CN115290767A - Dissolution rate determination method for 8 representative ingredients in red blood-guiding pill - Google Patents
Dissolution rate determination method for 8 representative ingredients in red blood-guiding pill Download PDFInfo
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- 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
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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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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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
- G01N30/62—Detectors specially adapted therefor
- G01N30/72—Mass spectrometers
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- 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
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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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- 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
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- G01N2030/065—Preparation using different phases to separate parts of sample
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Abstract
The invention relates to the field of pharmaceutical analysis and detection, and provides a dissolution rate determination method for 8 representative ingredients in a dao-chi pill, which comprises the following steps: preparation of mixed control solutions: taking 200mL of degassed hydrochloric acid solution with pH =1.0 as a dissolution medium, keeping the temperature at 37 +/-0.5 ℃, rotating at 80r/min, dropping a paddle into a container, sampling 2mL at 180min, and filtering with a 0.22 mu m microporous membrane to obtain the product; preparing a test solution: precisely sucking 1 μ l of the mixed reference solution and sample solution respectively, injecting into an ultra-high performance liquid chromatography-mass spectrometer, measuring, and calculating content by external standard method; the dissolution rates of baicalin, berberine hydrochloride, aloe-emodin, akebia stem phenylethanoid glycoside B, harpagoside, jasminoidin, paeoniflorin and forsythoside A are determined by an UPLC-MS/MS method, so that the quality of the radix hematite pill is comprehensively evaluated, and a reference can be provided for quality control and drug effect verification of the radix hematite pill.
Description
Technical Field
The invention belongs to the field of pharmaceutical analysis and detection, and particularly relates to a dissolution rate determination method for 8 representative components in red blood-guiding pills.
Background
The red-blood-guiding pill is prepared from ten medicines of forsythia, coptis chinensis, gardenia (fried with ginger), akebia stem, figwort root, trichosanthes root, red paeony root, rhubarb, scutellaria and talcum, is listed in a volume six of Taiping Huimin He Ji Ju Fang written by Song Dynasty Taiping Huimin He Ji bureau, is recorded in a edition 2020 of Chinese pharmacopoeia, and is clinically commonly used for mouth and tongue sores, throat pain, heart and chest dysphoria with smothery sensation, scanty and brownish urine and constipation caused by internal exuberance of fire. Most of the traditional Chinese medicine preparations are produced by the traditional process, and the quality of the products is uneven due to different raw and auxiliary materials, production conditions and processes of various manufacturers, thereby influencing the clinical curative effect of the finished medicines. The dissolution rate of a drug refers to the speed and degree of dissolution of the drug in a given solvent, and the dissolution rate directly affects the absorption and utilization of the drug in vivo. The dissolution rate inspection of the medicine is an effective means for evaluating the quality and the process level of the preparation, and can reflect the difference of the prescription composition, auxiliary materials and production process to a certain extent, so the dissolution rate inspection of the red blood-guiding pill is necessary. At present, the dissolution rates of 8 representative components of baicalin, berberine hydrochloride, aloe-emodin, akebia saponin B, harpagoside, geniposide, paeoniflorin and forsythoside A in the red-guiding pill are measured by adopting an UPLC-MS/MS method, and the dissolution rates are not reported.
Disclosure of Invention
The invention aims to solve the problems and provides a dissolution rate determination method for 8 representative ingredients in red blood-guiding pills, which comprises the following steps:
A. preparing a mixed reference solution;
B. preparing a test solution: taking 6 pills of the red blood-guiding pill water-honeyed pill, taking 200mL of degassed hydrochloric acid solution with the pH =1.0 as a dissolution medium, keeping the temperature at 37 +/-0.5 ℃, rotating at 80r/min, dropping a paddle into a container, immediately starting timing, sampling 2mL at 5, 15, 40, 80, 120, 150 and 180min respectively, simultaneously supplementing the dissolution medium with the same temperature and the same amount, and filtering by using a 0.22 mu m microporous membrane to obtain the red blood-guiding pill water-honeyed pill;
C. precisely sucking 1 μ l of each of the mixed reference solution and the test solution, injecting into an ultra-high performance liquid chromatography-mass spectrometer, measuring, and calculating content by external standard method;
chromatographic conditions are as follows: a chromatographic column: 2.6 μm in phenomenon C18 column, 2.1X 100mm; taking acetonitrile as a mobile phase A and 0.1% formic acid as a mobile phase B, and performing gradient elution; column temperature: 40 ℃, flow rate: 0.3ml/min; sample introduction amount: 1 mul;
mass spectrum conditions: electrospray ionization source ESI, scan mode: positive and negative ion simultaneous scanning, monitoring mode: multiple reaction monitoring mode MRM, positive ionization voltage: 5500V, desolventizing gas temperature: 500 ℃, negative ionization voltage: 4500V, desolvation gas temperature: at 500 ℃.
