CN113607839A - Method for detecting dissolution rate of bromhexine hydrochloride tablets - Google Patents

Method for detecting dissolution rate of bromhexine hydrochloride tablets Download PDF

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CN113607839A
CN113607839A CN202110865332.6A CN202110865332A CN113607839A CN 113607839 A CN113607839 A CN 113607839A CN 202110865332 A CN202110865332 A CN 202110865332A CN 113607839 A CN113607839 A CN 113607839A
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bromhexine hydrochloride
solution
dissolution
dissolution rate
bromhexine
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陈娟
王玉立
彭珊珊
张鑫
黄磊
彭熙琳
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Chengdu Diao Pharmaceutical Group Co Ltd
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • 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
    • G01N30/02—Column chromatography
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • 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
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N30/06—Preparation
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • 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
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N30/06—Preparation
    • G01N30/14—Preparation by elimination of some components
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • 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
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N30/06—Preparation
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    • G01N2030/146—Preparation by elimination of some components using membranes

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Abstract

The invention discloses a method for detecting the dissolution rate of bromhexine hydrochloride tablets, and relates to the technical field of detection. The method comprises the following steps: preparing a reference substance solution, preparing a test solution, measuring the content of bromhexine hydrochloride in the test solution by adopting a high performance liquid chromatography, comparing with a marked amount, and calculating the dissolution rate of the bromhexine hydrochloride tablets. The method provided by the invention is adopted to detect the dissolution rate of the bromhexine hydrochloride tablets, the dissolution amount is improved to more than 80%, the RSD is small, and the quality of the preparation can be reflected more truly.

Description

Method for detecting dissolution rate of bromhexine hydrochloride tablets
Technical Field
The invention relates to a detection method, in particular to a method for detecting the dissolution rate of bromhexine hydrochloride tablets.
Background
Bromhexine hydrochloride, english name: bromhexine hydrochloride, chemical name: N-methyl-N cyclohexyl-2-amino-3, 5-dibromobenzylamine hydrochloride, the structural formula is:
Figure BDA0003187339450000011
bromhexine hydrochloride has wide clinical application, is used for treating patients with sticky phlegm and difficult expectoration, such as chronic bronchitis, asthma and the like, has quick and complete gastrointestinal absorption, and reaches the peak value after being orally taken for 0.5 to 3 hours.
The absorption of the drug is the first step of the oral drug, and the dissolution of the drug is a precondition for the absorption, so the dissolution detection of the bromhexine hydrochloride tablet is very necessary.
At present, the detection methods for the dissolution rate of bromhexine hydrochloride tablets mainly comprise the following steps:
1) dissolution method of ChP2020/ChP2015 bromhexine hydrochloride tablets:
taking the product, determining dissolution and release by determination method (0931 second method of the general rule of 2020 edition of Chinese pharmacopoeia) with water 900ml as dissolution medium and rotation speed of 75 r/min, operating according to the method, taking 10ml of solution after 45min, filtering with organic membrane, discarding at least 5ml of primary filtrate, taking the subsequent filtrate as sample solution; taking another bromhexine hydrochloride reference substance about 16mg, precisely weighing, placing in a 100ml measuring flask, adding 4ml of ethanol, shaking for dissolving, diluting with water to scale, shaking up, precisely weighing 1ml, placing in a 20ml measuring flask, diluting with water to scale, shaking up to serve as a reference substance solution. Precisely measuring the sample solution and the reference solution by 50 μ l each, measuring according to the method under the content measurement item, and calculating the elution amount of each tablet by peak area according to an external standard method. The limit is 70% of the indicated amount and should be met.
The chromatographic conditions and the system applicability are as follows: octadecylsilane chemically bonded silica is used as a filler, phosphate buffer solution-acetonitrile (20:80, and the pH value is adjusted to 7.0 by using 0.5mol/L sodium hydroxide solution) is used as a mobile phase, the detection wavelength is 245nm, the column temperature is 40 ℃, the number of theoretical plates is not less than 2000 calculated according to a bromhexine hydrochloride peak, and a tailing factor is not more than 2.0.
