CN117054548A - In-vitro dissolution detection method of candesartan cilexetil tablet - Google Patents
In-vitro dissolution detection method of candesartan cilexetil tablet Download PDFInfo
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- 238000004090 dissolution Methods 0.000 title claims abstract description 170
- GHOSNRCGJFBJIB-UHFFFAOYSA-N Candesartan cilexetil Chemical compound C=12N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C3=NNN=N3)C(OCC)=NC2=CC=CC=1C(=O)OC(C)OC(=O)OC1CCCCC1 GHOSNRCGJFBJIB-UHFFFAOYSA-N 0.000 title claims abstract description 113
- 229960004349 candesartan cilexetil Drugs 0.000 title claims abstract description 110
- 238000000338 in vitro Methods 0.000 title claims abstract description 44
- 238000001514 detection method Methods 0.000 title claims abstract description 7
- 239000012738 dissolution medium Substances 0.000 claims abstract description 72
- 238000002360 preparation method Methods 0.000 claims abstract description 65
- 238000000034 method Methods 0.000 claims abstract description 41
- 238000001132 ultrasonic dispersion Methods 0.000 claims abstract description 27
- 239000002245 particle Substances 0.000 claims abstract description 17
- 238000012360 testing method Methods 0.000 claims description 90
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 48
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 45
- 230000001186 cumulative effect Effects 0.000 claims description 36
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 24
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 24
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 24
- 239000008055 phosphate buffer solution Substances 0.000 claims description 21
- 238000005070 sampling Methods 0.000 claims description 17
- 239000000725 suspension Substances 0.000 claims description 15
- 238000000227 grinding Methods 0.000 claims description 14
- 239000011550 stock solution Substances 0.000 claims description 14
- 238000007922 dissolution test Methods 0.000 claims description 13
- 239000007788 liquid Substances 0.000 claims description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000012085 test solution Substances 0.000 claims description 8
- 239000008363 phosphate buffer Substances 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 239000006185 dispersion Substances 0.000 claims description 6
- 238000005303 weighing Methods 0.000 claims description 6
- 238000007865 diluting Methods 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000002053 C09CA06 - Candesartan Substances 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 229960000932 candesartan Drugs 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 238000010829 isocratic elution Methods 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 238000009506 drug dissolution testing Methods 0.000 claims 6
- 239000003814 drug Substances 0.000 abstract description 32
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- 208000007530 Essential hypertension Diseases 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
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- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
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Abstract
The application aims to provide an in-vitro dissolution detection method of candesartan cilexetil tablets, which optimizes dissolution medium, dissolution medium flow rate, selection of dissolution instruments and the like by carrying out ultrasonic dispersion pretreatment on the candesartan cilexetil tablets, so as to realize that the in-vitro dissolution and in-vivo absorption of the candesartan cilexetil tablets are consistent. The method is used for building a three-dimensional internal and external correlation model, and can be used for screening preparations and establishing quality standards. The pretreatment of the application can expose the raw material medicine particles to promote dissolution, and can eliminate the influence of the compactness of the particles; the dissolution medium can effectively avoid the degradation of candesartan cilexetil in the dissolution medium, thereby effectively improving the accuracy, reliability and repeatability of dissolution data; can provide guidance for the process research of the prescription of the preparation in the imitation medicine declaration institute.
Description
Technical Field
The application relates to the technical field of analysis and detection of pharmaceutical preparations, in particular to an in-vitro dissolution detection method of candesartan cilexetil.
Background
Candesartan cilexetil is an angiotensin IIAT1 receptor antagonist for the treatment of essential hypertension. The stability and price of the candesartan cilexetil are found to be poor in the research of oral preparations of the candesartan cilexetil, and the problem of decomposition of the candesartan cilexetil in the preparation process and the placement process cannot be solved by the common preparation technology. The candesartan cilexetil tablet on the market at present can not achieve the curative effect consistent with the reference preparation due to the difference between the prescription and the process and the reference preparation, therefore, consistency evaluation is required, and the dissolution curve and the dissolution degree of the solid preparation are one of key indexes for evaluating whether the in-vivo bioequivalence test of the medicine is successful or not.
In the research and development process of the existing simulated pharmacy, the in-vitro dissolution curve of the simulated pharmacy is usually measured by using a traditional dissolution method such as a paddle method and a basket method, and then the correlation between the simulated pharmacy and the original grinding medicament is evaluated; in the hope that the imitated drug shows similar PK characteristics as the original drug in formal human body test. Patent CN104758252B provides candesartan cilexetil particles of a specific particle size range, a method for preparing the same and a composition thereof, and the dissolution of the composition is determined according to the related method of dissolution determination of the second part of the chinese pharmacopoeia 2010 edition. Patent CN101862325B discloses a pharmaceutical composition containing candesartan cilexetil and a preparation method thereof, and the pharmaceutical composition improves the stability of a main drug and improves the dissolution rate of the drug by preparing a solid dispersion; the patent carries out dissolution measurement according to a first method of XC dissolution measurement method of two appendices of Chinese pharmacopoeia 2005 edition.
The traditional dissolution method can only simulate the physiological environment of a human body simply, cannot achieve bioequivalence better, and cannot distinguish the dissolution behaviors of samples with different preparation processes well; which is prone to product development progress and bioequivalence test failure. Therefore, it is very necessary to develop a dissolution method which can eliminate the influence of other preparation processes and simultaneously realize the in-vivo and in-vitro correlation, and can better distinguish the dissolution behaviors of samples of different preparation processes, thereby better developing a simulated medicine with the same therapeutic effect as the original medicine.