Preferably, the mixed control solution is prepared by the following steps: accurately weighing appropriate amount of baicalin, berberine hydrochloride, aloe-emodin, akebia saponin B, harpagoside, jasminoidin, paeoniflorin and forsythoside A, adding methanol to obtain mixed solution containing baicalin 70 μ g, berberine hydrochloride 22 μ g, aloe-emodin 1 μ g, akebia saponin B1 μ g, harpagoside 2 μ g, jasminoidin 60 μ g, paeoniflorin 14 μ g and forsythoside A70 μ g per 1ml, respectively, to obtain the final product.
Preferably, the pH =1.0 hydrochloric acid solution preparation in step B: precisely measuring 9.00mL of hydrochloric acid, diluting with water to 1000mL, and shaking up to obtain the final product.
Preferably, the gradient elution procedure is as follows:
mobile phase gradient elution procedure
Compared with the prior art, the invention has the following beneficial effects:
the invention establishes a dissolution rate inspection method for determining red blood-guiding pill water-honeyed pills by using a UPLC-MS/MS method, and performs determination and analysis on dissolution rates of active ingredients of baicalin, coptis chinensis, rheum officinale, akebia stem, figwort root, gardenia, red paeony root and fructus forsythiae, namely baicalin, berberine hydrochloride, aloe-emodin, akebia stem phenylethanoid glycoside B, harpagoside, geniposide, paeoniflorin and forsythoside A in a prescription, so that the quality of red blood-guiding pills is comprehensively evaluated, and reference is provided for quality control and drug effect verification of the red blood-guiding pills.
Drawings
FIGS. 1-24 are the dissolution curves (with time as abscissa and dissolution rate as ordinate) of baicalin, berberine hydrochloride, aloe-emodin, akebia saponin B, harpagoside, geniposide, paeoniflorin, and forsythoside A in different dissolution cups of the same batch of red-blood-guiding pills respectively;
FIGS. 25-32 are graphs showing the average dissolution profiles (with time as abscissa and average dissolution as ordinate) of baicalin, berberine hydrochloride, aloe-emodin, akebia saponin B, harpagoside, geniposide, paeoniflorin, and forsythoside A in different batches of radix Paeoniae Rubra pills, respectively.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention aims to provide a method for measuring the dissolution rate of 8 representative components of the red blood-guiding pill, and the method adopts an UPLC-MS/MS method to measure the dissolution rates of baicalin, berberine hydrochloride, aloe-emodin, akebia saponin B, harpagoside, geniposide, paeoniflorin and forsythoside A. The content determination method adopts a paddle method for dissolution, takes hydrochloric acid solution with the pH =1.0 as a dissolution medium, has the rotating speed of 80r/min and has the sampling time of 5, 15, 40, 80, 120, 150 and 180min. Chromatographic conditions are as follows: and (3) chromatographic column: phenomenon C18 column (2.6 μm,2.1 × 100 mm); acetonitrile is taken as a mobile phase A,0.1 percent formic acid is taken as a mobile phase B, and the gradient elution procedure is shown in a table 1; column temperature: 40 ℃, flow rate: 0.3ml/min; sample introduction amount: 1 μ l.
Table 1 mobile phase gradient elution procedure
Detecting by a triple quadrupole tandem mass spectrometer; electrospray ion source (ESI), scanning mode: positive and negative ion simultaneous scanning, monitoring mode: multiple reaction monitoring mode (MRM), positive ionization voltage: 5500V, desolventizing gas temperature: 500 ℃, negative ionization voltage: 4500V, desolvation gas temperature: 500 ℃; the mass spectral parameters are detailed in table 2.