2) The dissolution method of the Japanese orange peel book bromhexine hydrochloride tablets comprises the following steps:
taking the product, determining by dissolution method (paddle method), using 900ml of water as solvent, rotating at 50rpm, and taking appropriate amount of solution after 30 minutes, discarding at least 10ml of primary filtrate, precisely taking appropriate amount of secondary filtrate, diluting with mobile phase 1 times, and shaking to obtain sample solution. Precisely weighing appropriate amount of reference substance dried at 105 deg.C for 4 hr, dissolving with mobile phase, diluting to obtain solution containing 4 μ g per 1ml, precisely weighing appropriate amount, diluting with water 1 times, and shaking to obtain reference substance solution. Precisely measuring 100 μ l of each of the two solutions, injecting into a liquid chromatograph, and recording chromatogram; the dissolution amount is calculated by peak area according to an external standard method, and the limit is 75% of the marked amount and is in line with the regulation.
The chromatographic conditions and the system applicability are as follows: octadecylsilane chemically bonded silica is used as a filling agent, 0.09% sodium heptanesulfonate solution-methanol-n-propanol (55:35:10, pH value is adjusted to 3.0 by 10% phosphoric acid) is used as a mobile phase, the detection wavelength is 246nm, the column temperature is 40 ℃, the flow rate is adjusted to ensure that the retention time of a bromhexine hydrochloride peak is about 6 minutes, the number of theoretical plates is not less than 2000 calculated according to the bromhexine hydrochloride peak, and the tailing factor is not more than 2.0.
However, researches show that, in the two methods, when water is used as a dissolution medium, the adsorption influence of the filter membrane is large, the difference of water detection results from different sources is large, and the quality of the preparation cannot be truly reflected, so that the research of a dissolution rate detection method of bromhexine hydrochloride tablets with high accuracy and good repeatability is necessary for better reflecting the dissolution and absorption conditions of the bromhexine hydrochloride tablets.
Disclosure of Invention
The invention provides a method for detecting the dissolution rate of bromhexine hydrochloride tablets, and aims to solve the problems in the prior art.
In order to achieve the technical purpose, the invention mainly adopts the following technical scheme:
a method for detecting the dissolution rate of bromhexine hydrochloride tablets comprises the following steps:
(1) preparation of control solutions: taking a proper amount of bromhexine hydrochloride reference substance, diluting the bromhexine hydrochloride reference substance with methanol to prepare a solution containing 0.4mg in each 1ml, precisely measuring a proper amount, and diluting the solution with a hydrochloric acid solution with a dissolution medium of 0.05-0.15 mol/L to prepare a solution containing 8 mu g in each 1 ml;
(2) preparation of a test solution: weighing 0.05-0.15 mol/L hydrochloric acid solution of a degassed dissolution medium, pouring the solution into a dissolution cup, after the temperature is constant at 37 +/-0.5 ℃, putting a bromhexine hydrochloride sample into the dissolution cup, controlling the rotation speed at 50rpm, stirring for 30 minutes, sucking 10ml of dissolution liquid, immediately filtering by using a microporous membrane, and taking the subsequent filtrate as the sample solution;
(3) and (3) high performance liquid chromatography determination: taking 100 μ l of each of the test solution and the reference solution, measuring according to high performance liquid chromatography, and calculating the dissolution rate of bromhexine hydrochloride tablet.
In the invention, in the step (2), the adding amount of the hydrochloric acid solution in the dissolution cup is 900mL, and the concentration of the hydrochloric acid solution is 0.1 mol/L.
In the invention, in the step (2), the microfiltration membrane is an organic microfiltration membrane, and the pore size of the organic microfiltration membrane is 0.45 μm.
In the invention, in the step (3), the measuring conditions of the high performance liquid chromatography are that octadecyl bonded silica gel is used as a filling agent, phosphate buffer solution-acetonitrile is used as a mobile phase, the volume ratio of the octadecyl bonded silica gel to the phosphate buffer solution-acetonitrile is 55-65:45-35, isocratic elution is carried out, the flow rate is 1.0-1.5ml/min, the detection wavelength is 245nm, and the column temperature is 40 ℃.