In vivo and in vitro correlation evaluation is a numerical model describing the relationship between the in vitro properties of a drug and the in vivo properties of the drug. The curative effect of the medicine depends on the blood concentration and the acting time of the effective part, but the medicine is simply dependent on in-vivo experiments to obtain data, has complicated operation and high experiment requirements, so that the in-vivo behavior of the medicine is particularly important to be accurately predicted by using in-vitro experiments through simulating in-vivo environment. By establishing a proper in-vitro dissolution rate determination method, combining in-vivo pharmacokinetic experiments to establish three-dimensional internal and external correlations, determining the in-vitro dissolution limit range of the preparation in different systems, providing basis for subsequent preparation production and quality evaluation, accurately predicting the in-vivo action characteristics of the medicine, finally guiding and optimizing prescription design, establishing more representative dissolution experimental rules, reasonably adjusting the preparation and the process, and improving the pass rate of bioequivalence tests.
Disclosure of Invention
Aiming at the defects of the prior art, the application aims to provide an in-vitro dissolution detection method of candesartan cilexetil tablets, which comprises the steps of carrying out ultrasonic dispersion pretreatment on the candesartan cilexetil tablets to expose raw material medicine particles to promote dissolution and eliminate the influence of the compactness of the particles; the dissolution medium is optimized to avoid the degradation of candesartan cilexetil in the dissolution medium, so that the accuracy, reliability and repeatability of dissolution data are effectively improved; the application ensures that the in vitro dissolution and in vivo absorption of the candesartan cilexetil tablet are consistent by optimizing the dissolution medium, the flow rate of the dissolution medium, the selection of a dissolution instrument and the like, and the dissolution method has in-vitro and in-vivo correlation, thereby providing guidance for the process research of the prescription of the preparation required by the imitation drug declaration.
In order to achieve the above purpose, the technical scheme adopted by the application is as follows:
according to a first embodiment of the present application, there is provided an in vitro dissolution test method of candesartan cilexetil tablet, comprising the steps of:
s1: pretreatment of test article: dispersing candesartan cilexetil tablets;
s2: preparation of test solution: a dissolution test is carried out by adopting a dissolution instrument, when the temperature of a dissolution medium reaches 37.0+/-0.5 ℃, a pretreated test piece is put into a dissolution cup, and sampling is carried out at a fixed time point to be used as a test piece solution;
s3: preparation of standard curve solution: precisely weighing candesartan cilexetil standard substance, placing in a measuring flask, adding solvent for dissolution, and shaking to scale to obtain candesartan cilexetil stock solution; taking candesartan cilexetil stock solution, and diluting the candesartan cilexetil stock solution by adopting a diluent according to a proportion to obtain a standard curve solution;
s4: and (3) measuring: measuring the solution of the test sample and the standard curve solution by adopting a high performance liquid chromatograph, and calculating the concentration of the test sample; and drawing a differential dissolution curve by taking time as an abscissa and the concentration of the sample to be tested as an ordinate, and obtaining a cumulative dissolution curve graph between the cumulative dissolution percentage and the dissolution time according to the differential dissolution relation.
Further, in step S1, the dispersion is dispersion by grinding or ultrasonic dispersion. After the test piece is dispersed, the influence of different compactedness among tablets prepared by different processes on the dissolution behavior of the test piece is eliminated, the drug active substances in the tablets are exposed, the subsequent investigation of the dissolution behavior differences of different test pieces is facilitated, and therefore, the process differences are deduced to cause inconsistent dissolution behaviors of the test preparation and the reference preparation. Compared with grinding dispersion, the ultrasonic dispersion has high accuracy and good repeatability of the dissolved data; because part of the powder sticks to the grinding dish and cannot be taken out during the transfer to the dissolution cup after grinding.
Further, the grinding and dispersing means that candesartan cilexetil tablets are ground into particles with the particle size smaller than 200 meshes by a grinding dish.
Further, the ultrasonic dispersion refers to that candesartan cilexetil tablets are put into a solution with the pH value less than or equal to 4.0, and the tablets are subjected to ultrasonic dispersion to obtain a suspension.
Further, the ultrasonic frequency of the ultrasonic dispersion is 20-40 KHz.
Further, the ultrasonic time of the ultrasonic dispersion is 5-30 min.
Further, the solution with the pH value less than or equal to 4.0 is hydrochloric acid solution with the pH value of 1.0-4.0.
Preferably, the hydrochloric acid solution with the pH value of 1.0-4.0 can be selected from hydrochloric acid solutions with the pH value of 1.0, 1.5, 2.0, 2.5, 3.0, 3.5 or 4.0.
Further, the volume of the solution with the pH less than or equal to 4.0 is 5-10 mL.
Further, the dissolution instrument is selected from a differential dissolution instrument or a two-chamber model experimental device.
Further, the specific structure of the differential elution device is described in patent CN 207263738U; the two-chamber model experimental set-up is disclosed in patent CN 211292844U.
In some embodiments, in step S2, a two-chamber model experiment device is used to perform the dissolution test, where the dissolution conditions of the two-chamber model experiment device are as follows: taking pH6.0 phosphate buffer solution containing 0.1-0.5% Tween 20 as a dissolution medium, wherein the rotating speed of a rotating basket is 50-100 rmp, and the flow rate of the dissolution medium is 2-8 mL/min;
further, the spin basket rotational speed is selected from 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100rmp; the dissolution medium flow rate is selected from 2, 3, 4, 5, 6, 7 or 8mL/min.