TABLE 2 qualitative and quantitative ion and Mass Spectrometry Condition tables
Preparation of mixed control solution: accurately weighing appropriate amount of baicalin, berberine hydrochloride, aloe-emodin, akebia saponin B, harpagoside, geniposide, paeoniflorin and forsythoside A, and adding methanol to obtain mixed solution containing baicalin 70 μ g, berberine hydrochloride 22 μ g, aloe-emodin 1 μ g, akebia saponin B1 μ g, harpagoside 2 μ g, geniposide 60 μ g, paeoniflorin 14 μ g and forsythoside A70 μ g per 1 ml.
Preparation of dissolution medium: preparing a dissolution medium solution according to a dissolution medium method in the technical guidance principle of dissolution test of common oral solid preparations, wherein the pH =1.0 hydrochloric acid solution: precisely measuring 9.00mL of hydrochloric acid, diluting with water to 1000mL, and shaking up to obtain the final product.
1. Instruments and reagents
1.1 instruments
AB SCIEX Qtrap 6500 ultra high performance liquid chromatography-ion trap mass spectrometer; analytical balance: mettler XPE26 (parts per million); mettler XS105 (one hundred thousand) (shanghai Mettler instruments ltd); KQ-400KDE ultrasonic cleaning instrument (Kunshan ultrasonic instruments Co., ltd.);
1.2 reagent
Baicalin (Zhongzhong institute, batch number: 110715-201117, content 91.7%)
Berberine hydrochloride (Zhongzhong hospital, batch number: 110713-201814, content 86.7%)
Aloe-emodin (Zhongzhong college, batch number: 110795-201308, content 97.8%)
Akebia phenyl ethanol glycoside B (middle school, batch number: 111910-201604, content 98.2%)
Harpagoside (Zhongzhong hospital, batch number: 111730-201709, content 95.9%)
Paeoniflorin (Zhongzhong hospital, batch number: 110736-201942, content 95.1%)
Forsythoside A (Zhongzhong hospital, batch number: 111810-201606, content 93.4%)
Geniposide (Zhongzhong hospital, batch number: 110749-201919, content 97.1%)
Reagent: methanol, acetonitrile and formic acid are all chromatographically pure, and water is ultrapure water. 10 batches of red-blood-guiding pill water-honeyed pills.
2. Method and results
2.1 chromatographic conditions
Acetonitrile is used as a mobile phase A,0.1% formic acid is used as a mobile phase B, the gradient elution procedure is shown in table 1, the flow rate is 0.3 mL/min-1, the column temperature is 40 ℃, and the sample injection amount is 1 mu L.
Table 1 mobile phase gradient elution procedure
2.2 preparation of control solution baicalin, berberine hydrochloride, aloe-emodin, akebia saponin B, harpagoside, geniposide, paeoniflorin and forsythoside A are precisely weighed respectively, and methanol is added to prepare a mixed solution containing 70 μ g of baicalin, 22 μ g of berberine hydrochloride, 1 μ g of aloe-emodin, 1 μ g of akebia saponin B, 2 μ g of harpagoside, 60 μ g of geniposide, 14 μ g of paeoniflorin and 70 μ g of forsythoside A in each 1ml, respectively, so as to obtain the product.
2.3 preparation of dissolution media: preparing a dissolution medium solution according to a dissolution medium method in the technical guidance principle of dissolution test of common oral solid preparations, wherein the pH =1.0 hydrochloric acid solution: precisely measuring 9.00mL of hydrochloric acid, diluting with water to 1000mL, and shaking up to obtain the final product.
2.4 dissolution Condition screening
2.4.1 examination of dissolution media: taking red-blood-guiding pills (batch No. 20201001) produced by manufacturer A as research objects, respectively taking 6 pills, placing the pills in 200mL of medium under 2.3 and 200mL of water dissolution medium, operating according to a propeller lowering method under the item of dissolution and release determination method of the general rule of China pharmacopoeia (four departments) of 2020 edition, and respectively placing the pills in the 2 dissolution media, wherein the results show that baicalin, berberine hydrochloride, aloe-emodin, harpagoside, geniposide, paeoniflorin and forsythoside A in the red-blood-guiding pills in the 2 media are best dissolved in hydrochloric acid solution with pH =1.0, are poor in dissolution in water, and comprehensively considered, the dissolution medium of the sample is preferably pH =1.0 hydrochloric acid solution.