Further, the concentration of the phosphate buffer solution is 0.02mol/L potassium dihydrogen phosphate, and the pH value of the 0.02mol/L potassium dihydrogen phosphate is 3.2.
Further, the volume ratio of the phosphate buffer solution to the acetonitrile is 60: 40.
In the invention, the calculation formula of the dissolution rate of the bromhexine hydrochloride tablets is as follows
Figure BDA0003187339450000031
Wherein the content of the first and second substances,
Asample (A): peak area of bromhexine peak of test solution;
Ato pair: peak area of bromhexine peak of control solution;
Wto pair: weighing bromhexine hydrochloride reference substance (mg);
Pto pair: content (%) of bromhexine hydrochloride reference substance;
Vsample (A): dissolution medium volume (ml);
Vto pair: the reference substance of bromhexine hydrochloride is diluted by times;
marking amount: 8 mg.
Furthermore, the dissolution rate of the bromhexine hydrochloride tablet is not less than 80%.
Compared with the prior art, the invention has the following beneficial effects: according to the invention, the accuracy and repeatability of the detection result are improved by optimizing the condition parameters in the dissolution rate detection process of the bromhexine hydrochloride tablets. The experimental result shows that the dissolution of the bromhexine hydrochloride tablet is detected by adopting the method provided by the invention, the dissolution amount is improved to more than 80%, the RSD is smaller, and the quality of the preparation can be reflected more truly.
Detailed Description
The foregoing aspects of the present invention are described in further detail by way of examples, but it should not be construed that the scope of the above-described subject matter is limited to the following examples, and that all the technologies implemented based on the above-described aspects of the present invention are within the scope of the present invention.
Example 1
(1) Preparation of control solutions: taking a proper amount of bromhexine hydrochloride reference substance, diluting the bromhexine hydrochloride reference substance with methanol to prepare a solution containing 0.4mg in each 1ml, precisely measuring a proper amount, and diluting the solution with 0.05-0.15 mol/L hydrochloric acid solution, preferably 0.1mol/L hydrochloric acid solution to prepare a solution containing 8 mu g in each 1 ml;
(2) preparation of a test solution: weighing 0.05-0.15 mol/L hydrochloric acid solution subjected to degassing treatment, preferably 900ml of 0.1mol/L hydrochloric acid solution, pouring the solution into dissolution cups, after the temperature is constant at 37 +/-0.5 ℃, taking 6 (or 12) bromhexine hydrochloride samples, respectively putting the samples into 6 (or 12) dissolution cups, controlling the rotation speed to be 50rpm, stirring for 30 minutes, sucking 10ml of dissolution liquid, immediately filtering with a 0.45 mu m organic microporous membrane, and taking the subsequent filtrate as the sample solution;
(3) and (3) high performance liquid chromatography determination: taking 100 mu l of each of the test solution and the reference solution, determining according to high performance liquid chromatography, taking octadecyl bonded silica gel as a filler, taking phosphate buffer solution-acetonitrile as a mobile phase, taking the volume ratio of the octadecyl bonded silica gel to the phosphate buffer solution-acetonitrile as 55-65:45-35, preferably taking the volume ratio of the octadecyl bonded silica gel to the phosphate buffer solution-acetonitrile as 60:40, carrying out isocratic elution at the flow rate of 1.0-1.5ml/min, preferably at the flow rate of 1.0ml/min, the detection wavelength of 245nm and the column temperature of 40 ℃, and calculating the dissolution rate of the bromhexine hydrochloride tablet according to a dissolution rate calculation formula. The dissolution rate is calculated as follows:
Figure BDA0003187339450000041
wherein the content of the first and second substances,
Asample (A): peak area of bromhexine peak of test solution;
Ato pair: peak area of bromhexine peak of control solution;
Wto pair: weighing bromhexine hydrochloride reference substance (mg);
Pto pair: content (%) of bromhexine hydrochloride reference substance;
Vsample (A): dissolution medium volume (ml);
Vto pair: the reference substance of bromhexine hydrochloride is diluted by times;
marking amount: 8 mg.