In some embodiments, in step S2, a differential dissolution test is performed using a differential dissolution instrument having dissolution conditions of: taking pH6.0 phosphate buffer solution containing 0.1-0.5% Tween 20 as a dissolution medium, wherein the internal circulation flow rate of the dissolution medium is 100-120 mL/min, and the flow rate of the dissolution medium is 2-8 mL/min;
further, the dissolution medium internal circulation flow rate is selected from 100, 110 or 120mL/min; the dissolution medium flow rate is selected from 2, 3, 4, 5, 6, 7 or 8mL/min.
Further, the dissolution medium is phosphate buffer of pH6.0 containing 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5% tween 20. Wherein, the phosphate buffer solution with the pH of 6.0 and 0.1-0.5 percent of Tween 20 is 1000mL of phosphate buffer solution containing 1-5 g of Tween 20.
Further, the fixed time point is 5, 10, 20, 30, 60, 90, 120, 150, 180, 240min.
Further, in step S3, the solvent is acetonitrile, and the diluent is acetonitrile.
Further, in the step S3, the linearity of the standard curve solution is 0.25-100 mug/mL; preferably, the standard curve solution concentration is 0.25, 0.5, 1, 2.5, 5, 10, 25, 50, 100 μg/mL.
Further, in step S4, the chromatographic conditions of the high performance liquid chromatograph are: the chromatographic column is ZORBAX SB-Aq C18 mm×4.6mm,5 μm, the mobile phase is acetonitrile, water, phosphoric acid and triethylamine solution with volume ratio of 70:30:0.3:0.3, the flow rate is 1mL/min, isocratic elution is carried out, the wavelength is 254nm, the sample injection amount is 10 μL, and the column temperature is 30 ℃.
According to a second embodiment of the present application, a model of the in vivo and in vitro C-level correlation of candesartan cilexetil tablets is established by the dissolution method described above.
Obtaining time T with in vitro cumulative dissolution rate of 50% by differentiating dissolution curve in step S4 50％ By T 50％ On the abscissa, with pharmacokinetic parameters C max Is an ordinate, and is linearly fitted; when R is 2 At > 0.9, a single point correlation between the dissolution parameters and the pharmacokinetic parameters was constructed. The model can be used for screening preparation prescriptions and making quality standards.
Compared with the prior art, the application has the beneficial effects that:
(1) According to the application, the test piece is subjected to pretreatment before the dissolution test, and after ultrasonic dispersion, the raw material medicine particles can be exposed, so that the dissolution of candesartan cilexetil tablets is improved; meanwhile, the influence of the particle compactness difference between the reference preparation and the tested preparation on the dissolution behavior can be eliminated, so that the influence of the particle size of the bulk drug is singly examined; the dissolution behaviors of samples with different preparation processes can be well distinguished, the control of the process of candesartan cilexetil tablets is facilitated, and the therapeutic effect of candesartan cilexetil tablets in human bodies is ensured.
(2) According to the application, the dissolution medium is optimized, so that candesartan cilexetil is ensured not to be degraded in the dissolution medium, and the accuracy, reliability and repeatability of dissolution data are effectively improved.
(3) The application optimizes the dissolution medium, the flow rate of the dissolution medium, the selection of a dissolution instrument and the like, thereby having higher distinguishing force for the candesartan cilexetil tablet type product; the in vitro dissolution and in vivo absorption of the candesartan cilexetil tablet are consistent, the dissolution method has in vivo and in vitro correlation, and the method can provide guidance for the process research of the preparation prescription required by the imitation drug declaration.
(4) The application provides a construction method of an internal and external correlation model of candesartan cilexetil tablet, which is used for constructing an in vitro dissolution method and an in vivo absorption single-point correlation by adopting an in vivo and external C-level correlation model obtained by the method, and the model can be used for screening a preparation prescription and making a quality standard.
Drawings
FIG. 1 chromatogram of sample solution in example 1
FIG. 2 standard curve solution chromatograms in example 1
FIG. 3 cumulative dissolution curve of dissolution method 6
FIG. 4 cumulative dissolution curve of dissolution method 9
FIG. 5 cumulative dissolution curve of dissolution method 10
FIG. 6 cumulative dissolution curve of dissolution method 11 (3 parallel experiments)
FIG. 7 is a graph showing cumulative elution profile of comparative elution method 1
FIG. 8 cumulative dissolution profile of reference and test formulations
FIG. 9 in vitro dissolution parameter T 50％ Pharmacokinetic parameters C after oral administration of the drug on an empty stomach max Linear fitting map
FIG. 10 in vitro dissolution parameter T 70％ Pharmacokinetic parameters C after oral administration of the drug on an empty stomach max Linear fitting map
FIG. 11 in vitro dissolution parameter T 50％ And pharmacokinetic parameters C after oral administration of the drug after meal max Linear fitting map
FIG. 12 in vitro dissolution parameter T 70％ And pharmacokinetic parameters C after oral administration of the drug after meal max Linear fitting map
Detailed Description
The following examples illustrate the technical aspects of the application, and the scope of the application claimed includes but is not limited to the following examples.