2.4.2 selection of rotational speed: the pre-test finds that the rotating speed has large influence on the dissolution of the product, and the dissolution conditions of the rotating speeds of 40, 80 and 120r/min are respectively considered, and the result shows that the dissolution of the red-blood-guiding pill is better at 80r/min and has distinguishing force, so that the 80r/min is selected for the dissolution research of the red-blood-guiding pill.
2.4.3 investigation of sampling time: the study subjects of 20201001 lot number dao Chi Wan were to examine the dissolution rates at 5, 15, 40, 80, 120, 150, 180, and 240min, respectively. The result shows that the dissolution of baicalin and other components reaches the balance within 180min, so the sampling dissolution time is determined to be 180min.
2.5 sample Intra-batch uniformity evaluation
Measured by a second method under the item of 'dissolution and release determination method' of the general rules of the four departments of the 2020 edition of Chinese pharmacopoeia, 3 different batches of 6 pills are selected for 1 test, 200mL of degassed hydrochloric acid solution with the pH =1.0 is used as a dissolution medium, the temperature is kept at (37 +/-0.5) DEG C, and the rotating speed is 80r/min. Dropping the paddle into the container, immediately starting timing, sampling 2mL (simultaneously adding equal amount of dissolution medium at the same temperature) at 5, 15, 40, 80, 120, 150 and 180min respectively, filtering with 0.22 μm microporous membrane, taking 1 μ L of filtrate, sampling, measuring the content of baicalin, berberine hydrochloride and other components, calculating the dissolution rate of baicalin, berberine hydrochloride and other components in different dissolution cups by dividing the dissolution rate of baicalin, berberine hydrochloride and other components in the dissolution sample by the maximum dissolution rate of each component, and drawing a dissolution curve by taking time as abscissa and the dissolution rate as ordinate. The results are shown in FIGS. 1-24. The result shows that the batch uniformity of different batches is good, the repeatability is good, and the accuracy of the determination method is high.
2.6 measurement of dissolution curves of samples in different batches
Taking 5 different batches of red blood-guiding pills, 6 pills in each batch, measuring according to a second method under the item of 'dissolution and release determination method' of general rules of the four departments of 2015 edition of Chinese pharmacopoeia, taking 200mL of degassed aqueous solution as a dissolution medium, keeping the temperature at (37 +/-0.5) DEG C, and rotating at 80r/min. Dropping the oar into the container, immediately starting timing, sampling 2mL (simultaneously adding equal amount of dissolution medium at the same temperature) at 5 min, 15 min, 40min, 80min, 120 min, 150 min and 180min respectively, filtering with 0.22 μm microporous membrane, taking 1 μ L of secondary filtrate, injecting sample, measuring contents of geniposide, baicalin and the like, calculating average dissolution rate of geniposide, baicalin and the like in different time red-lead pills by dividing average dissolution rate of geniposide, baicalin and the like in dissolution samples by maximum dissolution rate of geniposide, baicalin and the like, and drawing a dissolution curve by taking time as abscissa and average dissolution rate as ordinate. The results are shown in FIGS. 25-32.
In conclusion, the method can be used for determining and analyzing the dissolution rates of the effective components of baicalin, berberine hydrochloride, aloe-emodin, akebia stem phenylethanoid glycoside B, harpagoside, geniposide, paeoniflorin and forsythoside A in the prescription of the red-blood-stasis-removing pill, so that the quality of the red-blood-stasis-removing pill is comprehensively evaluated, and a reference can be provided for quality control and drug effect verification of the red-blood-removing pill.