Comparative example 1
Dissolution calculations were performed according to the method of the present invention example 1, except that the dissolution media were each acetate buffer at ph 4.5.
Comparative example 2
Dissolution was calculated according to the method of the invention example 1, with the difference that the dissolution medium was phosphate buffer, ph5.5, respectively.
Comparative example 3
Dissolution was calculated according to the method of the invention example 1, with the difference that the dissolution medium was phosphate buffer ph6.8, respectively.
(1) Comparison of the stability of bromhexine hydrochloride in the different media of example 1 and of comparative examples 1 to 3
Taking a proper amount of bromhexine hydrochloride raw material and self-made bromhexine hydrochloride tablet fine powder, dissolving and diluting the raw material and the self-made bromhexine hydrochloride tablet fine powder by using dissolution media (0.1mol/L hydrochloric acid solution, pH4.5 acetate buffer solution, pH6.8 phosphate buffer solution and pH5.5 phosphate buffer solution) to prepare a solution, placing the solution at room temperature, carrying out sample injection measurement at intervals, calculating the RSD of the peak area of a sample, and obtaining the result shown in the following table 1:
table 1: stability test results of bromhexine hydrochloride in 4 media
Figure BDA0003187339450000051
And (4) conclusion: the bromhexine hydrochloride raw material and the self-made bromhexine hydrochloride tablet are stable in a hydrochloric acid solution of 0.1mol/L, an acetate buffer solution of pH4.5, a phosphate buffer solution of pH6.8 and a phosphate buffer solution of pH5.5 for 24 hours.
(2) Selection of dissolution media
The applicant compared the dissolution rates in aqueous media of different origins (see the dissolution conditions of ChP2020/2015 bromhexine hydrochloride tablets) using pilot scale-up batches of self-made formulations (batch No. 20190503) and the results are given in Table 2 below.
Table 2: dissolution test results of bromhexine hydrochloride in 3 kinds of water
Source Dissolution rate% RSD％
Self-made purified water 77.6 5.9
Ultrapure water 105.9 5.4
Waha water 79.7 6.2
And (4) conclusion: the dissolution results for ultra pure and purified water differ by about 28%, which is very different. Water is therefore not suitable as dissolution medium.
In addition, the product is in self-made purified water, the filter membrane adsorption is serious, bromhexine hydrochloride solutions with different concentrations are not in a linear relation, and the linearity and the recovery rate can not reach the acceptable standard when methodology verification is carried out by adopting the self-made purified water as a dissolution medium. The linearity results are given in table 3 below.
Table 3: linear results of bromhexine hydrochloride using self-made purified water as dissolution medium
Figure BDA0003187339450000052
Figure BDA0003187339450000061
The recovery results are shown in Table 4 below.
Table 4: recovery rate result of bromhexine hydrochloride by using self-made purified water as dissolution medium
Figure BDA0003187339450000062
And (4) conclusion: bromhexine hydrochloride is added into self-made purified water, the concentration of the bromhexine hydrochloride is 4.093-9.822 mu g/ml (equivalent to 51.16% -122.78% of the measured concentration), and the peak area and the concentration are not in a linear relation (R is 0.9968).
Bromhexine hydrochloride in self-made purified water has an average recovery rate of 74.0% at a 50% level and an average recovery rate of 91.7% at an 80% level, which do not meet the acceptable standard. And therefore not suitable for choosing water as dissolution medium.
Meanwhile, the applicant discovers through a dissolution experiment that the bromhexine hydrochloride tablet cannot achieve final dissolution in acetate buffer solution with pH4.5, phosphate buffer solution with pH5.5 and phosphate buffer solution with pH 6.8. Therefore, 0.1mol/L hydrochloric acid solution was selected as a standard medium, and pH4.5 acetate buffer, pH5.5 phosphate buffer, pH6.8 phosphate buffer and purified water were selected as auxiliary media to perform the dissolution profile test.