Example 1
A method for measuring the dissolution of candesartan cilexetil outside a tablet body comprises the following specific steps of:
s1: pretreatment for test piece 1: candesartan tablets are put into 7mL of phosphate buffer solution with pH of 6.0, and ultrasonic dispersion is carried out for 10min at 40KHz to obtain suspension.
S2: preparation of sample solution: delivering a dissolution medium with the temperature controlled at 37+/-0.5 ℃ to a dissolution container through a constant flow pump, putting the suspension in the step S1 into a dissolution cup, continuously pumping the drug released by the candesartan cilexetil raw material drug in the dissolution process from the dissolution container along with the dissolution medium at the same constant flow rate, and sampling at a fixed time point to obtain a sample solution;
dissolution condition 1: the dissolution medium is phosphate buffer solution with pH of 7.4, the flow rate of the dissolution medium is 2mL/min, the dissolution medium is internally circulated at the flow rate of 100mL/min, and the sampling time points are 0, 5, 10, 20, 30, 60, 90, 120 and 150min.
S3: preparation of standard curve solution: precisely weighing candesartan cilexetil standard substance, placing in a measuring flask, adding acetonitrile for dissolving, and shaking to scale to obtain candesartan cilexetil stock solution; taking candesartan cilexetil stock solution, and proportionally diluting with acetonitrile to obtain standard curve solutions with the concentration of 0.25, 0.5, 1, 2.5, 5, 10, 25, 50 and 100 mug/mL;
s4: and (3) measuring: and measuring the sample solution and the standard working solution by adopting a high performance liquid chromatograph, calculating the concentration of the sample and calculating the cumulative dissolution.
The chromatographic conditions of the high performance liquid chromatograph are as follows: the chromatographic column is ZORBAX SB-Aq C18 mm×4.6mm,5 μm, the mobile phase is acetonitrile, water, phosphoric acid and triethylamine solution with volume ratio of 70:30:0.3:0.3, the flow rate is 1mL/min, isocratic elution is carried out, the wavelength is 254nm, the sample injection amount is 10 μL, and the column temperature is 30 ℃.
The specific structure of the differential elution apparatus is described in patent CN207263738U, and will not be described here.
The test found that the test solution (fig. 1) had an interference peak while the standard working solution was normal (fig. 2), which may be the candesartan cilexetil degraded in phosphate buffer ph 7.4.
Test example 1
Determination of dissolution Medium
To further determine the dissolution medium, the following screening test was performed:
preparation of standard solution: precisely weighing candesartan cilexetil standard substance, placing in a measuring flask, adding acetonitrile for dissolving, and shaking to scale to obtain candesartan cilexetil stock solution; candesartan cilexetil stock solution is taken and diluted proportionally with acetonitrile to obtain standard curve solutions with concentrations of 0.25, 0.5, 1, 2.5, 5, 10, 25, 50 and 100 mug/mL.
(1) Candesartan cilexetil tablet (specification: 8 mg) is respectively placed in 8mL of dissolution medium with different pH values for 5min, and the dissolution liquid is filtered by a 0.45 μm filter membrane to obtain filtrate as a test sample solution.
(2) Candesartan cilexetil tablet (specification: 8 mg) is respectively placed in 8mL of dissolution media with different pH values for ultrasonic dispersion for 5min, and is stood for 10min, and the stood dissolution liquid is filtered by a 0.45 mu m filter membrane to obtain filtrate as a sample solution.
The dissolution mediums are respectively as follows: a hydrochloric acid solution with a pH of 1.0, an acetate buffer with a pH of 4.0, a phosphate buffer with a pH of 6.5 and a phosphate buffer with a pH of 8.0.
Taking the solution (1) and (2), detecting by high performance liquid chromatograph, the result is shown in Table 1, C i Indicating the measured concentration of the test solution, and the amount of the drug indicated by the measured C i The calculated candesartan cilexetil content in the test solution represents the mass ratio of the candesartan cilexetil content in the candesartan cilexetil tablet (specification: 8 mg) in the test solution.
TABLE 1 dissolution rate of candesartan cilexetil in different dissolution media and under different conditions
As can be seen from the results of table 1, a large amount of interfering substances were detected in phosphate buffer ph6.5 and phosphate buffer ph8.0, indicating that candesartan cilexetil was eluted from the tablet and degraded. The candesartan cilexetil is dissolved in trace amounts in phosphate buffer solution with pH6.0 and acetate buffer solution with pH4.0, the dissolution amounts respectively account for 0.39% and 0.32% of active pharmaceutical ingredients in the tablet, the ratio of the candesartan cilexetil after standing for 10min does not change obviously, and a chromatographic peak does not generate an interference peak, which indicates that the candesartan cilexetil is not degraded in the phosphate buffer solution with pH6.0 and the acetate buffer solution with pH 4.0. In the pH1.0 hydrochloric acid solution, candesartan cilexetil was not detected, indicating that candesartan cilexetil is not dissolved in the pH1.0 hydrochloric acid solution.
Example 2
The study was a single-center, randomized, open, two-preparation, two-cycle, two-crossover designed human bioequivalence test of healthy subjects in fasting and postprandial states, with a washout period of about 4mL of venous blood from the subjects collected 0h and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 6h, 7h, 8h, 10h, 12h, 24h, 36h, 48h, respectively, prior to dosing for 7 days. Blood sample is centrifuged at 1700g at 4deg.C for 10min, and the plasma is taken and stored in an ultralow temperature refrigerator at-80deg.C, and the concentration of candesartan in the plasma sample is determined by using a validated LC-MS/MS method. Wherein reference formulation R is candesartan cilexetil tablet (KOKANDO co., ltd. Kureha Plant,8 mg); test preparation T 1 、T 2 Is candesartan cilexetil tablet (self-made preparation, 8 mg). Bioequivalence test results are shown in Table 2.