It is noted that, in the present application, relational terms such as first and second, and the like are used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Also, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (4)
1. A dissolution rate determination method for 8 representative ingredients in Daochi pills is characterized by comprising the following steps:
A. preparing a mixed reference solution;
B. preparing a test solution: taking 6 pills of the red blood-guiding pill water-honeyed pill, taking 200mL of degassed hydrochloric acid solution with the pH =1.0 as a dissolution medium, keeping the temperature at 37 +/-0.5 ℃, rotating at 80r/min, dropping a paddle into a container, immediately starting timing, sampling 2mL at 5, 15, 40, 80, 120, 150 and 180min respectively, simultaneously supplementing the dissolution medium with the same temperature and the same amount, and filtering by using a 0.22 mu m microporous membrane to obtain the red blood-guiding pill water-honeyed pill;
C. precisely sucking 1 μ l of the mixed reference solution and sample solution respectively, injecting into an ultra-high performance liquid chromatography-mass spectrometer, measuring, and calculating content by external standard method;
chromatographic conditions are as follows: a chromatographic column: 2.6 μm in phenomenon C18 column, 2.1X 100mm; taking acetonitrile as a mobile phase A and 0.1% formic acid as a mobile phase B, and performing gradient elution; column temperature: 40 ℃, flow rate: 0.3ml/min; sample introduction amount: 1 mul;
mass spectrum conditions: electrospray ion source ESI, scan mode: positive and negative ion simultaneous scanning, monitoring mode: multiple reaction monitoring mode MRM, positive ionization voltage: 5500V, desolventizing gas temperature: 500 ℃, negative ionization voltage: 4500V, desolvation gas temperature: at 500 ℃.
2. The method as claimed in claim 1, wherein the mixed control solution is prepared by the following steps: weighing baicalin, berberine hydrochloride, aloe-emodin, akebia saponin B, harpagoside, geniposide, paeoniflorin and forsythiaside A reference substances respectively, adding methanol to prepare into mixed solution containing 70 μ g of baicalin, 22 μ g of berberine hydrochloride, 1 μ g of aloe-emodin, 1 μ g of akebia saponin B, 2 μ g of harpagoside, 60 μ g of geniposide, 14 μ g of paeoniflorin and 70 μ g of forsythiaside A per 1ml respectively, and obtaining the product.
3. The method for determining the dissolution rate of 8 representative ingredients in Daihong pill according to claim 1, wherein the pH =1.0 hydrochloric acid solution preparation in step B: weighing 9.00mL of hydrochloric acid, diluting with water to 1000mL, and shaking up to obtain the final product.
4. A method as claimed in claim 1, wherein the gradient elution procedure is as follows: mobile phase gradient elution procedure
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| PCT/CN2022/138253 WO2024007532A1 (en) | 2022-07-04 | 2022-12-10 | Method for determining dissolution rates of eight representative components in daochi pills |
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| WO2024007532A1 (en) * | 2022-07-04 | 2024-01-11 | 河北省药品医疗器械检验研究院(河北省化妆品检验研究中心) | Method for determining dissolution rates of eight representative components in daochi pills |
| WO2024007531A1 (en) * | 2022-07-04 | 2024-01-11 | 河北省药品医疗器械检验研究院(河北省化妆品检验研究中心) | Method for simultaneously measuring content of 24 ingredients in daochi wan |
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| CN102139008B (en) * | 2010-02-03 | 2013-03-27 | 天津中新药业集团股份有限公司隆顺榕制药厂 | Quality control method of Xiaoer daochi tablet |
| CN114487154B (en) * | 2021-12-20 | 2023-12-01 | 河北省药品医疗器械检验研究院(河北省化妆品检验研究中心) | Method for detecting dissolution rate of Siji Sanhuang tablets |
| CN115290767A (en) * | 2022-07-04 | 2022-11-04 | 河北省药品医疗器械检验研究院(河北省化妆品检验研究中心) | Dissolution rate determination method for 8 representative ingredients in red blood-guiding pill |
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| WO2024007532A1 (en) * | 2022-07-04 | 2024-01-11 | 河北省药品医疗器械检验研究院(河北省化妆品检验研究中心) | Method for determining dissolution rates of eight representative components in daochi pills |
| WO2024007531A1 (en) * | 2022-07-04 | 2024-01-11 | 河北省药品医疗器械检验研究院(河北省化妆品检验研究中心) | Method for simultaneously measuring content of 24 ingredients in daochi wan |
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