The results of the dissolution profile of the reference formulation (batch 171318) in 900ml of 5 dissolution media are also determined and shown in Table 5 below.
Table 5: comparison of dissolution curves of reference preparations in different dissolution media
Figure BDA0003187339450000071
Remarking: the rotation speed of 0.1mol/L hydrochloric acid solution, pH4.5 acetate buffer solution and pH6.8 phosphate buffer solution is 50 rpm.
And (4) analyzing results: 15min in 0.1mol/L hydrochloric acid solution is more than 85 percent, so 0.1mol/L hydrochloric acid solution is selected as a standard medium; in pH4.5 acetate buffer solution, 45min is more than 85%; the product can not be completely dissolved in phosphate buffer solution with pH value of 6.8, reaches a final dissolution platform (about 30%) within 45min, and the dissolution and release behaviors in phosphate buffer solution with pH value of 5.5 and purified water are greatly influenced by water sources. Therefore, 0.1mol/L hydrochloric acid solution is selected as a standard medium, and pH4.5 acetate buffer solution, pH5.5 phosphate buffer solution and pH6.8 phosphate buffer solution are selected as auxiliary media for carrying out the dissolution curve detection. And the dissolution curve comparison study is carried out on the stability of 0 day and the final stage by adopting Wahaha water and selecting the rotating speed of 75 rpm. The dissolution curves of the phosphate buffer solution with the pH value of 5.5 and the water medium are greatly influenced by water sources, and are not used as the evaluation basis of dissolution similarity.
(3) Selection of chromatographic conditions
The determination method of the elution amount of the ChP2020/ChP2015 and the Japanese orange book bromhexine hydrochloride tablet has slight difference of mobile phases, so that a comparison study is carried out on chromatographic conditions by using a control solution prepared by 4 mediums, and the results are as follows:
A. determination method for dissolution amount in quality standard of ChP2020/ChP2015 bromhexine hydrochloride tablets
The chromatographic column is Agilent Zorbax SB-C184.6 × 50mm, 5 μm; the mobile phase is phosphate buffer (1.0 g of potassium dihydrogen phosphate is taken and dissolved by 900mL of water, the pH value is adjusted to 7.0 by 0.5mol/L sodium hydroxide solution, water is added to 1000mL) -acetonitrile (20:80), and 4 kinds of medium prepared reference solution are injected, wherein the main peak of the reference solution prepared by 0.1mol/L hydrochloric acid solution does not appear, and the mobile phase is a system with pH7.0, so the damage to the chromatographic column is large, and the dissolution amount is not measured by the chromatographic system.
B. Method for measuring dissolution amount of bromhexine hydrochloride tablets by adopting Japanese orange peel book
The chromatographic column is Agilent Zorbax SB-C184.6 × 50mm, 5 μm; the mobile phase is 0.09% sodium heptanesulfonate solution-methanol-n-propanol (55:35:10, pH value is adjusted to 3.0 by 10% phosphoric acid), the reference substance solution prepared by 4 mediums is injected, the solution prepared by 4 mediums can generate peaks, and the dissolution amount can be detected by adopting the method, but the method adopts an ion pair reagent as the mobile phase, has certain damage to a chromatographic column, and the dissolution amount is not detected by adopting the chromatographic system for convenient daily detection.
C. Mobile phase using content determination
The mobile phase of the content determination method is 0.02mol/L potassium dihydrogen phosphate buffer solution (2.74 g of potassium dihydrogen phosphate is taken and dissolved by 1000ml of water, 1ml of triethylamine is added, the pH value is adjusted to 3.2 by phosphoric acid) -acetonitrile (60:40), by adopting the method, the reference substance solution prepared by injecting 4 mediums can peak, the dissolution amount can be detected by adopting the method, and the method is consistent with the content determination method and is convenient for the quality study in the later period, so the method is selected as the dissolution amount detection method.