TABLE 2 BE test equivalent analysis results of test and reference preparations
From the in vivo BE test results performed on the two test preparations, it was found that the dissolution rate of test preparation T1 in vivo was slightly faster than that of reference preparation R; test preparation T 2 The dissolution rate in vivo was slightly slower than that of reference formulation R.
Example 3
A method for measuring the dissolution outside candesartan cilexetil tablet body comprises the following steps of dissolving a test piece by using a differential dissolution instrument, wherein the test piece is a candesartan cilexetil tablet reference preparation R and a test preparation T1, and the pretreatment and the dissolution conditions of the test piece are different;
dissolution method 2:
pretreatment 2 of test piece: adding the test piece into 7mL hydrochloric acid solution with pH of 1.0, and performing ultrasonic dispersion at 40KHz for 10min to obtain suspension;
dissolution condition 2: the dissolution medium is pH1.0 hydrochloric acid solution containing 0.1% Tween 20, the flow rate of the dissolution medium is 2mL/min, the dissolution medium is internally circulated at the flow rate of 100mL/min, and the sampling time points are 0, 5, 10, 20, 30, 60, 90, 120 and 150min.
Dissolution method 3:
pretreatment 3 of test piece: adding the test piece into 7mL hydrochloric acid solution with pH of 1.0, and performing ultrasonic dispersion at 40KHz for 10min to obtain suspension;
dissolution condition 3: the dissolution medium is pH1.0 hydrochloric acid solution containing 1% Tween 20, the flow rate of the dissolution medium is 2mL/min, the dissolution medium is internally circulated at the flow rate of 120mL/min, and the sampling time points are 0, 5, 10, 20, 30, 60, 90, 120, 150 and 180min.
Dissolution method 4:
pretreatment 4 of test piece: adding the test piece into 7mL hydrochloric acid solution with pH of 1.0, and performing ultrasonic dispersion at 40KHz for 10min to obtain suspension;
dissolution condition 4: the dissolution medium is pH1.0 hydrochloric acid solution containing 1.2% Tween 20, the flow rate of the dissolution medium is 2mL/min, the dissolution medium is internally circulated at the flow rate of 110mL/min, and the sampling time points are 0, 5, 10, 20, 30, 60, 90, 120, 150 and 180min.
Dissolution method 5:
pretreatment 5 of test piece: adding the test piece into 7mL hydrochloric acid solution with pH of 1.0, and performing ultrasonic dispersion at 40KHz for 10min to obtain suspension;
dissolution condition 5: the dissolution medium is pH6.0 phosphate buffer solution containing 0.3% Tween 20, the flow rate of the dissolution medium is 4mL/min, the dissolution medium is internally circulated at the flow rate of 110mL/min, and the sampling time points are 0, 5, 10, 20, 30, 60, 90, 120, 150, 180 and 240min.
Dissolution method 6:
pretreatment 6 of test piece: adding the test piece into 7mL hydrochloric acid solution with pH of 1.0, and performing ultrasonic dispersion at 40KHz for 10min to obtain suspension;
dissolution condition 6: the dissolution medium is pH6.0 phosphate buffer solution containing 0.5% Tween 20, the flow rate of the dissolution medium is 4mL/min, the dissolution medium is internally circulated at the flow rate of 110mL/min, and the sampling time points are 0, 5, 10, 20, 30, 60, 90, 120, 150, 180 and 240min.
The dissolution results of candesartan cilexetil tablets of different dissolution methods are shown in table 3.
TABLE 3 dissolution test results for different dissolution methods
From the dissolution results of dissolution methods 2 and 3, it can be seen that the cumulative dissolution rate of candesartan cilexetil is too low for the two dissolution methods, reference formulation R and test formulation T 1 There is no difference in dissolution behavior between them. Dissolution method 4 the dissolution of candesartan cilexetil was promoted by increasing the surfactant tween 20, and although the cumulative dissolution of candesartan cilexetil was improved, the dissolution behavior was not consistent with the bioequivalence test results of example 2. None of the dissolution methods 2, 3, 4 can achieve in vivo and in vitro correlation.
As can be seen from test example 1, candesartan cilexetil is not dissolved in a ph1.0 hydrochloric acid solution, and dissolution methods 3 and 4 promote dissolution of candesartan cilexetil by adding a large amount of surfactant, but the cumulative dissolution rate is still low. The inventor changes the dissolution medium into a pH6.0 phosphate buffer solution in which candesartan cilexetil can be dissolved, reduces the content of the surfactant, and promotes the dissolution of candesartan cilexetil by increasing the flow rate of the dissolution medium; as can be seen from the dissolution results of dissolution methods 5 and 6, the cumulative dissolution rate of the candesartan cilexetil, both the reference preparation and the test preparation, is far lower than the cumulative in vivo absorption in the bioequivalence test, and in dissolution method 6, the dissolution rate of the reference preparation is faster than that of the test preparation; this is in contrast to the bioequivalence test results in example 2; it is explained that the dissolution methods 5, 6 do not allow in vivo and in vitro correlation.
