profile according to claim 1, wherein the hydroxypropyl cellulose solution has a concentration by mass/volume of 0.005 to 0.05% in kg/L.
4. The method for measuring the dissolution profile of tacrolimus capsules according to claim 1, wherein the high performance liquid chromatograph uses a C18 chromatographic column: 150mm 4.6mm 5 μm.
5. The method of measuring a tacrolimus capsule dissolution profile according to claim 1, wherein the chromatographic conditions of the high performance liquid chromatograph are as follows: the column temperature is 60 ℃; the volume ratio of mobile phase acetonitrile to 0.1ml/L trifluoroacetic acid is 50: 50; the wavelength is 205 nm; the sample injection volume is 400 ul; the flow rate was 1.5 ml/min.
6. The method for measuring the dissolution profile of tacrolimus capsules according to claim 1, wherein the specific method for sample dissolution is as follows: measuring 900mL of dissolution medium, and placing the dissolution medium in a 1000mL round bottom dissolution cup, wherein the temperature in the cup is 37.0 +/-0.5 ℃, and the rotating speed is 50 r/min.
7. The method for measuring the dissolution profile of tacrolimus capsules according to claim 1, wherein the sampling method comprises the following steps: sampling at 30min, 60min, 90min and 120min respectively.
8. The method of claim 1, wherein the tacrolimus capsule dissolution profile is measured by filtration through a needle glass fiber filter.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103432099A (en) * | 2013-08-13 | 2013-12-11 | 江苏正大清江制药有限公司 | Tacrolimus slow-releasing capsule and preparation method thereof |
| CN106880617A (en) * | 2015-12-14 | 2017-06-23 | 山东新时代药业有限公司 | A kind of tacrolimus capsules |
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- 2021-05-27 CN CN202110581457.6A patent/CN113311092A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103432099A (en) * | 2013-08-13 | 2013-12-11 | 江苏正大清江制药有限公司 | Tacrolimus slow-releasing capsule and preparation method thereof |
| CN106880617A (en) * | 2015-12-14 | 2017-06-23 | 山东新时代药业有限公司 | A kind of tacrolimus capsules |
Non-Patent Citations (1)
| Title |
|---|
| 马苗锐等，: "他克莫司胶囊在4种溶出介质中的体外溶出特性研究", 《中国药房》 * |
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