(4) Examination of adsorption on a Filter Membrane
During sampling and filtering, the main component may be lost due to the adsorption influence of the filter membrane, so that the filter membrane adsorption needs to be verified.
1) Preparing reference substance solutions by using dissolution media respectively, dividing into 7 parts, directly injecting 1 part, and performing parallel determination for 6 times; and filtering another 6 parts of the filtrate by using a filter membrane, discarding 3ml of the primary filtrate, filtering 3ml of the primary filtrate each time, collecting 6 parts of subsequent filtrate, sampling 1 needle of each subsequent filtrate, and recording a chromatogram. The peak area RSD before and after filtration was calculated.
2) Because the organic membrane is adopted in the filtration of the eluate in the ChP2020/ChP2015, the filter membrane adsorption contrast of the organic membrane and the aqueous membrane is increased. The information of the filter membrane is shown in table 6, and the experimental structure of the filter membrane adsorption is shown in tables 7, 8, 9 and 10.
TABLE 6 Filter Membrane information
Name (R) Material of Specification of Source
Filter membrane 1 MCE 0.45μm×25mm Welch
Filter membrane 2 Hydrophobic PTFE 0.45μm×25mm Welch
Filter membrane 3 Polyether sulfone 0.22μm×25mm Jinteng medicine
Filter membrane 4 Nylon 0.22μm×25mm Jinteng medicine
Table 7: results of Filter adsorption test-control solution (aqueous Membrane-Welch MCE Filter)
Figure BDA0003187339450000081
Figure BDA0003187339450000091
And (4) analyzing results: the MCE water system filter membrane of Welch is adopted, the peak areas RSD before and after filtration are all larger than 2% under purified water, acetate buffer solution with pH4.5 and phosphate buffer solution with pH6.8, and the filter membrane made of the material is proved to have adsorption to the bromhexine hydrochloride main component.
Table 8: filter adsorption test results-control solution (organic membrane-Welch PTFE hydrophobic Filter)
Figure BDA0003187339450000092
And (4) analyzing results: adopting a Welch PTFE organic system filter membrane, under purified water and a pH6.8 phosphate buffer solution, the peak area RSD before and after filtration is more than 2 percent, under a 0.1mol/L hydrochloric acid solution, a pH4.5 acetate buffer solution and a pH5.5 phosphate buffer solution, discarding 3ml of an initial filtrate, and the peak area RSD before and after filtration is less than 2 percent. The filter membrane of the material adsorbs the main component of the bromhexine hydrochloride under purified water and phosphate buffer solution with the pH value of 6.8; under the conditions of 0.1mol/L hydrochloric acid solution, pH4.5 acetate buffer solution and pH5.5 phosphate buffer solution, there is almost no adsorption to the main component of bromhexine hydrochloride.
Table 9: filter membrane adsorption test results-reference solution (Jinteng filter membrane)
Figure BDA0003187339450000101
And (4) analyzing results: adopting a water system and an organic system filter membrane of Jinteng, under purified water and phosphate buffer solution with pH6.8, the peak area RSD before and after filtration is both larger than 2 percent, and under phosphate buffer solution with pH5.5, the peak area RSD before and after filtration is smaller than 2 percent. The filter membrane of the material adsorbs the main component of the bromhexine hydrochloride under purified water and phosphate buffer solution with the pH value of 6.8; under the condition of pH5.5 phosphate buffer solution, the main component of bromhexine hydrochloride is hardly adsorbed.
Preparing a 2.2 mu g/ml (the final concentration of the product) solution from the raw material of a phosphate buffer solution with pH of 6.8, continuously filtering the solution by using a filter membrane which is soaked and saturated, respectively adopting a glass syringe and a plastic syringe, respectively sampling 1 needle from the solution before and after the filtration, recording a chromatogram, and calculating the continuous filtration peak area RSD. The results are shown in Table 6.
Table 10: results of Filter Membrane adsorption test-control solution (different syringes)
Figure BDA0003187339450000102
Figure BDA0003187339450000111
And (4) analyzing results: the method adopts a Jinteng organic filter membrane, and after 12ml of primary filtrate is discarded by using a glass syringe, the filter membrane hardly adsorbs main components.