Example 4
A method for determining dissolution of candesartan cilexetil tablet body outside comprises dissolving a test piece by using a two-chamber model experimental device, wherein the test piece is a candesartan cilexetil tablet reference preparation R and a tested preparation T 1 The method comprises the following specific steps:
dissolution method 7:
s1: pretreatment 7 of test piece: the test piece is put into 7mL hydrochloric acid solution with pH of 1.0, and ultrasonic dispersion is carried out for 10min at 40KHz to obtain suspension.
S2: preparation of test solution:
when the temperature of the dissolution medium reaches 37.0+/-0.5 ℃, adding the test piece suspension pretreated in the step S1 into the dissolution cup, and sampling at a fixed time point to obtain a test piece solution;
dissolution condition 7: the dissolution medium is hydrochloric acid solution containing 1% Tween 20 and having a pH value of 1.0, the rotating speed of the rotating basket is 50rmp, and the flow rate of the dissolution medium is 4mL/min; sampling time points are 0, 5, 10, 20, 30, 60, 90, 120, 150 and 180min.
S3: preparation of standard curve solution: precisely weighing candesartan cilexetil standard substance, placing in a measuring flask, adding acetonitrile for dissolving, and shaking to scale to obtain candesartan cilexetil stock solution; taking candesartan cilexetil stock solution, and proportionally diluting with acetonitrile to obtain standard curve solutions with the concentration of 0.25, 0.5, 1, 2.5, 5, 10, 25, 50 and 100 mug/mL;
s4: and (3) measuring: and measuring the sample solution and the standard working solution by adopting a high performance liquid chromatograph, calculating the concentration of the sample and calculating the cumulative dissolution.
The two-chamber model experiment apparatus in step S2 is disclosed in patent CN 211292844U.
The specific steps of the dissolution methods 8, 9 and 10 are the same as those of the dissolution method 7, but the pretreatment of the test piece is different and the dissolution condition is different;
dissolution method 8:
pretreatment 8 of test article: adding the test piece into 7mL hydrochloric acid solution with pH of 1.0, and performing ultrasonic dispersion at 40KHz for 10min to obtain suspension;
dissolution condition 8: the dissolution medium is hydrochloric acid solution containing 0.5% Tween 20 and having pH of 1.0, the rotating speed is 50rmp, and the flow rate of the dissolution medium is 4mL/min; sampling time points are 0, 5, 10, 20, 30, 60, 90, 120, 150, 180 and 240min.
Dissolution method 9:
pretreatment 9 of test piece: adding the test piece into 7mL hydrochloric acid solution with pH of 1.0, and performing ultrasonic dispersion at 40KHz for 10min to obtain suspension;
dissolution condition 9: the dissolution medium is phosphate buffer solution containing 0.5% Tween 20 and having pH of 6.0, the rotating speed is 50rmp, and the flow rate of the dissolution medium is 4mL/min; sampling time points are 0, 5, 10, 20, 30, 60, 90, 120, 150 and 180min.
Dissolution method 10:
the candesartan cilexetil tablet is not pretreated, and the whole tablet is put into a dissolution cup;
dissolution condition 10: the dissolution medium is phosphate buffer solution containing 0.5% Tween 20 and having pH of 6.0, the rotating speed is 50rmp, and the flow rate of the dissolution medium is 4mL/min; sampling time points are 0, 5, 10, 20, 30, 60, 90, 120, 150, 180 and 240min.
Dissolution method 11:
pretreatment 11 of test piece: placing the test piece into a mortar, and grinding and crushing to obtain particles with the particle size of 200 meshes;
dissolution condition 11: the dissolution medium is phosphate buffer solution containing 0.5% Tween 20 and having pH of 6.0, the rotating speed is 50rmp, and the flow rate of the dissolution medium is 4mL/min; sampling time points were 0, 5, 10, 20, 30, 60, 90, 120, 150, 180.
The dissolution results of candesartan cilexetil tablets of different dissolution methods are shown in table 4.
TABLE 4 dissolution test results for different dissolution methods
Dissolution methods 7 and 8 were performed by replacing the dissolution apparatus with a stronger stirring strength than those of dissolution methods 2 and 3, but the cumulative dissolution rate of candesartan cilexetil tablets was still low, indicating that dissolution of candesartan cilexetil could not be improved well by increasing the surfactant content and stirring strength when using a ph1.0 hydrochloric acid solution as the dissolution medium.
As seen from the dissolution results of the dissolution method 9 and the dissolution methods 6 and 8, the cumulative dissolution rate was significantly improved, and at 180min, the cumulative dissolution rate of the reference preparation R was 78.2% and the test preparation T was found to be 78.2% 1 Has a cumulative dissolution rate of 87.5%, and is a test preparation T 1 The dissolution rate of (2) was faster than that of reference formulation R, which is consistent with the bioequivalence test results described in example 2, and the cumulative dissolution profile of dissolution method 9 is shown in FIG. 4. The method has the advantages that the phosphate buffer solution with the pH value of 6.0 and containing 0.5% Tween 20 is taken as a dissolution medium, and the dissolution is carried out by using a double-chamber model experimental device, so that good dissolution rate of candesartan cilexetil can be ensured under the condition that candesartan cilexetil is not degraded, and in-vitro dissolution and in-vivo absorption of candesartan cilexetil can be consistent.
The cumulative dissolution graph of dissolution method 10 is shown in FIG. 5, and from the dissolution results, it can be seen that at 240min, the cumulative dissolution rate of reference preparation R was 37.5% and that of test preparation T 1 The cumulative dissolution rate of (2) was 39.3%, and there was no significant difference in dissolution behavior between the reference and test formulations. Dissolution method 9 compared to dissolution method 10, reference formulation R and test formulation T 1 The cumulative dissolution rate of (2) is improved by nearly 2 times; test preparation T 1 The cumulative dissolution rate was about 10% different from that of the reference formulation R, and the dissolution difference was significantly increased. The dissolution method 9 is used for carrying out ultrasonic dispersion pretreatment on candesartan cilexetil tablets, so that the influence of compactness among different tablets can be effectively eliminated, and the influence of the particle size of the bulk drug is singly examined; meanwhile, after ultrasonic dispersion, the raw material medicine particles can be exposed, and the dissolution of the candesartan cilexetil tablet is improved. The pH1.0 hydrochloric acid solution is used as the pretreatment solution, so that the candesartan cilexetil tablet can be ensured not to be dissolved during ultrasonic dispersion, and the influence on the subsequent dissolution test is effectively avoided.
The in vitro dissolution trend of dissolution method 11 was consistent with the results of bioequivalence test in example 2, the dissolution rate of test preparation T1 in vivo was slightly faster than that of reference preparation R, but after multiple parallel tests of dissolution method 11, the results are shown in FIG. 6, and the dissolution result has large error and poor repeatability compared with dissolution method 9. This is probably because some of the powder was stuck to the grinding dish and could not be taken out during the transfer to the dissolution cup after grinding, resulting in low accuracy and poor reproducibility of the results.
Comparative example 1
The dissolution test is carried out on candesartan cilexetil tablets by adopting a traditional dissolution method paddle method (for comparison method 1), and specific dissolution conditions are as follows: 900mL of phosphate buffer solution containing 0.5% Tween 20 and having pH of 6.0 and rotation speed of 50rmp, and sampling and detecting at 0, 5, 10, 20, 30, 60, 90, 120, 150 and 180min respectively; the experimental results are shown in 5, and the cumulative dissolution graph is shown in FIG. 7:
table 5 cumulative dissolution of candesartan cilexetil tablets at different time points by the paddle method
As can be seen from the paddle dissolution results, there was no difference in dissolution behavior between the test formulation and the reference formulation, and the cumulative dissolution was only about 60%. It can be seen that the test sample was not subjected to ultrasonic pretreatment with respect to dissolution method 9, for reference formulation R and test formulation T 1 There was no difference in force, which is not consistent with the bioequivalence test results of example 2.
Example 5
The dissolution test of candesartan cilexetil tablet tested preparation and reference preparation is carried out by adopting a two-chamber model experimental device, and the specific steps are as follows:
s1: pretreatment of test pieces: putting candesartan cilexetil tablets into 7mL of hydrochloric acid solution with pH of 1.0, and performing ultrasonic dispersion at 40KHz for 10min to obtain a suspension;
s2: preparation of test solution:
when the temperature of the dissolution medium reaches 37.0+/-0.5 ℃, adding the test piece suspension pretreated in the step S1 into the dissolution cup, and sampling at a fixed time point to obtain a test piece solution;
dissolution conditions: the dissolution medium is phosphate buffer solution containing 0.5% Tween 20 and having pH of 6.0, the rotating speed of the rotating basket is 50rmp, and the flow rate of the dissolution medium is 4mL/min;
s3: preparation of standard curve solution: precisely weighing candesartan cilexetil standard substance, placing in a measuring flask, adding acetonitrile for dissolving, and shaking to scale to obtain candesartan cilexetil stock solution; taking candesartan cilexetil stock solution, and proportionally diluting with acetonitrile to obtain standard curve solutions with the concentration of 0.25, 0.5, 1, 2.5, 5, 10, 25, 50 and 100 mug/mL;
s4: and (3) measuring: measuring the sample solution and the standard working solution by using a high performance liquid chromatograph, and calculating the concentration of the sample; and drawing a differential dissolution curve by taking time as an abscissa and candesartan cilexetil dissolution concentration as an ordinate, and obtaining a cumulative dissolution curve between a cumulative dissolution mass fraction and dissolution time according to the differential dissolution relation.
The two-chamber model experiment device in step S2 is disclosed in the patent CN211292844U, and will not be described here again.
The test piece was a candesartan cilexetil tablet (KOKANDO co., ltd. Kureha Plant,8 mg) as reference preparation R, test preparation T 1 、T 2 Is candesartan cilexetil tablet (self-made preparation, 8 mg).
As can be seen from the cumulative dissolution curve (FIG. 8), the dissolution rate of the test formulation T1 was faster than that of the reference formulation R, and the test formulation T was dissolved 90min before dissolution 2 The dissolution rate of (2) is slightly slower than that of reference formulation R. The in vitro dissolution result is consistent with the trend of the bioequivalence test result in the embodiment 2, which shows that the in vitro dissolution method can effectively simulate the in vivo environment and simulate the absorption behavior of the medicine in vivo.
Establishing a model of C-level correlation in vitro and in vivo of candesartan cilexetil tablets by the dissolution method,
obtaining time T with in vitro cumulative dissolution rate of 50% by differentiating dissolution curve in step S4 50％ By T 50％ On the abscissa, with pharmacokinetic parameters C max Is an ordinate, and is linearly fitted; the fitting results are shown in Table 6, and the linear fitting patterns are shown in FIGS. 9-12. When R is 2 At > 0.9, a single point correlation between the dissolution parameters and the pharmacokinetic parameters was constructed.