From the results in tables 3-6 above, the following filter adsorption conclusions were drawn:
a Welch hydrophobic PTFE filter membrane is adopted for a reference substance and a sample solution prepared from 0.1mol/L hydrochloric acid solution, and after 3ml of filtrate is discarded, the filter membrane hardly adsorbs the main component of bromhexine hydrochloride. A Welch hydrophobic PTFE filter membrane is adopted for a reference substance and a test substance solution prepared by acetate buffer solution with pH4.5 and phosphate buffer solution with pH5.5, and the filter membrane hardly adsorbs the main component of the bromhexine hydrochloride after 3ml of filtrate is discarded. However, in order to minimize the detection error, it is selected to discard 6ml of the primary filtrate and perform the test.
A control sample solution and a test sample solution prepared from a phosphate buffer solution with the pH value of 5.5 adopt a Jinteng nylon filter membrane, after 3ml of filtrate is discarded, the filter membrane hardly adsorbs the main component of bromhexine hydrochloride, but in order to reduce detection errors as much as possible, 6ml of primary filtrate is selected in actual operation and then the test is carried out.
A reference substance and a test substance solution prepared from a phosphate buffer solution with the pH value of 6.8 adopt a Jinteng organic system filter membrane, the filter membrane is soaked and saturated in advance and then dried in the air, and a glass syringe is used for discarding 12ml of primary filtrate, so that the filter membrane hardly adsorbs main components.
The reference substance and the sample solution prepared from the aqueous medium are adsorbed by a Welch hydrophobic PTFE filter membrane, a Jinteng nylon filter membrane and a Jinteng polyethersulfone filter membrane, wherein the adsorption of the Jinteng nylon filter membrane is minimum.
Comparative experiment
Three batches of bromhexine hydrochloride tablets (6 tablets to be tested in each batch) are taken, the dissolution rate of the bromhexine hydrochloride is detected by adopting the method of the original Chinese pharmacopoeia 2015 edition or 2020 edition and the method provided by the embodiment 1 of the invention respectively, the detection results of each batch are averaged, and the results are shown in the following table 1.
Table 1 dissolution rate results
Figure BDA0003187339450000121
Wherein, the data of the 2015 edition or 2020 edition of Chinese pharmacopoeia refers to the 45min dissolution data in the dissolution curve of the purified water medium.
And (4) conclusion: the method detection and comparison before and after the change are carried out, the dissolution amount of the method after the change is higher than that of the method before the change, the RSD is smaller, and the quality of the preparation can be reflected more truly.
The results of the dissolution test analysis methodology are shown in Table 7 below.
Table 7: dissolution test analysis methodology validation results
Figure BDA0003187339450000122
Figure BDA0003187339450000131
Figure BDA0003187339450000141
And (4) conclusion: the determination method provided by the invention has the advantages of strong specificity, good reproducibility, high accuracy, high stability and high durability, and can better reflect the dissolution and absorption conditions of the bromhexine hydrochloride tablets.
The above-mentioned embodiment is only one of the preferred embodiments of the present invention, and should not be used to limit the scope of the present invention, but all the insubstantial modifications or changes made within the spirit and scope of the main design of the present invention, which still solve the technical problems consistent with the present invention, should be included in the scope of the present invention.

Claims (8)

1. A method for detecting the dissolution rate of bromhexine hydrochloride tablets is characterized by comprising the following steps:
(1) preparation of control solutions: taking a proper amount of bromhexine hydrochloride reference substance, diluting the bromhexine hydrochloride reference substance with methanol to prepare a solution containing 0.4mg in each 1ml, precisely measuring a proper amount, and diluting the solution with a hydrochloric acid solution with a dissolution medium of 0.05-0.15 mol/L to prepare a solution containing 8 mu g in each 1 ml;
(2) preparation of a test solution: weighing 0.05-0.15 mol/L hydrochloric acid solution of a degassed dissolution medium, pouring the solution into a dissolution cup, after the temperature is constant at 37 +/-0.5 ℃, putting a bromhexine hydrochloride sample into the dissolution cup, controlling the rotation speed at 50rpm, stirring for 30 minutes, sucking 10ml of dissolution liquid, immediately filtering by using a microporous membrane, and taking the subsequent filtrate as the sample solution;
(3) and (3) high performance liquid chromatography determination: taking 100 μ l of each of the test solution and the reference solution, measuring according to high performance liquid chromatography, and calculating the dissolution rate of bromhexine hydrochloride tablet.