TABLE 6 in vitro dissolution parameter T 50％ And pharmacokinetic parameters C max Constructing C-level correlated results
As is clear from the results in Table 6, R was expressed as fasting and postprandial at an in vitro cumulative dissolution rate of 50% and 70% 2 All are larger than 0.9, and the dissolution method can be related to in vivo absorption to form a plurality of single points, whether fasting or postprandial, and can be used for screening preparation prescriptions and making quality standards.
Claims (10)
1. An in vitro dissolution detection method of candesartan cilexetil tablets is characterized by comprising the following steps of: the method comprises the following steps:
s1: pretreatment of test pieces: dispersing candesartan cilexetil tablets;
s2: preparation of test solution: a dissolution test is carried out by adopting a dissolution instrument, when the temperature of a dissolution medium reaches 37.0+/-0.5 ℃, a pretreated test piece is put into a dissolution cup, and sampling is carried out at a fixed time point to be used as a test piece solution;
s3: preparation of standard curve solution: precisely weighing candesartan cilexetil standard substance, placing in a measuring flask, adding solvent for dissolving, and shaking to scale to obtain candesartan cilexetil stock solution; taking candesartan cilexetil stock solution, and diluting the candesartan cilexetil stock solution by adopting a diluent according to a proportion to obtain a standard curve solution;
s4: and (3) measuring: measuring the solution of the test sample and the standard curve solution by adopting a high performance liquid chromatograph, and calculating the concentration of the test sample; and drawing a differential dissolution curve by taking time as an abscissa and the concentration of the sample as an ordinate, and obtaining a cumulative dissolution curve graph between the cumulative dissolution mass fraction and the dissolution time according to the differential dissolution relation.
2. The method for detecting the dissolution in vitro of candesartan cilexetil tablet according to claim 1 wherein in step S1, the dispersion is dispersion by grinding or ultrasonic dispersion.
3. The method for in vitro dissolution test of candesartan cilexetil tablet according to claim 2, wherein the grinding dispersion means grinding candesartan cilexetil tablet to particles having a particle size of less than 200 mesh with a grinding dish;
the ultrasonic dispersion refers to that candesartan tablets are put into a solution with the pH value less than or equal to 4.0, and the tablets are subjected to ultrasonic dispersion to obtain suspension.
4. The method for in vitro dissolution test of candesartan cilexetil tablet according to claim 3 wherein the solution having a pH of 4.0 or less is a hydrochloric acid solution having a pH of 1.0 to 4.0; the volume of the solution with the pH less than or equal to 4.0 is 5-10 mL; the ultrasonic frequency of the ultrasonic dispersion is 20-40 KHz.
5. The method for in vitro dissolution testing of candesartan cilexetil tablet according to claim 1, wherein in step S2, the dissolution instrument is selected from a differential dissolution instrument or a two-chamber model experimental device.
6. The method for in vitro dissolution testing of candesartan cilexetil tablet according to claim 5 wherein the dissolution conditions of the differential dissolution instrument are: the dissolution medium is phosphate buffer solution with pH of 6.0 and containing Tween 20, the circulation flow rate in the dissolution medium is 100-120 mL/min, and the flow rate of the dissolution medium is 2-8 mL/min.
7. The method for in vitro dissolution testing of candesartan cilexetil tablet according to claim 5 wherein the dissolution conditions of the two-chamber model experimental apparatus are: the dissolution medium is phosphate buffer solution with pH of 6.0 and containing Tween 20, the rotating speed of the rotating basket is 50-100 rmp, and the flow rate of the dissolution medium is 2-8 mL/min.
8. The method for in vitro dissolution testing of candesartan cilexetil tablet according to any one of claims 6 or 7 wherein said dissolution medium is a phosphate buffer with pH6.0 containing 0.1 to 0.5% tween 20; wherein, the phosphate buffer solution with the pH of 6.0 and 0.1-0.5 percent of Tween 20 is 1000mL of phosphate buffer solution containing 1-5 g of Tween 20.
9. The method for in vitro dissolution testing of candesartan cilexetil tablet according to claim 1, wherein in step S3, the solvent is acetonitrile; the diluent is acetonitrile; the linearity of the standard curve solution is 0.25-100 mug/mL.
10. The method for in vitro dissolution testing of candesartan cilexetil tablet according to claim 1, wherein in step S4, the chromatographic conditions of the high performance liquid chromatograph are: the chromatographic column is ZORBAX SB-Aq C18 mm×4.6mm,5 μm, the mobile phase is acetonitrile, water, phosphoric acid and triethylamine solution with volume ratio of 70:30:0.3:0.3, the flow rate is 1mL/min, isocratic elution is carried out, the wavelength is 254nm, the sample injection amount is 10 μL, and the column temperature is 30 ℃.
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| CN118311216A (en) * | 2024-06-07 | 2024-07-09 | 湖南明瑞制药股份有限公司 | Rapid determination method for dissolution rate of sodium rabeprazole enteric-coated tablets |
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| CN117783459B (en) * | 2024-02-28 | 2024-05-07 | 沈阳科惠生物医药科技有限公司 | Drug dissolution curve determination method and system |
| CN118311216A (en) * | 2024-06-07 | 2024-07-09 | 湖南明瑞制药股份有限公司 | Rapid determination method for dissolution rate of sodium rabeprazole enteric-coated tablets |
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