2. The method for detecting the dissolution rate of bromhexine hydrochloride tablets according to claim 1, wherein: in the step (2), the adding amount of the hydrochloric acid solution in the dissolution cup is 900mL, and the concentration of the hydrochloric acid solution is 0.1 mol/L.
3. The method for detecting the dissolution rate of bromhexine hydrochloride tablets according to claim 1, wherein: in the step (2), the microporous filter membrane is an organic microporous filter membrane, and the pore size of the organic microporous filter membrane is 0.45 μm.
4. The method for detecting the dissolution rate of bromhexine hydrochloride tablets according to claim 1, wherein: in the step (3), the measuring conditions of the high performance liquid chromatography are that octadecyl bonded silica gel is used as a filling agent, phosphate buffer solution-acetonitrile is used as a mobile phase, the volume ratio of the octadecyl bonded silica gel to the phosphate buffer solution-acetonitrile is 55-65:45-35, isocratic elution is carried out, the flow rate is 1.0-1.5ml/min, the detection wavelength is 245nm, and the column temperature is 40 ℃.
5. The method for detecting the dissolution rate of bromhexine hydrochloride tablets according to claim 4, wherein: the concentration of the phosphate buffer solution is 0.02mol/L potassium dihydrogen phosphate, and the pH value of the 0.02mol/L potassium dihydrogen phosphate is 3.2.
6. The method for detecting the dissolution rate of bromhexine hydrochloride tablets according to claim 4, wherein: the volume ratio of the phosphate buffer solution to the acetonitrile is 60: 40.
7. The method for detecting the dissolution rate of bromhexine hydrochloride tablets according to claim 1, wherein: the calculation formula of the dissolution rate is
Figure FDA0003187339440000011
Wherein the content of the first and second substances,
Asample (A): peak area of bromhexine peak of test solution;
Ato pair: peak area of bromhexine peak of control solution;
Wto pair: weighing bromhexine hydrochloride reference substance (mg);
Pto pair: content (%) of bromhexine hydrochloride reference substance;
Vsample (A): dissolution medium volume (ml);
Vto pair: the reference substance of bromhexine hydrochloride is diluted by times;
marking amount: 8 mg.
8. The method for detecting the dissolution rate of bromhexine hydrochloride tablets according to claim 1, wherein: the dissolution rate of the bromhexine hydrochloride tablet is not less than 80%.
CN202110865332.6A 2021-07-29 2021-07-29 Method for detecting dissolution rate of bromhexine hydrochloride tablets Pending CN113607839A (en)

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Citations (2)

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Publication number Priority date Publication date Assignee Title
CN101502494A (en) * 2009-04-01 2009-08-12 王保明 Bromhexine hydrochloride freeze-dried injection and preparation method thereof
CN105085549A (en) * 2015-09-01 2015-11-25 山东罗欣药业集团股份有限公司 Cefaclor compound, medicine composition of cefaclor compound and bromhexine hydrochloride, and preparation of cefaclor compound

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Publication number Priority date Publication date Assignee Title
CN101502494A (en) * 2009-04-01 2009-08-12 王保明 Bromhexine hydrochloride freeze-dried injection and preparation method thereof
CN105085549A (en) * 2015-09-01 2015-11-25 山东罗欣药业集团股份有限公司 Cefaclor compound, medicine composition of cefaclor compound and bromhexine hydrochloride, and preparation of cefaclor compound

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